Science Friday - Scientists Are Uncovering A World Of ‘Dark Matter’ Carcinogens

Episode Date: February 5, 2024

Cancer, at its core, is a genetic disease: the result of DNA mutations that cause cells to grow out of control and develop tumors. And over the years, scientists have identified certain chemicals, called carcinogens, that are directly linked to those cancer-causing mutations, like those found in cigarettes.But the rates of some cancers, like colorectal and lung, are rising dramatically in certain populations, leaving scientists to wonder what carcinogens they might be missing, and how traditional models of detecting them are falling short.Last year, a landmark study published in the journal Nature confirmed a theory that toxicologists and cancer researchers had long suspected: that certain chemicals, like those found in air pollution, may not directly lead to cancerous mutations, but instead prime already vulnerable mutated cells to become cancerous. Some scientists have dubbed these chemicals “dark matter” carcinogens; they know they’re out there, exerting some kind of effect on increasing cancer rates, but they don’t fully understand what these chemicals are.Dr. Siddhartha Mukherjee, Pulitzer Prize-winning author and assistant professor of medicine at Columbia University, wrote about this scientific detective mystery in The New Yorker. This week, he joins Ira to talk about how scientists are rethinking their approach to identifying carcinogens, and why he’s hopeful for the future of cancer research in light of this new paradigm.Transcripts for this segment will be available the week after the show airs on sciencefriday.com. Subscribe to this podcast. Plus, to stay updated on all things science, sign up for Science Friday's newsletters.

Are we surrounded by carcinogens that awaken sleeper cancer cells in our bodies? Air pollution itself is an enormous carcinogenic burden. The number of exposed people is so large that the stakes become enormous. It's Monday, February 5th, and right again, it's Science Friday. I'm Cyfry producer Dee Peter Schmidt. Cancer is the result of DNA mutations that cause cells to grow out of control and develop tumors. And over the years, scientists have identified certain chemicals called carcinogens that are directly linked. to those cancer-causing mutations, like those found in cigarettes.

But the rates of some cancers are rising dramatically in certain populations, leaving scientists to wonder what carcinogens they might be missing and how traditional models of detecting them are falling short. Ira Flato talks to a cancer researcher to understand how scientists are rethinking their approach to identifying carcinogens, what role air pollution plays, and why he's hopeful for the future of cancer research. My next guest is Dr. Siddhartha Mukherjee, author of the Pulitzer Prize-winning book, The Emperor of All Malities, the Biography of Cancer.

He recently wrote an article in The New Yorker entitled, All the Carcinogens We Can't See. We routinely test for chemicals that cause mutations. What about the dark matter of carcinogens? Substances that don't create cancer cells, but rouse them from their slumber. Dr. Mukerjee is assistant professor of men. at Columbia University. Welcome back to Science Friday. Thank you. I'm a pleasure to be here. Nice to have you. All right at the very beginning, how scientists traditionally have gone about

trying to discover potential carcinogens. There's history in that, right? There's a lot of history in that. And just let me emphasize right at the offset why this is such an incredibly important thing. Because the world has been for the longest time, obviously for a good reason obsessed with cancer prevention. We would like not to have cancer to begin with. Cancer treatment is one thing. But the capacity to prevent cancer, so not have cancer to start with, is, of course, an incredible goal. And so the stakes for finding carcinogens are enormous. If you could prevent cancer, then you wouldn't have to bother about finding new treatments. And so we've gone about this in three ways. One way is a so-called aims test,

by Bruce Ames in the 1970s. Bruce Ames is a scientist. And Ames made the observation that since cancer is a genetic disease, it's caused by mutations in genes, things that cause mutations could be trapped or could be identified by their property to cause mutations in bacterial cells. And so Ames basically created the so-called Ames test in which you expose bacterial cells to the potential substance, potential carcinogen. and if it causes mutations, you can quantify the number of bacterial cells that have become mutant.

And he wrote this incredibly important paper called carcinogens are mutagens. And that's one way that we found carcinogens, things that cause mutations in bacterial cells and ipso facto cause mutations in human cells and cause cancer. The second way is to find cancer-causing agents by exposing, usually animals, mice or rats or rabbits, to the cancer-causing agent and seeing if you actually develop a cancer. And then you have to have a pathologist look through all the organs to cut the organs. And the third way is by looking at human populations. And there you can't usually identify a cause definitively but a correlation.

So for instance, obviously the great experiment, cigarette smoking connected with lung cancer. That's an epidemiological study. So those are the three kinds of traditional methods that we've used. And one big question is these methods can occasionally talk to each other, but they still, obviously, they miss some things that cause cancer. And we've known this for a while. We've known that they're substances that they'll fall through the cracks, like a coin falling in between a couch, because these three methods, although they're very powerful, they cannot capture all the carcinogens. And these mysterious carcinogens, I've described them as the dark matter of carcinogenesis. And these mysterious carcinogens are obviously things that we really want to hunt for because, as I said, the stakes are enormous.

