On the wall of Victor A. McKusick's office in Baltimore hangs a portrait of a sad-faced woman holding a six-fingered infant. The photograph, which he calls the Amish Madonna, was taken during McKusick's pioneering studies of the Old Order Amish of Pennsylvania 40 years ago. McKusick described genetic diseases in these and other patients long before there were tools to pinpoint the mistakes in their DNA.
McKusick is a white-haired, dark-suited figure, still vigorous and straight but, at 80 years old, slightly tremulous. Near the Amish Madonna portrait, he keeps a row of books holding the fruits of his patient and relentless efforts to place genetics in the mainstream of clinical medicine. First published in 1966 and now in its 12th edition, Mendelian Inheritance in Man is an ever-expanding catalog of human genes and the medical disorders associated with them. McKusick still oversees the compilation of the catalog that has earned him the honorific "father of medical genetics." His office is at the eponymous McKusick-Nathans Institute of Genetic Medicine, which is part of the Johns Hopkins School of Medicine, where McKusick has worked since World War II.
Some diseases are inherited in a recessive pattern, just as blue eyes are. Brown-eyed parents who each have a gene for brown eyes (B) and a gene for blue eyes (b) will have a blue-eyed baby if the child inherits both copies of b. Illustration by Dan Winters & Gary Tanhauser
McKusick became famous for linking genes to disease, but the slim single volume of the original Mendelian Inheritance in Man recorded no actual genes, although it described hundreds of genetic disorders. Their locations were unknown. The third edition reflects medical genetics in the early 1970s. "It recorded all the genes that had been mapped at that time," McKusick says with a smile. "It filled one page." During those early years, McKusick collected genetic disorders one by one, working alone at first and later assisted by staff and other associates. He culled the journals for rare conditions and wrote up his own observations. He watched as medical genetics grew from a research backwater into a hot spot of medical inquiry.
In recent years improvements in genomics—the detailed study of genes' structure and function—has greatly speeded his task. With automated sequencing machines and supercomputers, researchers have assembled electronic banks of genetic code and begun analyzing them for possible links to disease. In June 2000 their efforts yielded the first rough draft of the human genome sequence—a close reading of the 3.2 billion chemical letters that define our species and drive our cells. "Victor McKusick started this whole thing in motion," says Francis Collins, director of the government's National Human Genome Research Institute. "He's the guy who led us here."
In the meantime gene sequences have poured into the catalog, and the print editions of McKusick's opus have multiplied. à Since 1987 there has been an online version, Online Mendelian Inheritance in Man, accessible at no cost through a government Web site; at last count it contained more than 13,000 entries.
As the constellation of genomics has ascended, promising a skyful of medical benefits, the field has so far generated much more dazzle than useful applications. In that sense, little has changed. While he diagnosed and cataloged his patients' unfortunate ailments, Victor McKusick had no cures to offer. On the wall above his computer, the Madonna, her white cap imparting a sort of halo, looks down gravely. The doctor once used her photo for a Christmas card.
McKusick has always been aware that his interest in unusual genetic disorders could be considered "stamp collecting." "From the beginning," he writes in the preface of the latest Mendelian Inheritance in Man, "I have thought of these catalogs . . . as a photographic negative from which a positive picture of the human genetic constitution can be made." A history buff, McKusick likes to quote from a letter written by William Harvey in 1657: "Nature is no where accustomed more openly to display her secret mysteries than in cases where she shows traces of her workings apart from the beaten path."
The term disease gene bothers many scientists. They don't like promoting the idea, says Francis Collins, that "a gene's only reason for being in the genome is to create havoc." People are accustomed to reading about a newly discovered gene "for" this condition or that, even genes for behavioral characteristics such as those "for" homosexuality, manic depression, or risk taking. Almost always what is meant by the reports is that a gene with a different spelling than usual has been statistically linked to a certain trait. In comparison people who are not sick or who don't exhibit the trait carry the normal, or usual, form of the gene. Often the gene itself isn't identified, only its area on a chromosome.
