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 195os 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 1. 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 inbred 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 196os, 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 1,5oo 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 — particularly during the past o years. 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 6o,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 196o, 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 4o 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.
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 scary, 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 Uda Franka, 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: 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 www.NHGRI.NIH.gov. 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.