David C. Page (born 1956) is an American biologist who is a professor at the
Massachusetts Institute of Technology
The Massachusetts Institute of Technology (MIT) is a Private university, private research university in Cambridge, Massachusetts, United States. Established in 1861, MIT has played a significant role in the development of many areas of moder ...
(MIT). He was the director of the
Whitehead Institute
Whitehead Institute for Biomedical Research is a non-profit research institute located in Cambridge, Massachusetts, United States that is dedicated to improving human health through basic biomedical research. It was founded as a fiscally indep ...
and a
Howard Hughes Medical Institute
The Howard Hughes Medical Institute (HHMI) is an American non-profit medical research organization headquartered in Chevy Chase, Maryland with additional facilities in Ashburn, Virginia. It was founded in 1953 by Howard Hughes, an American busin ...
(HHMI) investigator. He is best known for his work on mapping the
Y-chromosome
The Y chromosome is one of two sex chromosomes in therian mammals and other organisms. Along with the X chromosome, it is part of the XY sex-determination system, in which the Y is the sex-determining chromosome because the presence of the Y ...
and on its evolution in mammals and expression during development.
Education and early life
Page was born in
Harrisburg, Pennsylvania
Harrisburg ( ; ) is the capital city of the U.S. commonwealth of Pennsylvania and the seat of Dauphin County. With a population of 50,099 as of 2020, Harrisburg is the ninth-most populous city in Pennsylvania. It is the larger of the two pr ...
, in 1956 and grew up in the rural outskirts of
Pennsylvania Dutch country
The Pennsylvania Dutch Country (Pennsylvania Dutch: ''Pennsylvanie Deitschland,'' ''Deitscherei,'' or ''Pennsilfaanisch-Deitschland''), or Pennsylvania Dutchland, is a region of German Pennsylvania spanning the Delaware Valley and South Central ...
.
The first of his family to go to college, Page attended
Swarthmore College
Swarthmore College ( , ) is a Private college, private Liberal arts colleges in the United States, liberal arts college in Swarthmore, Pennsylvania, United States. Founded in 1864, with its first classes held in 1869, Swarthmore is one of the e ...
, where he graduated with a
B.A.
A Bachelor of Arts (abbreviated B.A., BA, A.B. or AB; from the Latin ', ', or ') is the holder of a bachelor's degree awarded for an undergraduate program in the liberal arts, or, in some cases, other disciplines. A Bachelor of Arts degree ...
with highest honors in chemistry in 1978.
During his final year at Swarthmore, Page attended class just one day a week and spent the rest of his time researching
chromatin
Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important r ...
structure in the laboratory of molecular biologist Robert Simpson at the
National Institutes of Health
The National Institutes of Health (NIH) is the primary agency of the United States government responsible for biomedical and public health research. It was founded in 1887 and is part of the United States Department of Health and Human Service ...
.
In 1978, Page enrolled at
Harvard Medical School
Harvard Medical School (HMS) is the medical school of Harvard University and is located in the Longwood Medical and Academic Area, Longwood Medical Area in Boston, Massachusetts. Founded in 1782, HMS is the third oldest medical school in the Un ...
and the
Harvard-MIT Health Sciences Program, where he worked in the laboratories of
David Botstein at MIT and Raymond White at the
University of Massachusetts Medical School
The UMass Chan Medical School is a public medical school in Worcester, Massachusetts. It is part of the University of Massachusetts system. It consists of three schools: the T.H. Chan School of Medicine, the Morningside Graduate School of Biom ...
.
In White's lab, Page worked on a project to develop a
genetic linkage map of the human genome that would become a precursor to the
Human Genome Project
The Human Genome Project (HGP) was an international scientific research project with the goal of determining the base pairs that make up human DNA, and of identifying, mapping and sequencing all of the genes of the human genome from both a ...
.
The work relied on locating
restriction fragment length polymorphism
In molecular biology, restriction fragment length polymorphism (RFLP) is a technique that exploits variations in homologous DNA sequences, known as polymorphisms, populations, or species or to pinpoint the locations of genes within a sequence. T ...
s (RFLP). The first RFLP that Page found was from a site of homology between the
X chromosome
The X chromosome is one of the two sex chromosomes in many organisms, including mammals, and is found in both males and females. It is a part of the XY sex-determination system and XO sex-determination system. The X chromosome was named for its u ...
and Y chromosome, a coincidence that would set the direction of his subsequent career.
Page finished his
M.D.
A Doctor of Medicine (abbreviated MD, from the Latin ) is a medical degree, the meaning of which varies between different jurisdictions. In the United States, and some other countries, the ''MD'' denotes a professional degree of physician. This ge ...
degree in the spring of 1984 and started his own lab as the first Whitehead Fellow at the
Whitehead Institute for Biomedical Research researching the genetics of
XX male syndrome
XX male syndrome, also known as de la Chapelle syndrome or 46,XX testicular disorder of sex development (or 46,XX DSD) is a rare intersex condition in which an individual with a 46,XX karyotype develops a male phenotype.updated 2015
In 90 perce ...