Victor McKusick holds the pedigree of a large Kentucky family that has members afflicted with Marfan's syndrome. It is one of many inherited disorders he has studied since the 1950s.Photograph by Gillian Laub
Genes are both matter and message, structure as well as information. The structural component is the double-stranded DNA molecule, consisting of the nucleotides adenine (A), thymine (T), cytosine (C), and guanine (G). The information component lies in the order of those As, Ts, Cs, and Gs. That sequence, called the genetic code, tells the cell to assemble amino acids in order to make particular proteins.
A single gene may be hundreds or thousands of letters long, and if a mutation misspells some part of the sequence, disease may ensue. "I prefer the term 'allelic variation' to 'mutation,'" says McKusick, a stickler in his choice of words. He defines a disease gene as one having "disease-related alleles." An allele is simply a variant, a version with a different spelling, which may be inherited from a parent or arise at random.
The first disease gene to be mapped (traced to a chromosome) was for a type of red-green color blindness found mostly in males, in 1911. Researchers knew that the disease was passed down in families from mothers to sons. That pointed to a problem with the X and Y chromosomes, which are the sex-determining chromosomes. Girls have two X chromosomes, one inherited from each parent. If one of the X chromosomes is faulty, usually the other one will keep the girl healthy. But boys inherit a male-making Y chromosome from their father and an X chromosome from their mother, and so a bad X chromosome in them has no backup. All the early mapping of genetic disorders was to the X chromosome because researchers were studying disorders that affected only males. Another reason was that the X and Y was the only chromosomal pair that scientists could distinguish with their crude microscopes.
When McKusick joined the faculty of Johns Hopkins School of Medicine in 1946, gene mapping had hardly moved beyond the X chromosome. Genes were still abstractions, mysterious particles of inheritance. The problems caused by genetic errors were strikingly real, though. Odd and rare deformities often cropped up within inbred populations in recognizable patterns—patterns that conformed to rules laid down by Gregor Mendel, the 19th-century monk and botanist. In his breeding experiments, Mendel observed predictable patterns of inheritance. Geneticists call these patterns dominant or recessive, and they now recognize that many inherited disorders in humans, if they are not X-linked, are inherited as Mendel predicted.
Genes, as noted, are handed down in pairs, one from each parent. In dominant disorders, only one defective copy of a gene is required to cause disease. So a child will become ill if a sick parent passes along the faulty copy of the gene. The chance of this occurring is one in two. In recessive disorders, a child will become ill only if both copies of the gene are flawed. But the parents show no sign of disease because each usually has a second, healthy copy of the gene that can compensate for the problem. If both parents carry a gene for a recessive disease, the chance of having an afflicted child is one in four.
In the mid-20th century, tracking the pedigrees of Mendelian illnesses made genetics exciting to academics, but the field was discouraging for physicians. The difference was between medical genetics, a research interest, and genetic medicine, a clinical need. "When I went into it, people thought I was committing professional suicide," recalls McKusick, who had initially specialized in cardiology. Physicians would rather tackle infectious disease, using newly discovered antibiotics such as penicillin and sulfa drugs. Infections then were the big killers of humankind.
As scientists unraveled the structure and workings of DNA, they learned that genes make proteins and that proteins make the body run. A genetic disorder occurs when a misspelling, or allelic variation, in the DNA cripples or knocks out the corresponding protein. Diagnoses can be made on the basis of the missing or mutated protein. In a few cases, if the protein is an enzyme, the disease can be treated with dietary measures. An early success story was phenylketonuria, or PKU, a recessive disorder. Infants who lacked the enzyme for breaking down phenylalanine became mentally retarded. Eliminating foods containing phenylalanine can prevent the disease.
McKusick's first book, Heritable Disorders of Connective Tissue, published in 1956, included a description of Marfan's syndrome, a dominant genetic disorder. People with Marfan's have skeletal abnormalities. They tend to be tall, with long limbs, curved spines, and misshapen chests. Their eyeballs elongate, and they are prone to dislocated lenses and detached retinas. Their feet flatten beneath the weight of their bodies. The worst sign is an enlarged aorta, the artery bearing blood from the heart. It can fatally burst when the person is as young as 30. According to the National Marfan Foundation, "it is estimated that at least 200,000 people in the United States have the Marfan syndrome or a related connective tissue disorder." McKusick became a leading diagnostician of the disorder and traced its Mendelian pedigree in scores of families.
