Meta founder Mark Zuckerberg and his wife, pediatrician and philanthropist Priscilla Chan, announced on Wednesday plans to invest $250 million over 10 years to establish a new “biohub” in New York City focused on building a new class of cellular machines that can surveil the body and snuff out disease.
The new initiative, publicly revealed at the 2023 STAT Summit and previewed exclusively to STAT, is the latest program from the Chan Zuckerberg Initiative, or CZI, a company the couple founded in 2015 to help cure, prevent, or manage all disease by 2100. It joins the original San Francisco Biohub founded in 2016 and a Chicago Biohub founded earlier this year.
“About the five-year mark, we basically sat down and tried to assess what we thought was working well and what we want to double down on,” Zuckerberg told STAT. “And we thought that the Biohub model to bring a few universities together, coupling that with engineering and a long-term goal, was a model that was really doing well.”
The Chan Zuckerberg Biohub New York is still searching for a location to serve as home base but has already recruited a small team of scientists. In addition to the $250 million investment from CZI, New York state and New York City will chip in $10 million apiece.
The initial biohub in CZI’s network was diffuse in ambition but developed tools for analyzing large troves of data, particularly from single-cell sequencing, and did direct work on infectious disease. For the new hubs, CZI solicited specific grand challenges to be achieved in 10 to 15 years. The Chicago researchers will try to use tiny devices to decode the secrets of inflammatory disease — such as how immune cells malfunction to wreak havoc.
The new hub, consisting of researchers at Yale, Columbia, and Rockefeller, will essentially attempt the opposite: decode precisely how immune cells successfully sense and snuff out cellular fires, such as cancer and Alzheimer’s, in hopes of engineering cells that can detect and eventually treat conflagrations the immune system can’t see or can’t put out.
If everything goes right, it would eventually amount to an internal lab-built police, fire, and medical corps to stamp out disease before symptoms appear.
The vision, outside cell therapy experts say, pushes far beyond what cellular medicine has been able to achieve to date, but could be feasible with recent advances in immunology and cell-engineering. Carl June, the University of Pennsylvania CAR-T pioneer, compared it to something out of a Jules Verne novel.
“People have talked for a long time about having those little robots go around, but it was pipe dreams, because there was no way we could possibly ever engineer it,” said June, whereas now you could begin to imagine ways to do it.
Priscilla Chan said she had similar thoughts when first read the application from Yale’s John Tsang and Columbia’s Peter Sims, one of 58 proposals CZI received.
“When you first read it, it does feel like, ‘Is this a ‘Fantastic Voyage’?’’ Chan told STAT, referencing the 1966 film in which a submarine crew is shrunk down to repair a scientist’s injured brain.
As they consulted with experts, though, she said they began to see how it could be practically achieved.
After all, this is what the immune system naturally does, patrolling every organ to suppress infections, dive-bomb nascent tumors, or heal wounds, while retaining memory of past wars. It just struggles with certain enemies, especially ones that emerge with age.
“We know that cells go around, they do go into tissues, they do monitor things,” said Tsang. “But we cannot listen in to see, to hear what they’re doing.”
They’d start by breaking open that black box. How do different cells born in the bone marrow decide if they’ll make home in the stomach or the pancreas? Research has already shown that immune cells lodging in the lung look different from immune cells lodging in the liver. But were those cells born different, or have they been morphed by their accommodations?
Perhaps more vitally, how do the cells change when they see something suspicious? What tags are added or removed from their DNA to indicate alarm? Researchers will try to simulate these processes with organs-on-a-chip, on which cells migrate from a miniature bone marrow to miniature organs. They’ll also use new computational tools to analyze the immune makeup of blood samples taken from people at different life stages and organs from deceased donors.
Andrea Califano, a systems biologist at Columbia University who is directing the New York Biohub, said they hope to make significant progress on decoding the immune “language” in three years.
“I’ve been in science for a number of years now,” he cautioned. “I’ve never seen a three-year-plan actually come through.”
By year five, they want to be able to engineer cells that only go to an organ of choice, perhaps by leveraging a version of the artificial receptors, CARs, which researchers now use to guide T cells to kill cancer cells. And they want to engineer a cell to deliver a specific payload, such an inflammatory molecule to spark an immune response against a nascent tumor.