, or de la Chapelle Syndrome.
After Page won the
MacArthur "Genius Grant" in 1986, Page was promoted to the faculty of the Whitehead Institute and the
MIT Department of Biology in 1988.
In 1990, Page was named a Howard Hughes Medical Institute Investigator, and in 2005 he was named as director of the Whitehead Institute.
Research and career
Page has worked in several areas of
genetics
Genetics is the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) It is an important branch in biology because heredity is vital to organisms' evolution. Gregor Mendel, a Moravian Augustinians, Augustinian ...
.
Mapping the Y chromosome
In his work on de la Chapelle Syndrome in 1986, Page collaborated with the geneticist who originally identified the first XX male,
Albert de la Chapelle
Albert Fredrik de la Chapelle, MD, Ph.D (11 February 1933 – 10 December 2020) was a Finnish human geneticist, long-time head of Finland's first Department of Medical Genetics at the University of Helsinki, and subsequently professor of Human ...
, and geneticist
Jean Weissenbach to show that XX males carry a small piece of the Y chromosome.
In the following year, he reported that the gene
ZFY induced the development of the
testes
A testicle or testis ( testes) is the gonad in all male bilaterians, including humans, and is homologous to the ovary in females. Its primary functions are the production of sperm and the secretion of androgens, primarily testosterone.
The ...
, a finding which received a great deal of media attention since it putatively resolving a decade-long search for the sex-determining gene.
In 1989, a British team of scientists led by
Peter Goodfellow and
Robin Lovell-Badge
Robin Howard Lovell-Badge is a British scientist most famous for his discovery, along with Peter Goodfellow, of the SRY gene on the Y-chromosome that is the determinant of sex in mammals. They shared the 1995 Louis-Jeantet Prize for Medicine fo ...
began to report that the testis-determining gene was not ZFY, which led Page to review his data. Page found that he had misinterpreted his data because one of the XY females in his study had a second deletion at the site which proved to be the location of the real sex-determining gene. Launching a second round of media attention,
Nature
Nature is an inherent character or constitution, particularly of the Ecosphere (planetary), ecosphere or the universe as a whole. In this general sense nature refers to the Scientific law, laws, elements and phenomenon, phenomena of the physic ...
published his findings together with a paper from the British group that identified the sex-determining gene, which they termed
SRY
Sex-determining region Y protein (SRY), or testis-determining factor (TDF), is a DNA-binding protein (also known as gene-regulatory protein/transcription factor) encoded by the ''SRY'' gene that is responsible for the initiation of male sex ...
.
Despite a belief among geneticists that the Y chromosome contained few genes other than the sex-determining gene, Page continued to map the Y chromosome. He had already published
DNA-based deletion maps of the Y chromosome in 1986, and went on to develop comprehensive clone-based physical maps of the chromosome in 1992 and systematic catalogs of Y-linked genes in 1997. Page collaborated with a team at the
Genome Institute at
Washington University
Washington University in St. Louis (WashU) is a private research university in St. Louis, Missouri, United States. Founded in 1853 by a group of civic leaders and named for George Washington, the university spans 355 acres across its Danforth ...
to make a complete map of the Y chromosome, which they achieved in 2003.
To do so, Page and his colleagues developed a new sequencing technique, single-haplotype iterative mapping and sequencing (SHIMS), since mammalian sex chromosomes contain too many repetitive sequences to be sequenced by conventional approaches.
The development of SHIMS allowed Page to identify long palindromic sequences on the long arm of the Y chromosome, which he would go on to show made the Y chromosome vulnerable to the deletions that cause spermatogenic failure (an inability to produce sperm). In 2012, Page characterized the most common genetic cause of spermatogenic failure, the deletion of the AZFc region of the Y chromosome.
The lab also found that aberrant crossing over within the Y chromosome's palindromes underlies a wide range of disorders of sexual differentiation, including Turner syndrome.
Evolution of the Y chromosome
With the development of more detailed maps of the Y chromosome, in the mid-1990s Page began to find genetic evidence confirming the theory that both the X and Y chromosomes had evolved from
autosome
An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosomes ...
s, beginning with the 1996 discovery that a family of genes called
DAZ (deleted in azoospermia) had been transposed from an autosome to the Y chromosome.
In 1999, Page and his then-graduate student
Bruce Lahn showed that the X and Y chromosomes had diverged in four steps, beginning 200-300 million years ago. Later cross-species comparisons would show that while ancestral genes on the Y chromosome initially underwent rapid decay,
the remaining genes have remained stable for the last 25 million years, overturning the long-held view that the Y chromosome was going extinct.
