McKusick, Victor

Victor A. McKusick

Johns Hopkins University

For a lifetime career as founder of the discipline of clinical genetics.

It is rare in the complex world of modern medicine for one man to have essentially founded an entire branch of medicine. It is rarer still when that field comes to occupy such a central place in the mainstream of clinical medicine. Such is the case with Victor McKusick, universally recognized as the father of medical genetics, a preeminent teacher of teachers, and a great physician. As anyone who has ever seen McKusick with his patients knows, they idolize him.

As a young physician at Johns Hopkins in the late 1940s, Victor McKusick was training in cardiology, even though his true intellectual love was genetics. During his young professional life, scientists at Rockefeller proved (through studies of pneumococci) that DNA is the substance that transmits hereditary information from cell to cell. Not long after that, James Watson and Francis Crick reported that DNA is a double helix, giving the molecules of heredity a structural shape. And, of course, there was the well-known story of Gregor Mendel and his peas. But there was no such thing as medical genetics. McKusick helped invent it.

While developing “spectral phonocardiography,” an arcane predecessor to contemporary methods of assessing the status of the heart, McKusick studiously explored the patterns of inheritance among patients with connective tissue disorders and then promptly wrote a definitive book on the subject. That was in 1956. (He also contributed a text, Cardiovascular Sound in Health and Disease, to cardiology along the way.)

During the 1950s genetics, which Dr. McKusick describes as one of the few areas of medicine to begin in the basic research laboratory rather than at the bedside, was maturing. The correct number of human chromosomes was discovered (46), and the importance of dissecting rare forms of disease to uncover normal physiology was gaining acceptance. In 1957, A. McGehee Harvey, chairman of medicine at Hopkins, asked Dr. McKusick to create a new, distinct division of medical genetics — one of the first in the world. Dr. McKusick went at it with his customary subdued gusto. Every time he saw a patient, he wondered about the patient’s relatives and asked whether there was a connection between genes and disease. Quite often, he found one, linking individual disease genes to their native location on one of the 46 chromosomes.

Two years later, researchers discovered microscopically visible changes in the chromosome of patients with Down Syndrome — an extra chromosome 21. Researchers had been able to actually see a chromosome and determine its defect. With that, medical genetics acquired an anatomical base. Says Dr. McKusick, “Medical geneticists now had their specific organ — the genome — just as cardiologists had the heart and neurologists had the nervous system.” Dr. McKusick was out of cardiology for good.

In 1962, Dr. McKusick discovered that a uniquely consanguineous group of people, the Old Order Amish, lived not far from Baltimore in rural Pennsylvania. He identified an inherited form of hemolytic anemia among these people who seldom marry outside of the community fold. His discovery of certain liver diseases common to the Amish helped others correctly identify similar diseases in other population groups. And he identified two forms of inherited dwarfism that subsequently led to a lifelong commitment to the special metabolic and other diseases among patients who call themselves the Little People.

By early 1960s, graduate physicians were coming to Hopkins to study under Dr. McKusick who is remembered fondly for a monthly journal club he held at home with Anne, his wife and fellow physician. Students were directed to scour the literature for everything they could find related to new genetic observations. It was out of that growing compilation of amazing data that Dr McKusick got the idea for Mendelian Inheritance in Man (MIM), first published in 1966. Then it wasa volume that listed some 1,500 phenotypes which, following Mendel’s laws of inheritance, were presumed to represent the manifestation of a gene in each case. Then, with the advent of techniques including somatic cell hybrid mapping, and cloning, it became possible to connect genes to disorders with real certainty. Today, this cornerstone of human genetics, about to appear in its 12th, 3-volumed edition and now online, is genetics’ Rosetta Stone, holding within its electronic pages the clues to close to 9,000 genes. Many now are disease-linked, but MIM still lists phenotypes for which no gene has been located. The big job for the future is to bring genes and phenotypes together.

The comprehensive listing of genes and phenotypes represented by Mendelian Inheritance in Man (MIM) led quite naturally to Dr. McKusick’s next visionary idea — the human gene map. MIM is like a phone book with names and addresses. But a real map would not only show which genes reside on which chromosomes but precisely where they are located. In 1973, Dr. McKusick and colleagues organized the first of what was to become a regular series of Human Gene Mapping Workshops. It is no surprise that Dr. McKusick was then a leading proponent of the now famous Human Genome Project whose goal is to locate all of humankind’s 60,000-to-70,000 genes and decipher the sequence of the more than 3 billion individual nucleotides that comprise a complete human genome. Critics complained that mapping and sequencing the human genes was nothing more than mindless cataloguing of information without much biology to make the data useful. “Previous progress in gene mapping and the value of the results were apparently unfamiliar to the critics,” Dr. McKusick says. “At a birth defects congress in the Hague in 1969, complete mapping of the genes on the human chromosomes had been proposed as an effective approach to the solution of problems of congenital malformations and genetic disorders in general. That proposal came close on the heels of the first manned. moon landing in July 1969.”

