Three cancer researchers are among the first of 47 investigators to receive 5 years of funding through the Chan Zuckerberg Biohub. The financial awards, granted to scientists at the Biohub's three member institutions, will support early stage, high-risk foundational work at the intersection of biology and engineering.

Turning yeast into mini-factories for cancer drugs, engineering second generation chimeric antigen receptor (CAR) T cells, and imaging millions of individual cancer cells in vivo—researchers working on these ambitious visions have been named Chan Zuckerberg (CZ) Biohub Investigators, each receiving 5 years of no-strings-attached funding to promote novel research at the intersection of biology and engineering.

A project of the Chan Zuckerberg Initiative, the CZ Biohub is a private nonprofit research organization started in 2016 by Facebook founder Mark Zuckerberg and his wife, Priscilla Chan, MD. Investigators must work at a member institution—either Stanford University in California, University of California (UC), San Francisco, or UC Berkeley.

Competition for the prizes was fierce: From more than 700 submissions, 47 investigators were chosen—three of whom are pursuing cancer-related research—and announced in February. “We asked people to put forward their high risk–high reward ideas, the kind of thing that is too far out in front to get funded by traditional mechanisms,” says Stephen Quake, PhD, a professor of bioengineering at Stanford and co-president of the CZ Biohub. “Our criteria were to fund the best people and let them run with their ideas.” That included young investigators, who make up nearly half of the awardees. Senior investigators received $1.5 million; junior investigators received $750,000.

CZ Biohub senior investigator Christina Smolke, PhD, has pioneered the use of synthetic biology to take complex biosynthetic pathways from plants, animals, or bacteria and reconstitute them in yeast to rapidly scale up production of medicinal compounds, many traditionally purified from plants. Smolke, a professor of bioengineering at Stanford, recently created yeast that produce opioids, a proof-of-concept effort that required engineering and optimizing 23 sequential enzymatic processes. She is now turning her attention to cancer drugs—her group recently reported the reconstituted synthesis of the antiproliferative alkaloid noscapine. Her engineered yeasts are also providing researchers with previously scarce synthetic intermediates and novel derivatives that will help drug discovery.

Smolke's lab also develops synthetic RNAs for use as genetic on/off switches in cells. The CZ Biohub will help fund efforts to put that technology to work in immune cells, where it could allow tight regulation of the anticancer activity of CAR T cells, for example.

Kole Roybal, PhD, a CZ Biohub junior investigator at UC San Francisco and the Parker Institute for Cancer Immunotherapy, has also set his sights on improving immune therapies. He is using synthetic biology to engineer CAR T cells to recognize two or more tumor antigens, and to mount specialized responses via a new class of receptors he developed. According to his earlier work, multivalent CAR T cells are better equipped to distinguish tumors from normal tissue, which should minimize harmful cross-reactivity and the development of resistance. He foresees using these “smart” T cells to deliver customized antitumor immune therapies via the production of therapeutic antibodies, cytokines, or cytotoxins only in the tumor microenvironment.

The second CZ Biohub junior investigator, Stanford's Adam de la Zerda, PhD, wants to improve tumor imaging to let clinicians see 100 million cells in living tissues at single-cell resolution. De la Zerda has developed optical coherence tomography techniques to create 3D renditions of cells in vivo on a micro scale. His work could lead to the ability to visualize cancer markers for precise delineation of tumor margins during surgery, or to track treatment response.

While the grants provide important seed funding for these early-stage projects, the money is only part of the story, says Roybal. The CZ Biohub also gives him entree to a community of researchers and facilities that will speed up his work. “With access to a great network of scientists and infrastructure, I can do much bigger projects early in my career,” he says.

Smolke agrees, noting that the CZ Biohub community encourages interaction and collaboration. “The awardees are diverse and talented scientists, and are given the freedom and flexibility to work on difficult problems,” she said. “If you bring a community together around that, good things should happen.” –Pat McCaffrey