Discussion for Session 4 pp. 45-48 in Bioethics and the Impact of Human Genome Research in the 21st Century

Editors: Norio Fujiki, Masakatu Sudo, and Darryl R. J. Macer
Eubios Ethics Institute

Copyright 2001, Eubios Ethics Institute All commercial rights reserved. This publication may be reproduced for limited educational or academic use, however please enquire with the author.

Sugano: This session will include four papers on the basics of DNA polymorphism, by myself, and next Dr. Hayashi. We have time for one or two questions.

Kneller: It was a very interesting presentation. What is the timetable for depositing data into the databases? According to whatever guidelines exist, and according to your own practices, how soon do you deposit your data?

Hayashi: That is still not set. By the end of this fiscal year I hope to make this data open to the public.

Kneller: So you have data but it is not yet deposited?

Hayashi: Not yet.

Wertz: I am a sociologist not a scientist. We're always interested in differences within groups and differences between groups. You said that 48% of the SNPs had significant differences between Japanese and Caucasian populations. What about the differences within each group?

Hayashi: The difference within each group is given by allele frequency.

Wertz: In what percent were they different?

Hayashi: That varies between 0-50% as allele frequency.

Sugano: It differs between one SNP and another one. So if you take one SNP it may be high in Caucasians and another may not be.

Wertz: So the difference within each group was greater than the differences between two groups?

Hayashi: We are still going to examine the heterogeneity within the Japanese population by taking different samples from different regions of Japan. That is the only conceivable way to answer your question. It has not been done yet.

Sugano: The next paper is by Dr. Kawakami, are there any questions?

Leavitt: I am not a physician or a biologist, but a philosopher and a bioethicist, so I am very happy to be at a joint conference together with scientists who are providing us with the scientific and technological background. I often wonder if I would be impertinent to ask you and other scientific speakers if you could speculate more on the bioethical implications of what you are saying. I do not see the direct connection to bioethics. I find it extremely interesting and challenging to bioethics, and want to understand. Do you feel that there are any implications of your work for bioethical questions like human rights, or the just distribution of resources, or beneficence to patients, or the free choice of patients. That is what I wanted to ask to some speakers.

Kawakami: That is a very difficult question. Can anyone answer this?

Skolnick: I think my address will include some of these issues, and we can continue to discuss these issues after that.

Sugano: I think we will have some general discussion after that last paper in this session. Thank you Dr. Skolnick. We now have some time for discussion. Are there any questions?

Skolnick: I would firstly like to summarize again. There is a huge revolution going on. We now know the sequence of the human genome, in the next few years we will know the function of the proteins produced by this sequence, and will be learning many variations in the sequence that cause diseases. All of us bear variants that determine which diseases we are most likely to contract and die from. We will be able to know those, and to have drugs specifically aimed at preventing the disease from ever occurring. Catching it before there is tissue damage. This is a huge revolution. As large as the revolution, which brought about surgery, the conquering of infectious diseases, vaccinations against polio and small pocks. The huge medical revolutions of the last hundred years will pale, compared with the revolution that we are now about to enter. So the issues especially in the information era of who should have access to this data, when people should be tested, how the data should be used, are all issues that ethicists have to confront. But I hope that this does not mean that you will shy away from the challenge of confronting these issues and solving them, because this era means that we can all live better healthier and more productive lives. One of the big challenges is directing the attention to the third world, to the diseases of the third world. Because the resources that are being born on these issues are coming to large extent, directly or indirectly, through pharmaceutical companies. Pharmaceutical companies address markets that will buy their products. Which are essentially U.S., Europe, Canada, Japan, Australia, the first world. But the most dramatic use of this technology can be in the third world. By understanding the proteins and their functions of humans and of microorganisms that are responsible for so much disease in the third world, we can actually look at protein-protein interaction between the human protein and the virus or bacteria that are causing the disease and make drugs specifically based on that knowledge. Drugs and the drug industry in both first and third world will become knowledge based instead of empirical experimental trial and error. Also medicine will become knowledge based. We will re define diseases. In ten years, we will not refer to heart disease, breast cancer or depression as diseases. Because heart disease is a collection of 50 or 100 diseases. Depression is a collection of, who knows, 5,10,15 different diseases all of which have an appearance to the doctor of a symptom. So rather than describing diseases by their symptomology we will be describing them by their causality which we will know. Both their genetic causality and its interaction with the environment. We can affect these genetic predispositions by altering our environment, whether it is the food we eat, the quality of the air we breathe or the water we drink. It is not that everything is predetermined or predestined. But we will also be interfering with these predispositions with an artificial approach to altering the environment and that is what pharmaceuticals is. It is an attempt to alter the body's environment. It needs to be done specifically and differently for each human being. So if that is not a big enough challenge for ethicists, then I don't know what is.

