Lliçó magistral a càrrec de Bartha Maria Knoppers, directora de la Càtedra de Dret i Medicina de la Universitat de Montreal.


Conferència "The human genome, impact on genetics and society" a càrrec de Gert-Jan B. Van Ommen, cap del Departament de Genètica Humana de la Universitat de Leiden.

Intervenció a càrrec de la professora Bartha Maria Knoppers

Taula rodona "La genòmica al segle XXI. Els límits de l'ètica"

Lliçó Magistral "Of populations, banks and ethics"

Joan Planas: Bona tarda. First of all, I would like to welcome and thank doctor Bartha Knoppers for coming here to give us a talk about "Of populations, banks and ethics". També vull donar la benvinguda a tots els assistents en nom de l'Honorable Senyor Guitart, president del Consell Social. També us vull convidar a assistir a la resta d'actes d'aquestes primeres Jornades de Primavera, que duen el títol de "La Genòmica al Segle XXI. Els Límits de l'Ètica". Ara cedeixo la paraula a la doctora Montserrat Bordes.

Montserrat Bordes: Agraeixo al Consell Social aquesta iniciativa i a tots vosaltres la vostra assistència. Presentaré breument la doctora Knoppers. Actualment és professora de la Facultat de Dret de la Universitat de Montreal i membre del Centre de Recerca en Dret Públic, que recentment ha inaugurat la plana web HumGen. Va presidir el Comitè de Bioètica Internacional de la UNESCO quan es va redactar la Declaració Universal sobre el Genoma Humà i els Drets Humans. Tot i que la seva recerca en bioètica és més àmplia (per exemple, ha treballat en els drets dels infants), els seus interessos acadèmics se centren en la bioètica i el biodret en genètica, de la qual tractarà la seva conferència d'avui, "Of populations, banks and ethics".

After the lecture, you are invited to ask any questions related to the topic. Thank you again, doctor Knoppers, for coming and attending this congress. Now, up to you.

Bartha Maria Knoppers: The topics that I will be looking at are the following: Current approaches to genetic research in populations, normative frameworks, the principles for population research and, finally, the procedures for population research. We will begin by examining what is currently happening in terms of research in populations. What is happening in Iceland, in the United Kingdom, in Estonia or in Quebec, where I come from? Then we will look at the normative framework, that is if there are any norms, rules, guidelines or laws that govern population banks, even just ordinary DNA banking in families or communities. I think that you received from me some materials, a statement of principles, to have read for today. But if you have not done it, do not worry, I will explain it to you here. And finally, I will look at the principles and procedures for population research. In fact, the word principles sounds political or ethical. But what exactly does it mean in practice, when you confront families or politicians or populations? How does it really work?

I will start with the controversial topic: the current types of banks. There are four kinds of banks. We have RMGA, which is the Réseau de médecine génétique appliquée du Quebec, the Quebec Network of Applied Genetic Medicine. RMGA is made up of Quebec researchers who get together and share research findings such as interesting families, conditions or data that they have found. This is traditional research banking involving people who have familial conditions or diseases. Likewise, Sweden has kept all the DNA samples from its newborns. They take a blood sample from all newborns for immediately treatable diseases such as PKU, hypothyroidism, or tyrosinemia. You need to find these newborns right away before they begin to become mentally disabled. Those are two examples of what I call your classical, ordinary banks. They have been going on for a long time. I do not see this form of banking as raising particular issues. Access to these samples for research requires consent.

In the last ten years, in Iceland as well as in Estonia, in the field of human genetics, they decided that maybe DNA from their own people was a good economic resource for the biotech future of their country. In Iceland, if you go to the library you will see that everybody knows where everybody comes from. They already had genealogy and demography data, and a good health care system, but they were missing clinical data. Iceland's health sector data is very controversial, because it presumes consent. Every single Icelander is presumed to consent to have their health data sent to a centralized health database, unless he is opposed to it. Most people say that Iceland takes genes from people, but this is not true, because Icelanders still have to give consent for a genetic test. As soon as genetic data starts going into individuals' medical records, this data is also included in the centralized database. This presumed consent was very controversial, and ethicists around the world were worried. The government gave an exclusive license to Decode, a company founded by an Icelander, to have exclusive rights to the data. The result is a central database in the hands of one company who can exclusively use the data for a period of time. This is the reason why it is so controversial; it represents a state and industry monopoly on health information.

We also have the case of Estonia. In January 2002, they passed a law saying that every Estonian citizen when going to see their physician will be asked to give his consent for offering a DNA sample. If they accept, the DNA is coded and that person will be followed during his lifetime. If researchers find anything, they can get back to the physician with information of that person. It is a coded system and it goes through the person's physician.

In the Iceland databank, all the information that is entered is anonymized, except for age, condition and certain health information. So the information never goes back to the citizen and it stays in the databank. Iceland and Estonia then have "national population banks".

The third type of bank is commercial ones. We turn now to companies that used to do only clinical trials, and now are interested in the interactions between genes and drugs. They have decided to do genetics, genomics and pharmacology. They will do their classical clinical studies and they will ask participants for DNA. These commercial companies see genomics as the future, leading to pharmacogenomic trials to individualize drugs to people's genotypes.

The last type of bank is a new type of bank, a virtual one, i.e. it is banking via the Internet. In the United States, where people often do not have health care insurance, they will look for trials on their condition, like hypertension or asthma, via the web. They will see that they can sign up to be a participant in a research trial and are asked to send in their DNA. If you answer that you are a competent adult, you get a little package in the mail, you take a brush, you scrape the inside of your cheek and you send it in. You never see a physician and never talk to a genetic counselor but you are sending your DNA in case one day they find something. They never check if you are really competent, as for example you could be a 14 year old boy doing all this for fun, or you could be an 87 year old man who does not understand what he is doing. This is what I call virtual banking, and some companies of this type just went bankrupt.

These then are the four types of banking that I wanted to show to you: classical, populations, commercial and virtual.

What is so different about these kinds of banks and these kinds of population studies? Classical population studies look at communities by ethnicity, by origin: the Basques, eastern Quebeckers, people from Sardinia. We used to do population studies on recognizable traditional populations with very little scientific basis. We always need studies on traditional populations, but today, after having sequenced the human genome, we need to know normal genetic variation across all populations, all races, and all ages, healthy or sick people. Because if we do not understand this normal variation, we will not be able to do functional genomics, as the sequence map is not enough and the understanding of genetic diversity is a basic research tool. We really need to go across a whole population from age 0 to 90 to find out the normal polymorphic differences between all the citizens no matter their race, because people carry their genomes with them. In Montreal, for instance, where I come from, there are 27 ethnic communities. Every person in these communities has carried their genome with them from their country of origin.

We do not have this kind of research on whole populations, because people think that it is dangerous. Why is this study of human diversity, of normal genetic variation dangerous? Well, what if you found out that genetically you are probably closer to a person of another race, country or ethnic group than you assumed, and that your own politico-cultural community is not so "pure"? All the historical justifications for being better, genetically superior, justifying genocides and all kinds of historical property agreements with indigenous people for instance, walls, borders, may be biologically unfounded. In other words, most of our ideas about who we are politically, socially and culturally are not based on what we think that they are based. You can see why this is a very touchy topic. In general it is politically difficult to do.

The new banks are also complicated because if you look at ethics, like for instance the Nuremberg Code, the Declaration of Helsinki and all the other new declaration codes, most of them concentrate on the individual. You do not find ethics codes that talk about groups, communities or families. Instead, they talk about individual privacy, individual autonomy and individual confidentiality. If you see anything related to groups, it is about vulnerable groups. In the 1947 Nuremberg Code, children, women, pregnant women and incompetent adults were protected from research. But they realized that if they kept protecting these vulnerable groups, there would never be any research on paediatric conditions or on women who were pregnant, so they decided to include them under the Declaration of Helsinki in 1964.

Today most codes of ethics still talk about communities and groups at risk of being harmed. In Quebec, for example, what if they find out that there is more familial hypercholesterolaemia in one area than another? This will affect how people are seen, as they will be marked with a stigma. No one ever talks about protector genes, but about stigmatisation. So what do we do then? In Quebec, we are planning to do a project on genetic diversity in the whole province, which has 7 million inhabitants, based on a sample of 1% of the population. The United Kingdom plans to do a longitudinal study on 500,000 people.

What are the norms that we have to guide these studies? I am not going to go through the ethical frameworks of all these entities: UNESCO, WHO, CIOMS, HUGO, RMGA, etc. Each of these has a few articles that specifically address research in communities. But none of them have developed principles for such research, except for the RMGA. I will now turn to it, and it appears in the material that I sent to you for today's class. I will present you some principles: individuality, diversity, reciprocity, complexity, solidarity, security, accountability, equity, citizenry and universality. What does it mean that we still start with the individual but we end up at the international level?

We respect diversity because modern genetic research shows uniqueness, individuality, and diversity. The term complexity refers to the multicultural and multifaceted nature of genetic research. It is multicultural because of all the different origins and because many conditions are multifactorial. It is also multifaceted due to the social and economic aspects. Reciprocitymeans that you cannot only ask people for their DNA, but you have to keep communicating back with the patient. When you are testing people, you have to communicate all the harms that they can encounter. Solidarity refers to any country that wants to invest in a biobank. In this case, the same country should protect citizens from insurance or employment discrimination. In terms of accountability, there should be ongoing surveillance on such big projects. When I say equity I am referring to a concept that I will explain to you in a minute talking of risks and benefits. And a new concept is citizenry, which refers to the fact that citizens should be encouraged rather than frightened to participate in projects even where there is no direct, personal benefit to them. Participating in research it will not mean new drugs coming, and it will not mean better treatment. You are simply giving 30 ml of blood. It is very difficult to encourage citizens to give something for the benefit of humanity when in the rules governing most research you have to show personal benefit. Finally, there are duties to people in other countries, universality.

Generally procedures for population genetic research will be different from other types of genetic research. First of all, you have to go to the population. How do you do that? What method do you use? The television, the radio or go to every little town in a bus with some microphones on top? This is very tricky, because if you do too much communication the public thinks that you are selling things, but if you do not communicate enough, they think that you are hiding something. So this is a new requirement to say that you must consult. Are you doing an opinion poll? Are you scared of genetic research? This is a new field that has to be worked on, together with anthropologists, sociologists, etc. Recruitment has always been a problem in genetic research for two reasons. In the first place, when you recruit people in a region, often they presume that they are at risk for something. Or, you have communities that are so interesting for genetic research that you keep going back to them, such as people from eastern Quebec, Sardinians, Finns, etc. This latter form of research is gene hunting research, and is different from genetic variation research. Some people from these communities are tired of always being the focus of genetic research, because of oversolicitation. When you do population research, you do not necessarily want to look for disease genes, but also for normal genetic variation. Yet you get the reaction that people still think that this is because there is something wrong with them. In short, there are the issues of spreading risk during recruitment and not oversoliciting in defined populations.

If each person is genetically unique, we can prove it for the first time in history. At the same time, as a species, we are part of the human genome as opposed to the mouse genome. We all know now that there are not really many genetic differences between us and the mouse or the worm. Moreover, there is a level at which human genomic information belongs to humanity and not to the person, family, community or country. Actually, it is the human genome, as a species.

I do not know if you have ever seen any consent forms for DNA banking. Consent forms are about four or five pages long. They used to be one line, with a sentence like "I consent to give my blood for DNA research". At the bottom appeared the signature and the date. Today there is not an ethics committee in any industrial country that would accept a consent form like that. Now you get all kinds of options and choices. The form has become like a legal document, where you have to put initials at the bottom of the page. It has become very complicated. Moreover, the requirements of consent from France, Canada and Israel are different, and so samples and information cannot be shared. This must be simplified. It is the same for confidentiality. How can genetics be confidential when it is necessarily familial? We can think that research data is confidential simply because it is kept separately from medical records. The simple act of obtaining research data can affect participation in genetic research. For example, someone from an insurance company can ask: have you ever taken a genetic test? If you say yes, it does not mean that you ever had a diagnosis; it may be that the test was done when you were participating in genetic research. Sometimes it can cause harm in the sense that insurance companies will think that you have a condition of some sort.

Genetic data can cause problems also in deciding whether we have to keep the information confidential or share it with families. Physicians are not allowed to contact your brother, sister, or your children, because of the confidentiality requirement in the Hippocratic Oath. We have a case from the United States, where a father was dying from a familial form of cancer. There was a preventive treatment for this colon cancer and he said to the physician that he was not going to tell either his wife or his children, as he wanted it to be confidential. The doctor could not say anything, due to the Hippocratic Oath. At age 38 the daughter was diagnosed with the same form of cancer. She had two children. She went to see the doctor. He told her that as this was a familial disease, it must have been the same form of cancer that her father died of. She said to the physician that he should have warned her or told her mother that there was a hereditary disease in the family since some sort of preventive surgery could have been performed when she was 16 years old. If at that time they would have removed the polyps they would have prevented her from dying of cancer. They could have avoided her suffering and that of her two young children.

The matter went to court. The court held that, where there is a serious risk of the development of an identified condition and there is prevention or treatment available and the person at risk is identifiable, warning family members was not a legal duty, but an ethical privilege. In short, there are family issues on the one hand, but also community issues the other hand. Indeed, there is a study in France where they knew that young people were at risk for Macular Degeneration. The study was supposed to be anonymized, yet they knew exactly who these teenagers were. Because it was supposed to be anonymized, they could not communicate with the physicians. A treatment was available. They put posters up in the high schools and TV advertisements telling young people to go and get their eyes tested. They could directly approach the at-risk teens because they had to maintain confidentiality.

How then do you run a bank? How do you maintain confidentiality and yet also maintain the ability to do research, and transfer data to other centres, researchers or countries? What happens if you are a researcher here in Barcelona, you move to the United States and you want to take your samples or your families with you? Or what happens if you are one of those commercial companies and you go bankrupt? To whom do the samples belong? You have to have a framework for deciding that you can leave it to your individual researcher or your individual project to handle the complexity of banking issues. You really have to have an advisory group with rules for what happens with bankruptcy. When researchers have taken samples with them when they have left the country, the family's bank in the country of origin wants to know what happens with the project research as it is no longer in the country.

Another important issue is the communication of results. Every time that you publish a "finding" in a journal such as Nature, Science or Nature Genetics, the first thing that happens is that you get a phone call, asking you that since you have found a gene for a concrete disease, where can people go to get treated? As soon as a gene for a disease is identified, the public expects a cure, or at least a therapy or a drug, even a test. It is difficult to balance communication of knowledge that belongs to the public, and avoiding misleading the public by making them think that there is something that might be done about their condition.

One area besides consent and confidentiality that has major implications is commercialization. Every lab, unless it is a public lab, usually has either equipment or researchers, paid by industry. Your investors have the right to tell you what to do with the money they put in, i.e. you must get a return on investment. So it is necessarily a profit model. Who owns the information that comes from the DNA? If you look at the contracts signed between researchers and industry, there are clauses in there that say that I will not talk to a colleague, I will not submit an abstract and I will not publish without the approval from the sponsor. These are what we call in law "boiler plate" causes. In other words, it happens the same way as with any type of property. But shouldn't we have different rules for people working in health care research, such as arbitration and alternative dispute resolution? What about conflicts of interest? If you are a researcher and you are also a vice-president of a genomic start-up company, you will have to tell your research participants that you have shares in the company sponsoring the research. There are many issues affecting the freedom of researchers. If you are doing a masters or doctoral thesis in the United States or Canada you will not be put on a grant from industry, since your research supervisor, or your thesis director may be limited in the timing of the publication of the defence of your thesis.

Finally, there is the whole issue of patents. Some time ago I was talking to a researcher who has always had patents on genes. He told me that this is not new, as there have always been patents for different genes, as for example, the cystic fibrosis gene and the muscular dystrophy gene. Patents allow you to put your inventions in the public domain. Pasteur and Benjamin Franklin, for instance, had patents. The difference is what you do with the patent. There is a company called Myriad that has the patents for certain breast cancer genes, BRCA1 and BRCA2. These genes put women at a much higher risk for breast cancer than the 1 out of 9 risk in the general population. Myriad gave an exclusive license to a certain company. Thus only one specific company offers the genetic test for breast cancer and that company sets the price. The cystic fibrosis, the muscular dystrophy and all the other genes that were patented were not given exclusive licenses, which means that there was still competition and so prices go down. The current situation is so bad that some families in the United States with rare conditions are saying that they are not going to give the DNA of their children, father, mother or uncle unless they become applicants on the patent. Families want to get more involved in this whole issue but it is still an area that is not resolved, especially at the international level.

We now turn to ethics approval, which will also be a part of my conclusion in a few minutes. Ethics approval should include the monitoring of ethics research. But most ethics committees concentrate on possible discrimination and stigmatization. The creation of a data bank (with genetic material and information) and its use in population genetic research must avoid stigmatization as well as discrimination, and it should respect current laws and ethical norms in order to achieve solidarity. When we are dealing with population banks at the level of countries, it is difficult to know which ethics committee has authority. Spain, like France, has a national one. In the province of Quebec we have 77 research ethics committees, for a total population of 7 million. We cannot go to each of the 77 different committees; every time that we would go to a committee it would change something, so at the end the project would be scientifically impossible. Yet even at national committees you have the problem that people think in terms of monogenic Mendelian diseases. The committee members do not understand the new modern multifactorial complex genetics and certainly they do not understand population genetics. Furthermore, the research that you do should contribute to not only one condition, but to the welfare of that population. In some sense there should be some benefit for all citizens. This is called "benefit sharing". Benefit sharing is complicated by the fact that if you pay people you may be inducing them to participate. However, in Canada and most European countries it is illegal to do commerce in blood, tissues and DNA. You cannot give participants money to them because we are not allowed to buy DNA. There are some interesting examples of benefit sharing from South America and Costa Rica. South America said that maybe they will never get a patent for their population genetic research. They would go to Colombia, offer the research for free, as well as provide free public health nurses during the research. As not every test leads to a patent, if you wait until there is a patent and you give people the percentage of eventual profits, you may give them nothing. In Costa Rica, they gave to the local patient organisations some computers for communication. As you can see, there are different ways of benefit sharing.

Finally, the universality of the human genome says that you should share this information internationally. This is where data banks come in. It is very important that big international databases remain public, open and free. If you do not see information and databases as a global public good, we will end up like we did with patents, that is taking a fragmented private property approach to data. In my opinion, ensuring that this information remains a public good presents an incredible challenge. One of the reasons is the lack of respect in some parts of the world of basic human rights. It is hard to talk about global public resources, consent and confidentiality, autonomy, privacy, benefit sharing, reciprocity and complexity when you are in countries where basic human rights are not respected. If you have the privilege of participating in research in countries where human rights are respected you must take care before making information available to countries that do not, as there is potential for abuse of human rights if this information is used inappropriately.