The Royal Disease
In the 1960s he brought the same skills to the Old Order Amish in the farm country of Pennsylvania. Centuries of intermarriage among members in this small community have reduced the variation in their gene pool, making them more likely to exchange defective DNA. One genetic disease, called Ellis-van Creveld syndrome, intrigued McKusick. These patients have an extra finger on each hand, heart murmurs, and short stature. Although the Amish are notoriously suspicious of outsiders, the direct manner of this former New England farm boy eventually won them over. By studying their genealogical records, McKusick tracked the disorder's origin back to an immigrant who arrived in the United States in the 1800s. Either this man or his wife was the "founder" of this recessive disorder among the American sect.
The royal families of 19th-century Europe had a problem. Male descendants of England's Queen Victoria were strangely vulnerable to hemophilia. The partial pedigree (right) follows the branch of her family that yielded possibly the most famous hemophiliac in history: Alexis Romanov, son of Nicholas II, czar of Russia. Healthy family members are indicated in red. Affected members are shown in gold. Carriers, unaffected members who carry the gene and have passed it to a child, are shown in both colors. Historical records suggest the mutation causing the disease originated with Queen Victoria. (McKusick himself once suggested that the flaw could have been introduced in her aging father's sperm cells. He was 52 when she was born.) Victoria had an affected son, but all her daughters were healthy. Her daughter Alice, too, had healthy daughters and an affected son. Alice's daughter Alexandra married Nicholas II and had four healthy girls and a very sick son, Alexis. They solicited every kind of care for him, including the ministrations of the legendary Rasputin. The family was executed during the Russian Revolution; whether any of Alexandra's daughters inherited the flawed X chromosome is not known. It was the sex-specific pattern of transmission that tipped off geneticists to a problem on the X chromosome. Of all 23 pairs of human chromosomes, the X is the one chromosome sons inherit only from their mothers.Illustration by Dan Winters & Gary Tanhauser
McKusick had arrived at his calling. He researched the histories of hemophilia in colonial New England, familial Mediterranean fever among Armenians who had immigrated to California, and various recessive disorders in Finland. He scoured scientific journals—and asked his Hopkins students to do the same—for reports about medical genetics. The first edition of Mendelian Inheritance in Man, in 1966, formalized the collections. "It was on a mainframe, making huge printouts, before it was even in print form," McKusick says proudly.
McKusick soon realized that a piecemeal, descriptive catalog of Mendelian-type illnesses would never be comprehensive. The basic data about genes was missing. Moreover, for the more common illnesses that tend to run in families, like breast cancer and high blood pressure, multiple genes appeared to be involved, intersecting in unpredictable patterns. So in 1969 he proposed a "complete mapping" of all human genes, an idea that was 20 years ahead of its time because the technology to realize it did not yet exist.
Slowly, researchers began to map genes to particular locations on a chromosome. To map a gene is not the same thing as identifying it. As an analogy, think of rows of brick houses along an urban street. Each house represents a gene. A map can take you to the street (chromosome) and then to the exact address. But you have no sense of what is going on inside each house (gene). The inhabitants—the sequence of the gene—need to be identified.
The original technique of mapping genes involved identifying a disease-related protein and working backward with a variety of probes to locate the gene that made it. This approach was not only slow and cumbersome but also required knowing exactly what protein was causing the inherited disease. In the 1980s scientists devised a more powerful technique to close in on mutated genes for which the dysfunctional protein was unknown. Researchers sampled the DNA of afflicted family members and looked for a distinctive marker, a stretch of DNA they all possessed. The marker was like a lamppost at the head of a street, illuminating the likely location of the gene. By the end of the decade, they'd mapped enough markers to begin decoding the entire genetic landscape—the genome.
In 1988 McKusick was named the founder-president of HUGO, the international Human Genome Organization, which promoted the launch of the public consortium, in 1990. He also became a champion of J. Craig Venter, who had developed a way to capture genes en masse. When Venter split from the public venture in 1998 to found Celera, a private genomics company, McKusick cheered on both efforts and kept above the fray.
