pp. 165-171 in Intractable Neurological Disorders, Human Genome Research and Society. Proceedings of the Third International Bioethics Seminar in Fukui, 19-21 November, 1993.

Editors: Norio Fujiki, M.D. & Darryl R.J. Macer, Ph.D.

Copyright 1994, Eubios Ethics Institute All commercial rights reserved. This publication may be reproduced for limited educational or academic use, however please enquire with Eubios Ethics Institute.

Prevention and Therapy - Discussion

Takaku: Good afternoon, ladies and gentlemen. We would like to start session four, on prevention and therapy. Dr Platt and myself are chairing this session. Our first paper was from Prof. Kinoshita on the home nursing treatment of patients with incurable diseases. Thank you. I am afraid that there is no time for discussion now. Our next paper is on the legal aspects of treatment for disabled newborn babies. Thank you Dr Ienaga. Are there any questions or comments? Is it the case that this kind of legal case has not been a problem in the past?

Ienaga: Up to now this has not been taken to the courts. However, I talked to the members of some bioethical committees, and they said that they sometimes had to make very difficult decisions like these cases. I've also heard from some doctors that in the case of a severely handicapped child being born they allow this child to suffocate. But the Japanese Medical Association won't put that this is allowed in its guidelines.

Shoji: I'd like to talk about your final summing up of these four cases. In particular what I was interested in was this question of the patients and the authority of the courts and how these two interacted with one another. In C and J cases the courts seemed to be leaving the decision up to the doctor's discretion. But in this case how is this treated by the British Medical Association. What kind of criteria have been indicated to doctors, can you give us a slightly more detailed explanation of this problem?

Ienaga: In the 1960s there was nothing written in the BMA handbook on such severely handicapped newborn babies, but in the 1979 handbook it was written that the final treatment decision for severely handicapped children should be left to the parents. I don't think that Down's syndrome can be included under this clause. After this another two legal cases occurred, and maybe as a result of these, when in 1984 a new handbook was published, the clause on the parent's final right of decision was deleted. Rather it said the doctors should decide based on the parent's decision. It was thought to be undesirable for the parents to have made this decision to kill the child , so the form suggests the doctor makes the final decision. One reason for this change I think was that Dr Arthur had been indicted after being reported by someone within his hospital, and it was felt that it wasn't suitable that third parties should be involved in indictments in this kind of case. In these cases, which happened afterwards also, the local authority brought this case to court. Actually according to the newspapers the case was brought to court upon the initiative of an individual inside the local authority who had a Down's syndrome baby themselves, and who felt that what had been decided was wrong. In England one of the features is that a lot is left to the discretion and authority of the doctor, especially when we compare to the situation in the USA.

Takaku: Thank you, we must move on to the next paper, by Dr Nakanishi on the development of new strategies for gene therapy. Thank you Prof. Nakanishi, I am sorry that we have no time for questions now. We will take a coffee break now so please ask him personally.

Platt: Our next paper is by Prof. Yagi, speaking on the subject of gene therapy by means of liposomes. Thank you, I am afraid we are running behind schedule, so our next paper is by Prof. Wikler of the University of Wisconsin. We have some time for questions.

Cook-Deegan: I wanted to ask one question to find out if there is a possible distinction here. In the case of bipolar disorder, manic depression, it sounds like one of the reasons for doing this is that the patients have come back to their clinicians and said that "now that I'm myself again I would like to be kept from going into these peaks where I have uncontrollable behaviour". That essentially suggests that there's more of a Ulyssee's kind of situation, than in the case where you've got a continuous decline where it's not crystal clear what the nature of the self is at the moment. When you've got a periodic change that would be applicable for alcoholism and substance abuse, it is a different situation to dementia, where it is hard to argue, I think, that the person in 1993 would be able to say what their preferences would be in the year 2000, given that they're going to be a completely different person.

Wikler: Yes, that is a very important and profound point. Well, firstly with respect to the more ordinary psychiatric case, the cyclical nature of the ups and downs does suggest that there is a resting point at the trough at the bottom of the curves that represents the actual patient, and what the actual patient would really want. But not all patients do represent such cycles, so it is sometimes hard for the clinician to seize upon one mental state of the patient and say this is the real patient and the other one is his diseased self. So there is a certain amount of arbitrariness in the selection of moments at which you allow a patient to execute something as powerful as a waiver of one of there fundamental civil liberties, and this has been raised by the civil libertarians who opposed our prediction. I think this is one of their most important objections, though I would hate to see that deprive these patients of the possibility of using these directives.