From the Human Genome Project, we have to take into account the world's view of people, how they see their genes. The indigenous population in Canada, for instance, considers their genealogy to be in their blood. We can find the expression "blood brothers" or "blood sisters". So they have the conception that the family is in the blood. There are different attitudes and understandings of what is in the blood sample. Some people think that his own code is the expression of himself. So if you have their DNA you have them, because they think that they are the total sum of their genes. Let's move from research into clinical. In a country with a universal health care system, the common problem is that for every common disease there are genetic factors which play a role, and we have tests for many of them but they are very expensive. You will never be able to integrate them into the system without killing universal health care. Finally, we also have to take into account the non clinical integration. At the bottom of this pyramid that I have described we would have all the racial, ethnic and socioeconomic issues as well.

We are right in a science fiction story or in a surreal painting, with Darwin and the origins of humankind. In an ethics committee, national, international or even local, it is nonlinear, it is dynamic, it is epigenetic, there is no hierarchy, it is nothing that you can put into an equation. You are also dealing with unknown faces called ethicists and we do not know who they really are (I did not mean to insult any ethicist in the audience). People ask me if I am an ethicist, and I will answer that I am a law professor, simply because we are not quite sure; it is an unquantifiable entity in terms of accreditation, accountability, monitoring, as we have in the medical, legal or nursing professions, for instance. People in committees will say that something is legal but it is not ethical. Then everything gets shot down. If law is the minimum social consensus accepted in a given society, then ethicists on the committee, whatever their background is, can simply say that this is unethical and stop the research, as I have seen happen. So this is another surreal factor in this complex painting.

My reason for talking today about population genetics is due to my motivation to move your interest, knowledge or future in genetics, biology, biochemistry, bioinformatics, beyond what I call the Mendelian monogenic model. Move it into a level of families, communities, countries and humanity. Population genetics is a very controversial area, which will take ethics beyond the individual. However, this is my hope and I am ready to answer your questions. Thank you.

Montserrat Bordes: My question is about the UK Biobank. It seems that there are some scientists who are very supportive to the project, but some others think that it is a project without a protocol (The Lancet, March 2003) In any case, leaving aside those non-bioethical questions, it seems that in order to make a good use of the data, the samples should be anonymized but linked. According to current bioethical requirements, the consent cannot be unconditionally blanket, so there is here some controversy. Some people say that this may set a new standard for ethics in research with genetic samples. I would like to know your opinion on that point.

Bartha Maria Knoppers: The UK bio bank is a longitudinal study. They want to take people from the ages of 45 to 75 and follow them. They want to know each participant's major conditions and common diseases. They want to know his diet, where he lives, if he has a motorcycle (to be aware if he represents a risk person), if he is a careful or cautious driver. They want to know his income level, if he has stress and if he has any children. They are searching for the expression of the genotype and the phenotype. The most "direct" way would be to study participants' genotype knowing their phenotype (which necessitates knowing their identity). But that is ethically unacceptable. However, to fully anonymize the data such that it is impossible to track to identity of the genetic information is also problematic. You are killing the data, because it becomes frozen in time, i.e. once the anonymization is complete, the participant cannot be found again. If three months after anonymization I suddenly develop something which is not on the samples, this phenotypic information cannot be added. The solution is a double coding system, i.e. I give you my data, you put it with my clinical record, my family history, and you put a code on it. So now I am "xyz." When a researcher wants to use it a second code is put on it, "abc". Only the keyholder, who is not doing research, knows that first code "xyz" is the same as second code "abc". Suppose that in three months from now, another researcher is also interested in making a study about all females with two children, etc. The fact that I developed diabetes last month will be in my medical record. So this researcher will get my sample with the second code. He will not know it is me, but the information of my diabetes has been added. The data is continually enriched by further research. But since the researcher uses anonymized data, which is double coded, he can never discover the identity of the person. The researcher can always give back the information he discovered to the central bank. For example, say the researcher finds that to be married is an important social factor, because he or she found that all females of a particular age who got married under the age of 25 have a higher risk for heart attacks. (I should never have got married!). The researcher can send it to the keyholder, who will find the first code that corresponds to the second code off, and identify the females to whom the new discovery applies, i.e. those who married under the age of 25 and therefore have an increased risk of heart attacks. The information can go back to the clinicians and can be used in the treatment of these women. This is the advantage of a double coding system.

Xavier Estivill: In the UK they have started to take DNA samples from individuals that have been followed during more than forty years, from whom they already have a lot of clinical data and information. I know it very well because I was involved in the evaluation of one of these projects and all the main groups doing research in the UK were supporting this type of study. In these studies, all different clinical conditions, asthma, etc. were evaluated. These groups were born in the middle 50s. In fact, my question is what do you think about retrospective data?

Bartha Maria Knoppers: I cannot see any problem if I am living and you already have records on me from my birth and you take my DNA sample tomorrow with my consent. So I cannot see the problem on doing this if the people knew that the records would be collected and used.

It is different to use retrospective data with people who are aware of it, and retrospective data from dead people. Here you face a big problem because, legally speaking, daughters, sons or spouses cannot send the data from the dead.

There is a suspicion, when we are going into biology and research. It seems that there is something which is not transparent, which is something that you have to overcome publicly by speaking to a lot of people in order that they understand what the researchers are doing.

On December 26th, when they announced the birth of Eva, a cloning baby, the response from the public demonstrates this suspicion of the public. Media had nothing to say as Christmas was over the day before. But at the paediatric hospital in Montreal it attracted much attention and parents who were bringing in their children the next day, asked paediatricians if the hospital did cloning. They started to ask if, with the blood taken from their babies, they were going to make clones. The impact on how genetics is understood and how scientists are seen put us back five years.

Jaume Bertranpetit: I would like to proceed on the point of view that we were talking. Right now one of the aspects that is more challenging to biology is the relation genotype-phenotype. This is something that lacks a deep study and now is the moment to begin it. In many places this is impossible to begin or do it because of ethical concerns. To me, this kind of puzzling that some people are having now with this UK problems is because it is the first time that researchers say openly that they take genomes on individuals, and we want to know everything from the patient. This is the interesting point, so we have to break down the fear.

Bartha Maria Knoppers: People have a lot of worries. They think that maybe if they participate, their children will be branded in some way. The wrong aspect is the inability to understand the science. We really need to start with information that is modern, up-to-date, not information that believes genes are everything. Because as long as we stay in the model that genes determine who you are, which is the reductionist model, people will have those fears.

Xavier Estivill: We are used to identify genes that predispose to common conditions, especially common medical disorders. But I think that the impact that these studies will have, from the point of view of prevention, will be much lower because I think that it is clear that when we are dealing with highly penetrant mutations, as you mentioned before, like cancer or some other monogenic disorders from which we already have the genes, this is something totally different from all the other common conditions. I think that the major impact, and this is something that people have to understand, is the discovery of the biology that is behind all the different disorders. For most of these common disorders, like asthma, there already would be many genes and many variants, and one specific variant would give a risk that would not be very high. In the case that something is risky would allow to prevent better a condition.

Bartha Maria Knoppers: This is the reason for being interested in science at the population level. Pharmacogenomics involves finding out more about people who are at risk for asthma and all these mutations, but for whom the same product, because we understand the polymorphic differences as opposed to the gene for asthma, will have different effects. One of the goals of pharmacogenomics is to understand profiles of populations, and use drugs for "types" and not for individuals. That is why so much money is being put in pharmacogenomics. People see genomics as a chance to tailor drugs for people who have the same condition, but because of different mutation causing the condition they respond differently or they get killed, they have different reactions or they do not respond at all. And the same thing has to be done at the level of population and subpopulation. I am not sure. I do not know enough about it. There is a theory on it but I do not know it.

Now the little bit that they know of pharmacogenomics they are using it for the CYP enzymes. Researchers are now testing people before they go into research, because they are scared of being sued, especially in the United States, for not doing those tests before they accept people into research protocols. If you could have done a genotype test prior to accepting that person into your protocol, then the adverse reaction could have been avoided. I think that we are going to see genotyping as a safety and efficacy measure before we ever see it as a genotype-phenotype treatment.

Carlos Masdeu: At the beginning of the speech you talked about some countries like Iceland or Estonia that by default send the genetic data to a bank. My question is how the people from these countries have accepted it. I suppose that it was accepted by referendum. Those data are protected by the state and people there is happy about that. But I do not understand it, as I think that this situation is not possible. I suppose that everything began with campaign information and propaganda, and they started to know that white code people were not to manipulate their data.

Bartha Maria Knoppers: In Iceland there is a company called Decode that has a license from the government for the data. So it is not really the government but a private company that has the data, health sector database. In Estonia, there is a foundation which is the guardian of the data. In no country is the government the holder of the data. People would never have accepted it, because if a government has both a criminal bank, like we have now for criminals, and they have a genetic bank, for medical and scientific research, then a little sharing between the banks would be possible. One went into a company and the other created an independent company, a foundation where citizens sit on the foundation.

Carlos Masdeu: I still do not see where you put the line between the use of this information for the good of people and to use it to create something like a data bank.

Bartha Maria Knoppers: I am an idealistic person, but the possibility of abuse is always there. You do not want to be crazy and say that there is going to be cloning tomorrow or Gattaka in ten years. I think that we have to be virulent about the possibility that someone could use it to identify everyone attending university, for instance, as in the movie Gattaka, and then you create selected embryos based on better genotypes. That is where not only the ethics committees come in, but where the communication between scientist and the public is really important, because the public will keep an eye on science. The more transparent a scientist is, the more faith the public will have. The more involved you get, the more you will get laws you will trust. The United States, for instance, is the opposite case. They are very strict about public funding, what you do with money coming from the NIH, but in the private sector anything goes, you can have a catalogue, how many babies have they had, how all the women are, any prompts during pregnancy. They have a really well-defined system and you cannot abuse. I will give you an example, but it is so recent that you even have not read it yet. Let's take the Olympics. Suppose that we have a treatment for cystic fibrosis that allows the clearance and the enlargement of the lungs. Suppose that we also have a treatment for muscular dystrophy, which will take muscles and built up their potential. Those are legitimate gene therapies, but then you could have abuse of it. Like runners, sprinters, doing the Olympics using techniques meant to help sick people to enhance their performance. There is very little talk about enhancement therapy. If these types of legitimate therapy are used by athletes, it would be very hard to discover.

Joan Planas: You start answering the last question saying that we have to be vigilant of not falling at the Gattaca scenario. As we have to be vigilant, we can suppose that somebody has to play the role of the ethicist. In your opinion, which profile of person could play that role?

Bartha Maria Knoppers: First of all we have to decide if it is going to be a profession, because they carry a lot of power, like a delegation of responsibilities from ethics committees. These committees are composed of scientists, legal people and community representatives. I think there are four criteria for a professional. He is a person with expertise, responsibility, independence of judgement and accountability. I think they will have to start by accrediting the "ethics profession," i.e. the people who will sit on these committees, because they have so much power and so much responsibility. I think probably you would have to do exams, like we do in any other professions, or ongoing education. Ethics professionals could come from sociology, psychology, biology, law, I do not think it matters that much what field you come from. It matters that once you say that this is what you want to be, where do you want to go, what do you want to do, there is some process to make it sure that there is a minimum assurance of quality. We have private ethics forms now operating to give private ethics review to private companies. Again we have no idea how these things work. But the companies will say that they have ethics review. I used to teach family law. In the majority of cases we used to say that mediation was needed. Now we have a profession called mediators, who now have ten years of experience. So a minimum polity expertise is assured.


Joan Guitart: Agraeixo l'assistència a la professora Bartha Maria Knoppers, al professor Miguel Beato, a Jesús Acebillo, a Jaume Bertranpetit i a totes les persones que heu treballat en la realització d'aquestes jornades. Com molt bé sabeu, us parlo en nom del Consell Social, que és l'òrgan de participació de la societat a la Universitat. Amb aquestes Jornades de Primavera que s'inicien avui i amb els Debats Trimestrals pretenem fer possible que molts dels actes que realitza la Universitat Pompeu Fabra, així com la ciència i els treballs que desplega, siguin més coneguts i apreciats per la nostra societat. Esperem que molts dels aspectes que es tractaran aquí puguin ser objecte de debat i de reflexió.

El tema que tractarem avui és molt important. Com ja hem dit a la presentació, no podem posar barreres al coneixement. L'aplicació que en fem, per tant, ha de ser objecte de reflexió, preocupació i debat, així com també d'actuacions de tota mena. Volem començar les Jornades amb aquesta temàtica i prosseguirem amb d'altres Primaveres i amb els Debats Trimestrals, aprovats pel Consell Social, que es realitzaran sobre temes molt més puntuals. Ja només em queda expressar la satisfacció per l'inici d'aquestes actuacions i agrair un cop més l'assistència al públic. També vull donar les gràcies de manera especial a la Universitat i a totes les persones que fan possible aquest acte.

M. Rosa Virós: Dono la benvinguda al president del Consell Social, al professor Van Ommen, la doctora Knoppers, el professor Beato, el professor Bertranpetit, el doctor Acebillo, amigues i amics. Vull agrair públicament al Consell Social, i sobretot al seu president, l'organització d'aquestes jornades que contribueixen a una reflexió global sobre els avenços de la ciència. El que es digui aquí també repercutirà en els mitjans de comunicació. La societat necessita debat i arguments sobre les qüestions que afecten els éssers humans. La ciència i l'ètica són dues doctrines que han d'estar fortament unides. La ciència ha d'avançar, però no ho ha de fer a qualsevol preu i, per tant, cal que se'n marqui el territori i que se n'explorin les fronteres. Històricament, trobem casos documentats d'investigacions que s'han portat a terme a qualsevol preu. Per experimentar, s'han fet servir presos i malalts que estaven en hospitals i manicomis, i fins i tot vells d'asils. Això no ha passat en països llunyans, sinó en universitats i en hospitals de l'Amèrica del Nord i d'Europa al segle XX. L'ètica i la investigació no són, per tant, un tema banal, i cal afrontar-lo.

Com a rectora de la Universitat Pompeu Fabra, agraeixo la vostra presència i us desitjo un debat profitós. Declarem inaugurada aquesta jornada sobre "La Genòmica al Segle XXI. Els Límits de l'Ètica". Moltes gràcies a tots per la vostra assistència.

Jaume Bertranpetit: Bon dia a tots. Només us vull avisar del petit canvi en el programa. La professora Knoppers ha de tornar avui al Canadà; i com que ha tingut problemes amb els vols, perquè ha de passar per França, on hi ha vagues, ens presentarà la seva ponència abans. De manera que començarem amb la intervenció del professor Van Ommen i, en comptes de fer la taula rodona justament després, escoltarem les paraules de la doctora Knoppers. En acabat farem una pausa curta i continuarem amb la taula rodona, però sense la doctora Knoppers, que ja haurà intervingut abans.

Ara us vull presentar el doctor Gert-Jan B. van Ommen, que és una de les persones que en aquests moments està treballant i desenvolupant la genètica d'una manera molt poderosa a Europa. Ha estat un gran promotor de la genòmica i de la interfície amb la societat. M'agradaria destacar el seu paper en tres qüestions. En primer lloc, en l'aspecte d'investigador, ja que ha treballat en molts aspectes, tant en malalties genètiques amb anomalies neurològiques, com en casos que anomenem d'expansions de trinucleòtids. En segon lloc, també ha tingut un impacte molt gran com a president de la Human Genome Organisation (HUGO). L'època en què va presidir l'Organització del Genoma Humà va ser el moment en què es van produir els grans desenvolupaments de la genòmica. I en tercer lloc, m'agradaria assenyalar especialment la seva feina com a editor d'una de les revistes del ram que té un fort desenvolupament, com és el European Journal of Human Genetics. A més, s'ha preocupat enormement per la interfície entre genètica i societat, en el sentit de les aplicacions i els usos que se'n faran, i ha publicat en diverses revistes revisions sobre els temes de genètica, societat i les implicacions de les troballes o de les possibles intervencions de la genètica en el futur.

Ara us vull presentar el doctor Gert-Jan B. van Ommen, que és una de les persones que en aquests moments està treballant i desenvolupant la genètica d'una manera molt poderosa a Europa. Ha estat un gran promotor de la genòmica i de la interfície amb la societat. M'agradaria destacar el seu paper en tres qüestions. En primer lloc, en l'aspecte d'investigador, ja que ha treballat en molts aspectes, tant en malalties genètiques amb anomalies neurològiques, com en casos que anomenem d'expansions de trinucleòtids. En segon lloc, també ha tingut un impacte molt gran com a president de la Human Genome Organisation (HUGO). L'època en què va presidir l'Organització del Genoma Humà va ser el moment en què es van produir els grans desenvolupaments de la genòmica. I en tercer lloc, m'agradaria assenyalar especialment la seva feina com a editor d'una de les revistes del ram que té un fort desenvolupament, com és el European Journal of Human Genetics. A més, s'ha preocupat enormement per la interfície entre genètica i societat, en el sentit de les aplicacions i els usos que se'n faran, i ha publicat en diverses revistes revisions sobre els temes de genètica, societat i les implicacions de les troballes o de les possibles intervencions de la genètica en el futur.

Conferència "The human genome, impact on genetics and society"

Thank you very much for inviting me to this conference. I hope that I will be able to make myself understood. Unfortunately my Catalan is not good enough to make myself clear so I am pushed to make this talk in English.

Actually, what I wanted to outline is that a lot of the questions that we have on a daily basis are not new. It is a perennial question of nature and nurture. What is in our genes and what is in the surrounding? The answers to these questions are both equally important. Our genes have been selected to the surroundings for millions of years. The trouble is that the environment is very difficult to control for and so we can only understand the environmental influence better if we understand what the influence of our genes is. To let you know that this is not just a story, we have the example of the top ten drugs of 1998. From this group, nine out of ten are drugs that help us and our genes survive the environment. Only at the tenth position is the first drug that actually defends us from something of the outside. If we then look two years further on, in 2000, not only the prices have doubled, but penicillin is drop from the variances and these are all medications that help us to make it through life. You can study that from a genetic point of view.

A colleague of mine in the Netherlands decided to study headache, because he thought that headache is something genetic because you can get it from your parents. So for ten years they looked for the gene for migraine and at last they found it. I am not going to explain to you the whole story, but I want you to know that what they learned was that there existed an ion channel that transported calcium across the neurones. The actual interest of this question is that it really has changed the whole field of research in migraine and epilepsy. This is a clear example of where a sudden discovery can lead one. You also heard me say that this took ten years. At the time that I began working in this field the whole community of genetic scientists in the world only managed to find three diseases in three years, that is one disease per year, so it did not really go very fast. This was the reason why at some point people thought that the genome project would be a better way to solve it. At a macro level, the first five years of the process they were making maps. During the second period of five years, at a medium level, they were putting genes on the map. And in last five years, which are ongoing now at a macro level, they are discovering the human DNA sequence.

