soci 138

Chapter Title: Getting Their Organ Book Title: The Science of Human Perfection

Book Subtitle: How Genes Became the Heart of American Medicine

Book Author(s): NATHANIEL COMFORT

Published by: Yale University Press

Stable URL: https://www.jstor.org/stable/j.ctt32bqd2.10

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163

“VICTOR MCKUSICK, ‘FATHER OF MEDICAL GENETICS,’ 1921–2008,” ran the obit-

uary headline from Johns Hopkins. The British Medical Journal, the Lancet,

the NIH genome institute, and the March of Dimes all headed their obitu-

aries the same way. The popular science magazine Discover referred to him

as the “visionary researcher who is often called the father of medical

genetics,” and the online encyclopedia Wikipedia says that he is “widely

regarded as the father of clinical medical genetics.” “Rare is the scientist,”

wrote a Science magazine obituarist, “who is universally recognized as the

founder of a field.” Indeed, it is the sort of epithet that seems to place a

scientist in the pantheon with Gregor Mendel, Charles Darwin, and Isaac

Newton—people who lead revolutions, who create new disciplines out of

whole cloth. The term founder does not refer to McKusick’s prominent role

in guiding medical genetics as it morphed into molecular genetics and

genomics in the eighties or even the seventies; it refers to an origin myth of

“medical genetics” from the late fifties through the sixties. McKusick’s

moniker refers to paternity, not parenting.1

It is a strange family where the child predates the father. When McKusick

began studying heredity, medical genetics was not merely extant; it was, to

those working in it, vibrant, with a history stretching back decades. In the

Progressive era, physicians, public health workers, health reformers, and

geneticists studied the genetics of disease, establishing research methods and

disease model systems still in use today. The Treasury of Human Inheritance,

6

Getting Their Organ

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164 G E T T I N G T H E I R O R G A N

the first systematic attempt to catalogue pathological heredity, dated to the

first years of the century; surely Edward Blankenship, the English physician

whose work with Karl Pearson formed the core of the Treasury, could have laid

claim to parentage of medical genetics. In the twenties, Raymond Pearl had

brought genetics onto the margins of the medical campus with his Division of

Medical Genetics. Madge Macklin had coined the term medical genetics in

print in 1932, and she and others had practiced it under that name since then.

Laurence Snyder had taught the first course in human genetics for medical

students in the country in 1933 and a few years later had midwifed the

heredity clinics, where researchers approached many now-classic problems in

medical genetics with the limited methods—prevention, including eugenic

sterilization—and standard prejudices of the day. William Allan had founded

the first Department of Medical Genetics in the country. In the late forties and

early fifties, medical geneticists had gained a professional identity, with the

creation of the American Society of Human Genetics and its flagship journal.

Its founders had cast as wide a net as possible, embracing biologists, agricul-

tural breeders, old-school eugenicists, anthropologists, and physicians. By the

time McKusick became a father, then, his putative offspring already had a

long but morally ambiguous history, in which the founding principles,

methods, and administrative structures of the field were deeply entangled

with some of history’s worst abuses of biology.2

During the early years of McKusick’s career, in the late fifties and sixties,

genetics became established as a medical specialty, gaining standing in the

formal and rather rigid hierarchy of American academic medicine. Scholars

have called this a “critical period” and a “structural revolution,” but a closer

look at the preceding history reveals this moment to be a threshold, not a revo-

lution. Medical schools had established genetics programs at a rate of about

one or two every year since the founding of the heredity clinics in 1941. In

1956 Lee Dice retired, and as James Neel took the helm the Michigan

Heredity Clinic became the University of Michigan’s Department of Human

Genetics. The next year three new programs began: at the University of

Washington, the University of Wisconsin, and McKusick’s at Johns Hopkins.

McKusick’s was the most ambitious and the most systematic. He colonized

the Hopkins medical school, staking out administrative turf for his specialty

and carefully delineating its boundaries and its internal structure. He

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G E T T I N G T H E I R O R G A N 165

systematized the knowledge of heredity and disease, through numerous

publications, including a new catalogue of hereditary disease, the indispens-

able Mendelian Inheritance in Man. He proselytized for genetics as a medical

specialty, through publications, conferences, and especially an annual

summer course in Bar Harbor, Maine. And he baptized medical genetics in

numerous synthetic and historical reviews that gave the field an internal

narrative and creation myth. McKusick was neither visionary nor iconoclastic.

His contributions are voluminous but modest, even low-status: clinical case

studies, administration, teaching, cataloguing. He consolidated and codified

genetic knowledge of disease in a clinical context, and thereby legitimated

genetics among other physicians. He did not revolutionize medical genetics,

but through his tireless institution building and professionalizing activities,

he led the move to establish genetics as a specialty of mainstream medicine.3

Calling McKusick the father of medical genetics reflects an effort to

impose a break on a smooth and troubling history. The study of human

heredity and health evolved through the century, its methods, its profes-

sional identity, and its social relevance gradually accruing as it adapted to

each cultural moment. A narrative in which McKusick is the father of

medical genetics draws a comforting moral boundary between the contem-

porary genetic medicine we want to believe in as a positive moral good—and

the earlier eugenics we want to sequester in the distant past.

Coincidentally, in the fifties and sixties, a number of technical advances,

mostly small and low-tech, made academic hospitals attractive research sites

for geneticists working on medical problems. I will examine biochemical

and cell-culture techniques in detail in the next chapter, because their

crescendo came later. More important for the legitimation of clinical

genetics were the simple methods of studying chromosomes, long available

to organismal geneticists and finally applied to man in the fifties and

sixties. The unique identification of human chromosomes enabled medical

geneticists to identify, for the first time, actual physical correlates of genetic

disease. McKusick liked to say that other specialists all had an organ: the

cardiologist had the heart, the nephrologist the kidney. Cytogenetics,

he said, “gave us our organ.” The germ theory of genes—the Galtonian,

deterministic notion of gene as disease agent—became an organ theory of

genes.4

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166 G E T T I N G T H E I R O R G A N

* * *

Aptly, the alleged father of medical genetics was a twin. Victor A. and

Vincent L. McKusick were born on October 21, 1921, on their parents’ dairy

farm in Parkman, Maine. Their father was a gentleman farmer—he was a

college graduate and a former high school principal—and their mother had

been a schoolteacher. Vincent studied law and eventually became chief

justice of the Supreme Court of Maine, while Victor went into medicine.

There was a “good environmental reason for that,” McKusick said in an

interview in 2001, playing on the nature-nurture dichotomy that is never far

below the surface in human genetics. At age fifteen Victor developed a

severe infection resulting from an abscess. Doctors treated him with the

new drug sulfanilamide, one of the first commercially available antibacterial

drugs. “In the process,” he said, “I saw a tremendous amount of medicine

and a tremendous amount of doctors and decided this was for me. Vincent,

who did not have that experience, fortunately, continued his own course.”

Geneticists tend to like determinist jokes, and the writers among them savor

the prickles of Latin syllables. “Perhaps I would have ended up a lawyer if it

weren’t for the microaerophilic streptococcus,” McKusick quipped. He

matured into a tall, rail-thin man, with an aristocratic air that aggregated his

physician’s authority, old-school formality, and reserved New England

demeanor. Though he could be high-handed, he was kind and well liked. He

had a knack for telling stories and a superb memory to the end of his life. He

supplemented his memory with an ever-present camera, snapping candids

at lectures and meetings like a parent at a playground. Part of his reputation

as father of the field stems from his role as the field’s first griot. His narra-

tives are epic, precise, and uncannily consistent. They need to be handled

with care.5

McKusick enrolled at Tufts University in 1940, but the war effort acceler-

ated his plans. The medical school at Johns Hopkins, unable to fill its class,

accepted McKusick after six semesters of college. Under accelerated

wartime training programs, he earned an M.D. in three years, donning the

white jacket in 1946. He did both internship and residency at Hopkins, and

the university hired him to the faculty. He remained at Hopkins until his

death in 2008.

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G E T T I N G T H E I R O R G A N 167

McKusick went into genetics the way William Allan had done: he sought

out a geneticist for informal tutelage. There was no other way. Hopkins did

not yet offer a genetics course. His introduction to heredity came through

the clinic: in 1947 a fourteen-year-old patient presented with melanin spots

on his lips and inside his mouth as well as polyps in the small intestine.

“Right after that, another single case came in,” he said. “Then I had a family

in which three members were affected, indicating that it was inherited.” He

heard “through the grapevine” that Harold Jeghers, a Washington, DC,

physician, had five cases of the same combination of polyps and spots. He

said he surveyed the literature and found that a Dutch physician named

Peutz had described the syndrome in the 1920s. McKusick noticed the

hereditary pattern, and, consulting Bentley Glass from the biology depart-

ment, worked out the heredity. As Bateson tutored Garrod, as Snyder

tutored Allan, so Glass guided McKusick through the elements of

Mendelian genetics. McKusick published with Jeghers, although his name

did not make it onto the eponym: Peutz-Jeghers syndrome.6

Polyps and spots did not turn McKusick into a medical geneticist. He

went into cardiology and specialized in heart murmurs, utilizing the new

technique of spectroscopy to analyze heart sounds. “I got training in cardi-

ology because there was no such thing as medical genetics,” he said in 2001.