In a 2014 study, Page concluded that the conserved genes on the Y chromosome played an important role in male viability, since they were dosage-dependent genes with similar but not identical counterparts on the X chromosome that all have regulatory roles in transcription, translation, and protein stability. Because these genes are expressed throughout the body, Page further concluded that these genes give rise to differences in the biochemistry of male and female tissues.
In super-resolution studies of the sex chromosomes, Page has found evidence of an evolutionary "arms race" between the X and Y chromosomes for transmission to the next generation. In one study, Page found that human X and mouse Y chromosomes have converged, independently acquiring and amplifying gene families expressed in testicular germ cells. Another study found that the mouse Y chromosome had acquired and massively amplified genes homologous to the testis-expressed gene families on the mouse X chromosome.
The genetics of germ cells
Page used the mouse as a model to study the genetics of
meiotic
Meiosis () is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, the sperm or egg cells. It involves two rounds of division that ultimately result in four cells, each with only one copy ...
initiation, showing that
retinoic acid
Retinoic acid (simplified nomenclature for all-''trans''-retinoic acid) is a metabolite of vitamin A1 (all-''trans''-retinol) that is required for embryonic development, male fertility, regulation of bone growth and immune function. All-''trans ...
(RA) is the key factor which induces meiosis, as well as identifying several important genes crucial to the meiotic initiation pathway, including Stra8 and
DAZL. Page further discovered that the differentiation germ cells into
gametocyte
A gametocyte is a eukaryotic germ cell that divides by mitosis into other gametocytes or by meiosis into gametids during gametogenesis. Male gametocytes are called ''spermatocytes'', and female gametocytes are called ''oocytes''.
Development
T ...
s (
oocyte
An oocyte (, oöcyte, or ovocyte) is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in a female fetus in the ovary during female gametogenesis. The female ger ...
s in females or
spermatocyte
Spermatocytes are a type of male gametocyte in animals. They derive from immature germ cells called spermatogonia. They are found in the testis, in a structure known as the seminiferous tubules. There are two types of spermatocytes, primary and s ...
s in males) does not depend on meiotic initiation, as commonly thought, showing that germ cells deficient in Stra8, a gene that activates the meiotic pathway, are still capable of growth and differentiation.
Awards and honors
His honors and awards include:
* 1986
MacArthur Prize Fellowship
* 1989
Searle Scholar Award
The Searle Scholars Program is a career development award made annually to support 15 young faculty in biomedical research and chemistry at US universities and research centers. The goal of the award is to support to exceptional young scientists wh ...
* 1997 Francis Amory Prize,
American Academy of Arts and Sciences
The American Academy of Arts and Sciences (The Academy) is one of the oldest learned societies in the United States. It was founded in 1780 during the American Revolution by John Adams, John Hancock, James Bowdoin, Andrew Oliver, and other ...
(for genetic studies of mammalian sex determination; prize shared with Peter Goodfellow and Robin Lovell-Badge)
* 2003
Curt Stern Award,
American Society of Human Genetics
The American Society of Human Genetics (ASHG), founded in 1948, is a professional membership organization for specialists in human genetics. As of 2009, the organization had approximately 8,000 members. The society's members include researchers, ...
(for outstanding scientific achievement in human genetics)
* 2005 Member,
National Academy of Sciences
The National Academy of Sciences (NAS) is a United States nonprofit, NGO, non-governmental organization. NAS is part of the National Academies of Sciences, Engineering, and Medicine, along with the National Academy of Engineering (NAE) and the ...
* 2007 Fellow,
American Association for the Advancement of Science
The American Association for the Advancement of Science (AAAS) is a United States–based international nonprofit with the stated mission of promoting cooperation among scientists, defending scientific freedom, encouraging scientific responsib ...
* 2008 Member,
National Academy of Medicine
The National Academy of Medicine (NAM), known as the Institute of Medicine (IoM) until 2015, is an American nonprofit, non-governmental organization. The National Academy of Medicine is a part of the National Academies of Sciences, Engineerin ...
* 2011 Fellow,
American Academy of Arts and Sciences
The American Academy of Arts and Sciences (The Academy) is one of the oldest learned societies in the United States. It was founded in 1780 during the American Revolution by John Adams, John Hancock, James Bowdoin, Andrew Oliver, and other ...
(Class Speaker, Biological Sciences)
References
{{DEFAULTSORT:Page, David C.
Living people
Swarthmore College alumni
Harvard Medical School alumni
Massachusetts Institute of Technology faculty
MacArthur Fellows
Members of the United States National Academy of Sciences
Whitehead Institute faculty
Howard Hughes Medical Investigators
21st-century American biologists
1956 births
Scientists from Pennsylvania
People from Harrisburg, Pennsylvania
Members of the National Academy of Medicine