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Yale: Gender Matters (September 17, 2001)

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September 21, 2001

The only perspective I can credibly bring to the statement Gender

Matters is that of a scientist. I was trained as a biochemist here at

Yale in the 1950's. But, labels don't matter very much to biologists

any more and, depending on the circumstances, I identify myself

variably as biochemist, or molecular biologist, or geneticist. Modern

biologists, whether concerned with evolution, heredity, molecular

structure, or disease, define their work by the questions they ask.

Once a question is shaped, they turn to whatever methods are

needed to approach an answer.

If subdiscipline doesn't matter very much in biology these

days, does gender?

In one sense, it is a simplistic question whose

answer is of course `yes'. Gender, or that sense of the word that is

associated with biological sex, is determined by the particular set of

chromosomes

a great deal

individual, as

here at Yale.

and genes an individual animal inherits. This matters

o the biology, health, and behavior of the resulting

has been demonstrated by Sally Shawitz in her work

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Plants, with some exceptions, have taken a different

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(and some

organisms,

animals do the same). Many different kinds of single cell

like bacteria, manage very well without any sex at all

although they can, when the opportunity presents itself, incorporate

and use genes from another cell ... a fact that was established here at

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Yale by Lederberg and Tatum half a century

ago.

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However, the relation of gender to sex is aotw\topicltoday;L .

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gender u matter when a biologist determines what question to
ask. kkeeeid, that gender -6 lay a role in experimental or
observational Aresearch is to be successful.. .that is, if

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it is to advance knowledge and understanding of biology.

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The &tory has to do with breast cancer.

Anecdotal

historical information pointed to the possibility that breast cancer

could run in families ... not that all or even most breast cancer

appeared to be familial, but rather, some subset of the disease. A

3

collection of family trees showing several afflicted and other

unafflicted individuals cannot, in most cases tell us if the trait is the

result of genetic inheritance or of common environmental factors or

of both. Nor can experiments with model mammals like mice answer

the question for humans.

  Many knowledgeable physicians and scientists were skeptical

that genetics played any role in the tendency toward breast cancer.

The only way to obtain definitive data was to identify the candidate

gene or genes and demonstrate the dependence of familial breast

cancer on the presence of that gene in a mutated form.

Until this year, this was a very difficult task; the determination

of the human genome makes it somewhat simpler, but still not

simple.

gene's action.. ..what biologists call the phenotype, in this case,

breast cancer, does not necessarily say anything about the function,

characteristics, or DNA sequence of the gene. No real clues exist,

except pergaps serendipitously, about where to look among the 3

The problem was that knowing the complex outcome of a

4

billion DNA base pairs and tens of thousands of genes in the human

genome.

The person who started off the productive hunt for genes

associated with breast cancer was Mary Claire King, now professor

of biology at the University of Washington. King's undergraduate

education was in mathematics and in 1965 she went to Berkeley

where she decided to do her Ph.D. in biostatistics.

those years, a focal point for student unrest over the war in Viet

Nam.

personal, socially responsible agenda. She took leave and worked for

a while with Ralph Nader.

she used her mathematical skills to study human evolutionary

biology, and demonstrated that the chimp and human genomes are

99% identical.

Berkeley was, in

King's reaction to the closure of the campus was to pursue a

When she returned to graduate school

  Her first research job was at a UCSF Cancer Center, where

people were just beginning to recognize that genes and their mutant

forms were highly relevant to cancer quite apart from the question

of inheritance. That is, in our body cells, the perfectly normal genes

5

we inherit from our parents can acquire mutations that contribute

to a process whereby a normal cell becomes a tumor cell.

decided to investigate whether genes were responsible for at least

some cases of breast cancer.