At this time there was a discussion among the scientists. Those who were classical scientists were very much against doing all this work, because they thought that it was not really science but a "fishing expedition", it was not hypothesis-based and they knew that it would cost a lot of money. The proponents of the work argued that the hypothesis-based research is limited by existing knowledge, and if your knowledge is only 2% you do not have a lot to base your hypothesis on. And ultimately the genome project of coli bacteri, yeast and other organisms, for instance, learned that there was so much of biology still to discover that gradually people came around to see that it was a sensible thing to do. I think that the basic reason why people have become much more in favour of it is that it has also delivered a tremendous boost to the discovery of disease genes. You heard that in the beginning it was one per year, this is the harvest of only one year in 1993, with many major diseases found, and in the last year that I managed to keep track, in 1999, we were talking about four hundred different diseases discovered, more than one per day. And if we then realise that behind every single disease there are patient families, caretakers and the surrounding community, then there is a tremendous amount of value created by the type of research that has been done.

When the goal was set, the director of this project, Francis Collins, said that "a goal is a dream with a deadline". If you want yourself to say in 2000 we have got a DNA finished, you should realise that one year ago, in March 1999, this was all that had been done by the whole community. The red is reasonably well done and the green part of chromosomes is a little bit less well done. But in total this represented about 15%, and that was achieved in 30 years. So they only had one year to do the other 85%. When people suddenly realised what the task actually was you can see what happens per month and what has become available on the Internet during this time. As soon as people started to get the real focus suddenly they began to achieve and in May 2000 most of it was in a reasonable shape and two chromosomes, 21 and 22, were completely done. It was amazing that in June 2000 the first news of the genome sequence was there. I think that the most important point is that it was a race between a public and a private company. And in fact the public in the world, not the public project, is the winner because it has gone a lot faster. The race has attracted so much attention that both politicians and people went into it and the public had a lot of interest. This is very important because it represents powerful information that we have to work with for hundreds of years to come and even longer. We really need to pull in the public in the discussion as you just heard before. In addition, the fact that all this has been made available through the Internet means that many more smaller laboratories all around the world have been able to do the research in a much faster way.

The questions originated in our society cover all fields of health care: diagnosis, prognosis, therapy and prevention. Improvement, broadening and sharpening of diagnosis, and the options people have if they receive one diagnosis. Therapy and prevention basically go hand in hand, therapy probably will frequently be by means of medication, but sometimes lifestyle and prevention. Ideally lifestyle would play the biggest part with medication as a secondary.

The next question after having done the first sequence is to know where we are. The answer is somewhere on this light, but this is not very informative, because we are on the top of this light and where we want to be is on the bottom of this light. The difference is that we still have to add the tremendous amount of understanding an interfunction to get there, and that is a task that probably will keep us off the street in the years to come. The way that it has been done is not even new in our field. By comparing between the sequences of the mouse and humans, and the fruitfly and humans, the goal is to see what is conserved, what is the same. This has also been done by the linguists in comparing different languages. But there is something much more familiar to you all. If you buy or rent an old house and you cannot understand how the electricity works, then you just try to unscrew every plug at the same time and work out how the wiring is growing with a little radio in the wall outlets. In fact, this is exactly what we are also doing with animal research, because we cannot do it with humans. I think that the big importance of being able to do animal research is that in this way we can look retrospectively at how things are "wired".

Laboratories nowadays look very different to those of ten or twenty years ago. Now there are all sort of robotics and many things are being done in parallel. Robotics make less mistakes. I have to admit, though, that if they make mistakes, they are very real and important, but still it is a different way of doing science.

You may have heard the term pharmaceutical genomics. One of the big expectations nowadays is that we will find better drugs that fit more to specific individuals, to their physique, as opposed to current practice in prescribing drugs which goes against biological understandings. We have one size fits all type of medication. The patient goes to the doctor. There is a generic diagnosis and a medication is prescribed. That is all. But far too often it turns out that this medication does not work, and then a second medication is tried. Sometimes the second medication does not work either, for instance because the side effects are so bad that the patient will not take it. Then we have to resort to a third drug, and if there is still a patient, we can probably find something to cure him. This seems quite a pedestrian way of working and in the future we hope that in the same situation we can do a first test, match the disease process and the medication, and then of course you will be able to get the patient back on track again much faster.

When I present this, quite often people comment that this is very nice but will not work that way, because the pharma industry is not going along that route. They would have to make ten times as many medications for much smaller markets, which is very complicated and expensive. I think that this is correct as an observation, but it is not the full story. Of course, there are cost increases. There will be fewer blockbusters, the market subdivision will be major and this means that there will be many regulatory issues to solve. But this is not the full story, because there are also cost decreasing aspects. We will have much smaller clinical trials if we can cluster patients much better with their real disease and through these better statistics. As there is a lot of cost involved in this stage, the design of drugs in this respect may become cheaper. The outcome of the drug type line will then be higher than nowadays. If now you have a drug that works in 10% of the cases but you cannot understand why it does not work in the other 90%, then the companies have to put it in the shelf. But if you can separate the 10% of the patients where the drug does work and leave out the other ones, then actually you have a drug for that group. I think that the cost balance is not clear yet and there is also another major issue, which is that if we are better able to predict the workings of drugs we will have fewer late stage withdrawals, which is a major problem for drug companies, because they cost about half a billion to a billion dollars, and that is the reason why pharma companies have to have such full coffers and is part of the reason why drugs are so expensive. If they can reduce that risk, even by a factor of two, that is already a major effect. So the answers in the mid term, from five to ten years, is that we will have more effective drugs with less side effects and prevention of over treatment. In the longer term, from ten to thirty years, we will have drugs more specific to the disease and also those which by-pass the defect, what I would call genetic therapy. If we look still longer, what we actually would like to achieve is depicted on this slide. Suppose that humans are like this: a system in equilibrium, between the boundaries of what you call homeostasis, then something happens. At first, you will not see something on the outside, that is the effect because the system tries to compensate for it. Inside, it is different and it goes wrong. This is maybe the point where somebody goes to the doctor for the first time and goes away again waiting a while without worrying, and so on until it goes wrong again and ultimately this is where we see people in hospital. And what we of course would want is to be able to look inside here, because then we can protect people and try to cure them at an early phase.

This is half of the story. From the other half we can observe that we have moved very fast with every thing that we have been doing. In fact, we have the example of a little boy with Duchene muscular dystrophy. At first he was still capable of working. In 1985 we did the first DNA diagnosis ever done. That was in the Netherlands and it means that this person had to spend all his or her life to DNA diagnostics. This is something that we are tempted to forget. In the meantime we had Dolly, the headless frog, and cloning and a lot of other things. I can imagine that people say "aren't you going too fast? Do you still know where you have to go? Do you still know what you are doing?". We have to get this debate with society going and we have to stick the debate with society, because many people in society just consider themselves hopelessly people between DNA and the forces of life. Many people think that this might be our future, which is pretty scary. If everybody has a chip card like this with a photograph that tells you all these terrible things that you might actually get. Let me tell you that I have developed this slide for a talk at an insurance company. You can imagine that this company was a little bit anxious and they thought that they could find this guy and check him out from their system, then they eliminate the risk. But I can tell you if they try to check this guy out with all these risks, they will check out 97% of their customers. And everybody in this world can start an insurance company, not exclude anyone and have a perfect business plan, because everybody has a list like this and it is probably a lot longer and it not only has risks, but protective factors. It does not really say a lot and people should really think about this in a more detailed way. For instance, people cannot deal with risk, the chance of winning the football pool is 50%: you win it or you do not win it. But this is not how it is. If you have a twice elevated risk of schizophrenia, which occurs 1% in a population, then it means that the genetic factor which double that risk means that you have a 98% chance of not getting the disease while you have the risk factor. It is very different from this sort of Mendelian genetics that we have learned at school with red and white flowers, and crossing them to get pink, we just have to try to understand ourselves and explain to other people that we have to get away from determinism much more in the direction of probabilistic situations. How I look at things is much more depicted by this mobile of Calders where you have this equilibrium of a couple of weights. You cannot really predict what would happen if we hit one of those weights, if it would start to turn, if it would fall over. Actually, humans are like this but with thirty thousand weights, and so what happens is very impredictable. On the other hand, if we know a little bit about what might happen then we have more modalities for therapy. If one of these weights has fallen off, the whole thing is hanging out of kilter and if you do not know how it works, then you can only put back the same weight at the same place and that is what you might call gene therapy. But if you know a little bit how it works, then maybe you can put another rope at another place or cut off another weight at some place that you can easily reach or maybe hang an extra weight at some position in order to restore the equilibrium without being able to actually cure the original cause. There are many examples of that. Now, to round up, we have a task of communicating with the audience, as I have already said. A few years ago, I was phoned up for a telephone interview by a Belgium journalist. It was a very nice chat and we had a long discussion because he was well prepared. When I put down the phone I had the feeling of having done something wrong, because I had gone too far into a complicated view of the subject and I was quite concerned about this chat. Then I got the article by fax and I read it and realized that it was excellently done. He even managed to explain the right note to know quite well, which is a complicated issue to explain, so I went home quite happy. In the meantime, my wife was in the publishing business and found out the nature of the journal that this guy was working for. She said that the next time that I give an interview I should not waste my time and do something more useful than speaking to people from that journal. Then, two weeks later, when the journal was brought by my secretary, I found out what she meant, because it was like that. At first I thought that she was right, but later I realized that these journals have a far wider readership than Cell, Nature, or Nature Genetics, or whatever. Actually I think that it is quite good to have good information in public media and I think that this is part of our task. One of the things that of course has helped us there is the Internet. One of the other things that I think is important to realize is that there is this big debate about genetically modified food. And the reason why I hope that the health care is not going down the same route (and the opportunity that the health care should not go the same route) is that in the food business there is not really a natural intermediary between developers and the public. It is the grocery stores and the big companies and so on. But we do have a perfect intermediary in health care, which is the doctors. We really have to sort of take it in steps, and we have to try to inform the doctors. There are Internet sites for doctors with some information, like for example one from the Netherlands. The next part that we should take care of is the school kids, because the best way to get information across is when we educate the younger generation about how a lot of this science is not scary but is fun. In Amsterdam we have a big science museum, which is called New Metropolis. There are all sorts of laboratories there. People can do tests and also walk around. There is another one in Paris as well, where they have a laboratory part. I think that ultimately this is the best way to make the thing less concerning and scary. This is the way that geneticists look at families and clearly you see something missing here. This is how reality is. We really should understand that as long as we keep in mind that there is more behind genetics than family trees and everything, not all is lost. Let me show you a picture of my cats. The reason why I do this is the following: they were supposed to be all a seventh generation racially pure Blue Russian cats. But there is one who it is clearly not. It turns out that he has a homozygote mutation in a taiuozenes gene, at least this is what we think, because this disease is known in humans also, and it is called ocular cutaneous albinism. The interesting thing is that the other two are five/eighties brothers. The father is the same and the mothers are nieces. A lady cat is further away the pedigree. So these two share many more genes and there is only one gene that makes all the difference. But they share many more genes than these two. And that is not what you would look at, even me as a geneticist would think that these are one sort of cat and this one is a different sort of cat. (Let me tell what they think about themselves in a same way). We should realize that we cannot draw conclusions by looking at the outside, because we really have to go into it, sort out things in detail. Then, society will be reasonably happy with what we have been able to provide them with. Thank you very much.

Jaume Bertranpetit: Les preguntes les farem durant la taula rodona, un cop la professora Knoppers hagi acabat la seva intervenció. Ara donarem la paraula a la doctora, que ahir a la tarda ens va fer una conferència sobre els problemes ètics. Va tractar de les mostres humanes i dels bancs de teixits i de DNA que es fan servir en recerca i les implicacions ètiques. M'agradaria afegir que les implicacions ètiques de tot aquest camp són extraordinàries. Una de les discussions que encara hi ha i segur que hi haurà durant molt de temps és saber qui és el responsable que ha de vetllar perquè les mostres humanes tinguin un tractament i gestió adequats, respectables i acceptables. És a dir, establir l'encarregat que tingui la paraula per entendre-ho i per definir els paràmetres sobre què es pot fer. En aquest sentit, penso que la doctora Knoppers és de les úniques persones en tot el món que té més experiència en aquest camp, i és una de les professionals més escoltada. D'una banda, perquè aquest és un camp nou, en què no hi ha propietaris i on s'ha d'innovar contínuament. I de l'altra, perquè és un domini on ha entrat molta gent que parla molt però que acaba no dient res. Una de les coses que cal que agraïm a la doctora és que en aquests temes és una de les poques persones que explica fets importants, marca directrius i aporta respostes a algunes de les preguntes que contínuament ens estem plantejant.

La professora Knoppers ens donarà, per tant, la seva visió des de la bioètica. Tal com ella diu, hi ha molta gent que en aquests moments encara no sabem exactament què és fer bioètica. Ella pot ajudar-nos a establir-ne les bases, ja que la seva formació original és en dret i en aquests moments la seva implicació és extraordinària. Ha format part dels grans comitès de bioètica que han existit i dels que actualment continuen treballant en les dues organitzacions que més tenen a dir sobre tot això, la UNESCO i la Human Genome Organization, que continua fent una feina molt important. Thank you for coming, Bartha.

 Intervenció de la professora Bartha Maria Knoppers. Una visió des de la bioètica

I would like to continue a bit after Gert-Jan's excellent presentation by looking at a particular subject: genomic databases and what to do with the next step of the human genome project, that is to say where does all this information go and who does it belong to. I will start by looking at science in society and focusing on how society has reacted to all the knowledge that we have acquired. I will then present the controversies on this subject. Lastly, I will discuss future directions. I will try to do it within fifteen minutes.

First of all, I will start by presenting what is happening. I think that the presentation of Doctor Van Ommen has already illustrated the reaction to the promises and the hope that the scientific development has brought. People think that when you find a gene you are going to have a cure immediately. There are three genetic fallacies, as I call them, and I will talk about the first two, before turning to controversies. The first, as Van Ommen discussed, refers to determination: people think that genes determine who we are. Eureka! I may or may not have found a gene that causes indecisiveness. This is the idea that when you find the gene, then you can explain the person, as well as his behaviour. As Van Ommen said, the alternative to determinism is probabilism. Determinism is the reductionist model of genetics, based on Mendel's experiment on peas and the idea that we are our genes.

If you work in the area of law and ethics like I do, the result has been an over reaction by governments. They have adopted this conception of the genes or a similar model and they have adopted laws in forty American states and twelve different European countries, which say that since you are your genes we will adopt legislation accordingly. This means that you cannot ask a person if he or she has taken a genetic test, you cannot go into a medical record to see if a person represents a genetic risk or has a gene for obesity or schizophrenia. This deterministic model has led to an overt reaction and the integration into legislation of the biological reductionism model. Countries have not all adopted laws, but in the cases that they have, they have done it the same way in the area of insurance and employment. When you apply for a job or you ask for insurance, you may worry that they will find out something about you that you always had and they will miscalculate your risk. Employers will not hire you because one day you will cost them a lot of money, and insurers will not give you a premium because they like to be able to calculate the risk, but always calculate it in their favour and not in yours. If countries have not adopted specific legislation, some of them have taken existing human rights codes and they have added to the list the following premise: "You shall not make any discrimination based on sex, gender, race, civil status, nationality, sexual orientation, physical and mental handicap, or genetic characteristics". So if they do not use the legislation route, they can use the human rights route and they add genetic characteristics or genetic features at the end of the long list of discrimination. This also has disadvantages because again it promotes the reductionist model, implying that having a genetic risk means you are sure to develop a genetic disease. This is handicapping you in your human rights.

We are arguing against adopting either the human rights or the legislative approach, because what we really need, while we are still understanding and are scared about what the insurers and the military will do, is to put into human rights legislation not genetic characteristics as a forbidden ground of discrimination, but rather the phrase "of being perceived, regarded and treated as such" should be added. What is really discriminatory is treating people who have no signs or symptoms of any condition as if they are already ill. It is more perception of genetic risk that is handicapping, that is discriminatory, than actual genetics. In fact, if we want to slow down, if you fear the genetic springs, we had better not to adopt genetic characteristics or employment insurance legislation, but rather simply add "or being perceived as such" to human rights legislation.

The effect of exceptionalism is that personal data legislation, the one that protects you from the banks, from the state, from the marketing agencies, from the people who you do not want to get your name, address or telephone number, is being changed. Medical data legislation is being changed too in order to add a new category called genetic data. If the countries have not adopted the first route (i.e. insurance employment legislation) or human rights additions they go the following way: they take the data privacy model and they add genetics as a new category. Again, I would argue that this is the wrong route to take. First of all, personal data should incorporate medical data, even though this is sensitive data. Some countries, to not put medical apart, say it is a subcategory of privacy of personal data. Because if we add genetic data to different laws, like UNESCO, WHO and the Council of Europe are planning to do, then it becomes a zoo. That is, to say a genetic condition is not normal is not even a normal medical condition and it is something different from personal data and different from medical data. The result is that if we say that genetic conditions are not normal, by making laws on genetic data, first of all we cannot say what it is. Today we are into biochemistry, proteomics, and we also want to know if your cholesterol level is any different from being at risk of 1% of something genetic. We do not know what genetic data is, even if we create laws for it. The problem is that we stigmatise people, because a genetic condition is different from your medical condition, which is normal. So we slow down if not totally stop the integration of genetic risk as being normal as far as the human condition. I would argue, again, that genetic exceptionalism is a mistake.

Let's turn to some current controversies in the area of genomic databases. Doctor Van Ommen talked about the whole human genome project. The public sector is saying up to the level of the genome of the species this information belongs to humanity. We are not talking about your genetic profile or your risk profile, but about the human genome, as opposed to the mouse genome, for instance. So the human genome project, with many collaborators around the world, would make this information public every 24 or 48 hours. But the private sector would take that information and do its own research. And if you want access to their private database, you have to pay and sign a contract that gives away some intellectual property rights. Finally a leading announcement was made and everybody was supposed to be friends in front of the cameras, but it illustrated the benefits of the public way: the differences between publicly funded, publicly accessible research data made available to anyone in the world, and the private sector database, which exploited the public database, and is available to those who have the money to pay for it. I think that this says a lot and I will come back to it in my conclusion.