That July, as he has been every July but two since 1960, Dr. McKusick was in Bar Harbor, Maine where he directs a now legendary two-week course in genetics for scientists and medical practitioners. Held in conjunction with the Jackson Laboratory which breeds thousands of genetically useful strains of mice for research, the course is a mirror of what has happened in genetics in mouse and man during nearly 40 productive years. Dr. McKusick’s own work dominated the first phase of modern genetics — the association of genes and phenotypes. Now it is forming the background for functional genomics — the study of the physiologic behavior of genes. Dr. McKusick asked “what gene is it” so that his students, grandstudents, and now great-grandstudents can ask “how does the gene do its damage.” Through this scientists have also learned to distinguish genetics as the study of inheritance from genomics as the study of all genetically related disease, whether inherited or not. For instance, most cancer is a genetic disease, associated with gene mutations or disregulation. But not all cancer is inherited. There is one additional feature of Victor McKusick’s life that figures prominently in his career and that is his character. Dr. McKusick’s integrity, high standards of excellence, and personal compassion are what make him such a remarkable physician and teacher.

For a lifetime career as founder of the discipline of clinical genetics, pioneer of gene mapping in man, champion of the human genome project, and creator of Mendelian Inheritance in Man, Victor A. McKusick is honored with the Albert Lasker Special Achievement Award in Medical Science.

Award presentation by Joseph Goldstein

Victor McKusick is one of my heroes, and I am honored to present him with the Albert Lasker Award for Special Achievement in Medical Science. It is intimidating to attempt to summarize in several minutes the 54-year career of an academic giant like Victor. It may not be possible, but let me try.

Victor was born in 1921 in Parkman, Maine. He has an identical twin brother, Vincent McKusick, who recently retired as Chief Justice of the Supreme Court of Maine. Victor and Vincent were raised on a dairy farm in a tiny town of 500 people. They attended grammar school in a one-room school house. Their high school graduating class had 28 members. Vincent, the first-born twin, was the valedictorian, and Victor was the salutatorian.

It seems uncanny that Victor was born in 1921, a landmark year in the history of genetics. Two of the most influential lectures in genetics were presented within months of Victor’s birth. In 1921, Thomas Hunt Morgan presented the Coonian Lecture to the Royal Society of London where he summarized his theory of the chromosomal basis of heredity. Morgan had discovered that genes of the fruit fly are arranged in linear order on chromosomes and that a string of genes can cross from one chromosome to its partner chromosome linked together like beads on a string. These fundamental findings formed the basis of the human gene linkage map that Victor would pioneer 40 years later.

The second 1921 lecture was presented by Hermann J. Muller, at the annual meeting of the AAAS in Toronto. Muller advanced the concept of the gene as the basis of life by virtue of its unique ability to reproduce its own variations. In this lecture, Muller proposed that the newly discovered bacteriophage viruses, like lambda, could be used for genetic research because they also reproduced their variations. Muller made a remarkably prophetic statement, which I quote: “Perhaps we may be able to grind genes in a mortar and cook them in a beaker. Must we geneticists become bacteriologists, physiologists, physiological chemists, and physicists, simultaneously while being zoologists and botanists? Let us hope so.” Muller’s ideas 76 years ago were way ahead of their time and had little impact on his audience. His colleagues considered him a fanciful daydreamer.

The words and wisdom of Morgan and Muller must have reached baby Victor lying in his bassinet in Parkman, Maine, because Victor followed clearly in their path. He entered the world when the dream of genetics was just beginning to take shape, and his life’s work has given reality to that dream.

Like Muller, Victor McKusick is a dreamer. Let me tell you briefly about three of his dreams and how they have been transformed into realities.

Victor’s first dream occurred in 1939, at age 18, after reading an article in Time magazine that gave a glowing account of Johns Hopkins Medical School and how it was starting a new Institute for the History of Medicine. Victor had always been a history buff, and this article fired his imagination. He immediately developed a fixation on Hopkins, and after graduation from college, he applied to only one medical school—Hopkins. He arrived in Baltimore on Washington’s birthday in 1943, and he never left. Suffice it to say, he has spent 54 years at the same institution. This in itself is a remarkable achievement in academic medicine. Contrast Victor’s career with that of another academic giant, Lewis Thomas. After graduating form medical school, Dr. Thomas spent 45 years in 11 different institutions. Clearly, Victor doesn’t like to travel.

