Two formative experiences shaped Craig Crews’ path into drug development.
First, when he was still a child, his grandmother died from cancer at just 52 years old. “At the time, there weren’t very many treatment options,” said Crews, who is now the John C. Malone Professor of Molecular, Cellular, and Developmental Biology and professor of chemistry and of pharmacology in Yale’s Faculty of Arts and Sciences.
The second was a catastrophic airplane crash at O’Hare International Airport in Chicago in 1979, which occurred after an engine fell off shortly after takeoff and killed more than 200 people. At the time, Crews’ father, John H. Crews Jr., was a basic researcher at NASA studying how metals bend until they snap or fracture. As the world’s expert in fatigue and fracture of airplane wings, he was called in to help solve the mystery of what went wrong — and how to make aviation safer moving forward.
“I was at a young enough age that it made a big impression,” said Crews, who is also the executive director of the Yale Center for Molecular Discovery. “My dad, who I always thought was just a curiosity-driven basic researcher, had real-world impact with his research.”
Like his dad, Crews considers himself a curiosity-driven basic researcher, but he’s also always looking to translate his academic research into the real world. For years, he’s bridged the gap between academia and biotech as a professor and serial entrepreneur with three drug development companies under his belt. Recently, his third Yale startup, Halda Therapeutics, was acquired by Johnson & Johnson — a milestone for a company founded in New Haven in 2018 and built around a novel therapeutic drug for prostate cancer.
The idea of being able to create jobs and attract talent is one that I think meshes well with what we’re trying to achieve here, which is to make sure that Yale is strong and that the city that hosts Yale is strong.
In an interview, Crews discusses his work as a serial entrepreneur, translating research from the lab to the real world, and the growing biotech scene in New Haven.
The interview has been edited for length and clarity.
How did you get started as a serial entrepreneur? What has that journey looked like so far?
Craig Crews: My first company was Proteolix, which I started in 2003. It was based on a project that I had completed at Yale soon after my arrival in 1995. The project was very productive in terms of journal articles written, trainees trained, as well as getting me tenure. But I also recognized that it could help solve an issue in drug development. A particular drug being developed at that time for multiple myeloma [a rare blood cancer that is incurable] had a really bad side effect. Basically, it caused pain in the hands and feet of about 30% of treated patients such that they decided to stop taking the drug. This was a cancer drug, and they would rather pass away from cancer than to continue with the pain. I realized that the compound from my Yale lab could possibly help these patients since it worked slightly differently and might not have those side effects. It was a risk. It was a gamble. But I started my first company with investors willing to take that risk. Ultimately, we were right and today over 500,000 multiple myeloma patients have been treated with that drug.
That was my first company. I realized, at this interface of chemistry and biology we’re uniquely situated where we can do the basic research and also help with the application of that basic research and translate it into a company. So, Halda Therapeutics, my third company, is just a natural evolution of our work at the interface of chemistry and biology and at the interface of basic science and applied science here at Yale.
You’ve pioneered the pharmaceutical field of targeted protein degradation. Tell us about that research.
Crews: In 2001, researchers sequenced the human genome and determined all of the genes that makes a human a human. From that genome project, we also knew what all the potential drug targets could be. There were approximately 20,000 different types of proteins. At that time, we were developing drugs that bind to a nook or cranny on the surface of a disease-causing protein. Upon binding, the drug stops the target protein from functioning; that’s why we call that an inhibitor. The problem is that of the 20,000 different proteins, only about 25% of them actually could be, in theory, inhibited or blocked through the use of an inhibitor. For example, a disease-causing protein could lack a suitable binding site. Or the inhibitor might not be strong enough. What we and others recognized was that we needed to come up with a new way to make all of these different proteins pharmaceutically vulnerable. If we can’t do it with an inhibitor, how else could we go about coming up with a therapy that would be used?
There are a lot of proteins that cause disease simply by existing; they serve as a scaffold for other problem proteins to bind onto, and together this complex is what causes the disease. So we asked ourselves: Could we therapeutically address this issue by somehow making the problem protein not exist? Our solution was a new therapeutic modality we called “targeted protein degradation.” Essentially, we wanted to hijack the cell’s quality control system to degrade problem proteins. We developed two-headed, dumbbell-shaped drugs called PROTACs [proteolysis targeting chimera], where one end binds the problem protein and the other to the cellular protein degradation machinery, thus dragging the protein to the cell’s garbage can, and simply degrading it. It’s gone. So, we make the problem proteins go away through the use of these dumbbell-shaped drugs. That, in a nutshell, is targeted protein degradation.
You’ve long worked at the intersection of biotech and academia. Why is it important to bring these two arenas together? What does it mean for you to translate your work from lab to real-world impact?
Crews: Because I have a foot in both worlds, I can recognize that there are particular strengths in each. The strengths of academia are the creativity, the innovation, the excitement, and the pursuit of novelty. I often tell my Yale undergraduate advisees who are considering going into academia that I have the world’s best job. They pay me to be curious! On the other hand, the strength of the private sector company is its ability to execute. Industrial researchers have more drug development experience and more resources than we have in academia. They know how to take academic ideas that oftentimes can be admittedly rather vague and convert them into real drug candidates that ultimately help patients. I love being able to bridge both worlds.
Your companies are part of a growing biotech scene in New Haven. Tell us about the strength of the city’s biotech ecosystem.
Crews: My family and I have been residents of New Haven for 31 years. We live in the East Rock neighborhood and love and support New Haven. The idea of being able to create jobs and attract talent is one that I think meshes well with what we’re trying to achieve here, which is to make sure that Yale is strong and that the city that hosts Yale is strong.
You can imagine this works in many different ways. Not only are we hopefully strengthening New Haven’s tax base, but we’re also creating new jobs that could help in faculty recruiting, by offering opportunities for partners and spouses of faculty recruits. So, being able to create these high-tech jobs locally helps strengthen the entire ecosystem, both private and academic.
What is it about Yale that has led to such transformative science?
Crews: It’s the people. The students are fantastic. My colleagues are wonderful. They stimulate me, challenge me, and support me. I am very grateful for the opportunity to do what I love and give back in whatever way I can. My basic life’s philosophy is that we all have a role to play, and I’m very happy to be able to play my role.
