Jonathan L.
Tilly, Ph.D.
Director, Vincent Center for Reproductive Biology, Massachusetts General Hospital
Chief, Division of Research, Vincent Obstetrics and Gynecology Service, Massachusetts
General Hospital
Associate Professor, Department of Obstetrics, Gynecology and Reproductive Biology,
Harvard Medical School
Affiliated Faculty, Harvard Stem Cell Institute
Click here to email Dr. Jonathan Tilly.
Click here to view a brief biographical sketch of Dr. Jonathan Tilly.
Brief Overview of Tilly Lab Research
The long-term goal of my lab's work is to improve women's reproductive healthcare
and overcome infertility by applying what we discover through basic and translational
(preclinical) research. For over 15 years, a primary focus of my work has been to
understand the roles and regulation of the physiological cell death program apoptosis
in the mammalian ovary (Nature Rev Mol Cell Biol 2001 2: 838-848). The majority of our
work uses mouse models, which possess the advantage of relatively straightforward
genetic manipulation. Since we started this work in the early 1990s, we documented
that premature ovarian failure and infertility resulting from conventional anti-cancer
treatments involves the activation of apoptosis in oocytes (Nature Med 1997 3: 1228-
1232; Genes Dev 1998 12: 1304-1314; Mol Endocrinol 1999 13: 841-850). We then
validated an anti-apoptotic small molecule that protects the ovaries from anti-cancer
therapies and preserves normal reproductive function (Nature Med 1997 3:1228-1232;
Nature Med 2000 6: 1109-1114; Nature Med 2002 8: 901-902), and have recently taken
this small molecule into preclinical testing using rhesus monkeys as a model.
In related work, we have demonstrated that polycyclic aromatic hydrocarbons
(PAHs), chemicals present at high abundance in the environment and in cigarette
smoke, activate an orphan receptor-transcription factor (termed the aryl hydrocarbon
receptor or AhR) in oocytes, leading to de novo expression of pro-apoptotic genes
necessary for oocyte death (e.g., Bax) and early ovarian failure. Specifically, we
reported that the AhR is abundantly expressed in oocytes, and that Ahr gene
knockout in female mice leads to increased oocyte survival (Endocrinology 2000
141: 450-453). Moreover, in subsequent studies (Nature Genet 2001 28: 355-360;
Endocrinology 2002 143: 615-620), we have shown that the chemically activated AhR
induces Bax gene transcription in oocytes, and that expression of both the Ahr and
Bax genes are functionally required for these chemicals to cause oocyte depletion
and ovarian failure. Using a human ovarian xenograft model, we have further shown
that an induction of Bax gene expression and apoptosis occurs in human primordial
and primary oocytes following PAH exposure in vivo (Nature Genet 2001 28: 355-360).
These data have been expanded on in a comprehensive study that details the global
changes in expression of a large cassette of pro-apoptotic genes (in addition to Bax)
in the ovaries following PAH exposure, and the requirement for p53 in working with
the AhR to initiate oocyte apoptosis and follicle loss.
In addition to this work on pathological models of ovarian failure, we have shown
that targeted inactivation of the pro-apoptotic Bax gene in mice prolongs ovarian
lifespan into very advanced age, thereby eliminating the “mouse equivalent” of
menopause (Nature Genet 1999 21: 200-203). This animal model has allowed us to
explore, for the first time, the impact of sustained ovarian function on the aging
female body, and to decipher the contribution of age-related ovarian failure versus
the aging process itself to the manifestation of various health complications often
observed in women after the menopause (Proc Natl Acad Sci USA 2007 104: 5229-
5234).
Recently, the primary focus of our research changed from cell death to cell renewal,
based on our studies that challenge one of the most basic doctrines in our field by
demonstrating the existence of putative germline stem cells that support oocyte and
follicle production in the ovaries of adult female mammals. For example, we recently
provided evidence that juvenile and adult female mice retain proliferative germline
cells that, based on rates of oocyte degeneration and clearance, are needed to
continuously replenish the oocyte-containing follicle pool (Nature 2004 428: 145-150).
This project is now aimed at fully characterizing female germline stem cell function,
identifying the existence of such cells in humans, and developing new strategies
based on stem cell transplantation technologies for enhancing fertility and perhaps
delaying age-related ovarian failure.
Progress towards completion of these objectives is exemplified by a subsequent
publication from our group documenting the presence of early germ cells in bone
marrow and peripheral blood of adult female mice that are capable of generating
immature oocytes in the ovaries of chemotherapy-sterilized or genetically-infertile
adult female recipients following transplantation (Cell 2005 122: 303-315). Further,
we have shown in a very recent paper that bone marrow transplantation rescues
long-term fertility in adult female mice exposed to sterilizing doses of chemotherapy
(J Clin Oncol 2007 25: 3198-3204). These studies, coupled with our efforts to identify
specific genes and pathways that regulate the activity of germline stem cells in adult
mammalian females (Cell Cycle 2007 6: 2678-2684), are providing the foundation for
our ongoing development of a high throughput screening assay for identifying novel
“oogenic” factors as potential therapeutics. Although this work remains controversial,
independent corroboration from other laboratories is now available (see also Cell Cycle
2005 4: 1471-1477; Differentiation 2007 75: 93-99; Cell Cycle 2007 6: 879-883).