The second McKusick dream was to make genetics an integral part of clinical medicine. This dream began of all places in the cardiology clinic at Hopkins. In the early 1950s, Victor, who at that time was a card-carrying cardiologist, became fascinated with the Marfan syndrome, an inherited disorder in which affected patients show a bewildering array of telltale signs, such as long arms and legs, spiderlike fingers, dislocation of the lens, and calamitous rupture of the body’s main artery. Victor’s insight was to recognize that all of these seemingly unrelated findings must be due to the action of a single abnormal gene that disturbs the formation of connective tissue. As he saw more and more patients with other forms of inherited disease, he began to appreciate the importance of Mendelian genetics in sorting out challenging diagnostic medical problems.

In 1957, Victor took over the old syphilis clinic at Hopkins and transformed it into one of the world’s first medical genetics units. Today, 40 years later, there are 105 accredited clinical genetics units in North America, with 2000 trainees. Thanks to Victor, medical genetics has been evolved from a backwater academic discipline to one of the most active areas of clinical practice. Not bad for a farm boy from Parkman, Maine!

It’s not unreasonable to predict that in 10 years clinical genetics will be the largest and most pervasive of the medical subspecialties. As recently as 1960 there were 6 times more research papers devoted to hernias than to human genetics. Last year, there were only 54 papers on hernias and over 20,000 on human genetics.

Now for Victor’s third dream and the wildest of them all. Intrigued by genetic maps of the fruit fly, in the late 1950s Victor began to think seriously about a genetic map for humans. In 1960, he showed that the gene for an enzyme called G6PD was closely linked to the gene for color vision on the X-chromosome. Interesting, but then the X-chromosome is easy to map. After all, it’s not too hard to tell the difference between boys and girls. In 1968, Victor did something much more difficult: he mapped the Duffy blood group to chromosome 1. This was a landmark study in genetics. For the first time, a human gene had been localized to one of the 22 autosomes. These exciting findings were presented at the International Congress of Birth Defects in 1969. In his lecture, Victor made an audacious proposal, and I quote: “I propose that detailed exploration of the genetic constitution of man is ripe for an all-out attack. What we should know in full detail are the structure and geography of the chromosomes of man: the full nucleotide sequence of all genes determining the amino acid sequence of proteins and the location of each on the chromosomes of man.”

The reaction of the audience to Victor’s 1969 talk was as flat as a pancake. Much like the reaction to Muller’s lecture in 1921. Colleagues congratulated McKusick for his sense of humor and his fanciful daydreaming. Recall that this was 1969, three years before any of the technical advances in recombinant DNA and gene cloning that would revolutionize molecular biology. Undeterred by the polite, but restrained enthusiasm of the medical genetics community, Victor joined forces with Frank Ruddle at Yale, and together they organized biannual workshops directed at human gene mapping. The first meeting in 1973 attracted only 64 scientists, and only 31 genes were mapped. Today, we know the map location of 4500 genes of known function and 40,000 genes of unknown function. Victor’s wildest dream has now become a reality. As the champion of gene mapping, Victor played a crucially influential role, together with Jim Watson, in launching the once controversial Human Genome Project in 1989.

And now for the greatest of Victor’s many great achievements the creation: of a reference book indispensable to all human geneticists entitled Mendelian Inheritance in Man. Mendelian Inheritance in Man is a remarkable book that summarizes the facts regarding every human phenotype that has ever been described—over 8,640 at last count. This book could only have been written by a Renaissance figure, a nosologist, and syndromologist with encyclopedic knowledge of clinical medicine and genetics. Mendelian Inheritance in Man is now in its 11th printed edition and is online on the Web. It is affectionately referred to as the “McKusick Bible of Clinical Genetics.” I should point out parenthetically that the 11th edition actually looks and feels like a Bible. The pages are tissue-paper thin, and there are two columns of text printed on each page. The rumor is that Victor’s latest dream is to have the 12th edition placed alongside the Gideon Bible in every hotel and motel room in the world.

Some of you may have heard about Victor’s breeding Burmese cats, raising orchids, and maintaining a bank account in Russia. But I doubt that very many of you know that he is also a connoisseur of neckties. His knowledge of neckties, like that of everything else, is encyclopedic. Ten years ago, Victor and I were together at the NIH for a meeting. I was several minutes late and when I entered the room Victor announced to the Committee that I was wearing a necktie that had been made in Europe. The master diagnostician had spoken, and his diagnosis of a necktie with a European ancestry was correct. Victor then explained to an amazed committee that American neckties have diagonal stripes that run downward from right to left, while European neckties have diagonal stripes that run downward from left to right. But there are two things about neckties that Victor didn’t teach me—one is which way the diagonal stripes run on ties made in Japan, and the other is what to say to someone wearing a necktie with horizontal stripes.

Victor, the Lasker Foundation is proud and delighted to present you with the 1997 Special Achievement Award in Medical Science. Your contributions to the field of medical genetics are unsurpassed. More than anyone else, you have educated the medical community on the power of genetics to deal with human diseases, and at the same time you have convinced the scientific community that the human being is just as good a model organism for studying basic genetic mechanisms as are the more traditional models of lambda, E. coli, yeast, roundworms, and fruit flies. You are truly a jewel in the crown of 20th century medicine.