In the five years after, they want to have built a cell that can serve, at least in mice, as a reliable early detector for a disease, such as a neurodegenerative disease or a rare cancer. These cells might be outfitted with molecular recorders, a form of CRISPR that can allow cells to make edits to their own DNA. Potentially, they could “write” what they see and then die, leaching the DNA into the blood, which doctors could draw and sequence as dispatches from vital organs.
Eventually, they’d have cells that can, say, sense early signs of malignancy and automatically release a payload to solve it before the tumor can form.
Outside experts agreed the step-wise approach was logical, while leaving a lot of places where things could go wrong. Approved cell therapies can cure certain leukemia patients, but basically amount to mindless drones: They knew to kill one type of cell, and nothing else. The Biohub calls for far more sophistication.
“From the conceptual perspective, it makes a lot of sense,” said Yvonne Chen, a synthetic biologist at UCLA. “But from a technical perspective, there’s a lot of things that have to be figured out.”
How difficult will it be, for example, to decode the language of the immune system? Researchers today can’t reliably say what viral, cancerous, or miscellaneous protein a given T cell is supposed to target, despite decades scrutinizing their receptors.
And can they rewrite a cell’s circuitry at the scale they intend? Mammalian cells don’t love researchers’ hands mucking around their DNA. To make such dramatic changes, Califano said, researchers might use a harmless, easier-to-engineer bacteria that can sit inside the cell, like the tail gunner of an aircraft.
“It’s quite a leap here beyond what is being done in medicine today,” said Michel Sadelain, who built some of the first CAR-T therapies at Memorial Sloan Kettering Cancer Center, speaking broadly about the hub. But “I think this team really has the talent and technological diversity to put all the pieces together.”
It’s consistent with where the field is moving, he said. Cell therapies that are now in development try to repair injured heart cells, clean up aging and defective cells, and send signals to reconfigure the environment around a tumor. There have also been increasing efforts to engineer cells that can make “decisions,” only killing if specific conditions are met.
Longer term, they will also need to think of practical constraints: Cell therapies can be highly toxic, but to be used for prevention, they would have to be almost as safe as vaccines. And scientists would have to find a way to give them to patients that doesn’t involve intense chemotherapy.
“Most of us who understand immunology believe the cells are up to the task,” said Stanford immunologist Crystal Mackall, before noting the hurdles. “I don’t know how that would work from a practical point of view, but that’s not a reason not to do it, right?”
The biohub leadership are clear-eyed about the scientific challenges, while cautioning they have no plans to run clinical trials, and would spin out or license technology to companies if they reached that stage. A lot of the early work, they said, went into thinking about building operations with the highest odds of success.
“How people think about recruiting the leadership team, how people think about managing talent and coaching people over a 10- to 15-year period,” said Zuckerberg. “These are questions I think are actually really important if you’re organizing something that’s this big of a project.”
That brought its own ordeal. Although Tsang helped conceive of the idea, CZI initially tried to build the hub without Yale as a center, because it wanted to prioritize collaboration and thought New Haven, Conn., was too far from New York. Instead, it would build the hub around Columbia, Rockefeller, and NYU, which would bring expertise in targeting heart disease. Yale would still be involved but not as a core institution.
“Which was sad, in a way, because we really did a lot, I think,” said Tsang.
Then at the last moment, NYU pulled out. CZI pivoted, added Yale back in, and dropped the heart disease program.
Zuckerberg declined to discuss why NYU pulled out, deferring questions to the university. Neither NYU’s head of public affairs nor the researcher who would have led NYU’s component responded to requests for comment.
Other tensions around culture, personnel, and decision-making are sure to arise as the hub evolves, researchers said. To start, Califano is looking for researchers to staff four “cores” focused on cell engineering, computational approaches to interpret data, model systems, and single-cell research.
It’ll be tricky, he said, to find people capable of not only carrying out experiments but also pushing the technology forward, so they don’t become obsolete over a decade-long project.
“It’s just one of these ridiculously ambitious things, it’s not clear if it will succeed,” said Stephen Quake, CZI’s head of science. “So there’s a lot of risk about whether it’s really going to come together, but that’s sort of what we can do as philanthropies.”