Quintessential researcher: Q&A with Robert Weinberg

How would you summarize your research in a tweet?
Trying to understand the basic mechanistic principles of how human cancers arise.

What central questions drive your lab’s research?
How do disseminated cancer cells, once they leave a primary tumor and land in a distant tissue, figure out how to make a living? They face a difficult challenge and only rarely succeed. How they do it is still a bit obscure, and my lab group has been focusing a lot of energy on that particular question.

What was the greatest impact of your discoveries of the first human cancer-causing gene and the first tumor suppressor gene?
We began studying viral oncogenes in 1977, which led to the discovery of the first cellular oncogene Ras in 1979. I like to refer to this discovery as “an earned run” because of the work involved in identifying, isolating and cloning it. However, the subsequent discovery of the first tumor suppressor gene Rb in 1986 was “an unearned run,” since it fell into my lap thanks to work of post-docs Stephen Friend and René Bernards. These two discoveries laid out a template, or blueprint, for how one could, in principle, understand human cancer pathogenesis through the actions of either hyperactive oncogenes or inactive tumor suppressor genes. Until then these mechanisms were simply matters of speculation, that is, there was no direct proof that one could really use the tools of molecular biology that were then rapidly developing in order to reveal the mechanisms that allowed activated oncogenes or inactivated tumor suppressor genes to push forward the growth of genetically altered cells.

Why aren’t malignant tumors just content to stay put as they grow and get bigger?
When tumors begin in different sites in the body, the question is—are they intent on spreading? To my mind, metastatic dissemination of cancer cells from a primary tumor site to distant sites in the body is an accident that happens when the carcinoma cells increasingly create an inflamed tissue environment around them that, in turn, provokes these cells to begin to invade and ultimately to disseminate physically to distant tissues. Once they are there, they confront the problem of how they are going to make a living in these distant tissues. That remains one aspect of this problem that is essentially unsolved. In contrast, the question of how mechanistically cancer cells move from a primary tumor to a distant tissue, at least in the case of carcinomas, is basically solved in the context of understanding the complex cell-biological program often called the EMT—epithelial-to-mesenchymal transition—that imparts to carcinoma cells virtually all of the attributes that we ascribe to the cancer cells of high-grade malignancies.

How did the writing of The Hallmarks of Cancer come about?
Writing The Hallmarks of Cancer was an accident. Doug Hanahan and I were playing hooky one afternoon from a conference in Hawaii, and we were walking down the mouth of a volcano when we began to talk about the fact that, unlike the laws of physics, the laws of cancer biology were quite messy and not clearly conceptualized. Both he and I were products of an MIT education, so we had great faith in the powers of fundamental principles to explain all kinds of phenomena. And indeed, we perceived cancer research to be just a collection of phenomena. We began to discuss whether we could articulate a set of underlying principles that might enable people to undertake comparisons between different kinds of tumors. We wrote the review in 1999 fully expecting that, like most reviews, it would sink like a stone thrown into a quiet pond. It appeared in the first issue of Cell in January 2000. To our surprise, indeed total astonishment, it turned out to be very helpful in allowing people to understand the complexities of cancer in terms of a relatively small number of underlying mechanistic principles.

How did The Hallmarks of Cancer influence your own personal research?
I was able to create a dichotomy in my thinking about cancer progression. On the one hand, what are the principles responsible for creation of the cells forming a primary tumor? On the other, what principles or mechanisms are responsible for its metastatic spread? That dichotomy has strongly influenced my thinking, because I’ve often argued that the formation of the primary tumor is largely the responsibility of genetic mutations that strike the genomes of cancer cells, whereas the metastatic spread that comes after is largely the consequence of cell-biological programs that cannot be understood by sequencing the genomes of cancer cells.

Who are some of the mentors who have supported you throughout your career?
Arguably the person who supported me the most during my career was David Baltimore. I knew him when he was a graduate student at MIT in 1963-64, and it was he who helped make the necessary connections so that I could get a postdoc at the Salk Institute in 1970-71. It was he who whispered in the ear of Salvador Luria, who was the founder and first director of the MIT Center for Cancer Research, to hire me as a junior faculty member. David was the founding director of the Whitehead Institute and in 1982 brought me on board. So, in many respects, much of what I am is due to the fact that I had continuing support and inspiration from him.

How do you mentor and support the next generation of scientists?
Teaching and mentoring are as important as doing research. At MIT, every faculty member in the biology department is required to teach. Early on, I realized that training and mentorship in my lab are as important as the results that we produce from our work. They’re what ensure that cancer research continues to move forward. And so, for three or four decades I’ve actually been very active in mentoring the people in my lab. I have also been very active both at MIT and in the greater Boston community in organizing a series of meetings where young people have a chance to see how cancer research is conducted and learn how to thrive as independent investigators. In my own case, the explicitly stated goal of my lab is that the trainees who pass through the lab should be able to stand on their own two feet and launch their own independent research careers after they have left my lab. If they are unsuccessful in doing so, I regard that as a failure on my part.