Interview with Victor McKusick and Francis Collins

Victor McKusick has a special instinct for observing rare deformities, often in a handful of individuals, and then making compelling links to medical genetics. McKusick’s September 1997 interview with Francis Collins, director of the National Human Genome Research Institute, explores the birth of genetic medicine, and Collins takes a moment to tell how McKusick’s work aided him as a young medical fellow at Yale in 1981.

Part 1: Collins and McKusick Get Acquainted
After congratulating McKusick, interviewer Francis Collins explains how McKusick’s work aided him as a young medical fellow at Yale in 1981. The two scientists are soon talking animatedly about the positional cloning gene project.

McKusick: How are you, Francis?

Collins: I’m well, Victor. Congratulations.

McKusick: Well, thank you so much.

Collins: I am so delighted.

McKusick: That’s very kind of you to say. The Baltimore Sun quoted you extensively this morning, and I thank you for your kind remarks to the press.

Collins: I had a good time having the chance to make some remarks on such a happy occasion. I’m just delighted that this has come to pass, and it increases my faith in the Lasker Award mechanism that they got it right.

McKusick: Thank you so much. I just got a fax from Bert O’Malley, whom I don’t know all that well, congratulating me, which I was delighted to get.

Collins: How great. I haven’t seen the Baltimore paper. I don’t know if they repeated the anecdote that I told the reporter about my own first experience with deciding that you deserved the Nobel Prize. I’ll recount it now just in case. You’d be amused.

When I was a first year medical genetics fellow at Yale in 1981, being an internist, sent off to deal with the newborn nursery and other very, very small patients, I was constantly looking about for ways to get educated about this or that disorder that I’d never heard of. And I remember a particularly puzzling one where I was asked to see a fairly young infant who had intestinal obstruction and where the imaging studies suggested some sort of jejunal atresia. Sure enough, there was a family history of apparently the identical lesion in a sib.

So I went back to Uta Francke, who was my attending at that point, and described this case. She sort of scratched her head and said, “Boy, I don’t know. I’ve never heard of that either.” We pulled down your book and flipped through the pages and came to entry asterisk 243600, Familial Apple Peel Jejunal Atresia, and there it was, an absolutely perfect description of the condition that we had just seen. Whereupon, Uda said—I remember this so clearly—she said, “This is wonderful. Victor should win the Nobel Prize.”

McKusick: Good for her.

Collins: In fact I ended up writing a paper about that particular case which you now cite as Reference Seven under that entry. The circle is completed over and over again.

McKusick: That’s terrific. It occurs to me, I was going to ask you a substantive question, not that the other questions aren’t substantive. Do you keep up your positional cloning gene?

Collins: Yes, I do.

McKusick: Score. Yes, what’s that up to now?

Collins: 83.

McKusick: 83.

Collins: Now I’m fairly rigorous about what gets on the list. If it was a candidate gene, it doesn’t count even if it was a candidate gene that was only arrived at after a linkage suggested the right location. So it’s a list that’s going to eventually peter out because everything will be candidate genes, of course.

McKusick: Yes. That’s very good. How can I get access to that list?

Collins: It is now supposed to be kept up regularly on the Web site for NHGRI. So that’s I will, I’m not sure I can quite remember the path defined to it. I’ll send you a message. But I can fax you the current hard copy if you’d like.

McKusick: That would be the easiest if you could. Let me give you, can I give you my fax number?

Collins: Yes, right. I’m sure the people who are listening to this interview are going to all write it down, too.

McKusick: It’s 410-955-4999.

Collins: Okay, your fax machine is going to hum. As I understand it, this interview that Brady asked us to carry out is going to end up in an audio track on the Lasker Foundation Web site. Which is a place where I suspect quite a number of people will go to read more about you, and I’m happy to have been chosen as the person to conduct the interview. I hope this is okay with you?

McKusick: Absolutely. Fire ahead.

Part 2: The Genesis of Medical Genetics
When McKusick began medical school in Baltimore during World War II, the field of medical genetics had not yet been born. McKusick reminisces about the early pioneers.

Collins: Okay. Again, I’m going to ramble a bit and you should feel free to derail the whole thing if you think we’re on the wrong track. I guess I wouldn’t mind going back a bit to the beginning, since I suspect most of the people who listen to this won’t exactly know your entire history. At what point did Victor McKusick get interested medical genetics? When did you have this flash?

McKusick: When did the epiphany occur? I will go back over that story. As you probably know, I have been at Johns Hopkins uninterruptedly since Washington’s Birthday 1943, when I came to Baltimore to start medical school during the middle of World War II, never having been south of New York before, incidentally.