Now with respect to the Alzheimer's cases you mentioned, it is quite right that during a long decline it is hard to pinpoint any one point and say this is really them. And furthermore, almost certainly their preferences will change. But we can say a couple of things in response to that. One is that if it becomes possible to tell a 25 year old that they are at increased risk of developing Alzheimer's 30 years later, there is going to be a window of 10-20 years in which I assume there will be no hint of any symptoms whatsoever for this disease. So we can say that whatever a patient would want during that window of normality does represent the choices of a normal mature healthy individual, and to that extent we are in a more familiar position with respect to Alzheimer's than we would be with respect to manic depression, where it is so hard to find a patient at a resting place where we can say that this is the normal self. This also, however, points us to this paradox, where we are imagining the early self pitted against the latter self, because the more distant in time the execution of the advance directive and the disease, the more you have the younger person dictating to the older person what will happen to them. In a way, as Dr Cook-Deegan just said, this would not match the preferences of that person if normal at that time. The reason I think this is a profound philosophical question is that it raises the question of the unity of the self over time, and the extent to which we literally think that a person at 20 is the same individual as the person as 70, and therefore is in a position where they should be able to make decisions about the later self. My guess is that 20 year olds would welcome that power, but 70 year olds would regret it. Do we have one person here or two?

Bodurtha: Given what we have learned over these days of cultural differences, and not taking a strictly legal perspective, could you comment on decision-making and particularly the family role, with regard to definitions of self and time, and the degenerative neurological disorders.

Wikler: I would if I could, but would you like to. You seem to have something in mind so would you like to elaborate?

Bodurtha: I guess I'm struck with this mental playground in Fukui, how much that our legal and liability constraints in the United States frame how we do things. So that in my own involvement with my hospital ethics committee, frequently do we not only have lawyers on the committee, but certainly we ask the questions as you have done about where the person was when they signed or didn't sign the document. We have an array in Virginia of who is next in line in terms of making decisions around the last moments of life. I would at least speculate that, with all of the very nice talks that we've heard about folks with intractable neurological diseases, that there might be cultural contexts in which surrogate decision makers are not just a legal construct, as we have in the United States, where you can turn to legislation to say this is the next person, or use the verbal power of attorney. But there are cultural contexts in which people might turn to different family members in the situation that you describe, and do you feel better or worse about that?

Wikler: Well, that helps. There are certainly two features of this proposal, which in the context of your remarks, probably are pretty American. One is that this is a way to keep the family out of decisions, at least in the case of the advance directives that specify what treatment a patient should get. This is supposed to take priority over what a family may be saying. So the doctor, psychiatrist or neurologist who is treating the patient may be hearing the family through this ear, while reading the chart in which there is a letter from the patient when young saying "If I develop Alzheimers, as has been predicted for me," here is what should happen. The patient will have written that "I want this letter to apply as I first begin the descent into dementia". And these may be in conflict. Now in a different kind of society the family may take over decision-making much earlier than we would let them do in the United States. So the applicability of this directive might not seem so apparent. And the other thing is that in the United States the trend in law, that I am sure virtually everyone here knows, has been to give individuals a tremendous amount of freedom in decision-making in medicine, and this instrument is designed to bolster that still more. It says that the rights of decision making that patients now have when they are competent, should be extended into the period after they become incompetent, and according to this proposal, even during the period in which they are in transition. In other cultures where the individual may be considered only one part of the picture instead of 98% of the picture, as it is in the United States, the idea of bolstering that power still more through a proposal like this might not seem particularly wise.

Takaku: Thank you, so now our chairman, Dr Platt, from the Institute of Genomic Research will make his comments. Thank you, now we will have the paper of Dr Nishimi, that was originally scheduled for the final session on Future Directions in International Bioethics, but will be presented now. Thank you very much, are there any questions or comments?

Verma: At what stage is this project on human diversity at present?

Nishimi: Perhaps, Prof. McKusick can answer that a little more completely. From the US perspective, the National Science Foundation has committed US$1 million for this coming fiscal year, from October 1993. The project's organisers estimate that it would cost US$20-25 million in total.

Takaku: Thank you very much, now we would like to have some general discussion, and I will transfer the chairmanship to Dr Platt.

Platt: Thank you. I think it is clear from today's presentations that we are today in the biomedical research community faced with a mixture of coping, and caring, and hoping. You have had much food for thought, this is your opportunity to have an open discussion this afternoon.