King

A couple of basic facts may be helpful. Natural selection works

to build a genome containing genes that provide important

functions for the basic shape and life of an organism or to allow

appropriate responses to frequently encountered, changing

environmental conditions. Contrary to the biologists' short hand

that has been confusingly adopted by the public media, there are no

genes "fix" genetic diseases such as Tay Sachs, or Sickle Disease  or

cancer. Each gene is "fas" some normal function. But genes come in

different versions that reflect alterations .ink their DNA sequence that

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we call mutations. The versions of a particular gene are called its

alleles. Genetic diseases are associated with the presence of faulty

alleles.  People inherit genomes with a set of particular alleles, most

of which work normally and some of which do not and may be

associated with a predilection for a particular disease.

This is the

fundamental concept in the approach King took.

6

First, she searched the geneologies of some 1500 families from

the population at large including their medical histories (M-C. King

and L. Cavalli Sforza). This analysis convinced her that only one

copy of the allele causing breast cancer, if it existed, was necessary

to bring on the disease. Then, she had to search blindly in the DNA

from cells of the breast-cancer prone families to see if they shared

unusual alleles for any gene, alleles that did not turn up in families

without histories of breast cancer. When she started in 1974, it was

impossible to start by looking at genes one-by-one. Rather, she

looked for large segments of DNA with unique structures and even

that was a huge job of data collection and analysis.

She limited the

search to the DNA from families with a history of breast cancer in

which the cancers appeared before the age of 45; occurred in both

breasts; and I included those few families with afflicted males.  In all

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she analyzed 23 multigenerational families and 329 people, with

146 cases of breast cancer. It took 17 years.

Then, in 1990, King and six coauthors published an

electrifying paper in Science Magazine (Hall, JM et al.). They

7

identified a region of the long arm of chromosome  17 that occurred

in more than 30 different forms in the afflicted families but m& in

individuals who suffered late-onset breast cancer. Somewhere in this

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region, they argued, lay the gene whose alleles played a role in

causing breast cancer and, as it turned out, ovarian cancer as well.

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her l&fJ\w 4 reccek6t

Did King's gender play a role k-&irwmk?

As far as anyone

knows, breast cancer was not a factor in her own family. Yet

listening to her, it is plain that at least part of her motivation was to

address a disease of enormous concern to women. It was more

complex than that. Recently, King was asked why she had persisted

for so long when many others didn't even believe that a gene/alleles

associated with breast cancer existed. "I have (also) learned that it

is really important to follow your ideas even if everybody thinks

they are nonsense. There is objective proof out there.  One of the

great things about doing science is that you are looking for objective

reality. It is unlike a lot of other fields of endeavor in that way"

(Kelly S. Mccardle. 2001. in Portraits of Great American Scientists. L.

M. Lederman, ed. Prometheus Books, Amherst, New York).

8

Very quickly, other groups of scientists raced with King to

identify the actual gene in question.

international group lead by Mark Skolnick at Myriad Genetics, Inc.,

(and including scientists from the University of Utah, the NIH, and

McGill U. in Canada). A few years later, other biologists implicated a

second gene in other groups of families with breast cancer.

First to publish was an

And

evidence is mounting that even in cases of sporadic breast cancer,

that is with no inherited predilection, random mutations in these

same genes contribute to the origins of the tumors. A large number

of ~eQp.le now populate this field which is producing very

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interesting basic biological knowledge as well as information about

cancer.

substantial research funds are now available for grants.

One reason for the burgeoning of this research is that

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Th$ increase in support for breast cancer research was not an

accident. A year after Mary-Claire King's paper was published, the

National Breast Cancer Coalition was formed. This effective umbrella

lobbying organization now represents more than 500 different

organizations and several million patients and their families and

medical personnel.

Its goal is to eradicate breast cancer by the

9

promotion of increased funds for research into cause, treatment,

and cure of the disease as well as training of scientists. Since its

founding, the Coalition has seen a more than 600% increase in

funding (now greater than $700 million a year). This includes

obtaining an unusua commitment by the Department of Defense for

a multimillion dollar research effort. Notably, the Coalition

promotes public education on the biomedical research, the inclusion

of patients on committees determining access to research funding,

and maintains watchdog activities to assure that the federal money

is spent on research and not on bureaucratic projects (Science Mag.