I have been here uninterruptedly, as I say, since that time. We went through medical school in three years. Nine months, nine months, nine months, around the calendar and graduated in 1946 and did internship and residency on the medical service at Hopkins as an internist and went into cardiology. I studied heart sounds and murmurs for a long time using a method of analysis which was developed at the Bell Telephone Laboratories for analyzing speech sounds, called sound spectrography, which we used in an adapted form to study heart sounds.

Collins: Seems like a very respectable activity for an internist.

McKusick: Yes, yes. In fact, I published a big fat book called Cardiovascular Sound in Health & Disease, which was published in 1958 by Williams & Wilkins. My first book was, to get back to genetic medicine, was Heritable Disorders of the Connective Tissue, which was published in 1956. This points up the fact that when people ask me, why did you switch from cardiology to genetics? This wasn’t quite the way it worked. It was more a matter of phasing down cardiology and phasing up genetics for the switch. Of course, when I finished residency, there was no such thing as a specialty of medical genetics. That came later to some extent with myself.

My first piece of clinical investigation was on a genetic topic. In the month of June 1947, 50 years ago this past June, as I was finishing up my internship, I had a patient named Harold Parker, who was a 15-year-old boy who had melanin spots on his lips and inside his buckle mucosa. And he had a horrendous history of anticlinal polyps, mainly particular jejunal polyps. He had large segments of small intestine removed for inception. I thought this was an entertaining combination and subsequently collected four other cases, three of which were members of the same family, establishing there was something genetic here. I heard that Harold Jagers in Boston, who was then at the Boston City Hospital, had five cases.

In 1948, Harold Jagers came to Washington as a first full-time professor of medicine at Georgetown, and he invited me to join him in writing up these cases of polyps and spots, which we did. It was published in the New England Journal of Medicine in December 1949. In fact the article was split into two segments and was in two successive issues of the New England Journal of Medicine in December 1949.

Collins: I just called it up on the Web as we are talking here. I see you’re the middle author between Jagers and Katz, whoever he was.

McKusick: Yes, Katz was head of the medical service at Boston City Hospital that Jagers had been chief of, and they’d had these cases on that service here. He played, I must say, rather a minor role in the whole process.

Collins: But got to be the senior author.

McKusick: Jagers was very heavily involved. Francis, what I really learned from that was the principle of pleiotropism—that one gene could cause multiple effects. The naive individual would have thought, and I think perhaps that I was playing with that idea, that this could represent linkage of a spots gene and a polyps gene, something of that side. The principle of pleiotropism was drilled into me by Bentley Glass, who was my genetics mentor that I sought out at Hopkins at that time. When I was, meanwhile, back at the ranch, I was busily developing as a cardiologist and ran up against the Marfan syndrome because of the conspicuous involvement of the aorta.

The principle of pleiotropism struck me hard, that the dislocated lenses and the cardiac and other connective tissue manifestations could be interpreted as a defect in one element of connective tissue wherever it was in the body. I was off and running studying Marfan cases and looked around for other disorders that might be labeled with the expression that I invented, Heritable Disorders of Connective Tissue, and fell on osteogenesis imperfecta, Ehlers-Danlos syndrome, pseudoxanthoma elasticum, and the Hurler Syndrome—as we called it, the prototype mucopolysaccharidosis—and those were the conditions that had individual chapters in the first edition of Heritable Disorders of Connective Tissues.

Collins: The cutis laxa was not in the first….

McKusick: The cutis laxa was discussed, there was not a distinct chapter. It was listed in the differential diagnosis of Ehlers-Danlos, and I had a chapter at the end that discussed other possible heritable disorders of connective tissue. But it didn’t get big time billing in that first edition.

Collins: I see. That’s fascinating. I guess one of the questions I’ve wondered about, and I suspect people listening to this might also, especially if they’re young scientists: here you are sort of breaking ground in a new field that didn’t quite exist yet. Many of us have been so much benefited by a long list of impressive senior mentors that we sort of looked at as role models, particularly people like yourself—who were your role models? You mention Bentley Glass, was that sort of it? Did you feel kind of lonely sometimes, like I’m going in a direction that nobody else thinks matters?

McKusick: I don’t think I ever really did feel lonely in that regard. I think that I felt as though I had very good support in pushing forward in this regard. I had good moral and other support from my boss, the chairman of the department, A. McGee E. Harvey. The next event that was very critical was the development of the Moore Clinic as a genetics center, as a base for medical genetics at Hopkins.

Moore had developed a multifaceted chronic disease clinic at Hopkins. He retired July 1, 1957, 40 years ago now, and died a few months after that. Dr. Harvey asked me to take over this multifaceted chronic disease clinic that had a hypertension clinic, a tumor clinic that was the predecessor of our oncology center, a sarcoid clinic, a chronic liver disease clinic, and so on. The deal I made with him was that I be permitted to develop a division of medical genetics within the department of medicine co-equal with divisions like cardiology and gastroenterology and the other classic divisions, the argument being that genetic disease is the ultimate in chronicity and should legitimately take its place in the group of clinics.

