Scott Lowe thought that he wanted to be a chemical engineer… but he was wrong. He was fascinated by the amino acid structures that his college roommate was studying. This led him to biochemistry, genetics, and research. He then worked at places like Cold Spring Harbor Laboratory on Long Island and at MIT in Massachusetts. And, for the past few years, he has led a large team at the Memorial Sloan Kettering Cancer Center in New York City, one of the world’s most prestigious cancer centers. There, he studies processes related to cancer and aging, heading up the Cancer Biology and Genetics Program.
The winner of numerous research awards, Lowe is a member of the United States National Academy of Science, as well as the National Academy of Medicine. He was recently in Spain for the 20th anniversary of the Institute for Research in Biomedicine (IRB Barcelona), where EL PAÍS spoke with him about advances and challenges in cancer research, therapies to slow aging, as well as his views on the state of science in the Trump era.
Question. You were one of the first to discover the role of the p53 gene, the most-frequently mutated gene in cancer patients, which is found in approximately 50% of tumors. It’s known by a rather grandiose name: “The guardian of the genome.” What does it do? Is it important enough to deserve that nickname?
Answer. Yes, I think it deserves it. Basically, it functions as an alert system: when it detects a problem in the cell — such as potentially dangerous DNA damage — it responds by either eliminating the cell or stopping its division, thus reducing the risk of cancer. In the latter case, the cells are damaged, but they don’t die. They remain as if they’re floating; they’re known as “zombie cells” or “senescent cells.”
[The gene’s] biology is truly fascinating. We still don’t fully understand how p53 works, even though we’ve been studying it for over 30 years. But we do know that, when it malfunctions, the cell’s genome becomes very unstable and chaotic, leading to tumors that are difficult to treat.
Q. It’s striking that, despite its importance and centrality, there are no approved treatments related to p53. Some positive results have recently emerged from an initial clinical trial treating various types of tumors, but they don’t seem spectacular.
A. The thing is, many of the drugs we use inhibit the action of proteins that are overactive. However, the problem with p53 is that its function is lost… and restoring something with a drug is much more difficult. It’s true that the trial (which included patients with a very specific gene mutation, from among several possible ones) didn’t yield significant results, but trials always begin with patients in advanced stages who have already been treated, when it’s probably too late. I’m on the advisory board of the company developing the drug, so I have conflicts of interest… but it will probably work better if it’s eventually approved and can be used to treat patients in earlier stages.
This is an issue that comes up often: perhaps due to the design of the trials, useful drugs never get approved. But ethically, it’s difficult to accept that they start being administered earlier.
Q. You said that when the p53 gene receives a signal that something is wrong, it causes the cell to die, or become like a zombie cell. Apparently, this function provides immediate protection against tumors… but the accumulation of zombie cells over time also causes aging and increases the future risk of cancer. Is that correct?
A. Yes, although more research is needed to define [the gene’s] exact role. It often poses a problem for people — and even for those in the scientific community — when you say that something is both good and bad at the same time. It sounds like you don’t know what you’re talking about.
We’ve known about cellular senescence (when damaged or aged cells stop dividing, but refuse to die) since the 1960s, when Leonard Hayflick observed that tumor cells can divide indefinitely, but that normal cells eventually stop. Some thought that this process protected against cancer, while others thought that it was actually a [cellular] clock (meaning that cells had an internal counting mechanism, determining how many times they would divide). Today, it seems that both positions were correct.
What seems clear — and what has generated a lot of enthusiasm as a treatment option — is that, with age, more of these [senescent] cells are produced, meaning that the immune system struggles to eliminate them. As a result, they accumulate and cause inflammation and chronic damage. When these cells are eliminated in mice [that have various diseases], they improve in many cases and live longer. That’s why there’s so much interest in developing drugs that can do this.
Q. Senolytic drugs, designed to target and destroy senescent cells, have been talked about for a long time, but none are approved. Why?