Leavitt: I am happy that you related to some bioethically important issues. I have three questions. Although I am happy you related to some issues I am interested in, it does not necessarily mean that I agree. My first question is, you said that the Mormon population was eager to participate in this study. I was wondering what evidence you have of their eagerness. Did you get informed consent from all the individuals in the genealogy, or how did you go about doing that? My second question is something which troubles me more, I think that it is not yet proved that a gene or a set of genes is the sole cause of a disease. There may also be a need for environmental or psychological co-factors. One cause of disease is mental stress. I'm very concerned about the stress caused, even by routine mammography. So when you get into things like prophylactic mastectomy, this very much troubles me. I wonder what prophylactic double mastectomy does to a life of a perfectly healthy young woman. It may also prevent our seeking other cures for cancer, other cofactors, other ways of preventing cancer. My third question is that you have just discussed the third world. I have a question that has been troubling me ever since we heard Dr. Kneller. The tremendous investment that there is in medicine, it's a highly profitable enterprise, and much of the bioethics that we hear has to do about the rules of the game for profit-interested people like corporations, or like profit-motivated patients who want to make money from their tissues. What troubles me is the health of the poor people who are not going to be able to afford these drugs. My question is, with respect to the third world, should people in the poor countries have to respect the patenting of drugs. Wouldn't it be perfectly ethical for poor countries to start manufacturing a generic drug and sell it cheaply to its people?

Skolnick: Those are excellent questions. As I mentioned, the genealogy that we've used came from a public library, so there is no informed consent. It's been put there voluntarily by people and by their relatives. A lot of it's on the Internet now also. Of course we do get informed consent every time we draw blood on an individual. The cooperativity of Mormons is astounding to people who do epidemiological studies. They are basically extremely interested in making a contribution to humankind. And if by participating in a study can help not themselves, but their children or grand children, or unrelated people 100 or a 1000 years in the future, their perspective is long term enough, in general. They are interested to the extent that when we do rather invasive tests, we get huge rates of cooperation. So we've done fine needle aspiration of the breast, flexible sigmoidoscopy of the colon in our colon cancer studies, and transrectal biopsy of the prostate, which is really a nasty procedure, in our prostate cancer studies. I've had cooperation rates of over 90 to 95% in the spouses, the controls that marry into our pedigrees who are at normal risks. So it is huge and legendary. Secondly, I did address in the discussion just before, the issue of non-genetic factors, and they are also of importance. Interestingly, considering the two that you addressed, it turns out that Karen Norman, who is one of the ethicists I admire most, did a study and she has proven that knowing is better than not knowing, even if the knowledge is that you are affected with the gene. The amount of people reporting stress, and the various measures of stress she has used, of people who are affected with breast cancer susceptibility or Huntington disease, and of course those who are unaffected as well, have less stress compared with those who don't know. They also have stress about whether they are affected or not affected. In fact there are a lot of stress in the people who are tested who are not affected, which is called the survivors guilt, like "why did my sister get the gene I wish it was me". It is tough, but in fact knowledge, testing, knowing where you are going, knowing what's going on, reduces stress. Interestingly enough also for prophylactic mastectomy there have been studies of women specifically with prophylactic mastectomy to show whether they were happy or not, and there is almost 100% very happy with their operation. The surprising part is, they've studied women who had prophylactic mastectomy because they were in high-risk families that turned out not to have the gene. These are women who had their breasts removed because they are in high risk families, but they have then had the genetic test and found they were negative. They are still happy, because of the stress that has been relieved. The fraction of people who resort to prophylactic mastectomy is probably less than 1%. These are people who are under tremendous stress (cancer phobic) because they maybe nursed their mother for a few years and watched her die of breast cancer. They cannot even think about taking any risk, and removing a tissue at risk is a great relief to them. Again, it requires a tremendous counseling before coming to that decision. The surgeons of the world do not do this lightly. In response to your third question, you may be pleased to know that the third world is not subject to the patents. Patents are usually not filed in India, China, in places where there are no markets to the industrialized countries, so they are not restricted from violating those patents because they are not under patent laws. They do have to create the drugs in their countries, I think. I do know that Myriad files patents because we need to. It may shock you, but we have lost over $30 million to develop the breast cancer test. We hope that in this fifth year of testing we will about break even. We could not invest that much if we didn't have patents to protect this, and recover the development costs. It is necessary to have patents. We patent in the U.S., Japan, Canada, Australia, and Europe, so the patent problems in the third world does not exist.

Macer: What do you do in your company regarding the consent requirements for tissue or samples for further genetic research? Because you said you used the public database, but I imagine you are also taking samples for research and how do you get the consent after using a sample for one test and storing the sample, then do you have a consent form allowing its use in further research.