There was no such thing as medical genetics training at Johns Hopkins, but

there certainly was such a thing as medical genetics. Indeed, the field was

enjoying a growth spurt, triggered to a large extent by the recent formation

of the American Society of Human Genetics. Preparing for his 1952 presi-

dential address to the society, Lee Dice from Michigan polled his colleagues

for news about new heredity clinics around the country. Beginning with the

Cold Spring Harbor Eugenics Record Office, which he called the first

heredity clinic, he recounted how the idea, which he had been so central in

formulating, had spread to many institutions in the United States and

Canada. The Michigan Heredity Clinic was thriving; Jim Neel was assuming

increasing responsibilities and was the presumptive successor as Dice made

preparations for retirement. Besides Herluf Strandskov at Chicago and

Franz Kallmann in New York, there was the group in Utah, with F. E.

Stephens and Eldon Gardner. At the University of Toronto, Norma Ford

Walker was an associate professor of zoology and staff geneticist at the

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168 G E T T I N G T H E I R O R G A N

Hospital for Sick Children. In Montreal, F. Clarke Fraser, an M.D. and

Ph.D., had started up a division of medical genetics in the pediatrics depart-

ment at McGill University’s affiliated Children’s Hospital, focusing on his

specialty of dysmorphology, the study of skeletal and systemic defects. L. C.

Dunn, Frederick Osborn’s frequent adviser since the late 1930s, was

6.1 Victor McKusick, on the right, with his twin brother, Vincent, c. 1924. Courtesy of Alan Mason Chesney Archives, Johns Hopkins University

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G E T T I N G T H E I R O R G A N 169

planning an institute for the study of human genetic variation, which he

expected to open in the fall. And, like a genetic Johnny Appleseed, Laurence

Snyder seemed to leave behind a program in medical human genetics at

every institution where he held a job or gave a lecture—among them Wake

Forest, Ohio State, the University of Oklahoma, and soon the University of

Hawaii. To those in this expanding circle, the growth of medical genetics

was thwarted by the war, but it had resumed with added vigor in the late

forties. In the early fifties, the golden age seemed just around the corner.7

McKusick was not yet part of that club. He had no formal training in

genetics. He did not attend the AAAS or AIBS meetings where the ASHG

members congregated. He was an adept networker, but his world was the

parochial universe of the wards of Hopkins. In the course of his cardiolog-

ical experience, he encountered Marfan syndrome, a condition involving

heart problems, eye defects, and a tall, gangly stature (Abraham Lincoln is

often suspected of having had Marfan). Like Dice and Herndon in rural

North Carolina, McKusick sometimes spoke like a naturalist, collecting and

doing descriptive taxonomy. “I collected a large number of Marfan patients,”

McKusick said, “and analyzed the families from the pattern of inheritance

point of view and analyzed the individual cases from the point of view of the

clinical manifestations and natural history of the disorder.” He interpreted

Marfan as a pleiotropic disorder—one gene, many effects. Like Garrod

before him, he sought other similar conditions—in this case other heritable

disorders of connective tissue. In 1956 he published a monograph under

that title, which collected his findings on Marfan, Hurler syndrome, Ehlers-

Danlos syndrome, osteogenesis imperfecta, and pseudoxanthoma elas-

ticum, a peculiar condition in which the skin becomes so stretchy that it can

be pulled several inches away from the body. The book established McKusick

in the field of clinical genetics.8

* * *

That summer, he brought a talk on the heritable disorders of connective

tissue to Copenhagen, where the Danish medical geneticist Tage Kemp

presided over the first international congress of human genetics. The 1956

Copenhagen meeting looms large in the mythology of medical genetics,

because it occurred at what has become known as the birth of the field.

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170 G E T T I N G T H E I R O R G A N

McKusick called it a “very defining experience” in his medical-genetic

education. It is a trough in the medical-genetic landscape; events on either

side tend to roll mnemonically into the summer of 1956, and Copenhagen

gets credit for publicizing and therefore originating them.9

Nearly four hundred delegates attended, and fourteen countries sent

national committees to the meeting. The prewar and immediate postwar

cohort who had established the heredity clinics and founded the ASHG still

dominated the American committee, which included such representatives

as Sheldon Reed, Pete Oliver, Eldon Gardner, and Arthur Steinberg. An

ambiguous group of respected geneticists with Nazi ties represented

Germany: Otmar von Verschuer, Fritz Lenz, and Hans Nachtsheim all

sought reintegration into the international genetics community. The British

committee included Lionel Penrose, the Galton Professor, and Harry Harris,

a biochemical geneticist at London Hospital Medical College, among others.

Many Scandinavian medical geneticists attended, of course. Their noncoer-

cive medical eugenics established a model for volunteeristic state control of

heredity; several delegates reported on recent efforts to institute genetic

registration of infants as an experiment in socialized genetic medicine. The

formal government apparatus provided a supporting structure for voluntary

eugenics, which scientists such as Kemp deemed not only acceptable but

necessary for the responsible stewardship of the race.

The Danish minister of education, Julius Bomholt, opened the proceed-

ings by invoking the atomic age and how it had shaped human genetics as a

field. He stressed its role in making the prevention of “the occurrence and

spread” of hereditary disease a topic of intense interest. Kemp took up this

question in his presidential address, sharpening it in genetic terms.

Invoking H. J. Muller’s paradigm-generating paper of 1950, Kemp wrote,

“Within recent years, very much attention has been drawn to the dangers

which our load of mutations involves for the human race.” Indeed, Muller’s

paper, “Further Reflections on the Load of Mutations in Man,” followed

Kemp’s remarks in the proceedings. But one could turn this observation

around, Kemp noted, and recognize the “treasure of normal genes” we

harbor in our cells. Medical geneticists were the stewards of the gene pool.

“It is the task and responsibility of mankind in our generation, and in partic-

ular of the students of human and medical genetics, to protect this treasure

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G E T T I N G T H E I R O R G A N 171

and to shelter this heritage from harmful influences and threatening

hazards.” For Kemp, the “rise and rapid progress” of human genetics during

the previous half-century—particularly in blood group studies, radiation

genetics, population genetics, genetic epidemiology and control, medicoge-

netic registration, and genetic counseling—meant that the dream of genetic

control was at hand. “The time is drawing near,” he wrote, “when man can

control his own biological evolution and also command his environments

and conditions of life to an increasing extent.” The medicalization of human

genetics would enable mankind to at last realize the fantasy of self-directed

evolution.10

Much of the meeting concerned topics that would have been familiar to

any human-geneticist back to the beginning of the century. It featured twin

studies and pedigrees; studies of inbreeding and cousin marriage; studies of

color-blindness, hemophilia, and polydactylism; studies of race mixing;

studies of intelligence and psychological disorders. Medicine, anthropology,

and psychology still vied for predominance. President Kemp, describing

Denmark’s “medico-genetic or genetic-hygienic registration,” outlined a

method of field work indistinguishable from that of William Allan and Nash

Herndon:

A physician, who is trained as a specialist in the field concerned, makes a thorough investigation of the individuals with the disease or lesion in ques- tion and of their families, partly on the basis of hospital records, other docu- mentary material and genealogical investigations, partly by traveling about, visiting and examining the individual patients in their homes or by calling the patients to an institution or to some hospitals for observation and more thorough investigation. Through the studies of the various diseases and lesions their mode of inheritance, their etiology and pathogenesis, their clinical picture, their frequency and geographical or social distribution in the population, the possibilities of their treatment and prevention, and the effective fertility of the affected can be investigated.11

Although analytical techniques had grown more sophisticated since 1940,

the end was the same: “Using the experiences gained in the medico-genetic

registry it will be possible to exercise a genetic-hygienic or eugenic activity as

adviser on questions of sterilization, induced abortion, marriage, adoption

and special relief.” Such was the reality of preventive medicine in the atomic

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172 G E T T I N G T H E I R O R G A N

age. Although the bomb had rung in a new era filled with newly powerful

sources of genetic risk, the means for reducing and ameliorating that risk

remained about what they had been in the Progressive era. The gentle

socialism of northern Europe provided the centralization necessary to

consider such a project; American medical geneticists could only sigh and

hope for such a system.12

New methods lay on the horizon. Until this point, prediction of genetic

disease had been a statistical process: given known family history and the

inheritance pattern of a disease, what are the odds that this couple’s children

will have a given condition? Two local physicians, however, were experi-

menting with a technique that could potentially tell whether this baby would

have that disease. Earlier in the year, Povel Riis of Copenhagen County

Hospital and Fritz Fuchs of the University Hospital of Copenhagen had

published a letter to Nature describing a new method of determining the sex

of a fetus. In 1949 the Canadian Murray Barr had discovered a dense, dark-

staining body made of chromatin present in the cell nucleus of females but

not males. A dozen years hence, the reclusive English cytogeneticist Mary

Lyon would hypothesize (correctly) that the Barr body was an inactivated X

chromosome. But for Barr, the tiny cellular structure was simply a clinical

sign, an indicator of femaleness. From a blood test alone, he could establish

a person’s sex with near 100 percent accuracy: females were said to be

chromatin-positive; males chromatin-negative. Carefully inserting a six-

inch needle into a pregnant woman’s belly, Riis and Fuchs successfully

sampled the amniotic fluid, examined the cells, and ascertained the sex of

the fetus. The same year, three other groups claimed to have discovered how

to determine fetal sex, but again, Copenhagen gets the credit.13

In a pair of papers in the Copenhagen conference, Riis, Fuchs, and

colleagues described the possibilities for extending the method. First, they

used the “smear” method developed by Georgios Papanicolaou to determine

the chromosomal sex of patients with syndromes of sexual development,

such as Klinefelter’s and Turner’s. (The Klinefelter’s patients were

chromatin-positive; Turner’s chromatin-negative.) Then they considered the

possibilities for testing for genetic disease in the unborn. At this point, that

was limited to serology. If the fetal blood group could be determined as early

as the sex, they wrote—that is, by the fourth month—and the amniotic fluid

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G E T T I N G T H E I R O R G A N 173

