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Investigating Breast Cancer: Dr. Michael Wigler
Studying breast cancer at the single cell level
Read the transcript of the conversation below:
Chris Riback: I'm Chris Riback. This is Investigating Breast Cancer, the podcast of the Breast Cancer Research Foundation and conversations with the world's leading scientists studying breast cancer prevention, diagnosis, treatment, survivorship and metastasis.
Breast cancer and technology. At first glance, they seem like totally separate topics. After this conversation, you'll not only better understand the connection, but you'll be wanting to learn what comes next as you'll hear thanks to technology developed by our guest Dr. Michael Wigler in collaboration with BCRF colleague James Hicks. Researchers can now study breast cancer at the single cell level, setting the stage for the development of new diagnostic tools that will aid in therapeutic management of the disease. Since that discovery, Dr. Wigler has continued to go small focusing on the interactions between cancer cells and the host microenvironment. It's a fascinating approach.
Some background, Dr. Wigler is the Russell and doubled a professor of cancer research at the Cold Spring Harbor Laboratory in New York. He is a recipient of numerous awards and honors and is a member of the National Academy of Science and the American Academy of Arts and Sciences. Dr. Wigler also has been a BCRF investigator since 1998. Before our conversation though, and ask from me to you, I hope you like these investigating breast cancer conversations and if so I'd appreciate if you'd take a moment, go to iTunes and if you're so moved, leave a five star review. The ratings really matter, they go a long way to helping other people find the podcast. Thank you for considering my request. Okay, that's it. Here's my conversation with Dr. Wigler. Dr. Wigler, thanks for joining me. I appreciate your time.
Dr. Michael Wigler: My pleasure.
Chris Riback: Sometimes these conversations start broad and then go small. With you I feel like we should move in the opposite direction. You've been said to fight cancer one cell at a time. What does that mean?
Dr. Michael Wigler: Well, I gave a lecture a to a group of women that contribute to the lab and at the time that I gave a lecture we were doing some relatively revolutionary things with studying single cancer cells. So we opened up a field at that time that was around 2012 or 2013. And so I named my lecture fighting cancer one cell at a time because it sounded good. It is a bit of a misnomer, but I wanted people to be interested in what was going to come. And what I was describing at that time was working that had been supported in fact by the BCRF which involved looking at the changes that occur in each cancer cell and inferring stuff by doing that. And the kinds of things that we were able to infer had to do with cancer heterogeneity, which means are all the cancer cells cut from the same cloth or are there two tribes of cancer cells and what looks like otherwise a single tumor? Or they're more than that?
And we began to study that and one of our observations was that many cancers contain many tribes all ultimately descended probably from the same ancestor. But nevertheless, that ancestor has produced many different spawns, if you like. And that raised some important clinical and biological questions. The critical questions were if the cancer is heterogeneous, is that a worse kind of cancer? If the cancer is heterogeneous, are the different tribes helping each other or are they competing? And in the first case, the question is relevant to what you could call a staging the cancer. That is you want to know does somebody have a cancer that the patient and the physician are going to have to fight very hard to deceit or is the kind of cancer where the patient can look forward to having a successful outcome?
In the second question that had to do with biology, which we haven't gotten to the biology part of that yet, but it would provide a way where maybe you could turn cancer against cancer so that if the cancer cells are helping each other, maybe you only have to target one of the two cancer types and the other cancer would fold it's hand. If the cancers were competing there might be some other way in which you could utilize that to help the cancer defeat itself. So that was where we were at about 2012 or 2013 when I gave a lecture with that title. Subsequently, lots of people like that title, maybe they've taken that title and used it in their own lectures for a variety of different things.
Chris Riback: I hope that you get residuals on that. I mean you trademarks the whole thing, right?
Dr. Michael Wigler: I didn't and I can't be absolutely sure I was the first one to use it, but I think I was.
Chris Riback: So what happened before that? Because on the clinical side, what you're describing and me kind of listening to you and interpreting it as a lay person. So it's identified that I have cancer, whether that's breast cancer. First question is your work was it or was it not focused solely on the microenvironment of a breast cancer cell, one cell at a time? Or was it cancer cells more generally?
Dr. Michael Wigler: We tend to work on breast cancer whenever we can, but breast cancer is representative of all cancers. But when we can do work with breast cancer, we do work with breast cancer. Those experiments that I'm describing to you were done in breast cancer.
Chris Riback: I understand. And before that, let's say on the clinical side and this is me listening to you and trying to interpret just how huge this type of revolution would be. Before that it wasn't, so I learned that I have cancer or a woman learns that she has breast cancer and then the question was, well, how bad is it? How should we treat it? What needs to come next? And by being able to focus in the microenvironment on that single cell, what transformation from a real human point of view was able to come about because of that finding?