In this climate, where funding is more challenging for scientists, how do you encourage your trainees to pursue a career in science?
Whether they go into academia, biotech, big pharma or the law, I tell them that my only job as their mentor is to tune-up their brain. Once it’s tuned-up, I encourage them to figure out what they’re best at and what they enjoy doing most. So, I would say it’s more of a positive message rather than one that bewails the plight of research funding.

What is the best piece of advice you have ever received from a mentor?
It came from my father who said to me on a number of occasions—it’s all right to be successful, but don’t be too visible. This stemmed from his having fled Germany in the 1930s where, if you were too successful or too visible, one night the guys in the brown shirts would come knocking on your door. That advice has remained very much at the front of my mind. I’ve tried not to be too self-aggrandizing because, as I’ve often told my people, “success breeds envy and resentment.”

What are the greatest challenges facing the cancer research field?
I envision two big challenges on the horizon. The first is how to analyze complex data sets and glean some simple biological take-home lessons from them. Many claim that bioinformatics and artificial intelligence will solve the entire problem, but I remain very skeptical. The second is how to integrate the behavior of the genetic alterations ensconced in the cancer cell genomes with the transcriptomes—the repertoire of genes that are being transcribed in that particular cell. We don’t have a very clear picture about how the genetic changes and the epigenetic programs interact with one another to ultimately create the final biological phenotype of the cancer cell. Understanding and solving those two problems is critical to the future success of cancer research.

What do you think are the greatest opportunities in cancer research today?
I think the field as a whole is a bit stuck in the mud. We don’t really know how to break through all the obstacles that are preventing profound improvements in the way we treat cancer. Immunotherapy seems very attractive, and it might represent an enormous opportunity, if only we could figure out how to make it work in most kinds of tumors. At present, we don’t really know how to do that. So, I would argue that the greatest opportunity is to improve the efficacy of checkpoint immunotherapy so that it can be widely applicable to successfully treat a whole series of solid human tumors.

What are the areas of cancer research that hold the greatest promise for cancer patients?
I’m optimistic about four areas of opportunity. First is how to use the various existing treatments in combination. Second, how to potentiate the efficacy of checkpoint immunotherapy, which at present is quite limited in terms of its widespread applicability. Third, how to harness our insights into the metabolic aberrations of cancer cells in order to selectively hit them and, fourth, being able to switch aggressive carcinoma cells into a less aggressive state by eradicating or differentiating aggressive, undifferentiated tumor-initiating carcinoma cells.

If you had the resources and the power to eradicate any world problem other than cancer, what would you choose to solve?
Climate change. It’s the greatest challenge that threatens all of humanity. It’s gravity and breadth overshadow any other human problem. If we fail to address this problem successfully, there will be catastrophic consequences for our children and grandchildren.

Who are the scientists living or dead that you admire most?
The Nobel Laureate Dan Nathan at Johns Hopkins. He was a man of great success, great intellect and yet someone who was extraordinarily humble and self-effacing. For me, emulating Dan Nathan has always been a goal I’ve aspired to.

What moment in history would you have most liked to have witnessed?
The moment Hitler committed suicide in the Berlin bunker.

If you could write the title of the story of your life, what would it be?
One Step After Another: A Whole Concatenation of Accidents.

When you reflect on your career, what are you most proud of?
The 1979 paper in which we demonstrated that the DNA of a chemically transformed cell actually carried genetic information that could convert a normal cell into a cancer cell.

What were the values that were espoused in your household growing up?
Growing up in a family of European refugees, it was clear that the characteristics my parents and grandparents valued most in a person were, firstly, intelligence and, secondly, a sense of humor. If a person wasn’t too bright, that person could make up for it if they had a good sense of humor! Never do I ever recall their mentioning financial or material success in terms of how they valued other human beings.

If you had not become a cancer researcher, what other career paths do you think you might have taken?
A carpenter. There is something very satisfying about working with my hands. Starting in 1976, my wife and I built our cabin in New Hampshire and over the years added two more wings and a porch. In the summer, I’m a fanatic gardener and relish repairing things. Outside of the lab, I like to ponder simple problems like what size bolt will I use to attach a joist to a beam, and I’m endlessly fascinated by how things get connected and the design of complex structures. To this day, when we go by a construction site, I insist that my family stop so I can study what the workers are doing.