Select Committee on Science and Technology Minutes of Evidence

Examination of Witness (Questions 1 - 19)




  1. Professor Bobrow, welcome to the Science and Technology Select Committee. Thank you for giving up your time to be with us this afternoon to help us in an inquiry we are just starting into genetics and the insurance industry. I wonder if I could ask you, to start our proceedings, we have your CV in front of us and we know a lot about you, but I would like your CV to be partially written into the record, so I wonder if you would be so kind as to tell us about yourself: the expertise you have; the position you currently hold; and the work you are doing on genetics? I would be most grateful.

  (Professor Bobrow) I am a medical geneticist, by trade. I have been a medical geneticist, that is, I have worked at the interface of genetics and clinical application, since the mid 1960s, before the profession was invented, virtually. Initially, I worked at a Medical Research Council unit, devoted to things of this sort, in Oxford, subsequently became Professor of Human Genetics in Amsterdam, and then Professor of Paediatric Research at Guys, and although that name Paediatric Research is correct, actually it was a Department of Genetics. I have been for about five years Professor of Medical Genetics in Cambridge. I have had a general interest in matters of medical genetics and how genetics affect patients, therefore, for a long time. I have also had a reasonably long-standing interest in issues of genetics, ethics and public policy, have been a member of the Human Genetics Advisory Committee, of the Clothier Committee, the Gene Therapy Advisory Committee, the Nuffield Council on Bioethics, and probably something else.

  2. That is very impressive, and thank you very much. It gets us off to a good start. In your present position at Cambridge, do you have a team that undertakes any genetic research, and, if so, what is that team doing?
  (Professor Bobrow) I am head of a small department, which has within it other, independent colleagues of mine, who conduct research into the genetics of a variety of inherited diseases, which include Huntington's chorea, polycystic kidney disease, diabetes and various other neurological diseases.

  3. This Committee, in the last Parliament, did look at this subject of human genetics, as you may well be aware; I was not Chairman at that time, nor, in fact, was I on the Committee, but Dr Williams and Dr Jones were, and they reported in 1995. For all our benefits but also for the benefit of Dr Williams and Dr Jones, who probably need a bit of updating since 1995, can you tell us what the important developments and important work has been, in the last five or six years, in genetics?
  (Professor Bobrow) The headline of the last five years is that the sequence of the human genome is now essentially available on the Internet; there is still tidying work to be done, but the great bulk of that is there. That means that the groundwork for identifying those parts of the human genetic sequence which are responsible for variation between people will be unravelled, I am not sure how soon but it will be unravelled. Part of that variation is the genetic variation that will underlie many of the important differences in health and health outlook between people.

  4. Finally, before we go to Dr Gibson, would you say the developments in the last five years have been, in reality, greater and faster than you might have thought, if you were in 1990 looking forward? If, in 1990, I had asked you to predict what might happen between 1995 and 2000, has more happened than you might have thought?
  (Professor Bobrow) May I answer that in two different directions. Scientifically, I think that is undoubtedly the case. The speed with which technical developments, particularly in relation to sequencing but also other developments, have occurred has been, I think, very rapid, and that is easy to document. I think that the speed with which our knowledge of health effects has accrued has not been particularly rapid. If anything, I would say that it is roughly what I would have expected, which is very little, and I was very much at the pessimistic end of the market ten years ago.

  Chairman: Thank you very much indeed.

Dr Gibson

  5. I believe there are something like ten tests for seven sentinel conditions; could you say, just briefly, what these tests are for and then perhaps follow it up with a statement to explain to the Committee, where it says: "Genetic tests are very good at distinguishing those who carry a particular gene from those who do not. ... They are not at all good at predicting when the disease will start, how rapidly it will progress, and thus when death will occur." I would like you, if you could, just to take time to elaborate on that: the tests first, please?
  (Professor Bobrow) Clearly I am not prepared precisely to describe the tests that are in the ABI's policy document, but there are seven conditions, which include two that I have mentioned: Huntington's disease, polycystic kidney disease, a number of nerve and muscle degenerative disorders, one of the breast cancer genes, from memory. These are all conditions which are well recognised in the genetic clinic, that is, they are undoubtedly inherited conditions. The genes which, when disrupted, lead to these conditions are well known, and there are tests which are used in the clinic in order to distinguish people within a family who are, and are not, at risk of getting the disease because they have, or have not, inherited the gene. Some of the tests are technically more straightforward than others, but I do not actually think that the technical capabilities of the tests are particularly contentious, they are matters of record. The point at which I depart from the interpretations that have been made by others is that, in studying a genetic effect within a family, the question in general is, you know that, to take an example, Huntington's disease is caused by a specific kind of genetic change, and if you look for that change in individuals who are at risk you either do see it or you do not see it, and with a little bit of grey area in the middle, and there is a bit of grey area, but with a little bit of grey area in the middle, you are not left in doubt as to whether they do or do not have the gene. So, for the purposes of having a medical counselling interview, that one takes one a lot further forward. However, within the group of people who have the gene, some will get the disease, to take extremes, in childhood, and others, it is becoming increasingly recognised, will not get the disease at all until they are very old, and some, inevitably, will die of other things before they get the disease, and, therefore, although they have the genetic change, may reach a healthy age without it ever manifesting. Some of that variation, in the particular case of Huntington's, can be accounted for by differences in the precise nature of the genetic change, but even within individual classes of genetic change, which are otherwise indistinguishable to our techniques, there are variations in age of onset, of ten, 15, 20 years, between people who genetically look identical, and we do not understand the basis of that variation. But they still have a medical problem, they are still at high risk of getting the disease, but, in terms of a time-limited prognostic indicator, there is a considerable amount of ambiguity.

