David C. Page (born 1956) is an American biologist and professor at the
Massachusetts Institute of Technology
The Massachusetts Institute of Technology (MIT) is a private land-grant research university in Cambridge, Massachusetts. Established in 1861, MIT has played a key role in the development of modern technology and science, and is one of the ...
(MIT), 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 indepen ...
Y-chromosome
The Y chromosome is one of two sex chromosomes (allosomes) in therian mammals, including humans, and many other animals. The other is the X chromosome. Y is normally the sex-determining chromosome in many species, since it is the presence or abs ...
and on its evolution in mammals and expression during development. He was cited by
Bryan Sykes
Bryan Clifford Sykes (9 September 1947 – 10 December 2020) was a British geneticist and science writer who was a Fellow of Wolfson College and Emeritus Professor of human genetics at the University of Oxford.Harrisburg, Pennsylvania, in 1956 and grew up in the rural outskirts of
Pennsylvania Dutch country
The Pennsylvania Dutch Country ( Pennsylvania Dutch: ''Deitscherei'' Dutchery', also called Pennsylvania Dutchland ( Pennsylvania Dutch: ''Pennsylvania Deitschland'', german: Pennsylvania Deutschland), or simply the Dutch Country or Dutchland ( ...
. The first of his family to go to college, Page attended Swarthmore College, where he graduated with a BA 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 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 roles in r ...
structure in the laboratory of molecular biologist Robert Simpson at the
National Institutes of Health
The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late ...
. In 1978, Page enrolled at
Harvard Medical School
Harvard Medical School (HMS) is the graduate medical school of Harvard University and is located in the Longwood Medical Area of Boston, Massachusetts. Founded in 1782, HMS is one of the oldest medical schools in the United States and is consi ...
David Botstein
David Botstein (born September 8, 1942) is an American biologist serving as the chief scientific officer of Calico. He served as the director of the Lewis-Sigler Institute for Integrative Genomics at Princeton University from 2003 to 2013, where ...
at MIT and Raymond White at the
University of Massachusetts Medical School
The University of Massachusetts Chan Medical School is a public medical school in Worcester, Massachusetts. It is part of the University of Massachusetts system. It is home to three schools: the T.H. Chan School of Medicine, the Morningside Grad ...
X chromosome
The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex ...
and Y chromosome, a coincidence that would set the direction of his subsequent career.
Page finished his MD degree in the spring of 1984 and started his own lab as the first Whitehead Fellow at the
Whitehead Institute for Biomedical Research
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 indepen ...
researching the genetics of
XX male syndrome
XX male syndrome, also known as de la Chapelle syndrome, is a rare congenital intersex condition in which an individual with a 46, XX karyotype (otherwise associated with females) has phenotypically male characteristics that can vary among case ...
, 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 Augustinian friar wor ...
.
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, 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 (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testoste ...
, 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 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, in the broadest sense, is the physical world or universe. "Nature" can refer to the phenomena of the physical world, and also to life in general. The study of nature is a large, if not the only, part of science. Although humans are ...
published his findings together with a paper from the British group that identified the sex-determining gene, which they termed SRY.
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 or WUSTL) is a private research university with its main campus in St. Louis County, and Clayton, Missouri. Founded in 1853, the university is named after George Washington. Washington University is r ...
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 autosomes, 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
Bruce Lahn is a Chinese-born American geneticist. Lahn came to the U.S. from China to continue his education in the late 1980s. He is the William B. Graham professor of Human Genetics at the University of Chicago. He is also the founder of the Cen ...
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 initiation, showing that
retinoic acid
Retinoic acid (used simplified here for all-''trans''-retinoic acid) is a metabolite of vitamin A1 (all-''trans''-retinol) that mediates the functions of vitamin A1 required for growth and development. All-''trans''-retinoic acid is required in ...
(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
...
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 femal ...
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 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
The MacArthur Fellows Program, also known as the MacArthur Fellowship and commonly but unofficially known as the "Genius Grant", is a prize awarded annually by the John D. and Catherine T. MacArthur Foundation typically to between 20 and 30 ind ...
American Academy of Arts and Sciences
The American Academy of Arts and Sciences (abbreviation: AAA&S) 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, a ...
(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, a ...
National Academy of Medicine
The National Academy of Medicine (NAM), formerly called 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, Eng ...
* 2011 Fellow,
American Academy of Arts and Sciences
The American Academy of Arts and Sciences (abbreviation: AAA&S) 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, a ...