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16 years have passed since this interview, and during this time there been many changes in the world, in the field of hematology, and in my career as a hematologist.
Few would argue that the world has not become a more dangerous place since 1991. In my view the principal factor in bringing about this lamentable state of affairs has been religion, particularly extremist religion. However, the line between what we might designate "extremism" in religion and "mainline" is difficult to establish, and it is distressing to me to note how candidates in the current campaign for the Presidency of the United States pander to the religious right, and how each candidate seems to vie with the others in trying to establish their own closeness to God.
Hematology itself, like every field of science has suffered from changes in the world scene. Funding has become a major problem, even though the NIH budget has grown enormously in the past 16 years. In the 1991 interview I pointed out that spurts of funding followed by times in which funding did not grow was bound to create major problems, and this is, indeed, what has happened. It is increasingly difficult for young medical scientists to launch an independent career. The average age at which an M.D. scientist obtains his or her first RO1 grant is 43. No wonder that our young scientists become discouraged about a career in medical science. In the 1991 interview I pointed out that politically driven focus on certain areas such as AIDS or sickle cell disease had a serious negative consequences. Not surprisingly, this trend has continued. Often it is driven by talented and persuasive members of our own scientific community who "hype" their own areas of interest. The leadership of the NIH can apparently be convinced that areas that have dubious scientific merit are at the vanguard of science and need massive infusions of funds. Unfortunately, total funding is not increased, and these funds come at the expense of meritorious investigator-initiated research. An example is the current interest and massive funding for "personalized medicine" based upon genetic polymorphisms. My view is that while some small advances will result from this approach, they will not justify the diversion of resources that is taking place. The reason is a fundamental statistical one. When a large number of polymorphisms is examined the binomial distribution dictates that there will be many polymorphisms in which the frequency differs in the disease population when compared with the normal population. This can be taken into account by correcting for multiple comparisons, and when the number of comparisons is very large -- and the number will be between 100,000 and 500,000 in the case of whole genome scanning -- most true differences will be lost in the forest of random variation. The only ones that will survive scrutiny are the ones that are very large differences; these are the only ones that will be detected by gene scanning techniques. This major consideration does not even take into account the perturbing affect of population stratification, and efforts to correct for such stratification decrease the statistical power further.
My own interest in this area of research has developed from our own studies in which we have tried to better understand the variation in the phenotypes of patients with "single gene" diseases. As we have performed these studies I have become increasingly aware of the difficulties in identifying modifying genes, and have increasingly come to the belief that the effect of the genome as a whole on the phenotype is considerably less than I had assumed two decades ago. Instead, I believe that epigenetic modification probably plays a much larger role in determining disease phenotypes than has been generally recognized.
In my 1991 interview I pointed out that the involvement of past presidents of ASH with the society tended to be minor as new leadership emerged. This seemed quite appropriate to me, but somewhat unexpectedly my involvement with our society has increased in the past decade. I became a member of the Committee on Investments and Audit some years ago and some five years ago was asked to serve as its chairman. As a chairman of a standing committee I was privileged to become more active in the affairs of ASH and to attend the annual retreat. This allowed me to become better acquainted with the current generation of leaders of our society. The society itself has grown enormously and has been very successful. One major change in ASH has been the increased participation of foreign members. At the time that I was active in the leadership of our society for membership was deliberately restricted to eminent hematologists from other continents. Subsequently, the leadership of the society decided that there should be no barrier to hematologists from abroad joining our society. In effect this has transformed ASH into an International Society; there are now more participants from abroad in the annual meeting than from the US, Canada, and Mexico. While a large society may be a stronger society, size also has the disadvantage that it is more difficult to encounter colleagues from one's own hematologic community in a meeting with 20,000 attendees. In recent years the society has generously recognized the research work of my group by asking me to present the Don Thomas lecture in 2003 and by awarding me the inaugural Coulter award for Lifetime Achievement in Hematology this year.
In my 1991 interview I stressed the value of combining hands-on clinical activities with laboratory research. I still hold that view, but I also believe that the responsibility inherent in delivering health care is so great that there is an age at which one should probably no longer take on this burden, both from the point of view of the patient and the physician. I kept postponing my own decision in this regard, but finally decided that after I reached the age of 70 I should no longer see patients. My laboratory studies, however, have continued to the present time. They have taken an interesting turn, in that the major topic of my research is one that occupied me 50 years ago, viz. iron metabolism. There seems to me to be definite advantages to working in an area of science, leaving that area either because of a lack of innovative ideas or because the techniques that are needed to push ahead with the science are not available. Our work with the regulation of iron homeostasis is a good example of this principle. In the late 1950s and early 1960s we attempted to understand how the body regulated its iron content, but it became clear that the system was too complex for us to unravel with the tools at hand, and I abandoned this area of research for some 40 years. The development of molecular techniques that allowed one to clone positionally gene producing diseases made it seem to me that the time had arrived at which it might be possible to find the gene that caused hereditary hemochromatosis. We therefore embarked on an unsuccessful attempt to find this gene. But others were more successful and so the gene for hereditary hemochromatosis, designated HFE was identified. This has opened the way for us to carry out extensive epidemiologic studies, which overturned the conventional wisdom that hemochromatosis, as a disease, was very common. The disease is actually quite rare; it is the genotype that is common. This is one of several projects which, as noted above, have stimulated my interest in the dissociation between genotype and phenotype, and which is taught me that it is unlikely that a major portion of the variation of phenotype is, in point of fact, due to variation in other parts of the genome. There is a distinct advantage to returning to the field in which one has worked previously. The older literature, almost completely ignored by an unknown to my younger colleagues in the area research contains many valid pearls that can and should influence our interpretation of the more modern data. Although our ability to search the literature has been greatly expanded by computerization, and the some of the older literature has come "online", the pearls are often difficult to find, and I've found that my earlier experience in the field has sometimes been invaluable.
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©2008 Columbia University
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