Jon Tilly

A new era for human fertility research

Con­ven­tional wisdom holds that a human female fetus pro­duces roughly 7 mil­lion egg cells over the first half of preg­nancy. By birth, a baby has but  one mil­lion left and the number remains at about 200,000 once the body is repro­duc­tively mature. After menopause, none remains.

These num­bers have been around since the 1950s, when researchers phys­i­cally counted the number of healthy egg cells in human ovaries over the course of a life­time. They observed the total number of eggs pro­gres­sively decreased with age and assumed this meant no new eggs were being produced.

“It is an impor­tant assump­tion because it has guided every deci­sion made for five decades regarding how the ovaries form, func­tion, and fail,” said Jon Tilly, who joined Northeastern’s fac­ulty this fall as pro­fessor and chair of the Depart­ment of Biology.

The assump­tion held until 2004, when Tilly’s lab at the Mass­a­chu­setts Gen­eral Hos­pital pub­lished research that com­pletely over­turned this long-​​held par­a­digm of repro­duc­tive biology and could lead to novel clin­ical approaches to combat infer­tility and per­haps even stave off menopause.

At the time, Tilly’s lab had devel­oped very sen­si­tive ways to mea­sure cell death and was exploring basic sci­ence ques­tions such as why the body cre­ates so many eggs, only to use so few and let the rest die off.

Others had studied healthy egg loss over time, but Tilly was the first to mea­sure egg death. His find­ings were con­founding: the rate of egg cell death was actu­ally two to three times faster than the rate of healthy egg loss over time. Tilly explained it in terms of a bank account: if you have $1,000, with­draw $500, and still end up with $1,000, then there must have been a $500 deposit. But there’s no such thing as a deposit when it comes to egg cells. Right?

Wrong. Female fish, flies, and vir­tu­ally all other non-​​mammalian ani­mals have oogo­nial stem cells, a spe­cial kind of stem cell that cre­ates new eggs. Armed with this knowl­edge, Tilly’s group began searching for them in mam­mals, fig­uring they were the only log­ical source of new egg pro­duc­tion. “I dropped all the cell death work in my lab,” Tilly recalled, “and recon­structed it to focus on cell regeneration.”

Despite facing sig­nif­i­cant push­back from fellow col­leagues, who clung to long-​​held assump­tions that mam­mals don’t pro­duce new eggs, Tilly’s team pressed for­ward. It ulti­mately iden­ti­fied oogo­nial stem cells in mouse ovaries, puri­fied them, and showed that they do in fact pro­duce new, viable eggs. Then, in 2012, the team pub­lished research in which it iden­ti­fied the same cells in adult human ovaries and again showed that they pro­duce viable new eggs.

“We finally had proof that this basic event of germ cell renewal was con­served from flies to humans, not just in males, but in females as well,” Tilly said.

The dis­covery has opened the flood­gates for new clin­ical approaches. Now at North­eastern, Tilly and his col­leagues are applying their knowl­edge of oogo­nial stem cells to develop more suc­cessful fer­tility treat­ments. In 2011, Tilly co-​​founded Ova­Science, a Cambridge-​​based biotech­nology com­pany focused on devel­oping and deliv­ering new fer­tility options for women having dif­fi­culty con­ceiving a child.

In addi­tion to his fer­tility research, Tilly has for more than two decades aspired to find a way to stave off menopause as a means to increase quality of life in older women. Are his team’s dis­cov­eries the key to ful­filling his research objective?

“This is not yet a reality; it’s what we’re shooting for,” he said. “Ten years ago, egg cell renewal wasn’t even on the drawing board. Now look where we are now. Who is to say that 10 more years of work will not lead to a re-​​write of the entire land­scape of ovarian biology and aging?”

Originally published in news@Northeastern on September 20, 2013.

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