could be safely withdrawn at that stage, “then it should be possible to diag-

nose both sex-linked and blood-group-linked hereditary diseases at a stage

where pregnancy can be safely interrupted.” The paper was as speculative as

this makes it sound—they had only a couple of samples and were mainly

describing the possibility. It was a method in search of a technique. But if it

were successful, the authors saw potential applications in genetic preventive

medicine. The determination of fetal sex and fetal blood group—and poten-

tially other genetic properties in the future—they concluded, “would seem

to be of value in preventive eugenics.”14

Four years later, Riis and Fuchs reported aborting male fetuses from two

mothers with hemophilia. Each boy would have had a 50 percent chance of

having the disease. Under the Danish eugenics law, mothers had the right to

request termination of pregnancy if there were “close risk that the child, due to

inherited characteristics or to disturbance or disease acquired during foetal

life, may come to suffer from mental disease or deficiency, epilepsy, or severe

and non-curable abnormality or physical disease.” What they called preventive

eugenics we today would call prenatal diagnosis with therapeutic abortion.15

Such a procedure was still science fiction in 1956. Outside of X-linked

traits such as hemophilia, which can be identified from a pedigree, there

was still no significant cytogenetics of humans. Since the teens, Drosophila

geneticists had been mapping traits to specific chromosomes. They had

twenty years’ worth of fine-structure mapping data, based on precise and

consistent banding patterns brought out by staining the remarkable giant

chromosomes of the fly’s salivary glands. The genetics of other organisms—

mice, maize, the bread mold Neurospora—had followed. But human

genetics still relied on indirect methods. Although the debate over the

correct number of chromosomes in human cells had been settled back in

the 1920s, still the individual chromosomes could not be distinguished

uniquely under the microscope.

Within weeks of Riis and Fuchs’s Nature paper, however, a sheepish note

appeared from Joe Hin Tjio, then working in Zaragoza, Spain, and Albert

Levan, of the Institute of Genetics in Lund, Sweden: we seem to have had the

chromosome count wrong. They had looked only at lung cells, and they noted

that the result could conceivably be an anomaly, but their data strongly

suggested that humans actually have forty-six chromosomes, not forty-eight.

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174 G E T T I N G T H E I R O R G A N

McKusick remembered that at Copenhagen, “Tjio had an exhibit showing his

chromosome spreads, which you had to count as forty-six, without a doubt, in

number.” Further, Charles E. Ford and John Hamerton from Harwell

presented confirmatory evidence from a range of tissues. Copenhagen thus

tends to be remembered as the place and time that they got the number right.16

The human chromosome number is difficult to determine under the best

of circumstances—as Barker pointed out in 1927, the chromosomes are

small and numerous, and tend to clump together in the nucleus. Further,

the best techniques of the time for obtaining clear images of cell nuclei

involved fixing, embedding, and slicing the tissue very thin—thinner than a

cell nucleus—for viewing under a microscope. A given chromosome often

spanned more than one slice. Integrating a tangle of chromosomes at

different stages of condensation across multiple histological slices was

fraught with inaccuracy. Four technical advances led to a new means of visu-

alizing the nucleus. The first, tissue culture, was a significant and complex

development that occurred over many years. Animal cells had been cultured

for decades, but until 1950, human cells had proven refractory to culture

techniques (see chapter 7). The discovery of colchicine, a toxic compound

isolated from the autumn crocus, enabled researchers to suspend the cell

cycle at metaphase, the stage in which the chromosomes were most count-

able, looking like little sausage links. The other developments were humble,

almost trivial. In 1952 T. C. Hsu at the University of Texas accidentally added

deionized water rather than saline to his culture medium. The cells took up

the pure H2 O and swelled, spreading the chromosomes out within the

nucleus. And an old, low-tech method of preparing chromosome slides that

the plant biologist John Belling had developed in the twenties was at last

applied to preps of human cells: rather than fixing, embedding, and slicing,

you simply put a drop of culture medium onto a microscope slide, added a

coverslip, and squashed it flat with your thumb. This leaves the chromo-

somes intact, removing the ambiguity of integrating chromosome counts

across slices. All of these techniques had been available for years. Tjio and

Levan appear to have been the first human-geneticists to combine all four.17

Once researchers recalibrated their expectations, they were flooded with

data. Cytogeneticists trawled the margins of society for chromosomal anom-

alies among primitives, criminals, the mentally ill, and the sexually

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G E T T I N G T H E I R O R G A N 175

ambiguous. At the radiation genetics laboratory in Edinburgh, where Muller

had brought his X-ray machine back in the 1930s, a mutation group led by

William Court Brown, A. G. Baikie, and Patricia Jacobs examined sex chro-

mosome anomalies, as did Paul Polani’s group in London. They linked

“chromatin-positive” Klinefelter syndrome to the presence of an extra X

chromosome, leading to an XXY constitution, while “chromatin-negative”

Turner syndrome correlated with the loss of an X. They found a “super

female” who had a triple-X constitution. And in 1962 they found an XYY

“super male” in a population of “defectives” in a nearby mental hospital.

Court Brown speculated that there might be a correlation between violent

crime and the extra male chromosome. The bad blood, bad germ plasm, and

bad genes of earlier days had given way to the bad chromosome.18

Soon, researchers also linked non-sex chromosomes, or autosomes, to

disease. In 1959 the French physician Jerome Lejeune found that

“Mongolism”—which Penrose was campaigning to rename Down’s (today

simply Down) syndrome—correlated with an extra copy of the smallest

chromosome. Presence of an extra chromosome is called a trisomy. Most

trisomies are lethal in humans; they result in miscarriages. But several are

viable, and within five years, researchers had identified all of them.

Although the chromosomes could be counted, it was still several years

before they could be uniquely distinguished. Well into the sixties, recalled

the cancer geneticist Peter Nowell in 2007, “you couldn’t tell a 21 from a 22,

or a 7 from an 8.” Absent unique identifiers, researchers grouped similar-

sized chromosomes into lettered clusters, A through G. Alternative nomen-

clatures proliferated. Like the gene nomenclature debate in the 1940s, the

seemingly desiccated topic of chromosome standardization and nomencla-

ture in the sixties became partisan and passionate. In 1960 Theodore Puck

in Denver organized a workshop to negotiate a consensus, but it did little to

cool researchers’ tempers. Too many investigators had invested too much to

make any one naming system universally acceptable. “The risk that a

minority may be unable to accept the system as a whole,” cautioned the

workshop’s summary report, “should not be allowed to delay adoption by a

majority.” They agreed to number the chromosomes in descending order of

size, starting with the largest, designated chromosome 1. But lingering

ambiguities in cytological technique resulted in the smallest two being

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176 G E T T I N G T H E I R O R G A N

swapped; Down syndrome, trisomy of the smallest chromosome, is trisomy

21. Uncertainty remained throughout the decade. Even in 1969, McKusick

was still referring to “trisomy D” and “trisomy E.”19

Biochemical genetics, still on the edge of the radar screen, represented an

alternative to the organ theory of genes. The origins of biochemical genetics

lay in blood group serology. Blood group antigens are excellent genetic

traits; everyone expresses them and there is no ambiguity over which form

someone has. In recent years, researchers developed new methods for

analyzing and purifying other proteins as well (see chapter 7). Given a set of

clinical symptoms, phlebotomy and a few laboratory tests could identify

blood titers of molecules and compounds that correlated with disease.

Combining this method with pedigree analysis, twin studies, and/or

consanguinity studies, the researcher might be able to make strong claims

about the inheritance of the trait. The researcher still did not “have the

gene,” but with luck and skill one might get what appeared to be the gene

product. Within a few years, biochemical markers began to provide reliable

signs and predictors of simple Mendelian disease.