And that's what you mean by all the carcinogens we can't see. That is what I mean. I mean, yes, yes, of course. Yeah. I mean, there's a little bit of personal history that's interesting for me. It's been a little bit more than 10 years since I wrote the Emperor of All Malady's. And I am adding three major new chapters for the book because people have always been asking me, will you update the book so that it reflects, you know, what's happened in the last decade. or so. In one chapter, chapter, the first one is prevention and saying, what have we really

achieved in prevention in the last decade or so? And that's when I started digging. And one thing that was surprising to me is that, you know, the number of preventable human carcinogens with large impact. So chemicals that we can remove from populations and have a major impact on cancers, that number is quite small. And that surprised me because I said to myself, the rates of cancer, in certain populations, as you said, is going up. So there must be something, some behavior, some interaction that we're not catching, that is causing these rates of cancer to go up. But there's some alcohol there, there's increased obesity.

But I felt something was still missing in our understanding of personagenesis and thereby our capacity to capture this dark matter of personagenesis. And could that be? I know you're right. A large portion of your piece focuses on the paper. from the journal Nature last year about air pollution's role in causing lung cancer. Could that be one of those triggers? Absolutely.

So the data with air pollution is supported very strongly by epidemiological data. So if you look at lung cancers in non-smokers and you try to correlate that with a geographic map of places which have the highest levels of particulate air pollution, you see a lot of. a striking correlation. But that's epidemiological data. That's that's a correlation. It's not a cause. The important thing about the nature paper written by Charles Swanton's lab among many collaborators, the important thing about that nature paper is it identifies for us what the mechanism might be. And that's where the story gets interesting. Tell me, what do you mean? That's where the story gets interesting. So the story gets interesting because typically we think about, as I said, we think

about carcinogens as agents or substances that cause cancer by making mutations in a cell. Right. But what Swanton and his colleagues have found is that our bodies have pre-existing cells with mutations in them. They're just asleep. They don't cause tumors. They are, if you look with very careful genetic methods, you can find cells that bear mutations that would qualify them to be cancerous, but they don't.

don't cause cancer in the sense they don't divide, they don't form tumors, they don't have the properties of cancer, they don't invade. Now, this new class of carcinogens, which we've thought about for a long time, this new class of carcinogens are inflammatory agents that enable these cells to come out of their slumber, to start dividing and thereby cause cancer. So these are not traditional mutagens. These are not agents that cause mutations in the cell. What they do, in fact, is they cause an inflammatory response, a very particular kind of inflammatory response. And they, by virtue of creating this inflammatory response, they create the soil in which the seed of the cancer cell can grow. And remember, in this case, the cancer cells pre-exist.

They're already in your body. They just don't happen to be able to grow because the soil is not nurturing for them. So what Swanton and others have shown, and this idea has been around for a while, is that these inflammatory, agents essentially change the soil to a nurturing soil where these pre-existing clones of cancer cells can grow. And so might there be other agents around that we don't know about that can wake up these sleeping cells? Almost certainly there are other agents.

If you look at the literature, this has been known for a very long time. So back in the 1940s, there were two researchers who did an experiment that no one could fully explained. They painted mice with a cancer-causing chemical, and they got a few tumors, as expected. So this was a traditional carcinogen, which causes mutations in DNA, and as expected, they got a few tumors. But when they added an inflammatory agent called croton oil to the back of the animals, you know, there were hundreds of tumors. I think the rates, if I remember correctly, went up tenfold. So the idea that there are many other chemicals that can cause these, you know, inflammatory responses and thereby change the soil and thereby awaken a sleeping cancer cell,

there may be many. We just aren't looking for them. We don't have tests for them. And that's why I've called them sort of the dark matter of carcinogenesis. Could this dark matter explain how we have this incidence of colorectal cancer in young men and women in the U.S.? It's nearly doubled since 1995. And as you point out, certain pockets of the world have lung cancer rates and young non-smoking adults rising dramatically. Could we find something else that's waking these tumors up? Oh, absolutely. I think we can find other things. And absolutely, I think they exist. How would you go about finding them? Well, we have the beginnings of an understanding of what the process is. That's always how we begin this kind of detective story in science.

How do you find these hidden carcinogens? And one thing that we know that they do is that the activate a particular kind of immune cell called a macrophage. A macrophage is a professional immune cell whose job is to eat. That's why the word phage from, you know, from phagos, from eating, a macrophage is an immune cell whose professional job is to eat bacteria or debris or foreign particles and ingest them. And it turns out that with air pollution at least, these macrophages get activated. They probably, one reason is that they cannot fully, ingest them along the traditional way and destroy them. So they send off alarm bells into the immune system.

They send off chemicals saying there's a problem. We have a problem here. And what's interesting is that inflammatory milieu that these macropages create is the milieu, is the soil where these dormant cancer cells can now grow. So if you now know that mechanism, what you can do is you could ask the question, you know, instead of looking for mutagens using the classical Ames test, or instead of exposing animals to chemicals, I'm going to look for a macrophage activator. I'm going to devise a system where I can look for something that activates macrophages.

