July 5, 1996
(Dr. Schulman is Director, Genetics & IVF Institute, Fairfax, VA and Professor of Human Genetics, Medical College of Virginia)
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Some years ago, I was invited to join the Cystinosis Foundation and did so with pleasure as a life memeber. Not long thereafter, I was contacted by a very nice person who politely inquired who I was and what was the basis of my interest in the Foundation. It was then that I was reminded of Andy Warhol's widely-quoted quip about how "everyone is famous for 15 minutes."It is a great pleasure to be asked to give an address before this organization, united as all of us are by a common desire to understand and conquer cystinosis. We all know how serious a disease this is, and how extensive and distressing its implications are to its victims and their families.
My thougths are shared from the perspective of a scientist and physician, now aged 54, who devoted about one-third of his professional life to the full-time investigation of cystinosis. For most of the years between 1968 and 1983, I thought about cystinosis almost constantly. I was haunted, as many of you are, by the tragedy of this disease. I gave it everything I had to give. And in 1983, I made the hardest decision of my professional life which involved leaving NIH, turning my laboratory over to the capable hand of my junior associate, Bill Gahl, and re-directing some of my medical efforts into other hopefully productive directions. I felt at that time that I had done what I could do to advance our knowlege of cystinosis, and that major advances would continue to be made by other talented scientists -- especially Jerry Schneider, Jess Thoene, and Bill Gahl, who are well known to you -- along with numerous others all over the world. This hope has been realized. It is hardly necessary to point out to this audience how much progress, especially in the treatment of cystinosis, has been made in the last decade. Much more will be accomplished. My task today is to help you understand how we arrived at the present, to appreciate the terrific efforts that made that progress possible, and to tell the tale, from a personal vantage point, of the history of this evolution.
One hundred years ago, no one had ever heard of cystinosis although countless deaths from this disease undoubtedly occurred back into human pre-history. The first known description of the cystine crystal accumulations which characterize cystinosis was made in 1903, and it was not until the period between approximately 1922-1934 that the work of the European investigators Kaufman, Lignac, Fanconi, De Toni, Debre and others led to the recognition of the clear association between cystine crystal deposition and familial syndrome of renal dysfunction and impaired growth. Even after recognition of this syndrome, we should note that cystinosis was frequently overlooked as a cause of death because pathologists prepared tissue for examination in ways that dissolved way the cystine.
Cystinosis was also confused, as can even happen today, with cystinuria -- a wholly different disease with cystine crystals appearing in the urine, not the kidney. Indeed, Archibald Garrod -- the man credited with inventing the name "inborn errors of metabolism" in his famous Croonian lectures before the British Royal College of Physicians & Surgeons -- failed to make this distinction initially.
The recognition by Burki in 1941 that cystinosis could be diagnosed by slit-lamp examination of the eyes was a major advance facilitating reliable diagnosis. In the same year, bone marrow aspiration to identify cystine crystals for diagnosis was also introduced.
By then, World War II had engulfed Europe and then the world. Ladies and gentlemen, research is often a fragile flower which can wilt and die when the enviornment changes. While World War II did accelerate research in areas like nuclear physics and the introduction of the first antibiotics, many other research activities were halted. Almost no meaningful research on cystinosis took place during the War years and for nearly a decade thereafter -- one more sin to add to the massive burden of evil of the madmen and warmongers of that most troubled time.
World War II resulted in the destruction of medical research in continental Europe. England and the surviving major power, America, became the centers of most future research on cystinosis. A notable exception -- only to a degree, because he studied after the War in England before returning to Germany -- was the Heidelberger Horst Bickel whose team wrote an important monograph in 1952, which added considerable information about cystinosis, highlighting its patterns of Mendelian recessive inheritance and also emphasizing the pathological resemblance between cystine accumulations within certain cells and other accumulations in such disorders as Gaucher and Niemann-Pick disease.
In Britain in the 1950s, a number of famous investigators turned their attention to cystinosis research. These included the giants in the emerging field of inborn errors of metabolism, Charles Dent and Harry Harris. Most notable among the British investigators was Des Patrick, who later became a close friend of both myself and Jerry Schneider. In the 1950s and early 1960s, Patrick systematically performed a large number of carefully designed assays of the activity of the enzymes had normal activity in cystinotic organs, and that some apparent alterations in sulfhydrl-containing enzyme activities were secondary effects of cystine accumulation and not the cause of it.
Patrick's work gives the lie to the oft-repeated statement of some scientists that medical journals should not publish "negative studies." His was a classic negative study that freed up the energies of other scientists to study cystinosis from other directions. Patrick made other important contributions to cystinosis research -- including on the lysosomal hypothesis -- that I will mention later.
World War II led directly to the modern era of so-called "big government". This involved, in part, the enormous growth of U.S. federally-funded medical research through massive expansion of the National Institutes of Health (NIH) in the 1950s and 1960s. It was during these years that J. Edwin Seegmiller joined the NIH as one of many leading scientists who enjoyed extraordinary freedom to choose their research projects and to get the funding and the staff to do the needed work. Many of you may not have heard of Seegmiller, but his laboratory and its descendants have in fact been of overwhelming important in advancing cystinosis research. During his years at NIH -- he left in 1969 and changed his research directions in San Diego -- Jay was joined by such scientists as the ophthalmologist Vernon Wong, the biochemist Frank Tietze, the Canadian John Crawhall, the pediatrician Rodney Howell, Dr. Schneider and myself. I was in fact Seegmiller's last NIH fellow, and then ran his former lab after he left.