In 1961 the microbiologist Robert Guthrie developed a test for the rare

amino acid deficiency phenylketonuria (PKU). His method was a simple

bacterial inhibition assay: bacteria are cultured on an agar plate with a

compound (B-2-thienylalanine) that inhibits growth. Phenylalanine, the

enzyme missing in PKU patients, overcomes the inhibition. Thus blood

from a normal patient placed on the agar produces a bacterial colony, while

PKU blood does not. With modest training and skill, doctors and nurses

could learn to draw blood and fill the standardized spots on a “Guthrie card”

and send it to a lab where the culturing was performed. In 1962 W. J. Culley,

working in Canada, adapted paper chromatography to develop a more

involved but more quantitative measure of phenylalanine production. By

middecade, both the United States and Canada had implemented mass

screening of newborns. In the seventies, expanded genetic screening

encompassing wider geographical areas and more common diseases would

lead to the eruption of major ethical debates over medical genetics and fuel

the growth of professional genetic counseling. Archibald Garrod’s inborn

errors of metabolism, conceived originally as nonpathological markers of

individuality, had come to signify the agents of disease. Garrod had been

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G E T T I N G T H E I R O R G A N 177

interested in “soil,” but for most researchers, his inborn errors now

connoted “seed.”20

Yet Garrod’s original sense of the inborn error had begun a small renais-

sance. The 1956 Copenhagen meeting contained a small session on

biochemical genetics; almost every paper in it invoked Garrod, either

directly or by referencing the term or concept of inborn errors of metabo-

lism, often in the context of constitutional “soil.” The neoconstitutionalist

Roger J. Williams led off, making the case for his “genetotrophic concept,”

an updated, biochemical take on George Draper’s “panels” of constitution

(chapter 3). In 1956 Williams published Biochemical Individuality, a semi-

popular monograph describing the genetotrophic concept and of course

invoking Garrod in the title. Williams distanced himself from eugenics,

which he thought impossible to carry out with justice, and articulated the

concept that “heredity plays a role in all diseases; infectious, nutritional,

metabolic, degenerative, mental, psychosomatic.”21

The notion that heredity plays a role in all disease implies that genetics is the

fundamental science of medicine—that it underlies all biological processes

and therefore is involved in every aspect of health. A biochemical approach to

genetics makes such a view possible (though by no means necessary) thus:

genes were coming to be understood as somehow specifying proteins. Proteins

do the work of the cell; they constitute the receptors, enzymes, signals, and

structural molecules without which we would be inanimate bags of fat, sugar,

and water. If disease is a response to the body’s environment—and who could

argue that it is not?—it is somehow mediated by proteins. And therefore by

genes. If a given disease is a maladaptation, a genetic variant may underlie it. If

a disease is a normal response to a toxin or germ, there may be genetic variants

that confer resistance. In 1902 Garrod had written of the genetic basis of minor

chemical variations in metabolism, obesity, and the “various tints of hair, skin,

and eyes,” as well as “idiosyncrasies as regards drugs and the various degrees

of natural immunity against infections.” By the mid-1950s, a small contingent

of medical geneticists had begun to realize Garrod’s vision.22

In practical terms of building a nascent discipline, this all-encompassing

approach implies a strategy of infiltration. If you believe genetics lies at the

foundation of all medicine, and you want to spread the influence of genetics,

what you need to do is inject a bit of genetics into all the other departments

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178 G E T T I N G T H E I R O R G A N

and divisions of the hospital. Consult wherever you can, show your

colleagues how an understanding of genetics will improve their practice.

McKusick’s colleague Barton Childs was an infiltrator. His approach to

medical genetics provides a nice contrast to McKusick’s. Born on Leap Day

1916, Childs grew up in Chicago; till the end of his life he was a flat-voweled

midwesterner—candid, cantankerous, and deeply loved by those who knew

him. He was adopted, which amused him as a geneticist, he said, “because I

have no family history.” He was fiercely private: he refused to discuss his

personal life or feelings in interviews, and disliked being photographed.

Childs had a scientific temperament—analytical, experimental, quantita-

tive. Like McKusick, he came to Hopkins for medical school, joined the

faculty, never left. He became interested in pediatrics and joined the Harriet

Lane Home, Hopkins’s pediatric center.

Because hereditary conditions are present from birth, pediatricians see a

disproportionate amount of genetic disease. “There was a tremendous

number of children with anomalies,” he said in a 2001 interview, “and I

wondered what was known about them and read something about anoma-

lies and learned that there were two ways to study them. One was to take

something out of every bottle on the shelf and give it to a pregnant rat, and

not surprisingly, the rat would have deformed offspring.”23 This was the

clinical specialty of teratology. F. Clarke Fraser at McGill University was a

pioneer in this approach. “Everything was going towards environmental

causes of malformations,” Fraser said about his own entry into medical

genetics, in the late 1940s, “and I thought you ought to get genetics back

into the picture.” A plastic surgeon named Happy Baxter, he said, suggested

that he give the newly discovered steroid hormone cortisone to his experi-

mental animals, hypothesizing that he would see defects in the developing

spinal cord, or neural tube. “So,” Fraser said,

I stuck some into some pregnant mice, making wild guesses as to what the dosage was and so forth. And we got cleft palates, not neural tube defects. We showed very early that there were mouse strain differences in frequency from the same dose at the same stage and everything. That was the first demonstration, I think. It was the first normally used drug that would cause malformations in mice. It also was the beginning of bringing genetics into teratology.24

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6.2 Barton Childs, the Garrodian with no family history. Courtesy of Alan Mason Chesney Archives, Johns Hopkins University

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180 G E T T I N G T H E I R O R G A N

“That seemed a rather inelegant way of doing things,” Childs said. “I

found that the alternative way was to do genetics.” It is typical of the

rivalries between subspecialties to deny that the other is even doing

genetics. “The genes seemed circumscribed and rather fine in how they

worked, and that seemed a far superior way to understand the production of

anomalies.” Childs grew into one of the most passionate and articulate

Garrodian medical geneticists—clinical, biochemical, individual—and

inspired many contemporaries and younger medical researchers to follow

his path.25

As two of the few doctors at Hopkins with an active interest in genetics,

Childs and McKusick connected. With Bentley Glass from Biology and

Abraham Lilienfeld from Public Health, they formed the Galton-Garrod

Society reading group (chapter 1). They also developed lectures on genetics

that they presented to the medical students, although after a few years

McKusick took over the course himself. Although Childs and McKusick

established medical genetics at Hopkins together, Childs gets less acknowl-

edgment, even at his home institution. Childs, steeped in the Galton

Institute’s brand of Garrodian individualism, conceived of genetics as some-

thing fundamental to all of medicine. This meant trying to make the various

medical specialties more genetic, rather than establishing genetics as its

own specialty. His style of intellectual infiltration eventually colored all of

Hopkins’ biomedicine. Today, Childs’s philosophy of medicine, expressed in

his dense, elegant book Genetic Medicine: A Logic of Disease, lies at the core of

the Johns Hopkins medical curriculum Genes to Society, but he never

became the “father” of anything professionally.26

* * *

Whereas the Garrodian notion of genes-as-soil implies a strategy of infiltra-

tion, the Galtonian genes (or chromosomes)-as-seeds approach implies

colonization. McKusick proved to be a master colonizer. He had a receptive

intellectual and professional climate, unmatched resources and institu-

tional reputation, and the entrepreneurial acumen to exploit them in

building an institute of international renown. He used them to build at

Hopkins the most successful heredity clinic in the country, nestled in the

bosom of one of the hospital’s flagship departments.

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G E T T I N G T H E I R O R G A N 181

Hopkins was known as the American bastion of “scientific medicine.”

Traditionally, that had meant science as the handmaiden of medicine, the

rational explication and analysis of disease. In the Progressive era, the

constitutionalist and eugenicist Lewellys F. Barker established clinical labo-

ratories within the Department of Medicine, several of which gained admin-

istrative standing as “divisions,” or subdepartments. Under this structure,

Hopkins became increasingly supportive of curiosity-driven basic research

and known for the study of rare conditions. In 1929 Joseph Earle Moore

took over the Hopkins syphilis clinic, established in 1915. It epitomized

Barker’s vision: in it, a clinic and laboratory existed side by side, one treating

the disease, the other studying its biology. With the introduction of antibi-

otics after the Second World War, syphilis became much less interesting

therapeutically; it seemed basically solved. Moore expanded the syphilis

clinic into a generalized chronic disease clinic. He established ties with

researchers and clinicians around the medical campus—such as epidemiol-

ogists in the School of Hygiene—and at other universities. He developed an

informal exchange program with several hospitals in the United Kingdom,

with fellows traversing the Atlantic in both directions. He started a new

journal, the Journal of Chronic Diseases, that fit his broader interests.

Beginning in July 1955, Moore published in serial form many of the chap-

ters of McKusick’s Hereditary Diseases of Connective Tissue. Thus the study of

infectious disease morphed into the study of genetic disease.27

In 1954 Moore was diagnosed with prostate cancer; he would retire in

1957. His clinic would need a new chief. A. McGehee Harvey, chairman of

the Department of Medicine, had been expanding Barker’s system of

specialty divisions. He tapped McKusick as the next head of Moore’s clinic.

McKusick easily negotiated the establishment of a new Division of Medical

Genetics, which would be coextensive with the clinic but administratively

part of the hospital chain of command. The division of medical genetics was

formalized on July 1, 1957. Deftly, McKusick renamed Moore’s clinic the

Joseph Earle Moore Clinic.28

With the clinic, McKusick inherited Moore’s patient population and refer-

rals from around the hospital. He assumed Moore’s grants and maintained

his ties to the United Kingdom. He inherited Moore’s tradition of hosting

English fellows, who suddenly found themselves being trained as medical

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182 G E T T I N G T H E I R O R G A N

geneticists. “Many of them came early on to work in a chronic disease unit,”

McKusick said, but found themselves working on genetic problems. “I really

proselytized them to the field of medical genetics.” For example, Edmund

Anthony (“Tony”) Murphy was already a fellow in the Moore Clinic when

McKusick took it over and steered him toward human population genetics.