And there may be dozens of chemicals. And then I'll try to correlate that with epidemiological data or with animal data to try to see if these macrophage activating chemicals are indeed carcinogens. And if they can activate previously dormant cancer cells and activate them. And again, I remember the stakes are enormous here. These chemicals may be in the water. These chemicals may be substances that we think are harmless. But for some reason, when we ingest them, when we expose ourselves to them, they activate an inflammatory response.

And that inflammatory response is causing these dormant cancer cells to rise. So they may be a whole host of them. And one of them is air pollution. Air pollution itself is an enormous, enormous carcinogenic burden. even though the risk to an individual is small, because it's geographically present across such wide swaths of the population, then you think of parts of China, parts of India, where, you know, you have enormous amounts of air pollution. Even if you're increased risk of developing cancer and a non-smoker is small, the number of exposed people is so large that the stakes become enormous.

Now, it's interesting. You talked about, if I understand you, that certain promoters of carcinogen to wake up the cancer cells is inflammation. And if I were talking to a cardiologist now, that cardiologist would say the biggest promoter of heart disease is inflammation. Absolutely. In fact, you know, about four years ago, I wrote a column for the New York Times, which said that, you know, the two major diseases of the human population, especially in the West, are cardiac disease and cancer. And there is a common link between those two diseases and it's inflammation. In fact, we've known this for a while. And so the focus on inflammation, although it's new, it's also quite old, because we've known for a while that this is a connection between

two of the major killers of the population in the Western world. When we say the word inflammation, it's a little bit of a clown car, because, you know, you can stuff anything into that car. And people will say, oh, you know, I have inflammation from this, I've inflammation. Right. What we're talking about seems to be a particular kind of inflammation that seems to cause this increased risk of cancer by awakening dormant cancer cells. And as far as we know, it's mediated by macrophages, these particular immune cells. It has a particular series of chemicals that are responsible. And that's very helpful to know, because instead of using the word inflammation in a loose way, we can use inflammation in a very particular way and ask the question, what activates

these macrophages and how could they be responsible for? for this kind of information. Interesting. Do you think that AI is being used in everything might be able to help in this kind of work, this Sherlock Holmes search? Yes, absolutely. And in fact, our laboratory is looking at AI

very particularly for this, because one thing you can use AI to do is you can use AI to ask the question, where can I find correlates? So in other words, how can I look more deeply into human epidemiological data and ask the question,

who is likely to develop. So let's take the case of young men and women in the United States where colorectal cancers increase it. So if you could create a database and you could ask the question, well, let me create a database and ask where do they live? What have they eaten? What have they been exposed to? What are the commonalities? Is there some genetics behind it? If all of that data could be put in or compiled, we could use tools like AI to figure out what the correlation would be and thereby use that same tool to figure out where these hidden carcinogens might sit or lie. And in fact, we've been using traditional ways, traditional mathematical models to do this. AI is a superpowered way to do that.

So in the big picture then, and maybe appearing in your new updated version of your book, are you hopeful about this kind of future? Yes, I'm very, this is the kind of thing that really gets me interested. So in my clinic, I'm an oncologist, in my clinic in a typical month, I'll have dozens of patients who will come and say, doctor, I don't know why I got this cancer. I'm not a smoker. I don't, you know, drink excess alcohol. I have normal habits. I have no genetic history. My parents didn't have cancer. I have no family history. But here I am, you know, let's say 30 years old with colorectal cancer. Explain that to me. Why? And so it gives me real hope.

that if we could explain why we're getting these bizarre and interesting trends in cancer development, we'll begin to find new carcinogens and prevent cancer. That's a really hopeful thing for all this. And, of course, there's a policy implication. The policy implication is air pollution, we now know epidemiologically, using animal data mechanistically, we know air pollution causes cancer. So this is a call to countries around the world, but a call to countries like India, countries like China to say because cancer, it makes people sit up and take notice,

these countries need to really work hard on decreasing a carcinogen that's being released and exposing their populations to a risk of cancer. So the policy implications of this are also very big. So I'm hopeful that this will really be a wake-up call to not only define new carcinogens using these new methods, but also a wake-up call to various places where they've been sort of, you know, ho-humming about air pollution and now wake up while saying, you know, you're causing cancer. The big C is a word that wakes up everyone. Dr. Mukherjee, you have always been a font of knowledge and helpful for us to understand. Thank you for taking time to be with us today.

My pleasure and thank you for Science Pride. I'm a big fan. You're welcome. Dr. Siddhartha Mukherjee, assistant professor of medicine at Columbia University. That's it for today. Lots of folks help make the show happen, including Jordan Smudjick, Rasha Arredi, Charles Bergquist, Shoshana Bucksbaum. Tomorrow we'll learn why scientists

glued tiny striped capes on two termites. I'm D. Peter Schmidt. Thanks for listening.