Meanwhile, with genetic information mushrooming, McKusick and his helpers struggled to stay abreast of the field. In 1995, the National Center for Biotechnology Information took over the maintenance of the online version of Mendelian Inheritance in Man. Today McKusick, a staff of nine, and several freelancers comb the literature; they update the archives nearly every day. McKusick has broadened the criteria for entry so that a Mendelian scheme of disease is no longer required. Disease itself is no longer required. In these archives the number of genes described (genotypes) has now outpaced the number of disease descriptions, or phenotypes. For researchers and physicians the archive is the only bridge between the raw As, Ts, Cs, and Gs of genetic sequences and the human conditions presented in textbooks and examination rooms. "If you need functional information about the gene," says McKusick, "you need Mendelian Inheritance in Man." The staff doesn't even know the number of entries in each category of the online catalog. They're too busy gathering new information.
What makes Victor McKusick a giant? He is only an M.D. and admits to being unskilled in the laboratory—"not very able manually," as he puts it. When he was elected to the National Academy of Sciences in 1973, a few questioned whether he was a scientist or merely a "natural historian." McKusick replies: "There's a distinction, I've always thought, between the scientist, who knows more and more about less and less, and the scholar, who knows the background of his field."
His strength, like an oarsman's, is applied while looking backward. When he was promoted to physician in chief of the Johns Hopkins Hospital in 1973, McKusick attained a position held at the turn of the 20th century by the great diagnostician Sir William Osler. McKusick likes to show visitors the space under the golden dome of the central building where Osler wrote his famous medical manual. He compares his own catalog to Osler's work and to other intensively researched classics: the encyclopedia by Diderot et al. of the 18th century and Murray's Oxford English Dictionary of the 19th.
Mendelian Inheritance in Man takes about three-quarters of his time, he estimates. Most of his updating is done at his home computer, medical journals spread in front of him, but several days of the week he appears at his Hopkins office. There are conferences to plan, calls to return. McKusick has the telling accent of a Mainer and sometimes, too, the Maine abruptness. Look away and he is gone, departing the room in midthought or midconversation, not because his mind has wandered but because it has made a forceful, 90-degree turn to a more urgent matter.
"Medical genetics as a clinical discipline was instituted with me," McKusick declares, returning to his career. "I fostered the development of people in the field. In the 1970s medical genetics was a bit like nutrition, in that there weren't freestanding practitioners in the community. But in the 1990s, with the coming of chromosome and DNA tests, the development of reproductive and prenatal genetics, and the fact that there was so much more we could do in this field, we had the need for regulation and for the board certification of practice." In short, "I consider myself a teacher, a researcher, a physician."
Is there a deliberate order to the list?
"I'd prefer not to weigh them," McKusick replies.
Still, with human gene therapy far from being effective, what does the gene doctor do for the patient?
"I don't feel I've left clinical medicine," he says. "I pride myself on the fact that I still see patients. When I was department head, three times a week I made rounds with students."
McKusick stepped down from his medical school post in 1985, but he still serves as an unpaid professor and consultant at the hospital's genetics clinic. Today he will see a patient named Roy M. for his annual appointment. Roy M. has Marfan's syndrome, the condition McKusick investigated almost 50 years ago, when he was starting to compile the connective-tissue disorders caused by disease genes.
Rapping briefly on an examination room door, McKusick enters and finds a patient sitting in consultation with a young doctor. The patient, an African American, has long arms, which reach nearly to the floor. He has Marfan's syndrome, but he is not Roy M. McKusick withdraws, and shortly his own charge arrives. Surprisingly this man also is African American. His body appears normal, save for a surgical scar down the middle of his chest. The scar is proof of the value of a proper genetic diagnosis. Years ago Roy M.'s distended aorta and a faulty heart valve were replaced with plastic parts.
The patient's father had suffered a burst aorta in 1981, which revealed the Marfan's syndrome postmortem. Doctors examined the young Roy and found he had inherited his father's illness. Preventive surgery may have saved his life, but his disease continued. He couldn't go all out when playing sports. Now 30, he has been a heart patient for almost 20 years; he wonders whether he should have children. In the exam room he seems to move carefully and talk softly, as if he might strain himself.
After a brief exam, McKusick reviews the patient's medication and latest test results. He pronounces himself satisfied.