Samuel H. (“Ned”) Boyer IV came to Hopkins to work on heart sounds;

McKusick pushed him toward genetics as well, partly through sending him

back to England for a stint at the Galton Laboratory to learn biochemical

genetics.29

McKusick himself rounded out the section by running “clinical

genetics”—genetic counseling and diagnosis—thereby setting clinical and

scientific medical genetics side by side. One of the first projects he under-

took was to follow up on the patients from the largest study of constitutional

medicine to have been done at Hopkins: Raymond Pearl’s longevity study

from the 1920s. Pearl’s study, recall, was a clinical updating of the methods

of Davenport and the ERO (see chapter 3). McKusick recognized the value of

Pearl’s data and realized that he could multiply that value by following up

with the many patients who were still alive, as well as their children. He

gained access to Pearl’s files and even hired Pearl’s assistant, Blanche Pooler,

out of retirement to help him. He made the longevity study longitudinal by

tracking down patients and death records and even using “field work

sheets”—direct descendants of the record forms employed by Pearl,

Davenport, and Galton. Another nod to earlier methods of medical genetics

was McKusick’s study of the genetic diseases of the Amish, a set of repro-

ductively isolated communities in Maryland, Ohio, and Indiana, which in

some ways were an even better group than William Allan’s “gold mine of

heredity” in the North Carolina mountains.30

In February 1959 McKusick brought in Malcolm Ferguson-Smith,

another English postdoc, to set up a human cytogenetics laboratory—

among the first in the United States, if not the first. Back in the teens, when

Thomas Hunt Morgan’s Drosophila group developed its gene-mapping tech-

niques, the publications practically flew out of the labs. So it was for human

cytogenetics in the sixties. Although proficiency required practice and a

virtuoso cytogeneticist was a master indeed, the work required little special-

ized or expensive equipment, and postdocs, graduate students, and

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G E T T I N G T H E I R O R G A N 183

technicians could be easily and quickly trained to begin getting results. The

data, once standardized, were immediately interpretable and were directly

relevant to clinical diagnosis. In the 1960s, cytogenetics had a kind of

glamor; it had the same sex appeal as the germ theory in the 1880s or

eugenics in the 1910s—the allure of finding a single causal agent for a

medically important condition.31

Ferguson-Smith established “sort of an assembly line” of cytogenetics,

recalled Barbara Migeon, who worked in the lab, then ran it when Ferguson-

Smith left. Once a good-quality photograph was taken, in which all the chro-

mosomes could be seen and measured, the image would be enlarged three

thousand or four thousand times. Workers would then physically cut out the

individual chromosomes and sort them—chromosome 1, chromosome 2,

X, Y, and so forth. “We would all sit there and cut out chromosomes from

photographs and label them and put them in envelopes,” Migeon said.

“Then eventually you’d paste them,” she said, into an orderly display called a

karyotype. The process would have been familiar to Barbara McClintock,

working on maize chromosomes in the 1930s, or even Calvin Bridges and

Alfred Sturtevant, working on Drosophila in the teens and twenties. Once

the display was standardized, one could search for anomalies and correlate

them with the medical condition of the donor. “We were looking at all kinds

of individuals for the first time, and there were lots of hypotheses about who

might have an abnormal chromosome,” Migeon said.32

Sex chromosome anomalies and autosomal trisomies involved the

presence or absence of an entire chromosome. Soon, cytogeneticists

detected gross rearrangements, in which a piece of a chromosome was lost,

duplicated, or “translocated” from one chromosome or another. The

Ferguson-Smith lab specialized in the sex chromosomes and especially sex

chromosome anomalies such as Turner and Klinefelter syndromes. They

also described chromosome patterns in different human diseases and

different animal species, and they looked at the chromosomes of what they

still called “mental defectives.”33

In 1960, ninety miles to the north, Peter Nowell, a physician-scientist at

the University of Pennsylvania, and David Hungerford, a postdoctoral fellow

at nearby Fox Chase, found what at first appeared to be a new, albeit tiny,

chromosome. “We were looking at different kinds of leukemia” and trying to

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184 G E T T I N G T H E I R O R G A N

find a chromosomal correlation, Nowell told me. The British groups at

Harwell, London, and Edinburgh had been doing similar work. In

Philadelphia, the staff at nearby Presbyterian Hospital would draw blood, or

allow Nowell to draw blood, from leukemic patients so that he and

Hungerford could look at their chromosomes. In the acute leukemias, they

found no consistent chromosome abnormality. In one of the chronic leuke-

mias, however—chronic myelogenous leukemia, or CML—they found “this

little abnormal chromosome that was present in every cell of every case.”34

They realized it had to be a chromosome fragment. “What we couldn’t tell,”

Nowell said, “was whether it was a deletion or a translocation, because the

piece that was missing was so small that you couldn’t, in those days without

banding, tell whether the missing piece was stuck on some other

chromosome.”

Drosophila geneticists had long been able to stain chromosomes so as

to highlight characteristic patterns of light and dark stripes, which acted

like signatures for the various parts of the chromosomes. In 1917

Alfred Sturtevant had described in Drosophila a rearrangement called an

inversion—in which a chromosome segment breaks off and reattaches

upside down—by observing a reversal in the banding pattern. But there was

no way to make such discriminations with human chromosomes. All the

human-geneticists had to go on in the sixties was overall shape and size. “It

wasn’t until the seventies,” Nowell said, “when banding techniques came

along and specific cytogenetic changes in other leukemias, associated with

other leukemia types, were identified, that people came to really realize that

this was a way of identifying a particular genetic change that was clearly

central to the causation of the tumor.” The “Philadelphia chromosome” was

a landmark: the first cancer associated with a specific chromosomal change.

But technically, it merely represented human cytogenetics slowly catching

up to where Morgan’s fly boys had been back in the teens.35

McKusick emerged as the leader of a largely descriptive science of

medical genetics that was driven by the needs of the clinic. The character of

his Division of Medical Genetics at Hopkins was colored strongly by local

institutional traditions and style—and by McKusick’s skill in following and

using them. Genetics was always the handmaiden of medicine; McKusick’s

reference point was always disease—a set of morbid or debilitating

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G E T T I N G T H E I R O R G A N 185

symptoms. Like Maryland’s fertile forests of mixed hardwood, Hopkins

Hospital was rich in resources and had intense competition; it was teeming

with organisms vying for light, space, and nourishment. In this environ-

ment, McKusick competed successfully for resources by staking hereditary

disease as his territory.

Although in the long run, Childs’s integrative, Garrodian approach perme-

ated the medical school, in the sixties it was McKusick’s colonizing strategy

that grew the field and established his reputation. McKusick was interested

in discipline building. When asked why he asked for a division rather than

his own department, McKusick replied that “it would have been inconceiv-

able” to ask for a department. As director of a tiny department, he would have

been the runt of the litter, always the last to the teat. As a division chief, he

gained access to the director of the Department of Medicine—with Surgery,

one of the two most powerful men in the hospital. Childs, in contrast, had no

interest in administration or politics. “I declined to set up a genetics clinic”

in the department of Pediatrics, he said. He preferred to pollinate the other

pediatric clinics with genetics. “I thought that I would be a resource for the

department for people who had families with genetic diseases.” Where

Childs’s ideas sit almost anonymously at the core of Hopkins medical educa-

tion, McKusick’s name is on the letterhead of Hopkins’s McKusick-Nathans

Institute of Genetic Medicine. While Childs developed a reputation as a

visionary, McKusick became known as the father of medical genetics.

* * *

A different sort of ecology predominated in the Pacific Northwest, where

Arno Motulsky built a medical genetics program at the same moment as

McKusick. Like Wake Forest in 1940, the medical school at the University of

Washington, in Seattle, featured little crowding or competition but scant

resources. It was established in 1948, and five years later its programs were

still filling out. Robert H. Williams, an endocrinologist who had spent time

at Hopkins, Harvard, and Vanderbilt, was the chairman of medicine. He

had limited money but ample freedom to offer as he selected his faculty. As

McKusick brilliantly exploited the specific resources available to him at

Hopkins, so Motulsky adroitly took advantage of Washington’s penurious

liberty to craft a new institute.

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186 G E T T I N G T H E I R O R G A N

Born in 1923 to a middle-class Jewish family in eastern Germany, Arno G.

Motulsky made a harrowing escape at age seventeen from Hitler’s Germany;

the story is chronicled in the acclaimed nine-hour documentary Shoah.

Landing in Chicago, he said, “My whole life was now in front of me. I didn’t

have that many choices, because my father didn’t have any money—I didn’t

have any money.” Learning to get along without money became a specialty.

He worked as an animal caretaker in the virus research laboratory of

Michael Reese Hospital, where he learned about virology. Taking night

classes thrice weekly, he amassed enough credits to apply for medical school

at the University of Illinois, in Chicago. In 1943 he joined the U.S. Army.