He was very supportive of that idea and I inherited, at the same time, a training program that was supported by the Heart Institute that Dr. Moore had in that clinic. I redirected that to training people in a new field of medical genetics. I had many who came to me from the training, from the background of undifferentiated internal medicine, and increasingly afterward from pediatrics and so on—and from other areas like ophthalmology, neurology and all sorts of things. I proselytized them to this field—that this was a very exciting, intellectually challenging and useful area to develop.

Collins: Obviously, you were successful in a number of instances because I suspect many of those people turned out to be pretty convinced that you were right about the promise here.

McKusick: Yes, yes.

Collins: Did you imagine in those time periods, sort of back in the 1950s and early 1960s, that during your own professional lifetime, the actual DNA sequences underlying the majority of the disorders that you were busy describing, at least a lot of them, would be uncovered? That didn’t seem possible.

McKusick: No. It didn’t seem possible. The same year that Heritable Disorders of Connective Tissues was published, the correct chromosome number was finally established to be 46 rather that 48. I would never have dreamed that we would be so close, not just at getting the count right, but to having full chemical definition of the chromosomes. I wish I could claim that I saw this coming within 40 and 50 years, but really would never have dreamed that it would move as fast as it was. I became interested in gene mapping very early. This was a major theme of interest to us. In genetics courses in college, I found fascinating the mapping of the chromosomes in Drosophila, the precision there, and then in 1955 and 1956, the people like Newton Morton were looking at the linkage for elliptocytosis and Rh, and there were other linkages that were….

Collins: Were beginning to come out because you were fortunate enough, there was a protein polymorphism nearby.

McKusick: Exactly. One had this pitifully poor collection of markers to use. It was very arduous work that was possible.

Collins: Yes, there is hemochromatosis and then there were a lot of things that you couldn’t find. When the Botstein, Skolnick, Davis, White Paper came out in 1980, did this sort of immediately come to your attention that this is going to change everything?

McKusick: Yes. I think David will tell you that I wrote to him very early on and expressed an interest and thought this was really going to revolutionize the field. I think this was immediately recognized, not only by myself but by others, as a seminal paper.

Collins: Yes, it certainly has turned out to be that. I think it did take, in some people’s courts, a year or two for it to sink in. Obviously not in yours. Still I bet you were as surprised as a lot of people to see this actually result in a successful mapping of Huntington’s Disease only three years later with such a sparse map. Of course, maybe that’s more like Rh and elliptocytosis, you just happened to hit it.

McKusick: Yes, good luck. It was good luck in the case that the first autohomologous assignment—which was 19, the first chromosome—the first specific gene to be put on one.

Collins: So tell this story, because I think this is really fascinating.

McKusick: Yes, well the first, there were quite a lot of linkages known between 1951, when Moore and Copenhagen found that secretor (inaudible) and possibly he recognized, even possibly, (inaudible) dystrophy will link together. Of course it wasn’t known what chromosome they were on, and then these other linkages came along like elliptocytosis and Rh and Nail-Patella syndrome and the ABO, and so on and so forth. We didn’t know what autosome they were on.

Collins: Right. It must have seemed like an almost impenetrable problem.

McKusick: Yes, it really did. But the first strike for a specific assignment was in 1968, and this was done by a graduate student in human genetics in our program at Hopkins by the name of Roger Donahue—who is a well-known, cited geneticist in Miami now. He was doing his research on another topic, but like every graduate student in human genetics should do I think, he did his own chromosomes and found that he had one chromosome one which was unusually longer than the other—a heteromorphism—and it looked as though it had an uncoiled segment subjacent to the centromere. This was in the days before banding, just before.

When banding came along this was shown to be an unusually long heterochromatic region next to the centromere. He had both the gumption and the wit to do a linkage study in his own family. Perhaps I didn’t make it clear, of course, this was his own chromosome that he was finding this in. He had the wit to realize that this was probably a Mendelian character in the chromosomes. At least he hoped it was—a normal variation.

Collins: That he wasn’t somehow a new mutation for this. It might be sort of scary.

McKusick: And he had the gumption to do a linkage study because his family was quite widely scattered and…

Collins: Somebody must have encouraged him a little bit here with these ideas. I dare say this didn’t happen in a complete vacuum.