  6. Thank you very much. And if I can follow that up, the other tests that are coming on line, as it were, are there any predictions you can make about when they will come on line, when they might be used? And what do you think about the multifactorial conditions, like heart disease, for example, where there are, obviously, many genes involved; are the insurance companies ever going to be able to use that information, utilise it, in any predictive way?
  (Professor Bobrow) For most of the relatively simple inherited conditions, the things we call Mendelian conditions, of which there are several hundred, these seven are just exemplars, there are already tests of greater or lesser precision. If one takes the specific problem that we were discussing a few moments ago, of whether tests will be developed that will allow us to pick out speed of progression and time of onset of disease, I would have to say that it is not obvious to me, now, how and when we will learn about those things, nor even that that variation is genetic. I suspect much of it is not. On your second question, of the more complex disorders, which are more common, which most of us, in the end, meet during our journey and which are not inherited in a simple way, I think the jury is out. There is a very, very active research field attempting to identify genetic factors that contribute to diabetes and hypertension and rheumatoid arthritis and asthma, and pretty well anything else you can think of, and some genetic associations are being identified. But it is quite unclear at the moment whether these will lead to individual tests or groups of tests that will, between them, have a high predictive power, that they will really pick out people whose risk is very seriously elevated above the population risk, as opposed to being, say, two or three times above population risk; which is not, in my view, good enough, because if things are rare then two or three times a small number is still a small number. And when you are dealing with things like breast cancer, where the actual risk is not that uncommon, nevertheless, differences of two- or three-fold, we know they exist within the normal population, for all sorts of reasons, it does not lead to this hundreds of fold difference in risk that you get with the simply inherited conditions; and I am pessimistic that it will get there soon.

Dr Williams

  7. Can I come in with just a brief one? You are speaking with great restraint and accuracy in what you tell us, but are there other clinical geneticists out there that believe that the blueprint will be more predictive than that, or in certain instances, like in Huntington's or some of the genetic defects, where maybe in five or ten years' time, from just the blueprint itself, we will be able to say a good deal more, or are there some enthusiasts in the field that think there is more information here than you are telling us?
  (Professor Bobrow) Of course, there is always a spectrum of opinion. I think, if we take the specific question you asked me, which is whether there are people who believe that we will have tests that will predict time of onset and rate of progression of Huntington's disease, I do not know any such people, nor do I know of any scientific work that leads us to believe that we are seriously going to crack that problem. Every scientist believes that every problem will be solved, so I am not going to say never, but there is nothing on the horizon, at this stage, in my view.

Dr Gibson

  8. And you would not really think that the insurance companies can predict epistatic effects between genes, we are a long, long way from understanding that, we have never really understood the phenomenon, although it has been around for years, the interaction of genes and different chromosomes, for example? So they are nowhere near that, they are millions of years away from it, would you say?
  (Professor Bobrow) Millions of years is not the kind of thing that falls naturally from my lips; it is not easy to see it happening. And, even if leads emerge, I think one of the things that one needs to keep in mind is that finding genes that have influence is a first step; demonstrating quantitatively how large that influence is really requires studying people with those genes over a reasonable period of time in order to draw sound conclusions. So I do not think there can be any doubt that the horizon between now and the time one could have a validated, verified test that predicted the sort of the thing we are discussing must be certainly decades away.


  9. Just before we go to Dr Jones, Professor Bobrow, you did say, very early on, that, even if there is a gene that is likely to lead to some disease, you cannot be sure whether the person will get that disease in their childhood, in their middle life, or indeed not at all. To what extent then is it valid, and this is a qualitative question I am asking you, for insurance companies to use genetic information at all, in setting premiums, if scientists have no idea at all when this gene is going to kick in with its trouble, how can insurance companies say that someone should have a loaded premium, just because they have this particular gene?
  (Professor Bobrow) Can I go back and clarify something, because I have clearly left somewhat of an overstatement in the air. Some genetic conditions clearly manifest in childhood, pretty well always, and if I gave the impression that there was no idea of when things would start to have effects, that was not quite accurate. For those that start in adulthood, there is, in general, a relatively wide range of age of onset. The particular example that I was discussing of Huntington's, which is obviously a prime example, can have onset very early and very late, although those are the extremes; but, in general, it is a disease with onset about 40, plus or minus 15 years, and it is within that average range, of 40 plus/minus 15 years, that we do not know where to start or where to begin.