Like many of this second generation of medical geneticists, Motulsky bene-

fited from the V-12 program, which provided for accelerated medical

training. Finishing his B.S. degree concurrently with his first year in

medical school, he earned an M.D. from Illinois in 1947.36

Choosing an internship back at Michael Reese Hospital, he did a labora-

tory rotation in hematology, where he became interested in sickle cell

anemia. He met the geneticist Herluf Strandskov, one of the founders of the

American Society of Human Genetics. He soon realized that blood and

genetics went very well together. He loved research, and he cared about

clinical work. He began to focus on anemias.

In 1953 he got a call from Robert Williams at Seattle. In assembling his

medicine faculty, Williams sought talent rather than balance. When he

called Motulsky, he had already hired the respected hematologist Clement

Finch. Williams, Motulsky says, “figured two quite independent hematolo-

gists would be maybe too much and that I should have my own kind of

program. So he very smartly, in 1957, offered me to start a unit, a division of

medical genetics in the Department of Medicine, which was really unheard

of.” They had heard of it in Baltimore, Toronto, Salt Lake City, Minneapolis,

Ann Arbor, Madison, Austin, Columbus, Wake Forest, Norman, Hamilton,

and Saskatoon, but not many other places.37

“I had nothing to lose,” Motulsky said. It was a new institution with little

money and no reputation but a strong young adventurous faculty. “There

was no tradition,” he said, “so people could build up the way they thought it

was best.” This made the administration particularly open to experimenta-

tion. “If you had ideas and so on, they let you work at it,” he said. He was

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G E T T I N G T H E I R O R G A N 187

able to carry out research as well as see patients, to find his own mix of clin-

ical and research work. He started giving “bootleg lectures” in genetics

under the rubric of hematology. Motulsky did not romanticize this as a time

of standing up against the criticisms of an establishment; rather, his narra-

tive is one of autonomy and pioneering. “Really, I didn’t have encourage-

ment nor discouragement. They said, ‘Well, sounds like an interesting

opportunity.’ ”38

Motulsky identified as an infiltrator and a proselytizer. He “spread the

message of genetics,” he said, through giving rounds (medical lectures) and

other talks; these led to consultations, which increased visibility. He traveled

Europe, visiting the medical genetics clinics in Scandinavia, France, and

Great Britain. Like Barton Childs at Hopkins, he was particularly impressed

with Penrose and Harry Harris in London. When he returned, he success-

fully petitioned Williams for a teammate. And like Lee Dice at Michigan,

Motulsky sought to balance the clinical and basic research sides of his oper-

ation; he needed a Ph.D. on his team. He identified Stanley Gartler, a

biochemical geneticist at L. C. Dunn’s Institute for Human Variation at

Columbia.

Gartler and Motulsky specialized in G6PD deficiency. Like sickle cell

anemia and thalassemia, G6PD (glucose-6-phosphate dehydrogenase) defi-

ciency is a biochemical-genetic response to malaria. Individuals with a

single copy of the mutant G6PD gene are resistant to malaria; those unlucky

individuals who get two copies of the mutation have a tendency to hemolytic

(blood cell–rupturing) anemia. G6PD deficiency was first discovered in the

1920s, among workers on South American banana plantations run by the

United Fruit Company. Bayer Pharmaceuticals was testing new antimalarial

drugs and found that 10 percent of the black banana pickers developed

strong anemia in response to the experimental drug primaquine, a fore-

runner of modern antimalarials such as chloroquine. G6PD deficiency went

on to become a kind of model system for human biochemical genetics. In a

1957 article now considered a classic, Motulsky cited G6PD deficiency as an

example of a new line of research that promised to uncover the genetic basis

of idiosyncrasies in the patient’s response to drugs. Other examples

included a heritable resistance to the muscle relaxant succinylcholine and

liver damage caused by quinine. Because G6PD deficiency was a crude

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188 G E T T I N G T H E I R O R G A N

genetic marker, it also gave a new impetus for race as a medically relevant

trait: “Since a given gene may be more frequent in certain ethnic groups,”

Motulsky wrote, “any drug reaction that is more frequently observed in a

given racial group, when other environmental variables are equal, will

usually have a genetic basis. Investigations on drug reactions therefore

should include careful notation of the ethnic or racial extraction of the

patient.” Motulsky’s paper is often cited as a founding document in the field

of pharmacogenetics, the study of genetic variation in response to drugs,

and is considered a model example of Garrodian medical genetics. Indeed,

Garrod, in his classic 1902 paper on alkaptonuria, had discussed species

differences in response to drugs and infecting organisms, which, he said,

presumably have a chemical basis (see chapter 1). Two years after Motulsky’s

paper, Friedrich Vogel of Heidelberg, one of the first of a new generation of

German human-geneticists, coined the term pharmacogenetik. Vogel spent

time with Neel in Ann Arbor and became friends with Motulsky, later

publishing a textbook of human genetics with him.39

Motulsky, then, was cast more in the mold that made Barton Childs than

that of McKusick. Intellectually, he is biochemically oriented, Garrodian,

interested in human variation. He thinks of genetics as fundamental to all of

biology. His administrative temperament was infiltrationist. But his career

trajectory was very different from Childs’s. The liberal, flexible environment

in Seattle allowed him to homestead a new program at a new university,

without much competition for resources or defense of territory. Thus he

established the same type of unit there as McKusick had done at Hopkins,

even though he had the opposite administrative style. As in nature, nurture

matters.

* * *

Whereas for McKusick at Hopkins it would have been “inconceivable” to ask

for a separate department, in Madison, Wisconsin, it would have been

foolish not to. There, the brilliant young microbial geneticist Joshua

Lederberg established a model for medical genetics as a basic science.

Compared to the programs at Hopkins and Seattle, the Wisconsin depart-

ment was the least clinically oriented. In some ways, this program is the best

model for late-twentieth-century genetic biomedicine, because later

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G E T T I N G T H E I R O R G A N 189

programs did indeed “cross the street” from the clinical to the basic

sciences.

In 1947 Lederberg was finishing up a virtuosic dissertation with the

biochemist Edward Tatum, in which he demonstrated “sex” in bacteria. As

he wrote up his work and presented it at meetings, he was flooded with job

offers. The most attractive came from the University of Wisconsin at

Madison. Wisconsin boasts the oldest department of genetics in the country.

It was founded in 1910 in the university’s agricultural college, as the

Department of Experimental Breeding, a Progressive application of science

to farming. In 1918 it changed its name to Department of Genetics, and over

the following decades it evolved into a distinguished program in research

genetics, particularly plant genetics. The applied nature of the genetics

program fit well within the “Wisconsin model” of state-sponsored research

that in turn benefited the state.40

“There was determined opposition to Lederberg’s appointment,” recalled

the maize geneticist Royal Alexander Brink, the department’s longtime

chair. Brink drily noted that Lederberg, a New York Jew to whom New Haven

seemed provincial, had a “metropolitan” background. But Lederberg was

convinced that the faculty’s reservations about his urban upbringing veiled

their anti-Semitism, which indeed was widespread in American universities

at this time. As he put it later, the department decided, “Lederberg’s a Hebe

but he’s so damn smart let’s take him anyway.”41

Lederberg hardly knew a combine from a cow pie, and he didn’t care to.

His orientation had always been medical rather than agricultural. He had

spent from 1942 to 1944 at the College of Physicians and Surgeons of

Columbia University, before switching to basic science at Yale. He always

identified with medicine, claiming that his early training gave him a breadth

and perspective most scientists lack. Lederberg’s growing interest in muta-

tion, combined with an abiding passion for social responsibility and involve-

ment in political issues relating to science, led him to human and medical

genetics. In the late forties and early fifties, he supported his research with

funds from the Atomic Energy Commission (AEC). At a dinner at the house

of geneticist Curt Stern in Berkeley in 1953, he met John Zimmerman

Bowers, a Maryland native and an M.D. who, as Deputy Director of the

AEC’s Biology and Medicine Division, had gone to Nagasaki in 1949 and

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190 G E T T I N G T H E I R O R G A N

later shielded his eyes from the test blasts at Eniwetok atoll. Since then, he

had moved into medical education. At the dinner, Lederberg recalled

“berating him for the absence of genetics in medical schools.”42

In 1955 Bowers became the new dean of the School of Medicine at

Wisconsin. In contrast to the nationally known school of agriculture, the

medical school was solid but undistinguished, regional in orientation, and

focused more on teaching than on research. Bowers set about with an ambi-

tious program of reforms to transform it into a world-class medical school,

including formalizing and streamlining the administration and beefing up

the research programs. These activities did not endear Bowers to everyone—

in 1961 he resigned amid scandal—but he and Lederberg got on well. In

December 1955 Lederberg sent him a memorandum outlining his ideas for

a program in medical genetics. It would emphasize collaboration with other

medical school colleagues, research, and teaching (there was no mention of

clinical work). It could take one of three forms: an informal working group,

comprising faculty from other departments; a division, or subdepartment,

within a large department such as medicine or pediatrics; or an indepen-

dent, stand-alone department. The first two options had problems,

Lederberg said, the chief one being that without exceptional support from

the department chair and faculty, the program might “wither on the vine.” A

separate department brought administrative duties, yet Lederberg wondered

coyly and parenthetically “how strenuous could they be in a ‘one-gun depart-

ment’?” At the working end of the barrel, of course, was Lederberg. In

recommending a separate department, he was writing himself into an

aspiring administrator’s dream job description: a chairmanship with few or

no other faculty.43

Lederberg expressed an original, if idiosyncratic, vision of medical

genetics. “Medical genetics has been considered synonymous with human

genetics,” he wrote in the 1955 memo. Not synonymous with but subordi-

nate to: recall the debates over the house organ for the American Society of

Human Genetics in the forties (chapter 5). The founders thought of disease

states as a portion of human existence. But for Lederberg, health was the

general rubric, with human biology just one part of the equation. In his

mind, medical genetics therefore subsumed human genetics. Lederberg

identified his medical training as broadening, in contrast to what he saw as

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G E T T I N G T H E I R O R G A N 191