McKusick: No. We talked about it considerably. Linkage was very much the talk of the town in Moore Clinic. Jim Renick was there writing some of the pioneer computer programs for the very first computer program that was written for linkage analysis, and linkage was sort of a scarlet thread running through our research program in many ways—so the atmosphere was certainly there. We had this pitiful handful of markers and it just so happened that the Duffy blood group, locus, was very close to that heterochromatic region on chromosome one. If you look at the paper, the title said Probable Location on Chromosome One. The paper was in the PNAS, sponsored by Bentley Glass, incidentally. If you do a large score analysis, I won’t tell you, it’s a pitiful low large score, but.

Collins: Doesn’t make it to three, huh?

McKusick: Oh, far below. It was very quickly confirmed in other families.

Collins: Well, it’s a lovely story. Maybe you don’t need a larger score of three because you’re not doing a whole gene on search, you would have if you could have, but you didn’t have enough phenotypes to check out. So I don’t know what Newton Morton would say your large score had to be to really believe, but I bet it wouldn’t be three.

McKusick: Yes, I think probably the statistical people looking at it hard Newton Morton I think this may be true on the X chromosome, too. When you’re already, yes, it may be that you don’t have to.

Collins: It’s a lovely story. In fact that is the way that I always start out trying to explain linkage to medical students because it is a visual example. Otherwise they have to sort of think abstractly of how to follow chromosome inheritance in a family. Here you can see the thing. You can see that it’s different than its homologue. That very figure is the first figure in the chapter on linkage that Tom Gelehrter and I wrote for our textbooks. It never fails to sort of get a few people who look puzzled to go, oh, I get it, I get it. You’re following the chromosome separate from each and well, you can’t always see that there is an abnormality or a heteromorphism to track. You can sort of do the same thing with these microsatellites these days. So, it is really a wonderful story.

McKusick: Some interesting numbers: in 1968, when the first gene was split on the autosome, there were 68 genes that were confidently known on the X chromosome. I can state that figure with confidence because Mendelian (inaudible), first edition was in 1966, second edition was in 1968, and the X link catalog had 68 asterisks entries. Isn’t that cute?

Collins: That’s cute. Easy way to keep that one straight. But it went up a little faster than the years did, apparently. Substantial multiplier to be sure.

Part 3: Future Advances Look Promising
McKusick shares his insights on the future of medical genetics hovering on the horizon. Identifying susceptibilities rather than monogenetic abnormalities is essential, McKusick says.

Collins: Well, let’s sort of romp here forward a couple of decades or so because I think people probably are also very interested in your perspective of where we are now. Particularly, how has the practice of medical genetics changed from your perspective over what it was 10 or 20 years ago, and what is it going to be like in another decade or so? Are we really seeing this transformation where genetics becomes everything? And where every physician has to be a geneticist? Or have we oversold that notion?

McKusick: I think it’s inevitable that the level of sophistication in genetics of physicians, generally, has to be high enough to meet the demand because there aren’t going to be enough genetic counselors or board-certified medical geneticists to go around to cover everything. The public will demand it, undoubtedly.

As far as health, things have changed in the last 20 years that there are, of course, many more things that we can do in a diagnostic sense and in a counseling sense, and even to an increasing extent, in a management or treatment sense, than we could 20 years ago. The fact that it has become necessary to have a board, an American Board of Medical Genetics, indicates that the specialty had developed to the state where some regulation of training and practice is necessary.

Collins: Yes, I guess we are on that course that the late Roy Schmickle used to talk about—trying to convert geneticists from being the bookies to being the fixers. We’ll all welcome the day when we’re really good at that part as well. Yet, at the same time, those are hard fought, those advances that allow you to not only make predictions but actually to intervene successfully.

What’s your sense of, since I’m prone to ask these questions of almost everybody, how the genome project is going, Victor? Is this from your perspective turning out the way you thought it would? Is it different?

McKusick: Absolutely. Of course, I quote you, so this is coming full circle that I quote you and by your five-year pronouncement that it was ahead of schedule and under budget. I can still see holes, and it has been very interesting to see how it has gone. What was talked about in the National Academy of Sciences committee and mapping and sequencing the human genome was structural genome, extend this specific goal of the human genome project has been to locate every gene and sequence the whole thing. It’s interesting to see how functional genomics is entering the picture.

Collins: And more an intense study on variation, for sure, that we’re no longer hiding the fact that we’re interested in that. Which I think is good.

McKusick: Yes, absolutely.

Collins: It’s time to plunge into that in a genomic way as well.

McKusick: Yes, absolutely. You asked about the future of clinical genetics. I think that clinical genetics will be to such a large extent identifying susceptibilities rather than monogenic abnormalities, and that’s also where the variation obviously is critical to understanding.

Collins: Sure. Yes, maybe we are going the next iteration of Bob Stein, Davis Skolnick and White, where instead of focusing on a linkage map we could imagine focusing on identifying the functional variance in most of the 80,000 genes. Catalog those so that you can go directly to an association study. Not on your favorite candidate but on all the candidates in one fell swoop.

McKusick: Yes.