Billings: I'd like to direct a question to you, Dr Platt. I thought your presentation was quite interesting. In particular, TIGR in terms of its science and its approach to the genome, there are rather clear markers on how you can measure success of its approach as opposed to the NIH or DOE approach. You are in the process of setting up an ELSI programme, and I wonder what the markers of success for that program will be, given that the major criticism of the federal ELSI program has been the deficiency of effective public policy.

Platt: Having myself been in the crucible of biomedical research policy formulation, I am most humbled about the likelihood that I or any one else has the answer to any of the questions. The one thing that I do know, is that a broad exchange of views in an honest manner is the best method to come to consensus positions on issues to which there is convergence of views about what the norm should be or should not be. In this arena it is most likely that we will initially come as a world community to consensus about what should not be done, before we reach agreement about what, in each instance, should be done. But that will be done by broad exchange of views. TIGR hopes that its program will be complementary to, and a resource for, the programs already underway. We hope to bring additional resources, both intellectual and financial resources into this arena, and to perhaps engage the debate in a manner which is a little bit different to some of the other programs to date. The ELSI program until now has been a dramatic accomplishment with very little start up time. It has focused the world, as we said at the outset of this seminar, in a way that has never before happened in a large scale scientific enterprise on the issues that need to be addressed, not only by scientists but also by those who will have to apply the fruits of the scientific labour. We hope to be a responsible partner, that is why we are putting our cards on the table at the beginning. We will publish and will participate, and will work to be an honest collaborator in the world scientific community, that will hopefully be of some worth to others.

Matsunaga: I am sorry I don't know, to which organisation does TIGR belong.

Platt: TIGR is an independent research institution that was established about a year ago. It was funded by venture capital in the United States, that has set up a company that has received an assignment of intellectual property rights from TIGR. Just as a research university in the United States would typically have many partners for developing the output of its research laboratories, here we have one partner by an arrangement negotiated in advance. The idea was that by marshalling the resources together, and this was done by Dr Venter's idea, he could, while maintaining control and autonomy of the scientific idea, make it pure and clean, relative to what he could do by becoming part of a proprietary organisation, and assure that we would be able to move quickly. All indications are that we are moving quickly, it is for others to judge if we are as clean as we would hope to be.

Matsunaga: Where is it located?

Platt: In Gaithersburg, Maryland. I have some information for any one who is interested.

Leavitt: Dr Platt, Dr Nishimi in her talk raised a question of patenting of genetic information, which is a very big question. There are good arguments on both sides. I wanted to ask you whether you could clarify your own views on that subject, because your position would make your views interesting I think.

Platt: First, the sensation that was created by Dr Craig Venter, when he was at the NIH, because he is the named "inventor" on the applications filed by the NIH, is not related to TIGR. Except that if patents were issued, Dr Venter would be the individual who would have the rights, such as they are when you are in the government, to the invention. TIGR's position is independent of that controversy. TIGR as a research organisation has deferred to its commercial partner decisions about whether or not to file for intellectual property rights on TIGR discovery. TIGR's expressed position at the outset, and Dr Venter's, is that conventional patent policy in the United States is the preferred position. There is a great debate, for those of you not familiar with the intricies of the debate in the United States, that Dr Nishimi was eluding to earlier, about the patenting of partial and full sequences with or without established function. Our view on that subject is very clear, we think that it is a diversion to be preoccupied with the temporary status of US patent policy, which is subject to traditional legislative and regulatory developments. We think that in the next few years the debate about patents and intellectual property protection will be submerged, and will become much less important than the issues that are being discussed here today.

Cook-Deegan: I just wanted to follow up that clarification. One of the looming questions, if because of Craig Venter's status, the NIH abandons its patent claim, have you all thought about, given the rights that are in the 1986 Patent Act, would TIGR then step in to claim the patent rights that have been abandoned by the NIH?

Platt: I can tell you those are not TIGR's rights to claim. I can tell you that Dr Venter, after having spent much time with him, is tormented by the diversion that this issue has created. He has not faced the question whether he as an individual would claim, any proprietary matter as an ongoing matter, definitely. This is what one of our earlier commentators eluded to as a grey area.

Cook-Deegan: So what would happen then if NIH abandons its claims, even if Craig claims his personal rights, the agreements are such that this would be brought into the package under the domain of Human Genome Sciences.