the narrowness of science. “I started out as a medical student,” he told me in

1996. “That’s the broadest possible thing. Highly interdisciplinary: you’ve

got microbiology, biochemistry, pharmacology, physiology, anatomy, and

how this relates to pathology. You’re looking at disease changes and the

relationship of disease to the social milieu. Clinical observation is natural

history.” The genetics of disease-causing bacteria and viruses counted as

medical genetics, as did the genetics of model organisms for human

disease. To Lederberg, the medical man was acculturated, sensitive to

context and environment, attuned to real-world problems—he would have

found common ground on this point with William Allan or Nash

Herndon.44

The plan was to endow a chair for Lederberg, and to hire as faculty the

super-bright graduate student Newton Morton, just finishing his Ph.D.

under the population geneticist James Franklin Crow. Morton was good

enough that neither Crow nor Lederberg wanted to lose him, and he was

getting offers from other schools. The plan was approved in early 1957 and

formalized in May. But nothing actually changed. No laboratory space was

available at the medical school, although a new building was planned. So

Lederberg and Morton remained in their offices in the Ag school’s

Department of Genetics, a medical Monaco surrounded by agricultural

France. Lederberg left for Stanford soon after establishing the department

(he won a Nobel Prize a few months later). Crow, also a Ph.D., assumed the

chair; it was under him that the department actually moved into the medical

school, hired more faculty, and grew into a viable program. Crow obtained a

large grant from the Rockefeller Foundation and hired Robert DeMars in

somatic cell genetics and virology and, in 1960, the biochemist Oliver

Smithies and the cytogeneticist Klaus Patau. But the department’s character

remained true to Lederberg’s vision of a basic-science program in a medical

context. This was no heredity clinic.45

* * *

McKusick’s division of medical genetics, then, was one of many institutes,

departments, and divisions of medical genetics springing up around North

America in the late fifties and sixties. Yet it was McKusick’s that became the

hub. His laboratory produced more than its share of important results, but

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192 G E T T I N G T H E I R O R G A N

no Nobel-caliber discoveries. Rather, the significance of McKusick’s group

has more to do with low-status activities, such as compiling, teaching, and

promoting, than with glamorous scientific or clinical breakthroughs.

McKusick was tireless in promoting the field, and he had a knack for

parleying commonplace laboratory activities into institution-building

enterprises.

For example, in the late fifties, he started a journal club for the members

of the Moore Clinic to stay abreast of the field. Most lab heads have journal

clubs. But McKusick took a comprehensive approach. Exploiting the size of

his expanding group, he sought to collect, document, and summarize every-

thing published relating to medical genetics in a year. In 1960, in Moore’s

old journal, the Journal of Chronic Disease, he published a two hundred–page

review article called simply “Medical Genetics, 1959,” with himself as the

sole author and a long list of acknowledgments. (Today, all those acknowl-

edged contributors would be listed as authors; multiauthor papers were less

common then, and even McKusick’s partisans admit that he tended to be

autocratic about publication.) He followed that with three more successive

annual reviews. He then compiled these data into catalogue form, which he

first began to circulate as mimeographed copies. This was the first edition

of Mendelian Inheritance in Man, often known as MiM, or “McKusick’s

catalogue.” MiM was more extensive than Pearson’s Treasury of Human

Inheritance, and was encyclopedic rather than narrative in organization, but

it served the same purpose. By 1965 McKusick had begun keeping MiM in

computerized format for easy updating. Entries were built historically, like

entries in the Oxford English Dictionary, and McKusick and his team updated

them as new findings came in. In 1987 MiM went online, becoming OMIM,

and in 1995 management and storage shifted from Johns Hopkins to the

National Center for Biotechnology Information.46

Another of his discipline-building activities was the “short course” in

medical genetics, taught at the Jackson Laboratory, in Bar Harbor, on the

rocky coast of Maine’s Mount Desert (accent on the second syllable) Island.

The Roscoe B. Jackson Memorial Laboratory—later shortened to the Jackson

Laboratory, or simply “Jax” or “Jaxlab”—was founded in 1929 as a cancer

research facility. Clarence Cook Little, another student of William E. Castle’s

and a longtime eugenics advocate, was its first director. Under Little’s

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G E T T I N G T H E I R O R G A N 193

stewardship, Jax had tackled the cancer problem through mice as a model

organism, and it had built an international reputation in mouse genetics.47

McKusick, a Maine native, was drawn to it as a place to do good science amid

familiar beauty. In the summer of 1959, stopping through on the way to his

summer house up the coast, he met with the Jackson Lab scientist Earl

Green and John Fuller, the director. Returning to Baltimore, he sent round a

memo to the Hopkins medical genetics group, describing the plan the three

had hatched for a summer course, to be held the following year. McKusick

was impressed that at the Jax, “they do in mice the same things that we do in

human beings at the Moore Clinic . . . namely identify deviant phenotypes

and figure out whether they are genetically determined and, if so, how they

are inherited. Try to determine what the basic defect is and what can be done

to modify the condition.” The difference, of course, is that in mice you could

do breeding experiments.48

The purpose of the course was frankly evangelical. “One of the leading

functions of the course,” he wrote in a letter to Fuller, “would appear to be in

the recruiting line.” It would be, in part, an effort to draw boundaries around

their new field—an exercise in colonization. McKusick was partisan, a clini-

cian to the end. “Some criticize the designation ‘medical genetics’ and favor

‘human genetics,’ ” he wrote. “I do not agree, medical genetics states explic-

itly what we have in mind.” At first, he envisioned genetic knowledge and

enthusiasm trickling down from deans, advisers, and full professors to

bathe the headcount junior faculty and students. “What I have in mind,” he

wrote, “is a unique course, aimed at medical school faculty—persons of

instructor or assistant professor grade or higher, who want special instruc-

tion in genetics as an aid in their research and teaching.” But after the

first season, he had a two-tiered strategy: “Brain washing for recruiting: 1)

Top level; 2) youngsters.”49

McKusick used his network connections to raise funds to support the

course. He served on the advisory board of the National Foundation for

Infantile Paralysis (March of Dimes). The vice president for research at the

National Foundation was the distinguished Rockefeller physician Thomas

Rivers. “He was a Hopkins graduate,” McKusick said. “I had sent him a copy

of my book Heritable Disorders of Connective Tissue. . . . I think he was instru-

mental in getting me appointed to the Medical Advisory Board.” Once on

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194 G E T T I N G T H E I R O R G A N

the board, in 1959 he spoke to Rivers and to Basil O’Connor, the founder

and president, and arranged a grant. “The March of Dimes was the sole

support of the course for its first twenty-five years,” McKusick said, but that

was not quite true. He also secured supplementary funding from the

American Eugenics Society to supply student fellowships to cover tuition,

travel, and lodging. The American Eugenics Society was only too happy to

comply—so happy, in fact, that Frederick Osborn exaggerated its role,

believing it had directly subsidized the course. Indeed, the Eugenics Society

had a Medical Genetics Committee, which gave grants for coursework and

research and sponsored conferences attended by respected, mainstream

human and medical geneticists such as McKusick, Bentley Glass, and Lee

Dice. In the mid-1960s it surveyed thirty-one medical schools and found

that twenty-five were interested in learning how to incorporate medical

genetics into their curricula. The Eugenics Society invited McKusick to give

a talk on the integration of genetics into third- and fourth-year clinical

teaching. Through the sixties, the Eugenics Society continued to have a

presence in “serious” medical genetics.50

The Bar Harbor course seemed to slake a great thirst. McKusick received

some two hundred applications for forty-five slots the first summer, and by

1965 it had doubled to ninety students. Excessive class size was a common

complaint on otherwise strongly positive student evaluations. Lectures were

held mornings and evenings, with afternoons free for special study opportu-

nities, such as laboratories or tours of the mouse facility, or for leisure. The

Bar Harbor course built on a long tradition of summer courses at beautiful

seaside laboratories, such as Woods Hole, Massachusetts, Cold Spring

Harbor, New York, and the Naples Zoological Station, in Italy. Wise orga-

nizers knew that the facility itself was a major draw. Families were typically

welcome, and ample leisure time was built into the curriculum.51

The course quickly became a hub of McKusick’s networking activities. He

distributed copies of his massive reviews of medical genetics in the Journal

of Chronic Diseases, and, in the mid-1960s, he gave each student a mimeo-

graphed copy of his new catalogue, Mendelian Inheritance in Man. He

routinely nominated students in the short course for membership in the

American Society of Human Genetics. He happily godfathered spinoffs at

other institutions. “There is room for more of this sort of thing,” he wrote to

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G E T T I N G T H E I R O R G A N 195

