A few years ago, Dr. Stan Wang became obsessed with the thymus. The often overlooked organ plays a vital role in making and training immune cells to fight infections. Most people are born with a large thymus that dramatically shrinks with age, diminishing their ability to fight invaders.
The consequences of that were obvious to Wang during the pandemic, as many older people struggled to build and retain immunity to the coronavirus — even after getting multiple booster shots. At a rented lab bench in Cambridge, Wang worked on a technology that he hoped would one day solve that problem.
He’d learned that other scientists had coaxed stem cells to transform into thymus cells in a petri dish. When implanted in mice without a thymus, those lab-grown cells restored immunity. In early 2019, Wang founded a startup, Thymmune Therapeutics, to refine the technique for testing in humans. His initial goal was developing a treatment for babies born without a thymus — an extremely rare and fatal condition. If that worked, a shot of thymus cells might one day help rejuvenate immunity in aging people.
That bold vision has now attracted personal investments from several local life science leaders, including George Church, the Harvard University geneticist who has founded and advised dozens of biotech companies. Church told Wang — a former postdoctoral researcher in his lab — that his thymus cell therapy was “one of the most exciting” ideas he’d come across, since it “has the potential to impact almost every person on the planet.”
Wang’s startup recently raised $7 million in seed financing, bringing the total to $13 million, he said. Thymmune’s investors include the biotech venture capital firm Pillar VC and NYBC Ventures, the investment arm of the New York Blood Center. Biotech entrepreneurs and investors Mark Bamforth, James Fordyce, John Maraganore, Judy Pagliuca, Philip Reilly, and Mark de Souza pitched in, too.
Maraganore, the former founding chief executive of Alnylam Pharmaceuticals, a genetic medicines company in Cambridge worth more than $23 billion, said he was fascinated by both the near-term and long-term goals of Wang’s vision for what thymus cell therapies might do for rare and common conditions alike.
“If successful, it could be pretty transformative,” Maraganore said. “At the end of the day, we all age and die due to our immune system falling apart, and if there’s a way to reconstitute it, that would be pretty cool.”
Physicians once thought that the thymus, a small gland situated behind the breastbone, between the lungs, and above the heart, was a dispensable organ. But it plays a vital role in developing immunity.
“Its job is to basically be the schoolhouse for T cells, those critical cells in your immune system that help you fight everything from pathogens to cancer,” Wang said. From a young age, the thymus also teaches T cells about the inventory of molecules normally found in people so that they don’t attack their own body and cause an autoimmune disease.
“The thymus is perhaps the most important organ you’ve never heard of. Many folks don’t even know it exists,” said Thomas de Vlaam, an investor at Pillar VC. “If it works well, it’s unnoticeable, but once it starts failing for whatever reason, the effects are detrimental.”
Thymmune’s ambitions span the gamut of thymus biology, from replacing missing thymuses to bolstering shrinking ones, and its technology is largely based on work from a group of scientists at the University of California, San Francisco. In 2010, Audrey Parent, a postdoctoral researcher working with UCSF professors Matthias Hebrok and Mark Anderson, was trying to figure out how to make thymus cells in the lab for the first time.
Parent, now an assistant professor at UCSF, said the project involved a lot of trial and error to find a molecular recipe that could turn a stem cell into a thymus cell. “There was no recipe to do that at the time,” Parent said. “We looked at how the embryo does it, we tried to replicate what nature has been doing really successfully, and then transferred that into a recipe that you can do in a dish.”
Their results, published in 2013, used human embryonic stem cells to make thymus cells that were transplanted into mice that lacked a thymus. Crucially, the implants allowed the mice to make their own T cells. Thymmune has licensed patents from UCSF, and like many new startups in the stem cell field, it is forgoing difficult-to-source and ethically fraught embryonic stem cells in favor of induced pluripotent stem cells, or iPSCs, which can be made from adult skin cells.
Sometime in the next few years, Wang plans to start a clinical trial in children who are born without a thymus. “It’s a ticking time bomb where these kids usually don’t survive past one or two years,” Wang said.
The Food and Drug Administration approved the first therapy for the condition, called congenital athymia, in 2021. Slices of thymus obtained from organ donations, cultured in a lab and surgically implanted into an infant’s thigh, improved the chances of surviving the otherwise fatal condition to 76 percent after two years. “The results there have been fantastic,” Wang said. He hopes to replicate them and make an “off-the-shelf” product that doesn’t require organ donations.
If that approach is successful, Wang wants to use his company’s thymus cells as a therapy that helps people getting bone marrow or organ transplants recover more quickly and trains their immune systems to not reject the transplant. He also has plans to develop engineered thymus cells that can quell autoimmune diseases by retraining haywire immune cells to stand down and stop attacking the body.
Wang’s ultimate vision, and the one that’s especially invigorated investors like Church and Maraganore, is to inject thymus cells into aging people to bolster their immune response. “To be clear, there’s a lot more we need to do before getting to that point,” Wang said. “But that is the level of aspiration we’re aiming for. ... We want to provide everyone the opportunity for healthier aging.”