If we are looking at databases, we do not know if we can use them for research or for teaching without being sued for patents or copyright or limits on the license and so on. Europe and the United States have different perceptions of the exception made for using data for teaching or research without paying for a license. But no matter where you are, this has to be clarified. In all the discussions on intellectual property we need to know what is meant by "you can use it for research, teaching or scientific purposes". If we do not clarify, you will end up being sued or you will not do the research at all because you do not know who the owner of the data is, who has rights on the data. As with patents we end up in a real conflict that we have had for a decade, but this time over databases, and science will suffer as a consequence. In particular, international collaboration will suffer because of the increasing commercialization of research. It is the failure of governments to ensure that basic research is publicly funded and should continue to be so. I am not arguing against companies and industry and the usual discourse about those evil capitalists or whatever. I am simply saying that in every society we want to keep data free and open, with basic research remaining totally publicly funded and available. The reason is, and I talked about this yesterday, that we have problems with conflicts of interests, of confidentiality. Now researchers are no longer able to send data, samples and information between countries like they have always done. They have always collaborated in a way that reflects science as a humanistic endeavour for the benefit of humanity and not as an economic tool. These are two totally different models of science.

My last three minutes I will go on to future directions. In the next decade, we have to ensure that the information from the map of the human genome continues moving towards functional genomics, genotypes, normal variation genomics and so on. We have to begin by speaking the same language, a lingua franca or a common language, to know better how we describe the data. I am doing a study looking at about twenty-five documents talking about DNA samples. And the language used such as, coded, anonymized, double coded, bioidentified, to take just a few descriptions, means totally different things in different documents, databases and countries. If we do not organise or clarify the human genome project, an international endeavour, people will no longer be able to speak nor send their data and their samples to each other, because we do not use the same language to describe what is in the data. We need an international protocol, some sort of approach to sharing data, even in the private and the public sector, before it becomes too incomprehensible. There should be some reward for researchers who understand the data, who go beyond what is in nature, to make a diagnostic tool out of it, to create a database that takes rare data, curates it, annotates it, enriches it, and changes how we understand it. This should be rewarded just like patents and inventions. But this is very difficult to do without commercializing research thereby killing international collaboration.

We have two ideas on this respect. The first one is to have a central depository, which of course is the ideal. The second would be to create a rights pool. That is to say, to cluster the rights of these authors, these curators of these databases. This is not unlike music that is playing on the radio or the photocopies that people take of some chapters from a book that I have written and they use it, at the end of the year I think that I am paid eight cents per article in one cheque. There is a pool in Canada, called Copy Beck, which keeps track of every single person who makes copies of the articles. They write down the article and the number of pages. At the end of the year, you get a percentage from the knowledge that other people have used from you. When radio stations play songs, like for example when they play a Madonna song, the number of times that it is played is calculated on royalties or derived. So Madonna or any other artist does not have to run after people who illegally play the music because there is actually a system called rights pool that keeps track of everyone. I think it is equitable that if someone hits a database, which has been created by someone with added level of knowledge, there should be some sort of eventual return to that person for their intellectual input.

I would like to conclude on this particular point. The HUGO ethics committee, about a month ago, at its annual meeting, adopted a statement on human genomic databases. In order to avoid a genomic division between developed and developing countries, or industrialised and non-industrialised, global databases should be seen as global public goods. This is the real challenge: to move beyond our countries, our genome projects, genomics in Spain, or in Canada, and contribute to the welfare of humanity by considering these international databases as global public goods to be exploited for humanity. Thank you very much.

Jaume Bertranpetit: Thank you very much, Bartha. I hope that you do not mind staying here for a moment, while we ask you some questions. You have raised some interesting issues. But maybe the most shocking one is that when people talk in theoretical grounds, they talk about global public goods. But after all, these are only words. Mainly they are words of people thinking that they are very nice people doing all the best, but indeed they are very rich people taking care of themselves. The point I would like you to come is to which extent this question is done for humanity or it is to make healthier the rich.

Bartha Maria Knoppers: I am not as cynical as you are. I think that there are tools at the international level that attempt to create greater equity, and add something beyond the economic interest of individuals or countries. Global public goods are, for instance, the environment or goods that should not exclude anyone and should not encourage rivalry, because it is important to everyone that they be available. It is a new concept, only ten years old, that goes beyond the private interest of individuals or companies or rich versus poor. It takes about a quarter of a century usually for these ideas to operate at the international level and get into the culture. I will give a sad and cynical story that shows the difficulty of working at this level. I guess that you remember Grotius, the Dutch lawyer, who developed the law of the sea. Developed a couple of centuries back, this concept referred to the common heritage of humanity, which is a notion describing something belonging to humanity, for instance the sea or the air. This means that there is no private ownership and that the heritage of humanity has to be used for peaceful purposes, preserved for future generations, only to say few of the characteristics. When UNESCO was working on its Universal Declaration on Human Genome and Human Rights, the first article of this declaration said that the human genome at the level of species is the common heritage of humanity. Then they make considerations and talk about individuality and diversity. This did not go through, even though the responsible was UNESCO, a body devoted to international collaboration, interpretation and advancement of international causes. The reason is that it is a legal concept or, as you say, something invented by people, like I did myself on "global public goods." People see the American word "common" as being a threat. As the French translation of "heritage" is patrimoine, people see it as a property concept. Germans did not like it because the word "common" meant to them "state" or "national" because it had a historical meaning. All of these are difficult concepts. I am not a politician but I do think that is the level that we have to aim for. Whether we get there or not is a different story. Finally in a symbolic sense, UNESCO said that the expression appearing in a declaration would be "the heritage of humanity", and so they took the "common" out. That is as far as we got with the idea of the human genome being a patrimoine commun de l'humanité.

Jaume Bertranpetit: Ara és un bon moment per fer-li alguna pregunta a la doctora Knoppers abans de tancar aquesta primera part de la sessió.

Audience: The UNESCO declaration states the principle of no commercialization for patents of the human body, but nevertheless the US Patent Office takes a lot of patents of DNA sequences and they say that these are inventions, not discoveries, because they are isolated. Of course, this has a lot of bad consequences for medical assistance. Is there any way to fight against that?

Bartha Maria Knoppers: Article 4 of the Universal Declaration on the Human Genome and Human Rights says that the genome in its natural state shall not be the subject of pecuniary gain, which in French is called le gain pécuniaire. After six months of the writing of this Declaration there were only legal people involved, who were very carefully chosen, from China, the Soviet Union and Islamic and Arabic countries. The legal systems of all the countries were very different. The goal was to try and make sure that every word meant something legally and ethically speaking, in every single country. When they said that there was a natural state, they already assumed that intellectual property could apply similarly in the directive on biotechnological inventions here in Europe in 1998.

Vatner, who is famous for his privatisation of his database, is also famous because when he got an ADNH, early in 1990, he applied for patents on a whole area of what he thought that it would be interesting, that is to say neurological genes. This is something very similar to what happens in a game when you discover a country, you put little flags everywhere and you say that any diamond here belongs to you. You stick out your territory. This led to a complete change in the way genetic research was done. Suddenly the MRC in the United Kingdom and every scientific body said that they would better apply. This was on raw gene sequences, that we have not even found yet or they were sort out in the area. This created the whole problem of the race for patents on sequences and it took ten years before the US Patent Office, in December 2001, said "we will not give patents on genes of unknown utility and function. Everything has to be specific and substantial".

Applying for patents on sequences was blocking other people from working on other areas of the gene. It took a decade to prevent this, and during that time the HUGO, the Human Genome Organization, was very involved in the same raw sequences existing in nature. Under a good interpretation of patent law, these sequences of unknown utility and function should not be patentable, because nothing has been invented; the sequence is merely a discovery of what exists already in nature. However, there is no doubt that the reason is still controversial, as many genes have been patented. The people who have patented them before did it for two reasons. The first one is that if you apply for a patent you put your knowledge in the public domain, which is a good thing. It is better than trade secrets, like Coca-Cola. As you all know, the recipe for Coca-Cola is a trade secret. The second reason refers to what has to be done after putting the knowledge in the public domain. If you do not license it, then it is not exclusive, so people can compete, prices can go down, and it is accessible to anyone. Then you run into troubles with patents.

In my country, for the first time in Canadian history, we are proud of universal access to health care. But a long time ago, we had a bad experience having to do with the breast cancer gene. It happened that women in one province had access to it, but women in another province did not, because it depended on who could pay for it. Now the aim in modern universal health care systems is to make companies obtain legitimate patents that force them to do compulsory, non-exclusive licensing. This is really where the debate has come into practical terms, as patents have always existed. Pasteur and Benjamin Franklin had one, for example. But how do we use a patent system so that it does not destroy your health care system? What do we need to do to a DNA sequence to make it patentable? That is an unfinished debate. I know here in Europe the discovery and invention questions are still going on and that these are ongoing debates.

Gert-Jan B. van Ommen: Maybe I can add something at this point. At the end, these issues are going to go away to some extent. Now, with all the sequence publicly available on the Internet it is quite pointless to start patenting an unknown sequence which is already public. From now on, you can only patent things to which you have added your own inventiveness to find out what is doing. This is one thing. The other thing is the 400 or 1,000 genes on a chip are clearly the first example in diagnostics were the classical patent system is going to break down. This is also the line of thought of the HUGO committee, where you might have something like a clearing house or a patent pool, so the owner that has discovered a gene does not have to go after everyone who is using his or her discovery in a diagnostic chip. Then you may have some sort of a clearing house where you can make thousands of genes on a chip, because this is where the diagnostic is ultimately going and it will block progress if that would have to be done through individual patents and negotiating with Japanese, American, Canadians and Dutch, French, Spanish, and so on. I think that ultimately you will see that things are going that direction.

Bartha Maria Knoppers: The pool idea for both data and information of the genes on the chip is the way to go. That is to say it has to be absolutely clear that the patent lawyers do not get in the way.

Jaume Bertranpetit: Hi ha algú més que vulgui intervenir?... En aquest cas, aixequem la sessió durant un quart d'hora i tornem després per fer la segona part.

We will meet here again in fifteen minutes.

Taula rodona. La genòmica al segle XXI: els límits de l'ètica

Jaume Bertranpetit: Durant aquesta segona part les persones que estan a la taula faran una petita exposició. De fet, el punt inicial era "La Genòmica al Segle XXI. Els Límits de l'Ètica", i quan discutíem sobre això vam mirar quins podien ser els temes més interessants. Vam fer-nos una sèrie de reflexions i de preguntes, algunes de les quals són molt senzilles i que ara us indicaré breument. Aquestes qüestions les vam plantejar també a les persones que ara són a la taula.

En primer lloc, ens vam plantejar una qüestió amb diferents lectures possibles: "Per què volem conèixer encara més el nostre genoma?". La segona pregunta és: "Quina és la relació entre el coneixement del genoma i la salut? És veritat la creença que gràcies al coneixement del genoma podem curar?". La tercera qüestió fa referència a un aspecte que hem vist fa un moment: "Qui hauria de pagar aquesta recerca? És a dir, quin impacte tenen les organitzacions públiques i privades sobre el coneixement i el desenvolupament?". La quarta és: "Hi ha límits en les nostres intervencions? Els límits són imposats per la tecnologia, l'economia o l'ètica?". En cinquè lloc, ens preguntàvem: "Quins són els límits que pot haver-hi en aquesta intervenció i com es poden llegir respecte al que és teràpia o al que és millora? Juntament amb teràpia i millora, qui ha de prendre les decisions?". Crec que és el moment de començar a parlar d'aquest terme anomenat millora genètica, perquè en qualsevol moment sortirà i val la pena que ja n'hàgim parlat i discutit. També és important parlar-ne per tal de veure si és un tema prou rellevant. I, en darrer lloc, ens qüestionàvem la importància de l'educació i de la informació a l'hora de tenir una actitud responsable.

Aquestes són algunes de les preguntes. M'agradaria introduir-vos un esquema molt conegut i força entenedor. És un esquema que acaba de sortir i que forma part del que en aquests moments és la perspectiva del nostre coneixement de cara al futur, on som i cap a on volem anar. Aquest gràfic forma part d'un article que va aparèixer fa dues setmanes a la revista Nature, i el primer autor que el firma és Francis Collins, director del projecte públic del Genoma Humà (F. S. Collins, E. D. Green, A. E. Guttmadrer and M. S. Guyer. A vision for the future of genomics research. Nature 422: 855-847, 2003). Aquest esquema de què us parlo representa l'edifici del coneixement: cap a on ens durà el nostre genoma i on som en aquests moments, que només són els fonaments. Aquest esquema, per tant, es comença a construir a partir del Human Genome Project. Sobre la base trobem tres pisos, que es poden construir de mica en mica, tal com s'està fent ara al Parc de Recerca Biomèdica. En alguns centres només hi ha el tercer pis i en d'altres, el primer; però en tots els casos el segon pis sempre va sobre el primer i no al revés.

El primer pis tracta el que en anglès es designa com a genomics to biology, és a dir, la genòmica aplicada al coneixement dels sistemes vius. És el punt essencial, en el qual hi ha més estímul, perquè a partir del moment que obtenim aquesta informació podem començar a interpretar-la per conèixer el funcionament dels sistemes. Aquest primer pis és, per tant, la genòmica aplicada a la biologia i la fase de comprensió de les bases de la vida. El segon pis fa referència a la genòmica per a la salut. És essencial que gran part dels avenços en genòmica es produeixin en nom de la salut, però també cal tenir molt present que per tractar la salut abans hem de tractar la biologia. Aquesta idea és extremament senzilla: si volem entendre que un sistema té problemes de funcionament, hem d'entendre com funciona. Tots estareu d'acord que no us deixaríeu tocar el cotxe per un mecànic que no sabés com funciona normalment. Quan els vehicles s'espatllen, l'important és conèixer-ne el sistema de funcionament amb normalitat i saber què vol dir espatllar-se dins d'aquest sistema. Per tant, això és el que volem aconseguir en aquest segon pis, fase on recauen totes les promeses. És on hi ha tant l'impuls social per tirar endavant tots els nostres coneixements de genòmica com les grans aplicacions i la justificació de les inversions que es produeixen. El tercer és la genòmica a la societat. En aquests moments la societat comença a intervenir i a interferir en molts aspectes, i les implicacions poden arribar a ser enormes, ja que poden ser des d'implicacions estrictament ètiques i filosòfiques fins a aplicacions industrials, moltes de les quals comencen a existir. Al costat d'això hi ha un conjunt d'idees o d'estructures verticals que ajudaran a fer els passos des d'aquests fonaments de coneixement fins que aquestes possibles aplicacions siguin acceptables. Alguns dels passos són estrictament de funcionament, recursos, desenvolupament tecnològic o biologia computacional. D'altres són educacionals, de coneixement i d'acceptació social. Aquí tenim un dels puntals essencials, com ho és el training, la formació i l'educació, el saber com a necessitat bàsica per tenir una opinió basada en un coneixement. I, en darrer lloc, trobem el punt que hem tractat fins ara dels aspectes ètics, legals i socials del genoma. Per tant, aquesta seria la idea de la visió que tenim avui per arribar a completar aquest genoma. Tot just fa quinze dies es va anunciar que ja en tenim la versió amb una quantitat d'errors menor del que s'havia projectat inicialment i, per tant, es pot considerar com la primera versió definitiva del genoma.

Passem ara a les intervencions dels membres de la taula. Començarem amb el professor Beato, que és company de recerca i ben conegut per tots nosaltres. És el director del CRG, el Centre de Regulació Genòmica, un dels centres que ha creat el DURSI. També és professor de la Universitat Pompeu Fabra. Hem de considerar, per tant, que el professor Beato té un gran impacte dins de la nostra ciència, perquè amb la seva tornada al país ha donat tota una vida a aquest nou centre, que és i serà un dels grans centres capdavanters en l'estudi del funcionament dels genomes. Miguel Beato, puedes empezar cuando quieras.

Intervenció de Miguel Beato, director del Centre de Regulació Genòmica

Muchas gracias por haberme dado la ocasión de presentaros mi visión del genoma, que es algo distinta de la que estáis acostumbrados a oír. En general, cuando se habla del genoma se mencionan los genes, pero yo no lo haré. La biología moderna es una ciencia de la información, y la información biológica está contenida en la secuencia de las unidades básicas que forman las macromoléculas: los aminoácidos en las proteínas y los nucleótidos en los ácidos nucleicos, el ADN y el ARN. La biología debe investigar el proceso de pasar de la secuencia de los nucleótidos al fenotipo (al organismo adulto que funciona). Es decir, cómo esa secuencia de nucleótidos se convierte en una estructura con una cierta función, como es el fenotipo. Creo que éste es el problema básico.

El genotipo es lo que se pasa de generación en generación, la información genómica completa que no es sólo ADN. Cuando se genera un nuevo organismo no es sólo el ADN lo que se fusiona con el ADN de la célula germinal masculina y femenina, sino que es la cromatina, es decir, el ADN, una serie de proteínas y probablemente el ARN que los acompaña. Esto es lo que se fusiona y pasa de generación en generación. A partir de esa información se construye el fenotipo en cada individuo que se desarrolla, que es el conjunto de proteínas y otras macromoléculas que forman la estructura y determinan la función del organismo. Éste es el problema que hay que resolver: cómo se pasa de la secuencia de nucleótidos, de unidades básicas en proteínas, a este fenotipo. Yo creo que este problema no se puede resolver con una visión puramente genocéntrica del genoma, o sea fijándonos sólo en los genes. Creo que en el ADN hay más información, que es decisiva para saber cómo el genotipo se transforma en el fenotipo. Éste es el mensaje que yo quisiera haceros llegar, aunque sea un poco duro porque se basa en estructura y en química, y por lo tanto haya que echarle el diente. En el ADN hay más que genes, y tanto los genetistas normales como el 95% de mis colegas lo ignoran. Para ellos lo importante son los genes y el resto es basura, ADN basura. Puede que haya ADN basura, pero también contiene más información, y esto es lo que os voy a mostrar.