the course graduate David Bonner in 1962, “and the idea for a course at

La Jolla [California] seems like an excellent one. . . . I will be happy to

mention this to this National Foundation people if you would like me to do

so.” The course also fostered collaborations between McKusick’s group and

those of former “students.” “Please give my best regards to the other

members of your staff,” wrote the Harvard physician Park S. Gerald in a

follow-up note after taking the course. “Have Ned [Boyer] drop me a post

card when he can, telling of the results with the gorilla sera.”52

McKusick had a sharp sense of marketing. After the second year, he

pitched an article on the course to Tommy Turner, the dean of the School of

Medicine: “I was thinking that a good story for the Johns Hopkins Magazine

would be one on the Bar Harbor Course,” he suggested, even noting the

illustration possibilities: “The setting overlooking Frenchman’s Bay at Oakes

Center is, of course, very colorful.” The magazine did end up sending a

photographer to cover the course. A few years later, the March of Dimes

suggested inviting some journalists to visit the course. McKusick went along

with the idea, and in 1967 several science writers attended the last few days

6.3 Victor A. McKusick, networking at the Bar Harbor medical genetics summer course. Courtesy of Alan Mason Chesney Archives, Johns Hopkins University

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196 G E T T I N G T H E I R O R G A N

of the course. Special sessions were held in which researchers could

present current findings in lay terms, and the press was encouraged to write

them up.53

In 1968 the strategy backfired, when the outspoken population geneticist

Richard Lewontin was invited to give the summation. “The fact of the matter

is, I don’t really know anything about human genetics,” he began, disarm-

ingly. He then launched into an outsider’s critique of the field. In typical

form, his intent was constructive, his style abrasive. He began with the

recent suggestions, stimulated by a 1965 study by Patricia Jacobs as well as

a couple of recent criminal cases from the news, that men with an extra

Y chromosome have a tendency toward violence, aggression, and crime. An

antisocial behavior chromosome. A full-blown national controversy over

XYY males would occur in the mid-1970s, centered on Lewontin’s

colleagues at Harvard and MIT. But for now, Lewontin accepted the possi-

bility of a crime chromosome for the sake of argument. “I mused on it and

asked myself, from a clinician’s standpoint or a social engineer’s standpoint,

‘Where am I after I have found out that some unfortunate five-year-old has

an extra Y chromosome?’ ” The first question one needs to ask, he said, was

whether one should tell the child or not. “Do I do him any good if I tell

him?” he asked. “Do I increase the probability of his anti-social acts by

telling him?” No one knew the answer, he said, but he made it clear that he

suspected that the moral course of action for this and many other genetic

conditions was “to keep your trap shut.” Medical genetics still had too little

to offer therapeutically, and there was the potential for considerable psycho-

logical harm. The organ theory of human genetics was simply too limited.

Lewontin speculated on a future era of molecular medical engineering.

“When the day comes, if it ever comes, when human disorders will be cured

by fooling around with the messenger RNA, then indeed you’ll want to have

lots of genetical information, but so long as diabetes is treated by grinding

up animals or producing insulin in some other way, the fact—which is in

doubt, of course—that diabetes in one of its forms or other is inherited is

not very interesting.” In short, from a therapeutic perspective, medical

genetics had not yet achieved relevance.54

Lewontin went on to describe lines of current research he thought were

interesting, such as gene interactions in development, and emphasized that

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G E T T I N G T H E I R O R G A N 197

much about the genetics of behavior was extremely important and inter-

esting. The distinction was lost on Judy Randal, a journalist in the audience.

Randal apparently heard Lewontin’s talk as an attack rather than as a

critique. On August 15, her paper, the Newark Evening News, ran an article by

Randal damning medical genetics as a field. “Last week at a genetics course

on Mount Desert Island, Maine, a professor of zoology from the University

of Chicago took issue with fellow scientists,” she wrote. “About 100 doctors

and others had spent two weeks there among the idyllic pointed firs learning

about the arcane intricacies of genetics. Dr. Richard C. Lewontin told them

that most of the information they were getting was ‘not very interesting’ and

mostly ‘a waste of time.’ ” McKusick and Fuller were furious, the March of

Dimes leadership was chagrined, and for a while doubt was cast on the

wisdom of inviting journalists to the short course. The practice continued,

however, and to this day one can expect a flurry of news stories about human

genetics every August.55

* * *

McKusick, then, is not considered the father of medical genetics because

he made glamorous breakthrough discoveries. Certainly, he and his

group were prolific producers of knowledge—McKusick’s curriculum vitae

boasts more than seven hundred publications. But the bulk of his contribu-

tions were case histories, disciplinary reviews, and pedagogical surveys—

descriptive and synthetic, rather than analytical. He did eventually get an

eponym—McKusick-Kaufman (also called Bardet-Biedl) syndrome, which

occurs in about 2 percent of the Amish—and he made or supervised

numerous contributions to the genetics of specific diseases. But a syndrome

doesn’t make one the father of a field. His epithet derives from his activities

in the relatively low-status areas of compiling and cataloguing, teaching

and mentoring, administering and organizing. McKusick made himself

essential as a gatekeeper of knowledge, an impresario of intellectual

exchange, a broker of personnel, reagents, and data.

Similarly, the expansion of medical genetics as a whole in the 1960s was

founded on a foundation of humble technical advances, upon which were

built prolific sites of knowledge production and professionalization. The

greatest advances were in cytogenetics—a subspecialty launched by the

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198 G E T T I N G T H E I R O R G A N

combination of simple, preexisting techniques and the correction of a

decades-old error. But cytogenetics provided mainly diagnostic benefits, and

clinically speaking they were modest: “getting their organ” meant that

medical geneticists could predict more accurately who would develop one of

a small number of rare diseases. Admittedly, biochemical genetics was more

complicated. For a few rare conditions, such as phenylketonuria (see chapter

7), an environmental trigger could be removed, say, through the diet.

Nevertheless, in the overwhelming majority of cases, treatment in medical

genetics still meant prevention—either curtailing procreation or inducing

abortion after the fact.

What cytogenetics—and, to a lesser extent, the other subspecialties of

medical genetics—provided was not therapeutic breakthrough but a sense

of identity. They made it possible to think of oneself as a medical geneticist.

And as soon as one could, many did. After the initial rush of discovery of

“disease chromosomes” in the late fifties and early sixties, the most dramatic

transformations of the sixties were pedagogical, administrative, and

archival. Indeed, the activities that made McKusick the father of medical

genetics constitute perhaps the most important aspect of 1960s medical

genetics. The institutes, the courses, the journals and textbooks that mush-

roomed in the sixties were exactly the sort of professional infrastructure that

Lee Dice, Laurence Snyder, Madge Macklin, and the medical geneticists of

the thirties and forties had been striving for. The disciplinary infrastructure

that McKusick, Motulsky, Crow, and others helped create made possible the

advances that would soon place heredity at the very core of biomedicine. In

the sixties, then, medical genetics came of age.

The fruition of the sixties emboldened this new generation of medical

geneticists to new visions, new ambitions. Late in 1968, Roger Donohue, a

postdoc in McKusick’s lab, mapped a human gene—for the minor blood

group known as “Duffy”—to a nonsex chromosome (chromosome 1). The

same year, Torbjorn Caspersson at the Karolinska Institute in Stockholm

finally identified banding patterns in human chromosomes using quina-

crine mustard, which fluoresces when it interacts with DNA. Human gene

mapping could at last begin in earnest. At the end of the sixties, human cyto-

genetics had finally caught up to where fruit fly genetics had been in the

teens.

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G E T T I N G T H E I R O R G A N 199

It took McKusick only a few months to leapfrog from one gene to a grand

vision of the future. In 1969 he and the dysmorphologist Clarke Fraser orga-

nized a conference on birth defects, sponsored by the March of Dimes.

McKusick gave the opening remarks. “Twenty-five years ago,” he began, “a

technical development beyond anything previously achieved by mankind—

the harnessing of the atom—had been accomplished through the applica-

tion of resources far in excess of those ever before applied to a single

research project.” That summer, he continued, man had landed on the

moon, an “even more spectacular achievement,” again attained with the

application of huge resources to a rigidly directed research program.

McKusick then called for a medical-genetic moonshot:

I propose that detailed exploration of the genetic constitution of man is ripe for an all-out attack. The principles and broad outlines have been discovered. 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—the so-called “structural genes”—and the location of each on the 24 chromosomes of man—the 22 autosomes and two sex chromosomes.56

A human genome project. It would be twenty years before it became a

reality, and the sequence was achieved by methods and strategies inconceiv-

able to researchers in 1969. Indeed, getting there ultimately involved the

rejection of McKusick’s clinically centered approach, his organ theory of

genes, in favor of a radically new strategy rooted in biochemical genetics.

That strategy at last began to fulfill the old dream of engineering the human

body.

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