  10. So that was when you were talking about Huntington's?
  (Professor Bobrow) Yes.

  11. And, unfortunately, I generalised it across a lot of things; forgive me for doing that. If we go back to other genetic diseases, not Huntington's, for any one genetic disease, have you got a spread of age onset for that disease, plus or minus ten years, or so, which may be different, some may start at 25, plus or minus ten, others at 45, plus or minus ten; is that roughly the situation?
  (Professor Bobrow) There is general information on ages of onset; in general, the younger the age of onset the tighter the distribution, so that conditions which are obviously not germane to an insurance discussion, such as muscular dystrophy, the classical type, always has a childhood onset, give or take a few years. The older the average age of onset the more the variation. Most of the conditions, as I recall it, from that list, are young adult to middle-age type of onset, because those are the things that are the most germane to insurance discussions, and they all do have a spread of ages of onset, to a greater or lesser extent.

Dr Gibson

  12. Would it be even more complex if different mutations ended up with the same disease, for example, in sickle-cell, you have different mutations, different parts of the gene; is that true in these genetic situations you are talking about? You say a single gene, but are they indeed single genes or are they multiple mutations within the gene?
  (Professor Bobrow) They vary. For some of the gene loci, the changes, the mutations that cause disease, are quite variable, and they are one of the components that probably make it more severe in some people than others. For other conditions, the gene change seems to be fairly uniform, and there are other, as yet unknown, factors that influence progression.

  13. Does it relate to geography as well? You know how there is always this argument that certain groups of people have one mutation, others do not, so it would vary between different parts of this country, for example, there might be geographical variations in the mutations, whereas the insurance companies treat them all the same?
  (Professor Bobrow) To the best of my knowledge, within the limited group of Mendelian disorders, the really genetic disorders, that are in the ABI's current policy document, that is probably not so; they are probably not very sensitive to that kind of geographic variation. Getting into the more complex, multifactorial disorders, I would bet on it that you are right.

Dr Jones

  14. Just one quick point on that. Wellcome Trust, in their evidence, said that there were occasions when somebody who had got the genotype which was predictive for a particular condition did not actually develop that condition, and would you concur with that as well, even in Huntington's, for example?
  (Professor Bobrow) Yes. It is very well documented that, at one end of the range of Huntington's mutations, there are about 3, 4, 5 per cent of people who carry genes that clearly are abnormal, by current definitions, but they have not manifested the disease by age 70, or 75, something of that nature.

  15. As you know, because you were a member of the Human Genetics Advisory Commission, they recommended that there should be at least a two years' moratorium on the use of genetic tests. Could you explain the basis for that recommendation; and, also, why do you think the Government did not accept it?
  (Professor Bobrow) Clearly, I cannot speak for the disbanded HGAC. My personal understanding of the—

  16. Why can you not, you were a member of it?
  (Professor Bobrow) I was a member, but it is a body that is long gone and other people may have had different reasons for reaching a common conclusion.

  17. You must have discussed it amongst yourselves?
  (Professor Bobrow) We recommended a moratorium, and the arguments that persuaded me, and I suspect most others, that that was a good idea were that we felt that there were two things that weighed; one of which was a dearth of evidence, of actuarial genetic evidence, if I can use that, that would allow insurance companies to take well-founded decisions that were based on fact, that could be made transparent and that people would, therefore, presumably, feel more comfortable with. And the gathering of that evidence was going to take some time, two years was probably an underestimate, and it seemed to us reasonable that the tests should not be used until such time as the evidence had been accrued. Secondly, we were aware of the fact that there was already extant practice in the field, and it seemed to me that—

  18. So there was what practice?
  (Professor Bobrow) There was practice in the field, people were already asking for these tests. And it seemed a good idea, if one was moving from people doing what they thought they would like to do, to people having an agreed policy that would be implemented under some form of open regulation, to draw a line, stop the past and start the future again. And I think those were the two arguments that weighed in favour of a moratorium. As to why that did not appeal to Government, I fear that I have no insight, that I am prepared to speak about.

  19. You said in your memorandum that you remain to be convinced that insurance companies will use genetic information reasonably. Is that still your view, and, if so, why do you say that statutory regulation is undesirable in principle, even though you say it is probably unavoidable in practice?
  (Professor Bobrow) I have been having this discussion in various places for really a good number of years now. It seemed to me, possibly ten or 15 years ago, ten years ago, that the simple inherited diseases that we are looking at today are an area in which people who are pretty seriously disadvantaged do not need more trouble in their lives; and trying to load insurance issues on top of their medical issues could only be justified if the evidence was really clear and if the financial implications were significant. And I would have to say that I have been grievously disappointed at my complete inability to have any dialogue on these issues with most people from the insurance industry. That is one thing. The second thing is, I think that having agreed to the establishment of the Genetics and Advisory Committee, which was to look at, validate and agree a basis for using genetic tests, for the ABI to continue recommending that these tests should remain in use until they were declared invalid, rather than the reverse, I thought was an irrational and unfriendly way to come to the table over a difficult issue. Thirdly, there is a particularly difficult matter over insurance companies' very long-established practice of asking about family history, and it is one that has not come up a lot in the conversation so far.

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