Scientists Are Uncovering A World Of ‘Dark Matter’ Carcinogens
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.
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Siddhartha Mukherjee is a physician, scientist, and writer best known for his 2010 book, The Emperor of All Maladies: A Biography of Cancer, which was awarded the 2011 Pulitzer Prize for General Non-Fiction. His latest book is The Gene: An Intimate History. (Scribner, 2016)
IRA FLATOW: This is Science Friday. I’m Ira Flatow. 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 certain cancers like colorectal and lung are mysteriously 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.
My next guest is Dr. Siddhartha Mukherjee author of the Pulitzer Prize winning book The Emperor of all Maladies– 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. Mukherjee is assistant professor of medicine at Columbia University. Welcome back to Science Friday.
SIDDHARTHA MUKHERJEE: Thank you. Pleasure to be here.
IRA FLATOW: Nice to have you. All right, let’s begin right at the very beginning, how scientists traditionally have gone about trying to discover potential carcinogens. There’s history in that, right?
SIDDHARTHA MUKHERJEE: 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 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, to 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 Ames test invented 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 caused mutations in bacterial cells and ipso facto caused 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.
IRA FLATOW: That’s what you mean by all the carcinogens we can’t see.
SIDDHARTHA MUKHERJEE: 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 Maladies. And I am adding three major new chapters to the book because people have always been asking me will you update the book so that it reflects 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 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 are 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 carcinogenesis and thereby our capacity to capture this dark matter of carcinogenesis.
IRA FLATOW: And could that be– a large portion of your piece focuses on a paper from the journal Nature last year about air pollutions role in causing lung cancer. Could that be one of those triggers?
SIDDHARTHA MUKHERJEE: 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 striking correlation.
But that’s epidemiological data. 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.
IRA FLATOW: Tell me. What do you mean that’s where the story gets interesting?
SIDDHARTHA MUKHERJEE: So the story gets interesting because typically, as I said, we think about carcinogens as agents or substances that cause cancer by making mutations in a cell.
IRA FLATOW: Right.
SIDDHARTHA MUKHERJEE: But what Swanton and his colleagues have found is that our bodies have preexisting cells with mutations in them. They’re just asleep. They don’t cause tumors.
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 cause cancer in the sense that 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.
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 preexisting clones of cancer cells can grow.
IRA FLATOW: And so might there be other agents around that we don’t know about that can wake up these sleeping cells?
SIDDHARTHA MUKHERJEE: 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 explain. 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, there were hundreds of tumors. I think the rates, if I remember correctly, went up 10-fold. So the idea that there are many other chemicals that can cause these 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.
IRA FLATOW: Yeah.
SIDDHARTHA MUKHERJEE: And that’s why I’ve called them sort of the dark matter of carcinogenesis.
IRA FLATOW: Could this dark matter explain how we have this incidence of colorectal cancer in young men and women in the US? It’s nearly doubled since 1995. And as you point out, certain pockets of the world have lung cancer rates in young non-smoking adults rising dramatically. Could we find something else that’s waking these tumors up?
SIDDHARTHA MUKHERJEE: Oh, absolutely, I think we can find other things, and, absolutely, I think they exist.
IRA FLATOW: How would you go about finding them?
SIDDHARTHA MUKHERJEE: 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 they activate a particular kind of immune cell called a macrophage.
A macrophage is a professional immune cells whose job is to eat. That’s why the word phage from phagus, from eating. The 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.
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 macrophages 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 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, Ira, 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 there 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 presence across such wide swaths of the population– think of parts of China, parts of India where you have enormous amounts of air pollution. Even if you’re increased risk of developing cancer in a non-smoker is small, the number of exposed people is so large that the stakes become enormous.
IRA FLATOW: 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.
SIDDHARTHA MUKHERJEE: Absolutely. And, in fact, about four years ago, I wrote a column for The New York Times, which said that 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 can stuff anything into that car. And people will say, oh, I have inflammation from this. I have inflammation.
IRA FLATOW: Right.
SIDDHARTHA MUKHERJEE: 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 this kind of inflammation?
IRA FLATOW: Interesting. Do you think that AI– it’s being used in everything– might be able to help in this kind of work, this Sherlock Holmes search?
SIDDHARTHA MUKHERJEE: 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 cancer is increasing.
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 super powered way to do that.
IRA FLATOW: 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?
SIDDHARTHA MUKHERJEE: 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 drink excess alcohol. I have normal habits.
I have no genetic history. My parents didn’t have cancer. I don’t have no family history. But here I am, 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 of us. 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 ho-humming about air pollution and now wake-up call saying, you’re causing cancer. The big C is a word that wakes up everyone.
IRA FLATOW: 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.
SIDDHARTHA MUKHERJEE: My pleasure and, thank you for Science Friday. I’m a big fan.
IRA FLATOW: You’re welcome Dr. Siddhartha Mukherjee, assistant professor of medicine at Columbia University.