Collins: Obviously, there are pitfalls there in terms of false positives if you’re not careful how you control your cases and your controls. But still, if you get something, you’re done. It’s not like you have several more years of sifting through large blurring regions trying to identify what the responsible locust is. Your strategy gets you to it in one step, as it were.

I’m very excited about that. I think that is sort of the next quantum leap that one can anticipate. But to do it, we have another huge genomic effort in front of us, to catalog those variances. I think we ought to get on with it and not wait until the rest of the reference sequence is done. We could start some of that now.

McKusick: Yes, I agree. This is a very exciting area.

Collins: What are your concerns about medical genetics in the future? What are the things you’re worried about in terms of the way things are going, if there are any?

McKusick: I don’t know that I can identify any big concerns, really.

Collins: I’m relieved to hear to that. There are obviously fears in the public about how this information is going to get interpreted, used against them in ways that they will find obnoxious. The press is frequently also, I think, on one hand making statements that sound terribly deterministic about genes, and then decrying the fact that genetic research tends to make it sound very deterministic. Always caught in between those two.

Do you have any real concerns that we’re going to get through that? Do you think this is just sort of growing pains?

McKusick: I think it will come out all right in the not so long run.

Collins: I’m glad to hear you have that sense of optimism. And obviously, a lot of the hopes for the future also reside in this business of genes leading to therapies. I don’t know whether you’re, I’m sure you get asked, especially after winning an award like this—so, Dr. McCusick, how long is it going to be before all these wonderful discoveries….

McKusick: Yes, I know. I’m known as a physician…I can pontificate on any topic.

Collins: Yes, you can. People will take you very seriously, of course they did before, most of us. But you’ve expanded the possibilities.

McKusick: Yes.

Part 4: Illness Sparks Interest in Medicine
A physical ailment set the stage for McKusick’s success as a scientist. McKusick recalls how a long illness as a teen helped turn his attention to medicine. The young man was inspired by the doctors that trooped in and out of his hospital room as his body battled abscesses and ulcers on his axilla and elbow.

Collins: Just a couple of other questions, and then I’ll let you go because we’re probably going to wear out our recording tape here. Did your particular family circumstance, where one could say you were introduced to genetics in the womb by (inaudible), did that play any significant role in your affection for this particular field? Did that lead you this way? Did it change the way that you think of genetics because of your own personal experience in that regard?

McKusick: You ask the question in a much more sophisticated way than many people who have asked the same question. Did you go into genetics because you’re a twin? I can say the fact that my twin didn’t go into genetics would seem to belie that. I think that there is, and I can’t claim that was the reason of course, but it is significant, my twin, my co-twin is in the law and has done very well in the law, having been for 15 years Chief Justice of the Supreme Court in Maine. Why did he go into law and why did I go into medicine?

The reason was an environmental experience that I had that he did not have. When I was 15 years old I had a long illness, and in the summer of 1937 spent ten weeks in the Massachusetts General Hospital—which is almost unbelievable in this day of short hospital stays.

I had a microaerophilic streptococcal infection, which started as an abscess in my left axilla, and also a large spreading ulcer on my right elbow with undermined edges, which was something called a Meleney ulcer, named for Frank Meleney, a surgeon at Columbia. Due to microaerophilic strep, it was difficult to culture because it didn’t like oxygen very well and you had to culture it under special conditions. So it wasn’t cultured until I got to Boston. But then sulfanilamide came in 1937, and saved the day for me. And cleared it up quite rapidly and dramatically, and I have been well every since.

I’ve looked up my record at Mass General and they have pictures of my lesions and so on there. Brother Vincent was back on the farm that summer helping with the haying and all the rest, and I saw a great deal of doctors and thought this was something that I would like to go into. He didn’t have that experience.

Collins: I thought you were going to tell me he got in trouble with the law and learned a lot about the court system, but I guess not.

McKusick: No.

Collins: No, I’m sure he didn’t. He’s a very fine upstanding member of society, to be sure.

McKusick: Right.

Part 5: Closing Remarks
The two scientists admit they could probably talk longer, but like most good things, the interview comes to a close.

Collins: Well, this has been a lot of fun.

McKusick: I’ve enjoyed it.

Collins: I’m really honored to have the chance to ask you these questions, foolish though they may be. I appreciate your sort of telling some of these tales that really are quite remarkable. Once again, I think I speak for the whole field of medical genetics in celebrating the fact that you have been given this award. It gives us all a big shot in the arm to see that the field is being recognized in this way by what you’ve done. I think in many ways we all sort of feel in some part as though we are your kids, and so we’re delighted and honored and thrilled.

McKusick: Thank you so much.

Collins: So, congratulations.

McKusick: I appreciate this.

Collins: Okay, I’ll see you soon.

McKusick: Thank you.

Collins: Good bye.

McKusick: Good bye.