Andrea Califano on Harnessing the Immune System

The mission of the new Chan Zuckerberg Biohub New York–led by Columbia’s Andrea Califano, Dr, —sounds a little like the 1966 sci-fi epic, “The Fantastic Voyage.” In the movie, a team of doctors shrink themselves, and a submarine, to the size of bacteria and dive into the bloodstream of an important scientist to remove a life-threatening clot in his brain.

The CZ Biohub NY—announced on Oct. 18—will not of course shrink any physicians nor remove brain clots. But the mission may sound equally ambitious: A group of scientists from Columbia, Rockefeller, and Yale will attempt to engineer the cells of our immune system to act like miniature doctors in the bloodstream, detecting and eradicating diseases in their earliest states, years before they may produce detectable symptoms.

Leading the CZ Biohub NY is a transition for Califano, who’s known as a bit of an iconoclast in cancer research and whose unconventional ideas about cancer genetics have become broadly accepted only in recent years. (Earlier this month, the National Cancer Institute recognized Califano as a visionary thinker in the field of cancer genetics by presenting him with the 2023 NCI’s Alfred G. Knudson Award).

We spoke with Califano about the NY Biohub’s goals and why he thinks the immune system holds the key to a healthier future.

The goal of the New York Biohub sounds incredibly futuristic. I’m imagining going for a routine checkup where I’ll get an injection of bioengineered immune cells that will patrol my body for signs of diseases that may otherwise go undetected for years. And then getting another injection of cells that will fix any problems. How is this possible?

Yes, this is correct; that is the long-term vision but the Biohub will not be experimenting on patients. Rather it will create the scientific understanding, technology, and bioreagents that will make that vision ultimately possible. It will be up to biotech startups and pharmaceutical companies to turn these discoveries into clinical reality.

The reason why we became convinced this is actually possible is three-fold. First, to a remarkable extent, our immune system already does exactly this. It does not just fight disease-causing viruses and bacteria but it also patrols our bodies looking for and eliminating cells that harbor cancer-causing mutations before we ever get cancer and starts the process of wound healing. Indeed, cancer has to hijack the immune system to avoid being detected. Second, working with scientists from these three amazing institutions, we found that many of the individual foundational technologies to fulfill this vision are in fact already being developed by their labs. Finally, work in CAR-T therapy, where bioengineered cells are trained to recognize and kill cancer cells, have already been shown to be very valuable and safe to use in humans. So all things point to the fact that if we can better harness the immune system, we may transform our ability to detect disease and preserve the healthy state of our organs.

What needs to be learned to make this vision a reality?

One of the remarkable things about immune cells is that they come into contact with virtually all other cells in our bodies and keep a molecular memory of what they have “seen.” So, our initial efforts will be devoted to deciphering the molecular language that these “inspectors” use to learn what they may be telling us about incipient disease.

Of course, not all diseases are detected or fixed by the immune system; indeed, evolution does not care about diseases that do not prevent us from having an offspring, like post-reproductive age cancers, or diseases that make life miserable, like lupus, or progressive diseases that only kill us in our later years, like Alzheimer’s. So we will have to leverage what we know about disease to engineer and instrument our own immune cells to detect things that evolution has not yet taught them to see and fix.

Finally—and this is perhaps the greatest challenge—we will have to build mini-factories inside these cells to manufacture and release therapeutic molecules precisely at the site of disease, once they detect it.

We have a lot more to learn about how to send engineered immune cells to specific organs and how to program them to release therapeutics once they reach their destination.

Are you targeting certain diseases?

We will start with cancers that are currently too difficult to detect until they become largely untreatable, like ovarian and pancreatic cancer. We will also try to detect incipient neurodegenerative diseases, such as Parkinson’s, which incidentally starts in the gut, and Alzheimer’s. This is critical because a number of therapies are starting to emerge that can slow progression of these diseases. But they only work in the very early states, which typically go undetected.

We will also try to go after several issues associated with aging. We are not after the fountain of youth, but there are plenty of things we may do to preserve the health of our muscles and circulatory system that are damaged as we age, even without overt disease symptoms.