Quiero mostraros los tipos de información que contiene el ADN. Está claro que hay muchos tipos diversos. Sin embargo, hay uno que todos conocéis. Se trata de los famosos genes, que es la información que codifica para ARN y proteínas. Ya sabéis que esto está codificado en forma de trinucleótidos, o sea que tres nucleótidos codifican por un aminoácido, y así la secuencia del ADN determina la secuencia de las proteínas. A esta información habría que añadir el comienzo y el final de un gen, porque los aminoácidos deben empezar en algún sitio y terminar en otro. También deberíamos añadir todas las secuencias que determinan cómo un transcrito, el ARN que copia un gen, se convierte en una o muchas proteínas, pues como sabéis a partir de un gen se pueden hacer muchas proteínas a través del llamado procesamiento alternativo. Este proceso consiste en transcribir el gen de modo que genere diversos ARN y diversas proteínas, y esto también es una parte de la información genérica de los genes, que es un tema muy actual. Esta información representa menos del 5% del genoma humano, de la secuencia de ADN que transmitimos a nuestros hijos. Es decir, en la vista general el 95% es basura. En cambio, yo creo que no es basura. Ahora os mostraré cuál es la base de la información de este 5% que acabo de mencionar. El asiento es el apareamiento de las bases que forman los nucleótidos. Ya conocéis bases como adenina, timina, guanosina, citosina. Estos pares de bases que se forman entre A y T, o entre G y C, transmiten esa información desde el ADN hasta el ARN y a las proteínas. Este es el proceso normal que todos conocéis de la transcripción del mensaje genómico en ARN y luego la traducción en proteínas en el citoplasma. Esta información significa el 5%. ¿Qué más hay? Hay una información que yo llamaría "reguladora", que es la información que determina cómo, cuándo y con qué intensidad se lee o se expresa un gen. Dicho mensaje está escrito en un lenguaje completamente distinto. Son nucleótidos simples y es el ADN, pero no tiene que ver con los genes en sentido estricto. Esto no codifica para proteínas, sino que es leído por proteínas. Esto representa aproximadamente entre el 1% o el 2% del genoma, aunque puede variar.

Os mostraré brevemente el funcionamiento de todo esto. Si cogemos la molécula del ADN y miramos a través del eje de la doble hélice, y también observamos un par, como el T-A (timina-adenina), vemos que en el surco mayor de la hendidura grande cada par de bases tiene una identidad determinada, es decir, hay unos grupos químicos aquí, y una proteína que contacta el ADN a través del surco mayor reconoce estos grupos y puede leer la secuencia. Con la interacción entre el ADN y estas proteínas, esta secuencia determina si un gen se va a expresar en una célula del hígado, en una célula sanguínea o en una neurona, y con qué grado de intensidad, en cuánto tiempo y en qué momento. Ahora os mostraré un ejemplo. Generalmente estas secuencias son cortas y tienen una estructura a menudo palindrómica, es decir, hay un eje de simetría y la secuencia es una inversión repetida. Hay dos moléculas de proteína que interaccionan con cada uno de los surcos del ADN, reconocen esta secuencia, atraen la maquinaria de transcripción que lee el ADN y hacen que ese gen se lea. Esta secuencia no es así de simple, hay muchas más, y aquí os muestro una versión distinta del modelo para que veáis un poco mejor el ADN y la proteína.

De hecho, estas secuencias forman una especie de texto superpuesto en el ADN que se organiza en frases reguladoras. Colecciones de estas secuencias forman un contexto que es reconocido por grupos de estas proteínas, que son específicos por ejemplo de una célula especial. Una célula linfática, o sea hepática, tiene un conjunto de proteínas, reconoce un conjunto de secuencias en un gen determinado y hace que ese gen se exprese o no en este tejido. El resultado es un problema de combinatoria entre estas secuencias, pues una combinación de este tipo de secuencias puede llegar a ser treinta o cuarenta de estas pequeñas secuencias distintas reconocidas por proteínas distintas específicas de cada célula. Y cada célula tiene estas proteínas porque en el curso de la embriogénesis, esto es, el desarrollo embrionario, se han diferenciado las células para expresar conjuntos distintos de estas proteínas que leen el ADN. De este modo se explica que las células se diferencien progresivamente y cambien el patrón de expresión genética. Todas tienen los mismos genes pero expresan distintas combinaciones de genes. Esta es una visión un poco simple porque en realidad, a menudo, cuando las proteínas se fijan al ADN cambian su estructura, es decir, que el ADN no sólo está sirviendo para ser reconocido por las proteínas sino que induce un cambio de estructura en la proteína porque representa que hay una conversación entre el ADN y las proteínas que cambia la función de la proteína. Tengo algún ejemplo pero alargaríamos demasiado la presentación, así que no os lo voy a mostrar.

Esta información generalmente se olvida, pero es obvio que una mutación en este tipo de información reguladora tiene consecuencias dramáticas, porque aunque el gen esté normal y no tenga mutaciones, puede no expresarse en el lugar adecuado, hecho que genera una situación patológica, un defecto en la función. Las mutaciones en estos componentes reguladores son muy importantes. Pero hay más información, porque esto es sólo el 6%. Una información muy importante es un tipo que yo llamaría información topológica y que depende de las propiedades conformacionales del ADN. El ADN tiene una tendencia a estructurarse en el espacio de un modo especial, dependiendo de su secuencia. Sin embargo, acostumbra a ser de un modo que empieza a entenderse. Además, estas propiedades en el curso de la evolución se han seleccionado para determinar el patrón de expresión de los genes. Un ejemplo que se ve en bacterias, que son organismos relativamente simples, es un sistema muy clásico de regulación en bacterias; de hecho, es el primer sistema que se descubrió de regulación génica, que es la H-repressor en la bacteria Escherichia coli. Esta molécula, que se establece en el ADN en forma de un tetrámero, se fija a dos secuencias que están separadas, y cuando estas proteínas interaccionan generan una lazada de ADN, una especie de círculo de ochenta pares de bases en el cual se fija otra proteína que es esencial para la regulación. Es decir, la estructura que toma el ADN debido a la fijación de estas moléculas a estos sitios que reconocen de secuencias reguladoras cambia la conformación del ADN y hace posible que se fije otra proteína que inicia un proceso de regulación.

Aquí hay una propiedad conformacional de la secuencia que tiende a adoptar esta posición favorecida por una proteína, hecho que está implicado en la regulación de un modo decisivo. Pero el hecho de que el ADN no esté desnudo en nuestras células, sino que esté empaquetado con proteínas en cromatina, es mucho más importante para la regulación en nuestros genomas. Todo el ADN que tenemos en nuestras células está en cromatina y no hay ningún ADN libre. Entonces, la doble hélice se empaqueta en unas estructuras básicas que se llaman nucleosomas. Por desgracia, no hay excusa que valga, pues hay que entender qué es un nucleosoma si se quiere entender cómo funciona el ADN en nuestras células. Estos nucleosomas son unos discos aplanados de proteínas básicas, alrededor de los cuales la doble hélice se enrolla completamente casi dos veces. Este enrollamiento era esencial porque la longitud de ADN que tenemos en cada célula es de dos metros, y en cambio nuestras células tienen un diámetro muy pequeño y el núcleo celular tiene aproximadamente 2 x 10-6 de diámetro, o sea dos micrones. El problema sería equiparable a intentar meter cien kilómetros de un cordel dentro de un balón de fútbol. En el caso de que no metamos tanto ADN no habrá la posibilidad de generar organismos complejos.

El paso de tener el ADN relativamente desnudo como lo tienen las bacterias a tenerlo empaquetado en cromatina fue esencial para poder aumentar el tamaño del genoma y hacer organismos más complejos con posibilidades reguladoras más complejas. Todos los animales un poco complejos que conocemos tienen cromatina. Desde la levadura hasta la mosca o el gusano tienen este tipo de estructura. Se llaman organismos eucarióticos porque tienen un núcleo celular, el cual contiene todo el ADN en forma de estas partículas llamadas nucleosomas. El nucleosoma está compuesto por unas proteínas que se llaman histonas, que forman este cilindro y que proveen una serie de sitios de anclaje del ADN. Las histonas son cargas positivas. El ADN tiene muchos fosfatos a partir de los cuales crea una interacción iónica y dobla la hélice de un modo dramático. En realidad, doblar una doble hélice de este modo en un modelo es imposible, puesto que uno necesita neutralizar la carga como se hace aquí. La idea subyacente al doblamiento helicoidal es compactar el ADN. En un núcleo celular, cada cromosoma ocupa un territorio determinado, donde también encontramos los dos metros de ADN que forman nuestros veintitrés pares de cromosomas. El problema del embalaje consiste en que el ADN no se puede empaquetar de este modo porque se repele por la carga negativa y hay que enrollarlo en los nucleosomas. Cuando el nucleosoma se mira en detalle se ve que está compuesto por un tetrámero y unas histonas que se llaman H3 y H4, que no son demasiado relevantes.

Si todos los sitios son reconocidos, el gen se expresa. En caso de que no sean reconocidos, no se puede expresar. Este gen o promotor se organiza en un nucleosoma, que son las vueltas del ADN. Las histonas no tienen ningún papel simplificador. Según el lugar en el que se encuentre una secuencia, ya sea en la parte convexa de la hélice o en la cóncava, será visible desde fuera, porque estará ocupada por las histonas. Según esto, dependiendo de cómo se enrolle el ADN, se puede o no expresar un gen. Para tener la visión completa, si le das una vuelta de 90º a este nucleosoma ves que la posición 4 también está expuesta, mientras que la posición 5, que es muy esencial, está oculta y sólo se ve el surco menor, pues el surco mayor está mirando hacia el interior del nucleosoma y las proteínas tienen que ver el surco mayor para leer la secuencia. Es decir, la célula dispone de mecanismos para cambiar la estructura de estos nucleosomas y así permitir que se lea. Pero esos mecanismos son una parte de la activación y la inducción génica, y en condiciones normales este gen no se puede exprimir porque tiene sus secuencias ocultas en la estructura de la cromatina. Es decir, aquí tenemos una jerarquía de información que va desde la información que codifica los genes, pasa por la reguladora, que determina si los genes se van a expresar o no y cuándo, y acaba en la topológica, que determina el acceso a la información reguladora. Hay toda una jerarquía de datos que se ignoran cuando simplemente se habla de genes. Creo que esta información es muy importante para entender cómo la célula implementa sus mensajes genómicos. Os explicaré un símil para entender la influencia de la información topológica en la lectura del mensaje genómico. Se trata de un texto que lleva un mensaje oculto y cuando se organiza en cromatina, ésta introduce una orden superior y revela la información topológica que hay dentro del ADN. Para ver dicha información en la secuencia desnuda son necesarios unos programas muy especiales, unos algoritmos complejos que se están empezando a desarrollar. Estos datos, sin embargo, determinan realmente la expresión de los genes.

Estos son dos tipos de información adicionales a esta información clásica, pero aquí no se acaba todo. Estoy seguro de que hay muchas más informaciones en el ADN que no conocemos. Yo creo que hay que permanecer ingenuos frente al ADN y estar siempre dispuestos a descubrir cosas nuevas, porque en ese 95% de ADN que todavía no conocemos hay muchos misterios por descubrir. Tener la secuencia está muy bien, pero nos va a llevar demasiado tiempo descubrir su significado. Sin embargo, una de las cosas que seguro que ya se empiezan a conocer bien son las redes génicas, los dominios de cromatina, las grandes estructuras que permiten que conjuntos de genes sean regulados de modo coordinado. No voy a entrar en los detalles de esta cuestión porque es muy complejo, pero me gustaría daros un dato adicional importante para entender el mensaje genómico, que son los aspectos epigenómicos de la realización del mensaje genético. Hasta ahora siempre he hablado de secuencia de nucleótidos, como por ejemplo los genes, las secuencias reguladoras, el código topológico, las redes génicas, etc. Estas partes son secuencias de nucleótidos en las que el ADN no cambia su secuencia, es decir, no cambia su estructura química, sino simplemente se dobla de un modo o de otro, o es reconocido. Pero actualmente hay todo un capítulo que está en explosión referente a la epigenómica, que consiste en modificar la estructura química del ADN; esto es, modificar sus bases, especialmente por metilación. La metilación de las citosinas en estos dinucleótidos CpG se conoce muy bien. Para regular estos procesos es esencial que se lleven a cabo toda una serie de modificaciones de las histonas, que son las proteínas que forman el nucleosoma, hecho que constituye la epigenómica, que extiende el potencial informativo del ADN. Dicho proceso ocurre gracias al hecho de que todo eso se basa en que las histonas que forman el cilindro, además de esta parte globular en la que se enrolla el ADN, tienen unas colas.

Las colas de las histonas son substratos para modificaciones químicas, enzimáticas naturalmente. Son reconocidas por proteínas que las modifican o utilizan la información de la mutación para cambiar la lectura del mensaje genético. No entro en detalles, pero esto son las colas de las histonas y todas las modificaciones posibles, que son numerosas, y ha llevado al descubrimiento del llamado código de las histonas, que son combinaciones de modificaciones reconocidas por proteínas celulares durante la expresión génica, la división celular, la apoptosis y que se encargan de controlar todos estos grandes procesos. Y lo controlan a base de controlar también la condensación de cromatina. Si uno mira un núcleo celular a través del microscopio electrónico ve que hay zonas muy densas de cromatina, que se llaman heterocromatina, que es cromatina inactiva. Y hay zonas más claras, menos condensadas, que es la eucromatina, esto es, la cromatina activa, la que se está expresando. Pues bien, la transición entre cromatina activa e inactiva la controlan modificaciones de las histonas y del ADN por proteínas que interaccionan con el ADN y reclutan enzimas que metilan las colas de las histonas. Esto es muy general. De hecho metilan ciertos residuos en las colas de las histonas. Y estas proteínas modificadas atraen otra proteína que interacciona con estas histonas metiladas y a su vez esta proteína atrae el enzima que metila el ADN, es decir, la citosina del ADN. Cuando el ADN está metilado de esta forma se condensa en cromatina inactiva y se vuelve inactivo, hecho que se puede transmitir de generación en generación. Esta información se transmite durante la replicación del ADN a las células hijas y, por consiguiente, es una información que tiene consecuencias importantes para el comportamiento de la célula.

Os resumiré lo que he dicho hasta ahora, en concreto sobre este ciclo informacional. Como todos muy bien sabéis, la información codificante es el ARN mensajero, es decir, el código genético. Algunas de esas proteínas son reguladoras que leen el código regulador, la información que consiste en los pares de bases, hecho que reconoce la información reguladora del ADN, que en realidad especifica a su vez cuándo y con qué intensidad se va a leer esta información codificante. Por otro lado, tenemos unas proteínas especiales que son las histonas, así como también algunas proteínas más que no he mencionado, que organizan el ADN en cromatina. Ahí hay un código de nucleótidos, que tampoco he podido explicar, y todo este conjunto es la información topológica del ADN que determina el acceso a la información reguladora. Finalmente, existen estas otras informaciones más complejas, que no os he podido explicar por falta de tiempo, que son los dominios de cromatina, las redes génicas que a su vez controlan el acceso a la información topológica. La parte inferior que tiene que ver con cromatina está sujeta a regulación epigenómica por modificaciones covalentes de las histonas y del ADN. Es decir, la epigenómica imparte una función reguladora fundamental que modula la expresión de la información genómica contenida en la secuencia del ADN. Todo esto puede ayudar a resolver el dilema entre heredado y adquirido, porque esas modificaciones se pueden adquirir y probablemente van a suministrar nuevas dianas para intervenir en el tratamiento de situaciones patológicas.

Para retomar las palabras del principio de esta presentación, acabaré diciendo que lo que se transmite de generación en generación es muy complejo y que no basta con saber los genes, sino que hay que entender cómo la estructura de esta cromatina determina el patrón de expresión génica para establecer el fenotipo. Creo que todo lo que acabo de decir ya es suficiente. Muchas gracias por vuestra atención.

Jaume Bertranpetit: Gràcies, Miguel Beato. Em sembla que la visió de la complexitat que ens ha donat el Miguel és per tant molt clara. El missatge genètic té moltes lectures i el conegut compositor Joan Guinjoan fa un moment ens n'ha fet una a través de la música. En aquest sentit, també seria una altra lectura de l'ADN.

Continuem endavant amb la taula rodona. Ara ens parlarà el doctor Jesús Acebillo, que durant molt temps ha treballat en diferents empreses en l'àmbit de la indústria farmacèutica. El paper de la indústria farmacèutica en el desenvolupament del coneixement, en general biològic i biomèdic, és un paper que considerem secundari des de la perspectiva que estem vivint, des del nostre país i, en general, també a escala europea. Però en aquests moments, des de perspectives internacionals, la recerca des de les empreses privades té un protagonisme molt difícil de reconèixer des d'aquí, perquè senzillament aquí no n'hi ha o n'hi ha molt poc. Aquest és un dels temes que ens haurà d'explicar o que li haurem de preguntar. De fet, tenim l'explicació que ens ha donat el professor Van Ommen sobre les perspectives i la realitat de recerca basada en la iniciativa existents. Tot i que aquí nosaltres no en tinguem constància ni ho vegem reflectit, és un fet real. En aquests moments el professor Acebillo està a Novartis, però de fet té experiència en nombroses empreses. Entre els investigadors de la indústria farmacèutica és un fet comú canviar d'empresa molt sovint, fet que es deu als canvis de noms de les corporacions i a les fusions extraordinàriament complexes entre empreses, que als que estem fora d'aquest món a vegades ens són fins i tot difícils de seguir. Jesús Acebillo, pots començar quan vulguis.

Intervenció de Jesús Acebillo, president executiu del Grup Novartis a Espanya

Muchas gracias. Primero de todo quisiera agradecer a los organizadores de este evento su amable invitación. Durante los próximos diez minutos me voy a limitar a hacer algunos comentarios o reflexiones breves sobre las preguntas que nos pasaron los organizadores, y centraré mis comentarios en tres aspectos básicos. A) El primer aspecto se basa en la pregunta siguiente: ¿Qué retos tiene la genómica para la industria farmacéutica y la sociedad en general? B) El segundo hace referencia al manejo de las expectativas que genera la genómica, tema que para nosotros es de una gran relevancia. Este aspecto no se refiere solamente a las expectativas empresariales, sino a algo que es más importante, como pueden ser las expectativas de la sociedad, relacionadas con lo que significarían las políticas de educación o de información. C) Por último, me referiré brevemente a la dimensión económica o financiera, a la problemática consistente en las implicaciones que comporta financiar estos proyectos.

A) La primera parte se refiere a los retos. Debemos señalar, primero, que no cabe duda de que con la genómica entramos en un siglo nuevo. Con la genómica se ha acabado un ciclo, el siglo XX, y por lo que respecta a la fabricación de fármacos se tiene la percepción clara de que estamos en una fase final de ciclo. El gran drama es que todavía no sabemos cómo va a ser el siguiente ciclo, y ahí es donde se generan incertidumbre y expectativas. La genómica nos va a condicionar mucho y, como acabamos de ver con la presentación del doctor Beato, todo este fenómeno es de una gran complejidad. Gracias a la genómica, con el tiempo podremos tener un mejor conocimiento de la salud y de la enfermedad. Nos ayudará a tener una visión mucho más integral de la enfermedad. Tal y como comentaba Beato, el paso del genotipo al fenotipo es muy complejo, y en ese proceso no hay que olvidar que el entorno tiene un papel muy importante. Dicho entorno está condicionado por los hábitos de las personas, la nutrición, determinados procesos físicos y biológicos por los cuales se encuentra rodeado. Esta relación genoma-entorno es lo que realmente condiciona la verdadera expresión fenotípica.