Platt: The agreements that TIGR have with its commercial partner, provide for the intellectual property created by Dr Venter and the other scientists at TIGR while at TIGR to be transferred. Therefore I do not mind saying categorically that the prior effort of any of the scientists before they came to TIGR has nothing to do with TIGR, unless they wish to volunteer it. The point is that Dr Venter would like the reputation of himself and his colleagues to be judged ultimately by the quality of the science that he and his colleagues perform, rather than by this lightning rod which may or may not have been the most useful venue in which to air these questions. Though Robyn Nishimi and her colleagues at the Congressional Office of Technology Assessment are putting together a compendium of world views on this subject. I guess that study was elucidated by the creation of this controversy. Maybe Robyn would like to add something to this? We should have some questions for other people.

Osawa: I would like to ask Dr Platt, I don't know whether this question is proper to ask you or not, but one month ago I watched a television program by NHK, treating the theme of the Human Genome Project. In that program there were examples of discrimination by insurance companies towards ladies with a family history of cystic fibrosis and Huntington's disease in the United States. I was very shocked by this story, is there any plan to prevent these practical problems by the work of TIGR.

Platt: What TIGR hopes to do is to help elucidate the discussion. The issue of the use of genetic information being used as a basis for risk classification in the insurance industry, which is a euphorism in many contexts for genetic discrimination, is a subject of great concern to both the life and the health insurance industries. The life insurance industry has a task force working on this subject because they recognise the clear potential for this information to be dramatically misused. There are governmental bodies looking at this subject both at the national and state level. In the area of health insurance Mrs Clinton, as has been alluded to here and in a number of contexts, is very familiar with the subject of genetic discrimination, and the administration in Washington is very concerned that the potential change in health care policy in the United States remove a major impetus for risk classification, which is the availability of health care insurance. This would come from a more universally available health care policy of a basic nature, without regard to pre-existing conditions. The existence of pre-existing conditions is what has driven many people in the United States to be afraid to change jobs or getting a serious chronic illness, and that problem in part is being attempted to be addressed as part of the administration's proposals on health care reform.

Wikler: I don't know if you were referring to the group Alex Capron is chairing. I am a member of it, and I should point out, that the stance of the industry as we're hearing it, is not that they are completely opposed to the use of this information, and they don't regard the use of genetic information as always discrimination. They are concerned about somebody who finds out by a genetic test that there is a high probability that they are going to die young, so if this person has this information protected by privacy law, they could go to an insurer and take out a huge amount of life insurance. This is a very good bet against the insurance company, as they know something the insurance company doesn't know. Now if they do that the insurance company is going to lose money on that person, and the next time around they are going to raise the rates for everybody. So the effect of allowing individuals to keep this information private is to raise the cost of life insurance for the average individual. The insurance companies are very interested in being able to offer the lowest price insurance that they can for the best risks because they will sell more insurance and make more profit, that is their side of it. On a social level we need to ask ourselves, and this group which has been working for a couple of years now, is asking, whether we think that the person who gets this information and has an advantageous position, if you want to think of it like that, vis-a-vis the insurance company, do we really want to give them that policy advantage, and the corresponding disadvantage to the average person who doesn't know what risks they have. It's not a question which has an obvious answer.

Platt: Thank you, surely there are other areas of interest.

Billings: I wanted to ask Dr Nishimi a question. I thought your discussion of the diversity project was the best that I have heard so far. I wondered whether you could envision what characteristics a population would have that would not benefit, and should not participate in such a project should be. One could envision that simple participation in the diversity project might increase the stigmatisation of a politically undesirable subpopulation within a particular country or local. I wonder whether there might be other kinds of groups, or characteristics of groups, that one could envision, that would make it undesirable to participate?

Nishimi: I think that there are several things that might make it undesirable for a group to participate. Including the issue I mentioned about commercialisation of any population cell line, if in fact that population did not benefit, financially or health wise for example, from that I did not mean to indicate that there were no benefits or risks.

Matsunaga: Since the chairman is a lawyer I'd like to ask what genetic discrimination means. I personally think that discrimination in ethical terms should only apply if it is concerned with human dignity and human basic rights, but how about different treatment according to phenotype or clinical symptoms, I don't think it is discrimination. Genetic discrimination is discrimination with respect to genotype not phenotype, is that right?