We are talking about a research plan that will extend into 10 to 15 years. And this is exactly what the Biohub mechanism allows us to do, in contrast to research that only gets funded for three to five years.

This project reminds me of the Human Genome Project. When it launched, it seems we heard similar predictions: You’ll go to your doctor, get a read-out of what’s in your DNA, and that’ll predict your future health. And eventually treatments could stave off those diseases.

This has actually worked out much more than people think. For instance, we would not have an entire class of targeted therapeutics for cancer if the ability to read genomes had not taught us which mutated genes to target. To be fair, it is really hard to think of any current drug development project that does not leverage the knowledge of our genomic sequence.

Sure, this is not exactly what people had hailed as the genomic cure era, but this is because genomes are much more complicated. For instance, there are more genetic mutations or germline variant patterns that could potentially produce cancer or diabetes than atoms in the universe. In addition, there are contributions to disease (the famous nature or nurture) that are not written in our genomes.

As a result, in terms of diagnostics, which is an important component of precision medicine, the best our genome can do for us is to help us predict the risk of developing a disease. But this is also why leveraging the immune system, which has been honed by millions of years of evolution, gets us three quarters of the way there. We don’t have to re-discover everything from scratch, we just need to go that last mile to adapt it to detect and fix what we want.

The actual current state of our cells and tissues, which is affected by both genetics and the environment, is the best reporter of any diseases we are developing. And it’s exactly those states that we are trying to read and decipher by harnessing the immune system.

You’re well known as a former physicist who’s taken an unconventional approach to understanding cancer, which is now leading to clinical trials of new treatments. How did you get involved in this project?

I got involved because of two reasons. First, I really enjoy building environments dedicated to doing totally novel science and to recruiting the best talent. For instance, in 1997 I created and directed the IBM Computational Center, which grew quite large by the time I left. I also started three biotech companies and created the Department of Systems Biology at Columbia. In addition, my lab research is fully devoted to transforming biological matter into programmable matter, by elucidating the proteins (which we call Master Regulators) that represent the mechanistic determinants of cell state.

So, even though I came into this project a little late, I was really excited to learn that John Tsang at Yale and Peter Sims at Columbia had already developed this idea of reprogramming the immune system. So, I guess it is a bit of alignment between the ability to build new scientific programs and the specific type of science my lab does, which is devoted to integrating both computational and experimental approaches. The latter is, to a large extent, the “raison d’etre” for the new Biohub NY.

The New York Biohub brings researchers together from Columbia, Rockefeller, and Yale. Why is it important to bring a group like this together? Is what you want to accomplish not possible in the way scientists are currently arranged in their own universities?

We are talking about a project that is so ambitious and potentially so rewarding that no individual lab can hope to achieve it. We are talking about a project that we can think about only if we can identify dozens of individual technologies, know-how, scientific breakthroughs that no individual institution could hope to provide. This is why the connection between these three, geographically proximal institutions is so critical. Yale has perhaps the leading department of immunology in the country. Rockefeller, albeit a smaller institution, is chock full of talent, as shown by one of the highest concentrations of HHMI investigators in the United States. And Columbia has been a leader in combining cutting-edge computational and experimental approaches to study biological mechanisms. Therefore, even on paper, this is a match made in heaven.

This said, the promise of a true integration of talent can only come to pass if the investigators from the three institutions will really come together and collaborate. This is why Biohub funding will require all the investigators to convene at least twice per month at the physical Biohub to present their science, discuss potential interactions, and draft the future trajectory of the Biohub science and accomplishments.

The initial set of interactions has been nothing short of extraordinary. We have a lot of collaborations between individual labs. Let’s call them pairwise interactions. But the ability to create a hub and spoke model where the Biohub concepts will become the guiding light for dozens of investigators is simply on a different scale. Not only do we have an opportunity to create a dream team, but we also have the funding to keep it operational and on target for the next 10 to 15 years.

In my opinion, the Biohub model is truly the only credible and realistic path to achieving something as ambitious as what the investigators from these three institutions have dreamed of. And even if some of the goals we have set do not come to pass, the novel science and understanding of the immune system generated by this collaborative effort will be incredibly exciting.