A. No, none are approved despite the hype, and that can damage trust in science. My opinion is that we’ve identified quite a few senolytics, but we don’t really know exactly how they work. And some of them can be toxic, which is important [to consider], because the people who’d receive these treatments would typically be frail. We need rigorous science, because we also don’t want to eliminate the positive aspects of these cells.
I was very skeptical until I started seeing it in my own lab. Corina Amor, a Spanish student who was in my lab, developed genetically engineered T-cells to target senescent cells. Until then, these T cells (called CAR-T cells) had only been used against cancer. But what she showed me one day was quite shocking; it almost seemed magical.
In any case, we need to delve deeper. The message right now is that there may be some truly powerful biology involved in these mechanisms, but at the moment, we don’t know enough to make it work.
Q. You’ve also researched pancreatic cancer in mice. And you’ve seen that mutations alone aren’t enough for the cancer to develop: the surrounding environment also needs to be damaged. And you’ve tested combinations of treatments that seem to work well in the lab. How do you think these kinds of results should be communicated to the public?
A. Yes, in that first study with Direna Alonso (now a group leader at IRB Barcelona), we found that our bodies accumulate mutations, but cancer tends to arise in areas with chronic inflammation. There’s something in that environment that, let’s say, “triggers” the cancer.
Regarding the communication of results in mice: it’s a big problem that I’ve seen many times, because both researchers and journalists may want people to be interested in the study. The challenge is to convey to the public how interesting the breakthrough and the discovery process are, while also acknowledging the uncertainty and what we don’t know. It has to be engaging, but you can’t say it’s going to change their lives immediately. It’s a challenge, but I think it’s possible to do it… even if the other way is easier.
Q. On the topic of mutations and cancer, James Watson — the co-discoverer of the double helix structure of DNA — wrote an article a few years ago saying that cancer research had become obsessed with genetics, but that it would never be the solution. Do you agree?
A. Well, I attended many of his presentations. He was trying to stir up controversy, which is good, because it makes you think. But sometimes, he was too extreme. I think there’s no doubt: DNA research and precision medicine have improved the lives of millions of people with cancer, but it’s also true that many times a cure isn’t found because of other mutations. I think that, when it was first seen to work, everyone jumped on it, as later happened with immunotherapy. That’s one of the reasons why governments should fund science, because pharmaceutical companies want to help patients… but in the end, they want to make money. And that may not always [lead to] the most open-minded approach.
Q. Besides having had Spanish students and collaborators, back in 2018, you spent a year at the CNIO, the Spanish National Cancer Research Center. What’s your opinion on the state of science in Spain?
A. Yes. And, before that, I was already a member of [the CNIO’s] Scientific Advisory Board, so I visited frequently. My impression is that there are very creative scientists in Spain. And I was impressed by the quality of the PhD students. In the 2000s, when the IRB was also created, I really thought that, scientifically, Spain was going to be the place to be in Europe. There was a lot of investment… but then, the financial crisis hit. And, for example, in the case of the CNIO, it never fully recovered. I think funding needs to be improved, because the working structures and the people are there.
Q. And in the United States? What repercussions is the Trump administration having on research?
A. The feeling, above all, is one of uncertainty. The initial recommendations were to cut funding by 40%. That hasn’t happened yet, [probably because] many people were laid off from the National Institutes of Health (NIH) and the process of reviewing projects has become very slow. Right now, it’s difficult to make plans, because we don’t know if there will be a reduction in resources. And normally, if you’re not sure, you become more conservative and don’t spend. There’s a lot of concern.
I think that, at this moment, we’re not as proud of American science as we used to be. For example, in my lab, [we once] had about 50 students from Europe… but now, we’re not receiving applications. There may be a whole generation that doesn’t come. And even students in the United States may be asking themselves: why would I want to pursue a scientific career? On the other hand, although it’s too early to say, I think there’s a pro-science movement. The situation has motivated many people to try to explain its value.
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