News Stories).  [ KV\OW Ic%~C.L ab'' rww\

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The second story concerns the search for a genetic

predisposition or predilection for male homosexuality in at least

some subpopulation of contemporary male homosexuals in the US.

The study was undertaken by Dean Hamer, a brilliant biologist with

a substantial record of outstanding research in other, what I might

characterize as main-stream areas of molecular genetics. The search

for possible genes followed much the same path as .the breast cancer

work. Hamer assumed that only a small subset of male

10

homosexuality might be inherited, just as only a small subset of

breast cancers have inherited genetic origins.

Verification of the homosexual phenotype was challenging

and had to depend on inherently problematic psychological

methods. Once phenotype was determined or at least estimated, the

goal was the same as with breast cancer ... only the identification of

particular allele(s) that was specifically associated with

homosexuality would allow any firm choice between environmental

and genetic effects.

Unlike the breast cancer situation, the initial period of this

research turned up a serendipitous clue. The multigenerational

family trees Hamer collected indicated that the genetic trait, if it

existed, was delivered to men from their mothers. Two brothers, for

example might be gay and have gay male cousins born to their

mother's sisters and gay maternal uncles. Their fathers and paternal

relatives were not gay. This is exactly the inheritance pattern for

diseases known to be related to genes on the X chromosome. So, the

gene search could be limited to the DNA on the X chromosome, and

11

the rest of the genome, which King had to include in her work,

could be ignored. Hamer and his colleagues  found that the

particular DNA characteristics on one region of the X-chromosome

showed a statistically significant correlation with homosexual

orientation. This region comprised 4 million base pairs and several

hundred genes.

After the results were published in 1993 (Hamer et al, 1993),

this story pretty much ended. Others who tried to reproduce the

work obtained variable or negative results. Observations like these

are very sensitive to the details of family characteristics, data

collection, and analysis. Definition of the phenotype, depending as

it does on self-description, is uncertain. Moreover, the number of

families available for analysis was small compared to the large

number of families with recurring breast cancer.

Very likely, the massive media attention that engendered

homophobic public reaction was also discouraging, especially as

Hamer works at the NIH, a federal institution that was leary about
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continued funding.  The work was put aside. Within the last year,

12

however, Hamer's lab has picked it up again. The data from the

Human Genome Project makes it feasible to take a targeted

approach to relating the DNA changes to particular genes.

Hamer chose an interesting question to ask, but also a

politically sensitive one. His own homosexuality certainly influenced

the choice of question. Although he has never been secretive about

his sexual preference to friends, family, and colleagues, he rightly

declined to respond to media questions about his homosexuality.

Like King, his personal outlook may have influenced his choice of

research projects, but the resulting data must be evaluated and

interpreted on their merits.

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The influence of personal concerns are also apparent with

scientists who choose to investigate diseases that afflict members of

their families, like cancer and juvenile diabetes.  But once the

problem is chosen, success depends on putting aside personal

aspirations and wishes and replacing them with scientific reality and

rigor.

13

REFERENCES

M-C. King and L. Cavalli-Sforza. 1988.  Proc. Natl. Acad. Sci. 85

3044-

J.M. Hall, M.K. Lee, B. Newman, J.E. Morrow, L.A. Anderson, B. Huey,

and M-C. King. 1990. Linkage of early-onset familial breast cancer to

chromosome 17q21. Science. 250: 1684-1689.

Science Magazine, News stories. Volume 274, pp. 709-710.1996.

Volume 277, p. 889. 1997.

D.H. Hamer, S.Hu, V.L. Magnuson, N. Hu, A.M.L. Pattatucci. 1993. A

Linkage Between DNA Markers on the X Chromosome and Male

Sexual Orientation. Science. 261 321-327 1993.