Skolnick: All of our access to human subjects to date has been done through the University of Utah where there is the Inter-mountain Health Care System which is a hospital. They have Institutional Review Boards, and they follow all the procedures that all geneticists around the world use for consent. Some consents are broader, where some are narrower to specific studies. So every patient is consented through the University of Utah or Inter-mountain Health Care.

Macer: Yes but the consent requirements are different in different places, so I wondered what particularly did the University of Utah use.

Skolnick: Well those have changed every two or three years. The awareness of the need to make consent more rigorous is constantly changing. Basically the guidelines are established in the U.S. by the Center for Human Genome Research. These are pretty much dictated and followed down to the specific research. I can send you the consent forms if you want.

Wertz: How much do the tests cost, at present? When will they be affordable and useful in the third world? Is anybody developing BRCA testing in the third world without a patent and at an affordable rate?

Skolnick: The tests cost for a full sequence of 35 thousand bases are $2500. That sounds like a lot but by calculation it has been shown that the number of years added to your life by having the test is similar to cessation of smoking or taking a hyper-tension medicine. This study was published in New England Journal of Medicine, not by Myriad. If you divide US$2500 by the thousand days of life you add to a person, it's costing you $2.50 a day, the cost of a Big Mac, to have your mother, your sister, your daughter undergo BRCA1 or BRCA2 testing. So it's expensive because it's a very expensive procedure, and it's not getting cheaper. It is even more expensive if not done by this automated procedure. It's not a question of patenting; it's expensive to study 35 thousand bases. Nobody in any research group has been able to offer it cheaper. Regarding the question about the third world, the third world's problem is not BRCA1 or BRCA2 testing. It's getting specific research done to address the diseases there. While you could save thousands of lives through that testing, it's trivial, which if you excuse me as I hate to say this when talking of humans lives, but compared with the tens of millions of lives that die from cholera, or diarrhea or malaria, and the things that do need to be addressed in the third world.

Wertz: Is the three years of additional life is based on having prophylactic double masectomy?

Skolnick: I do not believe that is correct.

Wertz: It is whatever decision you make after the test?

Skolnick: Yes, if you just know the test you save. If a young woman takes oral contraceptives for 6 years, has her family, then when she's done producing her children, have her ovaries removed and goes on tamoxifen she still has a high rate. That's not a small regime, but these genes have 92% life-time incidence of having breast or ovarian cancer. Ovarian cancer is 85% lethal. When ovaries are removed, 28% of them have been shown to harbor a tumor. These tumors are not detected without removing the ovaries and they kill the woman. So taking tamoxifen which lots of women do, having their ovaries removed through a hysterectomy at menopause, saves your life. This is not a mastectomy.

Wertz: What percent of women who have the tests are going through this regime?

Skolnick: I do not know that. The prescription that I showed is now coming out and being taught at the American Society of Clinical Oncology, and is becoming a standard of practice. Because it is a relatively low rate of intervention. Mastectomy is not part of the intervention scheme. There are issues for some women when they are having their first tumor removed, whether they should have a contralateral mastectomy, which is having the other breast removed since they are having their other breast removed for a tumour removal. But even that is a minor issue. Breast cancer is even a minor issue. It is ovarian cancer that is the big issue for these genes.

Vogel: In principle I share your optimism regarding the attitudes of the general population towards the challenge of the genetic age. However I wish to make two important additional points. The first one is that based on my experience in the German population, it is always a severe psychological problem to talk about the risks with the people involved. Because some want to hear something, or those who don't want to hear something. It is always a very important psychological challenge to the geneticists, especially for the medical geneticists. This means that your system can only work in cooperation with excellent medical geneticists, who are on the one hand informed on the recent progress of the science, and on the other side are actually able to communicate this message to the people. I would also say there are very useful roles that might be played by self-help groups. Groups of infected individuals who can help one another in accepting and working with these risks. This is a very important group in the general public. The second point I want to make is on priorities in the third world. A couple of years ago I gave a lecture in a human genetics congress in India, where I said that the primary challenge for scientists in third world countries should be different from the primary challenges in Western countries. Some of these scientists thought that I was suggesting a problem of lower scientific value, a typical arrogant attitude of a Westerner, however this is certainly not the case, but the contrary. The problems you mentioned were in connection with infectious diseases. I only wish to add leprosy, where very strong genetic components are involved. This is a very important priority. As to patenting we could discuss many hours, and in principle I agree with you that patents are necessary, but I would restrict the area of patenting in some cases much more than you as a representative of an industrial company would do.

Skolnick: I agree with you, and will just make one more final comment. Remember that if BRCA1 or BRCA2 testing becomes cheap enough, and easy enough that a lab wants to set it up in India or in China or in Africa, they can do it. There are no patents to stop them.

Sugano: Thank you very much I would like to close the session and thank all the speakers.


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