Platt: I do not believe that any legal system that I am aware of has developed a definitive answer to this. What I think of when I hear the term is a categorisation for regulatory or some type of punitive purpose, in a prejorative sense, attached to someone's genetic characteristics. In that context, you heard from Michael Yesley this morning a superb examination of the problem of behavioural genetics. I was involved in that discussion about what to do, and the question was, even assuming that one could posit that there was a gene marker that might be said to predispose certain individuals to a higher tendency of aggression, is it fair, ethical, or even remotely scientifically valid, in the view of many, to say that because that point might be true, that therefore you can conclude that the person is predisposed to criminal behaviour. In many contexts and situations aggression is a positive attribute, and it is the degradation of science, that I think of in one context, where there is discrimination based on the applications of scientific information. The second is when information is used for purposes for which it was never intended. For example, I think every society represented within this room, will be faced within two decades, if not earlier, with the question of whether their legal and police system should have a DNA identifier as a human marker for individuals. Who should have access to this data? Discrimination based on individual characteristics could readily result from the availability of that information. That is a very long answer, I don't know whether I have answered your question.

Matsunaga: As a human geneticist, I think that criminal behaviour is determined largely by social factors. A little may be genetic, but the most decisive is environmental factors, so first you have to remove bad environmental conditions.

Takebe: I want to go back to the insurance issue raised by Dr's Osawa and Wikler. If the risk is concerned with Mendelian characters, it may be always be dealing with minorities, but if you consider common diseases like those discussed by Prof. Kondo and others this morning, I think that there may be the order of 10-20% of the total public for each disease. I wonder if the committee mentioned by Prof. Wikler, chaired by Capron, may support the higher premiums for that type of background.

Wikler: Well, the group is at least a year away from reaching any conclusions, so I couldn't make any prediction. The situation with regard to life insurance might be different for people who are interested in very large policies, as opposed to people who are only interested in relatively small amounts, to make sure that their children and surviving spouse, don't have a severely degraded style of living. Now the person who comes in and makes a million dollar bet on their life may seek to deliver a boost to their family's income, because its a better investment than they could make by playing the stock market or any other means, if they have this information. There is no particular consensus that every person should have that right to benefit tremendously at the expense of the insurance company or other people who lack this kind of genetic data. What it requires is for us to have a consensus on whether there should be some sort of social guarantee that your survivors won't be terribly hurt by the loss of your wage earning activity, which is a different thing from that which normally presents itself in very big insurance policies, except for the case of very wealthy individuals.

Lo: I may not have just understood, but it seems to me that you are very confident that the entire feat to sequence 100,000 genes of human beings will probably be in your hands within one to two years from now. Is that correct?

Platt: To be precise, we believe that we will have identified the vast majority of unique human genes by the EST single pass sequencing method within a year.

Lo: If that is the case then, do you think that the NIH or DOE genome project has to be modified? Because if that is going to be accomplished by 2005, but this is going to be one or two years?

Platt: The identification that we are embarked upon, which will be published at the end of 1994 or early 1995 for the benefit of the community with the sequencing data is the beginning of what we believe will be a beginning of at least a generation long project to complete the sequencing and to find the functions of the genes, to find out how they interact, and to find out from gestation through death, how they are expressed in various tissues. And what this means in terms of the biological markers, presymptomatic diagnosis potential, and prevention and therapy of disease. The fact of what I have said has also staggered scientists at each presentation where Dr Venter has made the point, but we have in our databank the data to prove the point of where we are, has lead Dr Francis Collins and his colleagues at the NIH to tell us that they are not very much longer interested in the single pass sequencing of human genes, because we will have finished that project, so they are moving onto full length sequencing, and they are moving onto mapping, and in doing the functional analysis that will yield the payoff that all of us in this room desperately hope will come soon. Rather than it being the end of the project, and we hope that we are right, that within the next few years scientists involved in biology will have the equivalent of what chemists have had in the Periodic table of the elements. This is the beginning rather than the end of the effort.

Lo: Well I certainly think that is good news to everyone here.

Platt: We have another five minutes remaining.

Clarke: Can I go back to the insurance issue again. There are probably people here who know more about the details than I do, but in the Netherlands, I think there is a useful model, where health insurance is in part socialised and in part private, but payments do not depend upon genetic testing. In life insurance, as Dr Wikler was saying, genetic testing is not considered for small and modest levels of insurance, but for unusually large levels of insurance. Then insurance companies have to be given all the information that might be concerned. There might be someone who knows more about the details in Holland than I do.

Takaku: Thank you. I think there is no further discussion, so we would like to finish this session, thank you very much.

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