Además de conocer mejor la enfermedad y la salud, también tendremos un conocimiento más amplio de los sistemas biológicos. Sin duda, esto podría tener un impacto muy positivo en la vida de los pacientes, en sus familias y, en último extremo, en la sociedad. Creo que es importante no perder de vista esta dimensión. La genómica tiene impactos claros en el desarrollo de fármacos, pues afecta a todos los puntos de la cadena de valor del medicamento, como luego comentaré. La genómica ha abierto el paso al diagnóstico genético, que tendrá una gran relevancia por las expectativas que genera, por los condicionamientos de determinismo que pueden dar lugar a interpretaciones negativas. Genera, por tanto, un gran reto de transferencia de conocimientos.

En mi opinión, uno de los grandes problemas que tenemos ahora es que estamos en unas fases muy iniciales de este nuevo ciclo, y tenemos por tanto una sobrecarga absoluta de información y de datos que no sabemos procesar adecuadamente. Poco a poco, debemos consolidar y procesar toda esta información para integrarla en el stock global, en las reservas de conocimiento global de la biomedicina. Cuando se llegue a almacenarla en dichas reservas de conocimiento global, la información será verdaderamente aplicada. En todo caso esta complejidad hace que se tengan que maximizar las colaboraciones entre empresas privadas, universidades e industria. Me gustaría añadir, por último, el reto que implica la genómica en aspectos relacionados como la ética, la responsabilidad social, la información y la educación. Ya para terminar con este primer apartado, dos comentarios relacionados con el potencial impacto de la genómica en la cadena de valor de la industria farmacéutica o, mejor dicho, del medicamento.

Primero se refiere a las expectativas que genera la genómica en nuestro sector industrial, que son, como no podía ser de otra forma, muy elevadas sobre todo en lo referente a los proyectos de investigación básica. Las empresas farmacéuticas todavía no están utilizando de forma sistemática estos nuevos instrumentos metodológicos, aunque estamos seguros de que en pocos años será la norma. En términos generales podríamos decir que a nivel mundial la industria farmacéutica gasta en investigación y desarrollo, con tecnologías de genética, cantidades todavía marginales. Eso no significa que no exista el deseo de incrementar los esfuerzos en estas nuevas técnicas, sino que de hecho es muy difícil tomar decisiones contrastadas en la asignación de recursos entre proyectos con distintos niveles de riesgo. La genómica implica un nuevo paradigma para nuestro sector industrial, puesto que puede cambiar la forma de investigar y desarrollar nuevos fármacos, y modifica así mismo aspectos regulatorios claves ligados a la aprobación, a la producción y a la distribución de fármacos, al marketing y al modelo financiero, etc. Por decirlo en otras palabras, cuando la genómica sea una realidad en términos de aplicabilidad, estaremos hablando de que el sector industrial farmacéutico será completamente distinto, pero todavía estamos lejos de esa situación.

En I+D, el reto que implica la genómica es muy evidente. La gran mayoría de las estructuras de investigación que tiene la industria farmacéutica están basadas en tecnologías convencionales del pasado siglo. De hecho, esto puede ser uno de los retos iniciales, su reconversión sin que caiga la productividad. Ésta es la razón principal por la cual la mayoría de las experiencias en la actualidad se hacen fuera de los propios laboratorios internos. Es más cómodo y eficiente financiar centros externos que están trabajando en proyectos específicos en base a proyectos de cooperación con entidades terceras. Esto también es un paradigma nuevo, pues la industria farmacéutica no ha trabajado clásicamente con colaboradores externos, lo que implica una complejidad mayor, así como unas competencias ligadas a la coordinación de proyectos multicéntricos que hay que desarrollar. La genómica nos va a llevar así mismo a un desarrollo del diagnóstico genético de las personas y, por lo tanto, a una capacidad de crear subgrupos de pacientes que podrían reaccionar de forma distinta ante determinadas terapias o que tendrían diferentes tipos de respuesta frente a enfermedades concretas o a efectos secundarios. Iremos sin duda hacia terapias más individualizadas, a tratamientos más etiológicos y menos sintomáticos. Con todo esto, lo que desconocemos ahora es el impacto de estas nuevas tecnologías en la productividad de la I+D farmacéutica, aspecto éste estrechamente relacionado con el costo y precio de los nuevos desarrollos. Como siempre ocurre, hay hipótesis para todos los gustos en relación con los impactos en productividad, lo que evidencia que el tema no está claro.

Actualmente el costo promedio para desarrollar un fármaco es de unos ochocientos millones de euros, que es una cantidad enorme. Frente a este dato, nos preguntamos si con la genómica los desarrollos futuros serán más baratos o más caros. De hecho, éste será un elemento clave para el modelo económico farmacéutico del futuro. Fíjense ustedes que el modelo económico actual de la industria farmacéutica se basa en comercializar productos con un nivel variado de diferenciación, que son utilizados por pacientes muy diversos, generalmente en volúmenes elevados, los blockbusters. Evidentemente, aquí surgen preguntas muy relevantes cuando miramos al futuro. No será lo mismo el modelo económico de estos fármacos generales (antihipertensivos), que los que generarían productos más específicos ligados a la medicina individualizada del futuro, que se consumirían por menor número de pacientes (subgrupos) y a un costo que todavía no conocemos si será mayor o menor, pues desconocemos si en la práctica los desarrollos con las nuevas metodologías serán capaces de reducir los costos de desarrollo e incrementar la productividad de la investigación. Por todo ello, lo que me gustaría resaltar es que con todo esto y desde el punto de vista del modelo financiero, modelo económico o modelo de negocio -como le queramos llamar- los interrogantes son enormes. En todo caso, y por la experiencia de cambios tecnológicos anteriores, casi siempre los impactos reales de cambios son más lentos de lo que en un inicio se estimó. Creo sinceramente que esta afirmación puede ser aplicable al caso de la genómica que hoy nos ocupa.

B) El segundo punto que quería comentar era el relacionado con las expectativas que genera la genómica. Una de las preguntas que nos pasaron los organizadores hacía referencia a la razón por la cual queremos conocer más sobre nuestro genoma. Aquí podemos hacer varias reflexiones. La medicina preventiva -y la genómica será un elemento clave en el desarrollo de la medicina preventiva- es realmente una necesidad económica para garantizar la sostenibilidad económica de los sistemas públicos. Por tanto, la primera reflexión es que si la genómica mejora la medicina preventiva iremos en la buena dirección, ya que iremos hacia sistemas sanitarios más sostenibles. Algunos ejemplos de estas tecnologías los encontramos en las vacunas basadas en ADN de bajo costo, que son realmente una de las grandes esperanzas que existen hoy en día para la fabricación de vacunas de forma masiva y barata para países en desarrollo. Como expectativa tenemos la posibilidad de cribar la susceptibilidad genética de las personas, puesto que supone una gran oportunidad para poder modificar el riesgo de estas personas a padecer estas enfermedades. No obstante, esto implica medidas claras de prevención de dietética y educación en general, y todavía estamos bastante lejos de tener experiencias concretas y positivas al respecto. En mi opinión, la comunicación poco escrupulosa de la caracterización del genoma puede condicionar expectativas no realistas y frustración. En todo caso, yo creo que sería muy importante que se ampliaran los estudios contrastados de base poblacional extensa antes de transmitir a la sociedad una información que pueda llevar a errores. Relacionado con este aspecto del manejo adecuado de las expectativas, nos encontramos con la importancia de la educación y la información a la sociedad de dichos desarrollos tecnológicos. Exagerar la importancia y las expectativas clínicas puede causar frustración, como decía antes. Debemos tener claro que cambiar los comportamientos y los estilos de vida es uno de los temas más complicados que hay.

Ofrecer información genética no incrementa necesariamente el nivel de motivación por estos cambios de comportamiento. Un aspecto negativo es que todavía hay que desarrollar intervenciones efectivas sobre grandes volúmenes de población que incentiven el cambio de hábitos tras recibir información genética. Por eso me parece muy relevante una noticia publicada en el British Medical Journal del pasado mes de abril, en la cual se indicaba que la comisión de genética humana del Reino Unido recomendó al gobierno británico que prohibiera la venta directa al público de kits para pruebas genéticas. Creo que es un aspecto muy relevante. En mi opinión, tenemos demasiadas expectativas puestas en la genómica, que no son realistas a corto plazo, y la mayoría de la población no es capaz de evaluar las consecuencias inmediatas. Además, los grandes cambios no van a darse en breve, sino que requerirán períodos de tiempo mayores para convertirse en realidades. Creo sinceramente que los científicos tienen que hacer un esfuerzo especial en transmitir información con rigor a la sociedad, de una forma que pueda ser procesada adecuadamente por ésta.

C) Por último, me gustaría añadir dos comentarios más sobre el tema de la financiación de estos proyectos de investigación y reflexionar respecto a quien debe pagar dichos desarrollos. En mi opinión, el estado interviene corrigiendo y sustituyendo el mercado cuando éste falla en la tarea de producir o asignar bienes. En este contexto, por tanto, la producción de conocimiento básico suele considerarse como un bien público global. En nuestro país el contexto es un poco diferente. España es un contexto donde existe un bajo desarrollo de políticas científicas basadas en la cooperación entre el sector público y el privado. Algunos aspectos explican esta situación, como por ejemplo el clásico divorcio entre la universidad y la empresa, la poca masa crítica de recursos humanos y de tecnología, el déficit tradicional en infraestructuras competitivas internacionalmente y, en muchos casos, una cultura empresarial muy localista. Si a todo eso añadimos que se produce en un entorno como es España, en el que hay una alta intervención y regulación estatal, con un contexto económico altamente restrictivo y todo ello en un entorno tecnológico cambiante, el resultado final llega a ser un verdadero cóctel explosivo. Va a ser difícil que seamos capaces de dar un quantum lib y de salir de la situación en la que estamos. Nos encontramos anclados en el 0,9% del PIB invertido en gastos de investigación versus el 2% en el promedio de Europa. Pero lo que todavía es peor, es que cuando analizamos ese 0,9% del PIB, podemos observar que gran parte de la investigación que se realiza es muy competitiva. Todavía está por demostrar que los esfuerzos recientes efectuados en los últimos dos años (pacto entre la industria farmacéutica y Ministerio de Sanidad) a fin de poder inyectar recursos adicionales al sistema, sean capaces de generar resultados positivos.

Esto me lleva ya al último comentario, que está relacionado con la distribución de recursos y la asignación de prioridades. Para hablar de este tema me gustaría referirme a los comentarios de la Organización Mundial de la Salud cuando habla del Gap 10/90, del cual seguro que habrán oído hablar. El Gap 10/90 es un concepto que proviene de un hecho muy sencillo de entender, "cada año se gastan en el mundo unos setenta billones de euros en investigación biomédica, pero sólo el 10% de esta cantidad se invierte en el 90% de los problemas sanitarios mundiales más graves y relevantes". Esto quiere decir que, de acuerdo con las recomendaciones del Global Forum on Health Research de las Naciones Unidas, es importante revisar la prioridad y la asignación de recursos, así como también incrementar los recursos y la eficiencia de la investigación. Esperemos que la genómica nos ayude a incrementar su eficiencia y productividad, por medio de colaboraciones sólidas entre administración, universidad e industria. Como todos conocen, la salud es crucial para el desarrollo, la lucha contra la pobreza y la seguridad global. Nada más y muchas gracias por su atención.

Jaume Bertranpetit: Moltes gràcies, Jesús Acebillo. Ja per acabar la ronda, tornarà a intervenir el professor Van Ommen. De fet, abans ens ha fet una xerrada més general i ara m'agradaria que ens donés la seva visió sobre aquests problemes de la genòmica de cara al futur.

Intervenció del professor Gert-Jan B. van Ommen

Well, I must confess that I have already spent most of my thoughts, but maybe I should explain my reactions to some of the things that I have been hearing. One of the things that I heard that doctor Beato said was that it is so important that through genomics we can understand the mechanisms of how it works. On the one hand, I agree and I think this is actually quite important. But on the other hand, my personal view is that the most that we have done so far in understanding mechanisms is finding the explanation for why drugs that we knew that work, actually worked. I will give you the example of calcium channel in migraine. Before we already knew that drugs that affected the serotonin levels were effective against migraine, but at that time nobody knew what they were exactly and researchers were looking at the wrong level. Afterwards they saw the calcium as a key actor, so they actually found out what the drugs were exactly. I think that having all these mechanistic insights is fine, but in the beginning it already helps if through the insights of the drugs, which have been designed by trial and error, we understand how they work. Then genomics will help us to increase the efficiency of the next step, which is to make them with fewer side effects or make them more targeted. As we understand how they work, it is easier to improve them better in the mode of action. That is why I think that even for a long time we will probably be designing drugs on a sort of trial and error way, it is very helpful if we have inroads. Then due to the mechanistic insights we can improve drugs in a much faster way.

I thought that it was in a sense a little bit ironical that scientists were more optimistic and that people from the pharma industry were more pessimistic, because usually at least it is the other way round. We are the skeptical ones and the pharmaceutical are always trying to sell the drugs. But I think this is actually quite good in the total of interactions. I think that it is important that academia and industry find modish what you say on communication with each other and it is very good not to overpromise in this field, but there are a lot of examples from the past where being able to cluster diseases actually allowed us to improve. Fifty years ago, if people have had hepatitis they looked yellow. Some of them could be cured, but some others could not. But they had no idea if it was hepatitis A, B, C, D or E. Nowadays they actually have all the different forms of this disease identified, and now we even know that some drugs that work very well against hepatitis B are actually very bad for people with hepatitis C. It always helps to define disease entities. In this respect I think that I am fairly optimistic that at the short notice we will be able to do something even with existing medications in terms of targeting to specific groups.

Then I also wanted to express my opinion on what Bartha Knoppers said about the databases, before the interval. I think that to get ourselves sorted out on databases is of much more importance that many people realized. In fact all these promises about being able to get more personalized medicine will stand or fall with the ability to do more epidemiological research, and to look at population isolates, big family cohorts, disease cohorts, and there is a tendency of the regulation, specially in Europe, that is making such an over chute. I do not know how this in Spain is, but in the Netherlands nowadays patients are better protected against their doctor than against their disease. That is a situation where you would not want to be. You would be able to have some intermediate and all these arguments about informed consent are fine, but specific informed consent, which is making its way into the legislations in many European countries, says that for every next research you have to go back to the patient and ask it again. This is not going to work. In the field of philosophy people are gradually understanding that it does not work because the tale is wagging the dog. We designed this informed consent because the research was not transparent and people were coerced. Informed consent is a tool against transparency and coercion. Now it gets to be a goal in itself. You need to go back again and say that nowadays we have the Internet and we have other identification points on privacy, so we should go back and say that what you really want to avoid is coercion and what you really want to enhance is transparency. As soon as health care research, such as doctors and biologists, can show that they have been at least as clear as they could about what their goals are, and that people is not coerced in a sort of way, things will start to roll on. Then in many senses we can probably deal with more generic consent for research in all the things in the future. But now and then we have to go to people and explain everything to them. This is all I wanted to say on this aspect.

I did want to get back to Beato's point on what is in the other 95% of the DNA because I really could not agree more that there are many languages written through the DNA. It is not only genes, promoters or regulators; it is actually what Beato has said: epigenetics, like little flags that are being put by generation and sometimes even by more than one generation. I think that this is the promise of the more holistic type of genome research. Nowadays, you can look at how systems react to one small perturbation and this whole of having the genotype separated from the phenotype is probably a wrong conception. We have DNA. Apart from it we also have RNA, and even inside the DNA we have histones and modifiers. So between genes and expression there are several steps, and then between the RNA and the cell there are also several steps, and finally between the RNA and the protein and the metabolized there are more steps. No matter where you are on this staircase, if you stand on a certain step and you look back, you are looking at the genotype and if you look forward you will be looking at the phenotype. There is a phenotype, which is not visible like you and me but in the tissue you have what we call an endophenotype. If you are doing epidemiological research and you look at people's brain by MRI, or you look at people's spine to research arthrosis, then you talk about endophenotype, that is something which is not on the outside, but it is upstream of the outside. This whole idea of genotype and phenotype is more about what causes what. There are even feedback looks, but if you look more upstream, backwards as you might say, then you look at the genotype and it may be the DNA, the histones, and the RNA, if you are standing on the protein step of the ladder. But if you stand on the RNA, everything which is downstream is phenotype, so it is a bit of how you conceive it.


Jaume Bertranpetit: Voldria que comencéssim una última part de debat o de preguntes creuades, i demanaré també a les persones del públic que hi intervinguin. D'entrada, però, m'agradaria fer una pregunta molt senzilla als membres de la taula, que és si realment existeix aquest divorci tan gran entre coneixement i aplicació cap a la salut. És a dir, d'una banda, tal com se'ns ha plantejat, des de la recerca bàsica fins a l'aplicació farmacèutica, hem arribat a entendre que aquests dos mons no es parlen; però, d'altra banda, totes les grans inversions, totes les excuses a l'hora de fer el genoma humà eren que ens havien de curar. Realment ens han enganyat o ha estat una trampa social per intentar fer-nos creure que tenim un camí per fer recerca bàsica i que tindrem les bases per a una recerca aplicada, ja que aquesta és l'única manera d'atraure molts fons.

Ara m'agradaria que expresséssiu les vostres visions des de la perspectiva de les grans iniciatives en recerca genòmica, per exemple, sobre si hi ha hagut un comportament "amb males intencions". És a dir, si fins i tot s'ha enganyat a l'hora d'intentar aconseguir uns finançaments o uns fons per a alguna cosa, amb unes finalitats que sembla que no són tan clares com haurien de ser.

Jesús Acebillo: Evidentemente hay una excelente relación y una muy buena comunicación entre el mundo de la investigación básica y el mundo aplicado. De hecho, se trata del mismo contexto y del mismo quantum. Creo que en el fondo estamos hablando de un tema de manejo de expectativas, en términos de tiempo.

Creo que es muy importante no olvidar que la industria farmacéutica es el paradigma de lo que los expertos llaman sectores de ciclo largo. Este concepto se refiere al tiempo que tarda un medicamento en salir al mercado, pues desde que se empieza a investigar en un proyecto hasta que sale al mercado raras veces pasan menos de quince años. Los indicadores de eficiencia y de productividad actuales son los establecidos. Todos esperamos que se mejoren con la genómica, porque se está invirtiendo mucho dinero para que eso ocurra. La productividad es la siguiente: de cada 20.000 moléculas que se trabajan en screen, sólo una sale al mercado al cabo de quince años. Esto hace que todo el desarrollo de fármacos tenga este desfase.