"So it sounds OK?" asks Roy M., meaning both his heart and his future.
"It sounds as though you're doing well," McKusick says firmly. "I wouldn't do anything differently. Good to see you as always, Roy."
This patient knew what was wrong with him. He was not in distress, unlike certain families who show up at the Hopkins clinic from small communities in distant states, wondering why their daughter is sick, why their son is not normal. McKusick and his colleagues diagnose the patient and treat symptoms as best they can. The doctor has admitted that his eyes light up when he comes across a phenotype that is new, another entry for the catalog. It's fair to say that Victor McKusick embodies both interpretations of the word clinical, one having to do with the medical clinic, the other indicating a coolness or coldness of vision.
McKusick's studies of Old Order Amish communities in Pennsylvania helped fire his interest in medical genetics. One of his pedigrees traced the inheritance of the disorder affecting this child born with 12 fingers. Photograph Courtesy of Victor McKusick
"It's a great comfort to families who come to me to have a label," he says, "even though there's not much we can do. Then they can find other families, join support groups. . .."
He pauses, turns his head to the side, and defends his approach: "The intellectual challenge of genetic disorders, yes. There's the fascination of the problem of the definition. But please don't label me as lacking in empathy for the patients and their families. It doesn't help them for me to be scared off by the pain of their situation. You have to put up with that. If I were undone by one patient, well, I've had dozens of such."
He pauses again, framing his reply. "Osler's most famous essay was titled 'Aequanimitas.' He meant that in order to do your best for your patients, you have to maintain a certain equanimity."
That the two Marfan's patients in the clinic were African American raises another ticklish question. No, says McKusick, Marfan's isn't more common among African Americans than among other groups. It is just chance that the two were here. Nor do genes tell us much about race. Racial characteristics are due to relatively few genetic variants. Compare any two human beings in the world, an African with a European, say, and their DNA will be on average 99.9 percent alike. But the human genome contains so much DNA that it accommodates all their innate individual differences in health.
That holds true for the two men at the clinic. Within the 0.1 percent of their differences were allelic variations of Marfan's syndrome. Different spellings of the disease gene resulted in different phenotypes—their dissimilar physical appearances.
The medical conditions that interest genomics researchers and drug companies are not Marfan's or Ellis-van Creveld syndromes. They are cancer, heart disease, arthritis, and diabetes: complex disorders involving multiple genes. The permutations in DNA that contribute to heart disease or high blood pressure are almost endless. Although the genes you inherit play a part, that part is neither decisive nor quantifiable. A family history indicates a risk, but an individual's genetic susceptibilities are so tangled that Mendel and a million monks could never have figured them out.
That's why possessing the complete DNA sequence of humans won't produce medical miracles any time soon. It's not just because of our variability. Genes make proteins and proteins interact in ways we don't understand. In a recent publication McKusick warned: "In general, the HGP [Human Genome Project] increases the gap between what we know how to diagnose and what we know how to treat. . .. There is also risk that the gap will be widened between what science really knows and what the public thinks is known."
But ever up-to-date, McKusick serves on the scientific advisory board of Celera, the private company that produced the genome sequence at the same time as the public effort. Like many other genomics companies, Celera plans to sell information about genes that may lead to new vaccines and drug therapies. Throughout the industry, human genes that may or may not be disease genes are being patented willy-nilly.
Does McKusick worry that the pharmaceutical industry's thirst for disease genes is distorting research priorities?
"Science is a self-correcting activity, where the truth will out," he says. "But competition within the biotech industry may also be a correcting factor. The profit motive isn't necessarily bad. It gets things done, as the sequencing projects have shown. The alliance between the academy and industry is essential."
He does allow that drug companies are neglecting the rare, single-gene aberrations—the very disorders he built his career on. "There are orphan diseases that might benefit from new enzyme therapies," he says. "But [the neglect] is not a new problem. Overall I'm happy with what I see. Medical genetics, or genetic medicine as we can call it now, has never been more exciting."
Check out the Lasker Foundation site: www.laskerfoundation.org/library/mckusick.
Online Mendelian Inheritance in Man: www.ncbi.nlm.nih.gov/entrez/ query.fcgi?db=OMIM.