Hay un ejemplo que siempre suelo poner, porque esta verdad se confirma cuando hay una enfermedad nueva. Es el ejemplo del sida, que al ser una enfermedad nueva que apareció a principios de los 80 podemos utilizarla como modelo. Lógicamente, el impacto social en aquel momento fue enorme, y el impacto político todavía más. Los decisores políticos y la sociedad se planteaban cuál era el papel que jugaba la industria. Era necesario encontrar una solución (un medicamento) para que la gente no muriera, pero los primeros antiretrovirales no empezaron a comercializarse hasta al cabo de diez años (Sector de ciclo largo), esto es a principios de los 90. En resumen y como conclusión, en sólo diez años se pasó de una enfermedad que a principios de los 80 tenía una mortalidad anual del 85% a ser, 10-15 años más tarde, una enfermedad crónica con una mortalidad inferior al 2,5% anual. Pero no olvidemos que fueron necesarios casi quince años para conseguirlo.

Estoy convencido de que la genómica puede hacer que esos períodos se reduzcan. Pero todavía estamos en unas fases muy iniciales para asegurarlo. No creo sinceramente que sea positivo enviar mensajes excesivamente optimistas, porque la gente que tiene problemas tiene prisa por solucionarlos, aunque esto es sólo mi opinión personal. O sea, hay que pensar en la gente que tiene determinadas enfermedades; a estos pacientes no les ayuda nada que les digan que se ha descubierto un gen y que se va a solucionar su enfermedad, porque con toda probabilidad él no lo va a ver. Digo con toda probabilidad aunque puede haber alguna excepción a esta norma. Por ejemplo, nosotros como laboratorio, hemos desarrollado Glivec, un producto que es uno de los paradigmas del desarrollo rápido como consecuencia de la genómica. Pero no deja de ser una excepción. Actualmente el 80% de los productos en desarrollo, de las moléculas en screener, no proceden de la investigación genómica. Por desgracia, todavía estamos en una fase muy precoz en la aplicación de estas metodologías. De hecho, estamos hablando de unas metodologías completamente nuevas, con el agravante de que requieren grandes inversiones y que además requieren un tiempo. Este tiempo nos servirá para que podamos pasar, con mas fiabilidad, a la aplicabilidad.

Gert-Jan B. van Ommen: I think that the time is really one important factor, but also the money in the sense that for academic research, as opposed to industrial research, you have to find your finding at the Muscular Dystrophy Association, at the government and at the Cystic Fibrosis Association. Indeed, it is very difficult. I have never found a really good 100% honest solution for not raising hopes and keeping hope alive. It is very complicated.

In the society everybody wants to get against research done. If I see how many people of 80 or 90 years are lonely, have no family anymore, all have old age depression. Then you can think that maybe people do not want to live longer nor spend a longer time living, but they actually would want to spend a shorter time dying. This is a big difference. You want to give them more time in health, so they are still mobile and they can go alone. I think that when we can not even do that it is all wonderful that we can make them take ten years older. But this is not the solution, as it is precisely what you were saying before on, for example, changing people's attitudes: it is not the easiest thing to do. Our biggest epidemic nowadays is the metabolic syndrome and we know its cure, which is eating less and moving more. But nobody does it. The fault is partly of the industry, because they make the cookies and they want us to eat more and more. It is a very complicated issue, but I still think that sometimes you cannot help it. There is a very funny research done by an English doctor about five years ago. He took two groups and he looked for attitude changes. The two groups suggested stopping smoking. One group was men with important problems and the other group was men with their first cardiovascular attack. You may guess which group was more loyal to the therapy and the group where the proposed therapy is not going to work. 55% of the men with the important problems stopped smoking and only 25% of the men with their first myocardial infection stopped smoking. Too much depends on what the perceived gain of people is in the whole. If the perceived gain is very important then people will change their attitude. I think that with the lists that you have as soon as we are capable of getting away from the average risk, we try to do it. If we only have the information that everything is bad for us, except for low concentrations of salt and sugar, at least we have to follow these instructions and try to do our best. But it is true that doctors have to be much more specific: you cannot do this, or you cannot eat more fat, you cannot have a drink or two, you should not drink coffee or smoke. As soon as we are on that level of changes, my hope is that we can help a little bit that people change their attitude.

Miguel Beato: No creo que se pueda añadir mucho. Pienso que el factor tiempo es lo esencial y que realmente estamos en el comienzo de ver los primeros frutos de lo que es la investigación dirigida por la genómica. Glivec es un ejemplo. Pero yo soy optimista y creo que en el futuro va a haber muchos casos semejantes, pues es una cuestión de paciencia. Pero tampoco quiero irme sin mencionar que los científicos han pecado en el pasado por haber levantado expectativas infundadas, como el ejemplo de los oncogenes. Cuando fueron descubiertos se creía que el cáncer ya estaba resuelto. Creo que hemos aprendido a hacer un proceso de aprendizaje, pues las cosas son más complejas y debemos ser un poco más prudentes. Creo que hoy en día cuando se descubre un gen a nadie se le ocurre decir que el problema ya está resuelto, aunque represente una vía para afrontarlo de un modo más racional. El futuro está en las enfermedades multifactoriales. La genómica va a aportar información importante en enfermedades complejas y más generales. Y como ya se ha dicho antes, va a permitir una clasificación. Creo que ahí hay un gran futuro.

Jaume Bertranpetit: En les malalties complexes, la genòmica implica tota la interacció que abans ja s'ha dit de genotip-fenotip. És a dir, la comprensió dels fenotips complexos és, sens dubte, la frontera que tenim. Però, ja per acabar, a mi m'agradaria parlar -en relació amb aquesta imatge de la revista Nature- d'una trobada que va tenir lloc fa justament dos dies. El professor Francis Collins, que és el director de l'Institut del Genoma Humà dels Estats Units i el gran promotor d'aquest camp, va fer una conferència oberta al públic per a milionaris nord-americans. Després de fer una descripció de l'estat de la qüestió durant cinc minuts, va dedicar els cinquanta minuts restants a donar expectatives en la salut. Això va ser fa dos dies davant d'un públic format per persones altament influents dins dels estaments dels Estats Units. Per tant, va dedicar cinc minuts a explicar les interaccions i cinquanta minuts a oferir expectatives dels diagnòstics i teràpies que es faran. Va acabar convencent el públic que tot el que s'està descobrint és enormement important per a la salut de tothom, inclosa la seva, que en el fons són els qui pagaran els diners necessaris per fer recerca.

A mi m'agradaria que ara obríssim el diàleg amb els comentaris que vulgueu. Hi ha moltes persones aquí que teniu moltes més coses a dir que alguns dels que estem a la taula, i vull que us sentiu totalment lliures no només de preguntar, sinó també d'afegir, de dir o de reflexionar. Té la paraula en Jordi Camí.

Jordi Camí: Voldria afegir uns comentaris a aquesta interpretació que són contradictoris. Jo crec que els científics necessitem aconseguir una credibilitat per part dels que prenen les decisions polítiques i, per tant, dels que posen diners per poder mantenir el sistema de producció de coneixement. En conseqüència, forma part de les nostres regles del joc intentar convèncer que la nostra tasca té sentit, que val la pena fer-la i que en el fons la societat se'n beneficiarà. El joc ha de ser així, tot i que de vegades tenim molt poc èxit. En alguns països han tingut sempre molt més èxit que el que nosaltres hem tingut aquí.

Però una cosa que està del tot demostrada és que el temps és un factor molt important a l'hora de reduir el desfasament que hi ha entre les expectatives que es creen i l'evidència que té la perspectiva de la indústria farmacèutica pel que fa a quan s'entrarà en matèria. I, de fet, el factor temps són diners. És a dir, en recerca és un tema de recursos i també de personal especialment format. Tot i això, el tema recursos és fonamental, i amb l'exemple de la sida en tenim una demostració. Més recentment, amb la SARS hem vist com en poc temps s'ha pogut córrer; s'ha anat de pressa en el diagnòstic, i per tant tot és un problema de voluntat política, de recursos i, és evident, de gent especialment formada.

Un cop dit això, m'agradaria remarcar que és molt important no oblidar que els científics tenim una responsabilitat molt gran. Crec que el discurs que va fer Francis Collins és excessivament arriscat. No vull dir que fos irresponsable, sinó que el vaig trobar arriscat per diversos motius. Primer, com que tots som humans, hi ha científics que potser són més ingenus i creuen que realment és veritat tot el que Francis Collins va dir, tot i que també n'hi ha que són més desaprensius. Però jo sé perfectament que ho fa per obtenir fons i per obtenir més suport. Aleshores, un element clau en aquesta interpretació, que és una peça que falta, són els mitjans de comunicació. Entre aquests investigadors més desaprensius hi ha els científics vedets, el vedetisme. I el matrimoni permanent que aquests tenen avui en dia amb els mitjans de comunicació també és molt important per interpretar el que està passant. Hi ha una responsabilitat empresarial i professional molt important del periodisme i de les empreses. Crec que sovint els mitjans de comunicació fan un mal favor al que s'espera de la ciència i al seu futur. Si aquest Nadal no s'hagués donat crèdit a aquells farsants que insistien a haver clonat una persona humana, probablement no hauria augmentat el conservadorisme que hi ha amb relació a la recerca amb cèl·lules mare i, probablement, tampoc no hauria augmentat la percepció negativa de l'opinió pública respecte de la ciència, amb un increment dels temors que les enquestes a Europa estan reflectint de manera preocupant.

Ja per acabar, m'agradaria fer una crítica més al sector on estem. Torno al discurs de Francis Collins. Em sembla que, sense fer-ho expressament, som poc responsables a l'hora d'emfasitzar les expectatives i les sorpreses en positiu que vindran amb la recerca genòmica pel que fa als aspectes de la individualitat i de la medicina predictiva. I, en canvi, no emfasitzem la importància que això pot tenir amb relació als principals problemes de salut que hi ha al món i amb relació, també, a la majoria de la població, que és la més desafavorida. Considero que el parlament de Francis Collins és un discurs elitista, que pot tenir sentit als Estats Units, però no en té en alguns països d'Europa. És catastròfic als ulls de les persones que viuen a l'Àsia, a l'Àfrica o a Amèrica del Sud i que també llegeixen el diari, ja que se'ls està explicant que vénen més progressos i avenços, però que només en podran gaudir uns quants. Això és tot. Moltes gràcies.

Jaume Bertranpetit: Sí, i aquests que en podran gaudir són, sens dubte, cada vegada menys. Donem la paraula a Joan Guitart, president del Consell Social.

Joan Guitart: Em sembla que fins ara s'ha explicat tot molt bé. Com dèieu, estem en la fase del projecte genòmic, en els fonaments. I també heu coincidit quasi tots que és un problema de temps, i que, tal com deia Jordi Camí, és un problema fonamentalment de diners i d'inversió.

També em sembla que queda molt clar que la indústria farmacèutica requereix i aplica uns diners considerables per a cada nova molècula que surt en el transcurs del temps. Això és un procés tan llarg que en aquests moments es dediquen pocs diners a aquesta investigació perquè encara està en fase de projecte i, per tant, en un element molt bàsic, com ja ha quedat clar. D'això en podem deduir que la major part dels recursos, i amb el temps probablement continuarà sent així, són recursos públics. Als Estats Units aquests provenen de diferents fonts, és a dir, els sistemes de finançament estan molt més diversificats. En certa manera, són fruit de la col·laboració privada, però també hi ha una bona aportació de recursos públics, i sembla que continuaran produint-se en el futur.

D'altra banda, també ens trobem que hi ha unes possibilitats d'informació extraordinàries, a les quals us heu referit moltes vegades. De fet, Internet dóna possibilitats de comunicació molt ràpides entre científics i ofereix enormes quantitats d'informació i de documentació.

La pregunta que jo em plantejo és si és possible pensar que es podria articular el que dèiem que podria ser l'expectativa de solucions per a la salut, sobre la base d'una coordinació de recursos públics, i amb la creació d'un gran organisme internacional que d'alguna manera evités treballs innecessaris, que coordinés recerques i que formulés un programa mundial. De moment, tot això es fa a través de la figura del senyor Collins, però és realment possible? O bé, en el fons, cada país o investigador es queda, en certa manera, en la soledat del segle passat?

Jaume Bertranpetit: Crec que tenim la persona més adequada per parlar d'aquest tema: el professor Van Ommen, ja que fins fa poc era president de la Human Genome Organization, que és l'organització de científics internacional més important que hi ha hagut en tota la història.

Gert-Jan B. van Ommen: This is a multifaceted question. I must say that personally I am not very much in favour of international regulating bodies, because you get a lot of bureaucracy. I am not convinced that in order to direct science this is the best way to go. For instance, this sort of non political way that is done in America in the NIH is much better, and I think that it would be quite a good thing for Europe if we would get a sort of European Science Agency like the NIH, which is really driven by science more than by the bureaucrats and the rules from the European Union. In that respect I think that we should look at systems that work and try to copy them.

On the other hand, there is something a bit different between Europe and the United States related to these things, which is the role of the entrepreneurial scientist. It is not a secret than 90% of the patents are in the United States. What is interesting here is that in fact the top four agencies that are making money through licences in the US are public bodies, such as NIH, DUE or Howard Hughes. There are a few ones more, and probably I do not mention the right ones. In the United States it has been perceived, much more than in Europe, that the real source of innovation, and so the place where the money is best spend, is academia. Here in Europe we still have the pharmaceutical industry and biotech industry on the one hand, and the academia on the other hand. In Europe, we are seriously hampered by several aspects of the international regulations, that is for instance that nearly in all the other countries there is what we call a grace period, which means that if someone publishes about research, he still has half a year or one year to spend before finding a patent. In Europe as soon as you have written something up or you speak about it your patent is dead. That has been defended by European industry by saying that this situation forces scientists to think ahead of protecting their intellectual property, but what it actually means in academia is that the typical European scientists find it complicated to think about patenting or intellectual property protection, because they have to do it at the same time as they are writing their article for Cell or Nature or Science, so they are in this competition with the American counterparts. The Americans can safely just first write their Cell paper and then just put the whole thing on the desk of the patent office, because it is not their problem and have the patent application done. In Europe this cannot be done. You just have to do it side by side and it gives the sense of complicatedness of the whole IP protection.

I think that this causes a big difference in the money that we should have been able to generate for innovative academic research in Europe. For this reason, I would be quite in favour of alterations of this patent law. It sounds funny from a scientist to be in favour of this aspect of patent law, but if you look at the effect of how it is being done and what I just said, we should look at where it works and then copy it. All the arguments that I have heard so far against the grace period, for instance, are from European industry, and I think that the American biotech and pharma industry is a lot more innovative and a lot more advanced typically than anything in Europe. If you talk about how to generate money, public funds are limited. Governments have their own priorities and typically in the governments there are not many academics, so academic research in the governments is not a very high priority and this is something that we have to live with, as it was mentioned before as well. They have a big funding for genomics and they make hundred million or ten million available, and then they call you up a week later asking if it is already done. They have no idea of anything. They want us to do it in three months, deliverable at milestones and you just made a contract on what sort of research you are doing and after three years they are yelling at you, not only for the fact that you have not done what you have promised to do three years ago, but also because you have done something much better, but that was not what you promised. This is how science works, and it is very difficult to explain. We have to find our funding in different ways, that is to say that we have to make more interaction with industry, make more of our inventions and generate more money by licensing our findings. I think that this is the more sensible route.

Jaume Bertranpetit: Potser un dels punts més negatius d'això és que, amb aquests últims anys d'experiència amb l'organització, la Unió Europea no sigui l'entitat que faci més promeses de cara al futur de la recerca. Això realment és un problema greu i trist, ja que no sembla precisament que estiguem començant una època àgil i brillant de cara a la gestió de la recerca dins del marc europeu.

Té la paraula Luis Pérez Jurado, professor de genètica.

Luis Pérez Jurado: A mí me gustaría hacer algún comentario que va en la línea de lo que ya ha dicho en la mesa el doctor Acebillo y en el público el doctor Camí. También creo que se han vendido expectativas desmesuradas para la realización del proyecto del genoma y que aún se siguen vendiendo. Eso es lo que ha planteado el Gap 10/90. Obviamente, el proyecto del genoma puede beneficiar a la ciencia del 10% de la población, y lo que se necesita en el resto del mundo es claramente que se le pueda llevar agua potable y que se mejore la nutrición. Partir de esta premisa no es del todo adecuado, puesto que dicha deducción tampoco es válida en tanto que es una suposición desmesurada por la necesidad de conseguir fondos.

Obviamente, el proyecto del genoma humano es la base y los cimientos para el conocimiento biológico. Toda la gente que trabaje en ciencia va a poder utilizar la información del proyecto del genoma para hacer biología, para entender mucho mejor cómo ocurren las enfermedades, cuáles son los mecanismos patogénicos de todas las enfermedades y entender el organismo. Lo que va a aportar para la salud el siguiente piso no tiene ni mucho menos la misma anchura. Todos somos conscientes de que es así y de que hay unas áreas del conocimiento que se van a beneficiar mucho más y otras mucho menos. Todos los científicos estamos muy interesados en utilizar la misma tecnología, pero hay un área clara del conocimiento que incentivó el proyecto del genoma. Dicha área es la genética, la genómica, la genética médica, que es la que más se está beneficiando, puesto que en genética, los genes son absolutamente determinantes. Poder determinar los genes permite la posibilidad de establecer al menos un diagnóstico y, a medio o largo plazo, establecer también medidas terapéuticas. En este sentido, ya ha habido problemas de salud que se han solventado o mejorado a nivel poblacional y se ha disminuido la incidencia de unas enfermedades concretas, aunque sólo afecte a un porcentaje de la población relativamente pequeño. Si asumimos la prevalencia que se establece en las enfermedades genéticas, éstas se dan en menos del 7% de la población durante toda su vida, o sea que hay que convencer al 93% de la población de que van a tener alguna mejora también del proyecto genoma.

Hay otra área del conocimiento que se beneficia claramente y de manera inmediata. Es el caso del cáncer, puesto que es un mal genético y en las etapas precoces también se trata de una enfermedad genética determinada por un solo gen. O sea que las medidas de diagnóstico para el cáncer ya están repercutiendo claramente en la salud. Pero creo que la promesa de mejora real de salud para las enfermedades multifactoriales está muy desmedida. Conoceremos más y mejor cómo ocurren, cuáles son sus mecanismos, aunque ya los tenemos bastante claros, puesto que es muy demostrable que evitar que se fume tiene una repercusión sobre la salud mucho mayor que conocer cuáles son los siete genes que están implicados en los mecanismos de acción nociva de los productos químicos y de los productos tóxicos del tabaco. Sin embargo, está claro que entenderemos muchas cosas, y si conseguimos medidas de salud pública convencionales y estándares, mucho más. Todo ello depende de si nos imaginamos el edificio de la genómica con un segundo piso, en el cual se encuentra la genética médica y el cáncer con dos habitaciones grandes y el resto ocupa un lugar muy pequeñito. A modo piramidal, también hay un tercer piso en el que el porcentaje de la sociedad que realmente se beneficia de ello va a ser mucho más pequeño que no toda la sociedad, puesto que va en detrimento de que se mantenga la financiación. Dicha financiación para el proyecto del genoma ha sido hecha a nivel internacional, en gran cantidad y con la pretensión de mantenerla durante muchos años. Lo que digo ya se ha tocado, pero me gustaría recalcar que el objetivo de esta financiación siempre ha sido el mismo del principio. Se ha hecho con el consentimiento por parte de la comunidad científica porque todos queremos "estar en el carro" y todos queremos ser financiados para poder por lo menos actuar en el primer piso, que es lo que nos importa. El conocimiento de la genómica está condicionando que se generen falsas expectativas para la población.

Jaume Bertranpetit: Moltes gràcies. Ara tornarà a parlar Jesús Acebillo.

Jesús Acebillo: Yo querría hacer un comentario muy breve sobre el tema del tiempo del desarrollo, porque han habido varios comentarios en relación a que el tiempo dependía del dinero. De modo general, estoy de acuerdo con esto. Sin embargo, debo decir que no es del todo cierto, en el sentido de que el tiempo en el desarrollo de un fármaco es un hecho estructural. Con el nivel de información y conocimientos que tenemos ahora, lógicamente todo puede cambiar, aunque no estoy diciendo que de hecho acabará pasando. El desarrollo clínico de los fármacos tiene una serie de fases con unos tiempos determinados y con unos volúmenes determinados de pacientes y de información, con una cronicidad en el nuevo tratamiento para los pacientes. Eso no es modificable, hasta que no lo cambien las autoridades reguladoras en Estados Unidos y en Europa. En otras palabras, un producto para una enfermedad crónica, que tiene que ser testado en pacientes antes de ser aprobado, va a requerir un determinado tiempo de desarrollo. No importa si se gastan 100 ó 200. Por tanto, no es un tema en el que se pueda echar la culpa a la industria por no gastar más dinero aquí. La variable tiempo no es lineal ni directamente proporcional a los recursos utilizados. La regulación de la investigación y de los procesos de aprobación de fármacos son así mismo claves. Este es uno de los aspectos a los que antes me refería como "cambios de paradigma" que puede condicionar este nuevo ciclo. Aunque debo volver a insistir en que estos cambios de regulación siempre son complicados y costosos en el tiempo.

También deseo hacer una segunda reflexión sobre el tema de la aplicación. Insisto una vez más en que la sociedad no va a percibir esta revolución genómica de forma inmediata, puesto que además puede haber patologías muy concretas, como se ha explicado ahora con el caso del cáncer. El Glivec es un ejemplo, la leucemia mieloide crónica con una mortalidad elevada (cerca del 90%), que después del tratamiento específico mejora de forma muy significativa, aunque esto no deja de ser más que un ejemplo en patologías muy concretas (monogénicas). En patologías crónicas multifactoriales (poligénicas) la situación es muy distinta. Por supuesto, la genómica va a ayudar a hacer mejores desarrollos, pero esto son pequeños cambios, no son quantum y necesitaremos tiempo para visualizarlos con claridad.

Jaume Bertranpetit: Moltes gràcies.

Rafael Argullol: A mi no se'm fa gens estranya aquesta escenificació d'assemblea del senyor Collins davant de milionaris americans, ja que en el fons estava venent paradisos. Aleshores, els milionaris són els que actualment poden comprar paradisos. I per això crec que pot ser legítim aquest tipus d'intervenció si la finalitat és recollir fons per a la recerca, encara que sigui molt simbòlica de l'atmosfera de la nostra època. En aquest sentit, m'ha cridat l'atenció el final del segle XX en comparació amb el final del segle anterior. El final del segle XIX es va caracteritzar per un horitzó de vendre paradisos col·lectius. De fet, l'hegemonia partia de les ideologies revolucionàries, on la ciència hi tenia un determinat paper però d'alguna manera integrat amb aquest horitzó de paradisos socials. En canvi, el final del segle XX, per raons que tots sabem, s'ha inclinat decisivament cap a un horitzó de paradisos individuals, i és aquí on la ciència ha jugat un paper determinat, amb la mateixa popularització de la ciència i, dins d'aquesta, de la genòmica. Jo fins i tot recordaria una variació important de les expectatives populars de la ciència al llarg del segle XX. Recordo que quan era nen, i potser també quan era estudiant, les màximes expectatives populars no estaven situades en el terreny del microcosmos sinó del macrocosmos, en la cursa espacial. Estem parlant dels anys seixanta. En canvi, l'últim terç del segle XX, i concretament l'última dècada del segle XX, han estat dominats per expectatives populars al voltant del microcosmos humà i, fonamentalment, en el cas que aquí estem discutint, de la mateixa genòmica, de l'enginyeria genètica. Això ha tingut una traducció molt clara en la premsa i a la resta de mitjans de comunicació. Des de fa uns anys he observat l'augment del nombre de pàgines dels diaris d'informació general que estan dedicades a la ciència i a la medicina, però molt especialment a l'àrea que estic comentant. Segur que s'ha analitzat la repercussió d'aquestes pàgines en la indústria mèdico-farmacèutica. És curiós que en aquestes pàgines els dos punts més rellevants en els quals ha acabat el segle XX són el mite de l'eterna joventut i el mite de la immortalitat. El que li passa a la mare del doctor Acebillo és un fet que s'ha transmès de manera popular.

Quina és, per tant, la reflexió que em plantejo sobre el que hem comentat aquí? D'una banda, em fa la impressió que, d'una manera excessiva, el que en aquests moments podria ser la veu de la ciència amb un determinat front d'avantguarda com pot ser el que s'està debatent aquí, massa sovint està mediatitzat pels mitjans de comunicació i per les expectatives que aquests creen. Per tant, es caracteritza per una ocultació de les expectatives que crea la indústria mèdico-farmacèutica i per la poca mediatització, així que podria ser allò que abans es deia de la consciència de la ciència. De fet, en la primera meitat del segle XX abunda la literatura de científics que, en l'òrbita d'un paradís que no ha de ser purament individual, parlen de la consciència de la ciència. Em fa la impressió que un dels grans problemes de la nostra època és que s'ha creat aquest enorme desequilibri entre expectatives certament populars creades per certs sectors de la ciència, entre ells la genòmica, centrades en dos mites molt populars: el de l'eterna joventut, amb totes les traduccions que té, i el de la immortalitat, també amb totes les seves traduccions. Però això deriva decisivament d'aquesta venda de paradisos individuals. Aleshores, manca una transmissió de la ciència que clarifiqui les expectatives, que atorgui una consciència a la ciència, que contraposi el pes dels mitjans de comunicació i dels interessos que hi ha darrere dels mitjans de comunicació i que d'alguna manera equilibri de nou una esperança de paradís individual amb una esperança de paradís col·lectiu. És a dir, que vagi amb la perspectiva social de la mateixa medicina.

Encara hi ha un últim punt filosòficament molt rellevant. Juntament amb el fascinant món que la genètica està creant en les últimes dècades, és evident que popularment també s'està creant el que podríem anomenar una nova perspectiva perillosa. És el que fa un moment s'ha titllat de nou determinisme. Des del punt de vista filosòfic això és molt important, perquè de la mateixa manera que es creen aquests mites d'eterna joventut i d'immortalitat, també es crea un altre mite en què el vell problema de viure entre llibertat i destí queda d'alguna manera dominat pel fet que hi haurà una predeterminació. Com que depenem mecànicament del genoma, quan la ciència matisa tots sabem que no és així. Però estic parlant d'expectatives populars, que són les que realment arriben a la societat, en una època històrica en què la consciència de la ciència pràcticament no es manifesta. I aquest predeterminisme podria ser en els pròxims temps molt perillós.

Jaume Bertranpetit: Moltíssimes gràcies.

Gert-Jan B. van Ommen: I would like to respond to Rafael Argullol, but the last comment is more or less in the same direction. You are basically talking about this intention between hype and hope. My view on that, which is a bit a cavalier view, is that hype is good too, because what I hear you say is that there has been an increasing amount of attention paid by the newspapers and the media to genetics. Of course, a lot of this is exaggeration and hype. But the only way that you get to the right information is through this complicated and painful process of missed information, restoration and sorting out. I even think that Jurasic Park, Dolly, the headless frog and cloning had their purpose, and no matter what happens ultimately population gets out of such a crisis with more information than it went into it. Now everybody thinks that to clone a human has not worked, and before everybody thought that Israelians really managed to do so. I am not saying that this is the best way to proceed, but you have to create interest in the public, and that is the same with funding for science in the governments, as you have to create the interest. This was the point that I wanted to make for your remarks. I could not disagree more than thinking that all this is mostly benefiting medical genetics, rare diseases, diagnostics and prognostics. I think that you are missing the opportunity that this could be one possibility to get more funds. Many multifactorial diseases -and I think the speciality is like internal medicine, rheumatology, nephrology, neurology, etc.- will all get genetic components. And many of those multifactorial diseases, it is not that you have monogenic diseases and then you have a big nothing and then you suddenly have polifactorial diseases with ten or more, it is that if things are not caused by one or two genes, but they are caused by two or three and then four or five, and it is very difficult for us to sort it out. The only way we can sort it out is through models. That is one of the reasons why I always keep maintaining that we should go on also studying rare diseases, because everyone is speaking about animal models and these are the human models for multifactorial disease.

If you take hyperlipidaemia then you have familial hypercholesterolaemia and familial combined hyperlipidaemia, LDL receptor deficiency, and you have a couple of those monogenic disorders and so this whole cardiovascular problem is more several clusters of diseases. The trouble is many of the industrial arenas cannot invest in rare diseases, because the market is too small to spend the funds for developing therapies.

As soon as they start going into rheumatism or hypercholesterolaemia, they will find out that they have twenty orphan diseases at their hands for different sections of it, so the difference between multifactorial and orphan diseases will be basically go away to some extent, and they will be able to invest the money to develop therapies, which is going to be very difficult other than with public funds for really rare diseases like cystic fibrosis or Duchene. They are frequent but still they are extremely rare. Once I spoke with a person from the pharma industry and he honestly said that the worse that could happen to them is that one of the therapies for one of those orphan diseases would work. What happens is you get twenty patients in a clinical trial that suddenly step out of their real chair and you have no money for the other 5,000 in the country or somewhere else. Unless governments get their act together on designing a solid reinvestment strategy for expensive therapies, I can predict that pharma industry is not going to spend a lot of money in trying to find cures for orphan diseases. Then, the worst that could happen to them is that it works. So you know that it works, but there is no money to provide it to the public. This does not happen in multifactorial diseases, because there are so many people affected by hypertension and heart disease, that it is much easier to find funds for those diseases.

Jaume Bertranpetit: Un moment, Xavier. Perquè en Luis vol afegir alguna cosa.

Luis Pérez Jurado: La verdad es que estoy absolutamente de acuerdo con todo lo que se ha manifestado ahora. Mi argumento es un poco más global, en el sentido que para las enfermedades multifactoriales va a haber genes implicados y se van a poder discernir los genes implicados. Pero en la mayor parte de las enfermedades multifactoriales, la cardiopatía isquémica, las enfermedades mentales, la contribución para cada individuo de genes va a ser muy inferior a la contribución ambiental globalmente. O sea que la repercusión global de la información genómica para la salud de estas enfermedades es mucho menor que las expectativas que se han creado, aunque obviamente el entendimiento de la biología de estas enfermedades y la posibilidad de desarrollar fármacos para ellas va a incrementarse de manera paralela o similar a lo que ocurre para las enfermedades monogénicas. Pero si tenemos en cuenta que el poder de los genes no es determinante, sino que sólo es un poder de genes que da un factor pronóstico relativo muy modificable por el ambiente, la base es que el conocimiento del ambiente y la modificación del ambiente es superior a aquello que va a venir de la información del genoma humano.

Jaume Bertranpetit: Hi ha un aspecte, que ha sortit diverses vegades, que és el paper que hi juguen els mitjans de comunicació. En Xavier Duran té molt a dir-hi. Pots començar quan vulguis.

Xavier Duran: Moltes gràcies. En primer lloc voldria felicitar l'organització i els ponents per l'interès d'aquestes jornades i pel nivell i la claredat de les exposicions. El que acabo de dir crec que també es pot relacionar amb el paper dels mitjans de comunicació. Sovint pensem en el periodista que escriu i no pensem en qui decideix realment què s'escriu, quan es publica o s'emet i quina extensió o durada ha de tenir. Jo em pregunto quants directors de diari o d'altres mitjans, caps de secció o caps de redacció del país voldrien posar-se al dia en aquests temes i escoltar aquestes ponències tan interessants.

Sovint ens centrem en el periodista que a partir d'una nota de premsa o d'un article ha malinterpretat o potser ha titulat malament. Però en canvi no anem més enllà. A part d'exigir rigor, també cal valorar que aquest debat científic i ètic apareix cada cop més sovint als mitjans. Això ha millorat en els últims temps. Però si ens fixem, per exemple, en les tertúlies de ràdio i televisió, veurem que hi apareixen ben pocs científics o persones qualificades, per no dir cap, que puguin expressar una opinió científica consistent. I, en canvi, són espais que creen opinió entre el públic. Crec que per donar més rellevància a aquests temes hem d'intentar canviar la idea que la ciència tracta temes molt especialitzats i de coneixement específic. Els periodistes hem d'introduir el missatge social, que en aquesta jornada s'ha tractat sovint.

S'ha parlat de desigualtats, d'impacte humà i de moltes altres coses, a part de gens, proteïnes i bases. I crec que aquest és un punt molt important. De vegades es pensa que el científic només explicarà el funcionament de les molècules i no anirà més enllà. Per sort, n'hi ha molts que poden anar més enllà. Però, a més a més, sense el coneixement bàsic previ és impossible anar més enllà i preveure quines conseqüències poden sorgir. Per tant, hem de demanar rigor i jo m'incloc, com a periodista científic, en aquesta exigència. Però crec més important que qui pugui intenti fer veure, als que realment decideixen de què s'informa i quan, que aquests temes són importants i s'han de tractar de manera rigorosa.

D'altra banda, dels molts temes que es podrien tractar i les moltes preguntes que es podrien fer jo vull comentar dues coses. En primer lloc, s'ha parlat de les falses expectatives. Podem obtenir informació que serveixi per diagnosticar, però no per guarir. Aquesta informació pot arribar a ser negativa o contraproduent? L'assessor genètic intenta esbrinar si a la persona que és a la consulta del metge realment li serà positiu saber que en el seu patrimoni genètic té certes deficiències o anomalies, si això repercutirà positivament en la seva salut. Hi ha molts factors que intervenen en la possible manifestació o en l'evolució d'una malaltia, a part dels gens estrictes. Cal esbrinar com influirà la informació en el canvi d'hàbits, l'estat anímic de la pròpia persona, l'actitud vital que aquesta persona prengui. I això pot fer desaconsellable donar aquesta informació, de la mateixa manera que en altres casos pot ser molt positiu.

En segon lloc, cal prevenir que aquesta informació no arribi a la persona sinó a empreses que la poden utilitzar. Moltes mútues i empreses d'assegurances diuen que si es mesura la tensió arterial a les persones que volen subscriure una pòlissa o se'ls fa una anàlisi de sang, per què no es pot obtenir més informació? Ja que la medicina ho permet, per què no es poden utilitzar els tests genètics? Si en cert moment no es volen subscriure pòlisses o assegurances de malaltia o de vida a certes persones, la societat se n'ha de fer càrrec igualment. Per tant, ens podem trobar que amb aquestes eines, si les empreses les utilitzen i ho fan malament, acabem carregant més sobre les espatlles de l'Estat l'atenció d'un gran nombre de persones. Actualment es debat l'estat del benestar i el seu futur. Crec que també cal incloure-hi aquestes possibilitats sobre el diagnòstic genètic. I no només per impedir discriminacions a l'hora de subscriure assegurances -o en la selecció de personal- sinó també perquè podem acabar carregant en els pressupostos públics el tenir cura d'un gran nombre de persones que les empreses privades no admetran per por dels costos que els podria ocasionar.

Jaume Bertranpetit: Aquests reptes són complexos i difícils. Els tenim sobre la taula i les implicacions que se'ns posen van molt més enllà. És a dir, aquí hem plantejat primer les implicacions científiques i després les aplicacions cap a la salut, les implicacions socials i les implicacions que han sortit fa un moment, que serien més filosòfiques o ètiques. Però en aquest punt de les implicacions socials sens dubte és on més ens hem d'implicar i on més diàleg se'ns ha d'obrir. El professor Van Ommen volia contestar.

Gert-Jan B. van Ommen: Well, I think that one of the things that I already did show in my talk is that insurance companies will never apply tests that will exclude a significant percentage of their potential customers. We are not getting more and more ill, but more and more healthier. What they want to exclude is the very specific high risk like Huntington's disease or myotonic dystrophy people. Even when speaking to people from the insurance in the Netherlands and in England as well, I am not so concerned if they would want to go to those many genetic tests. How will these many genetic tests look? We have three excellent genetic tests nowadays, which are blood cholesterol, blood pressure and blood glucose. And that is the sum of many genetic factors. What would an insurance company or somebody who is testing for somebody's health rather do? Put 4,000 genes on a DNA chip and spend the fortune to test all its customers on this DNA chip for his 4,000 genes? Or simply major the resultants of these 4,000 genes just put a little rubber band and just look at the dial and then say you have to high blood pressure. I just simply fail to see the real predictive value of those genetic tests. What my neighbour has said is that there are so many things other than genes that determine these things and environment, and there are so many probabilistic situations in it that in the actuarial part of insurance companies people know perfectly well what they do: they stick with their guns because they work and they pick out the highest risks at the lowest loss of people paying insurances. I do not think that the concern for the genetic test will replace all the other ways of trying to gage the other people risks. This is going to be a very serious risk in the future. But that is a very frequently encountered opinion in the media and it is very difficult for us, because it is complicated to get through that and to try to replace those fields with more moderate and less deterministic ways of looking at genes.

Jaume Bertranpetit: Thank you very much.

Voldria donar per acabada la sessió. M'agradaria que veiéssim que les complexitats sobre les quals hem parlat han agafat diferents vessants. Encara que quedin molts punts oberts, penso que hem assolit bona part dels propòsits que ens havíem fixat inicialment. Voldria agrair als ponents de la taula les seves aportacions, i a la gent del públic tant les seves aportacions com la seva presència. Moltes gràcies i donem per tancada la sessió.