Dr. Michael Wigler: We're still in the stage of acceptance. You have to understand that medical practice is understandably highly conservative and I think the clinical community as far as I know are using single cell analysis only in the research environment, it's not made its way to clinical testing. The closest that we've come to that is a collaboration with people in the prostate cancer area. In prostate cancer there is a big problem as to whether or when somebody detects cancer, should they have their prostate removed? It's a little different than breast cancer. Breast cancer you see a lesion, you take it out. Prostate cancer, they're not quite sure when you see a lesion, they don't really have the luxury of, it grows differently than in breast cancer.
It spreads out more quickly than in breast cancer within the prostate. So there the question is should the patient had their prostate removed or not? So prostate cancer as a field is in greater need of evaluating the severity of a cancer than is the population with breast cancer. So the deal that is maybe closest to adopting single cell technology are the people who looked at prostate cancers and are trying to determine whether the prostate needs to come out or not. But in breast cancer it's not yet really too much on the horizon. It seems clinical but it's not the clinical practice, it's in research. And you could still ask for breast cancer just how aggressive one should it be with the chemotherapy.
I'm not a clinician but there must be decisions that the clinician has to use that measure the aggressive as to the treatment on the one hand versus the risk on the other. Both on one hand so coming to the cancer and the other of having side effects from the treatment. So that equation is a delicate equation. If I were breast cancer patient, I would want information about what is my relative risk of various therapies, all that information is not yet being integrated into the advice I think that people get when they show up with breast cancer. Currently people use, and I I'm to understand I'm not a medical doctor, but people by and large use pathology and a few molecular markers, maybe three or four different molecular markers to classify the cancer's risk to the patient. But I think one can do better than that. But that will happen slowly over time.
Chris Riback: Is that because of the understandable conservative nature of medicine? Is it because people in any field are accustomed to doing things the way they have done them? Which makes a lot of sense.
Dr. Michael Wigler: That's certainly part of it. The other part of it is that to know anything you have to do a fairly large study and those tend to be very expensive. Now if you're a drug company, you're willing to spend $10 million or $20 million up to $100,000,000 to test the efficacy effect, efficacy of a drug. But if you're a diagnostic company or you're just a pathology lab at a hospital, you don't have that kind of resources. So it's partly economics, partly tradition.
Chris Riback: I'm curious about the technology involved and how one starts to discover facts on a single cell basis and really working in that microenvironment. Going back to my first question to you, so often as I'm privileged to have these conversations the ideas kind of start really big and it feels to me and you'll tell me if I'm interpreting your work incorrectly, you are laser focused in going down to the cell level. Are you able to explain how that technology works in kind of lay person's terms? How did that technology advance? What should we know about that technology?
Dr. Michael Wigler: You're asking this as sort of this article interest? How did we get to that? Oh, that's easily explained and it's very understandable. But let me start with a little personal history, I'll be very pleased. I was one of the first labs to start studying human oncogenes. These are the genes that cause cancers to grow and a large hope has been and it's been born out in many cases. So if you understand the oncogenes and you develop drugs against them, you'll therapy for cancer. It's been most effective in some of the leukemia's. Only partially effective in other solo cancers are some examples now known as in lung cancers where by targeting oncogenes you have success. But around 2000 I developed techniques to find oncogenes that were finding too many of them.
And it was very clear that this was a tremendous jungle of great complexity. And so my work shifted to estimating individual patient risk. And everything that I'll talk to you about that we do today is the result of that change in emphasis. So up till about 2000, we were in the sort of cancer gene discovery research area, and then after 2000 we were in let's get a sense of what this individual's cancer genome looks like and what information can we gather broadly about the patient's cancer from that. We discovered in the first half decade that the total number of disruptions to the cancer genome correlated very well with the threat of the cancer. So I often talk about these scars, that the cancer genome has scars and the scars.
And these scars arise by fighting probably with the patient's immune system to get more blood to the tumor. These are the mutations that the cancer had to accumulate as it is struggling for dominance. And the more scars it has in some sense the closer it is to dominating and to killing the patient. So we had this observation, we published it, I think it was in 2006 and there were some exceptions to this and the exceptions bothered me. The exceptions were there were patients that seemed to have pretty mild looking tamed cancers who nevertheless died. So we thought about why that would be and we came to the conclusion that either these were different kinds of cancers or that the cancer was sampled incorrectly. So when you look at a sample, you take a specimen of it and that might not have been represented if a ball descends in the cancer, you're looking at a little region.
And so we said, well, we're going to have to do something about the possibility that cancers are heterogeneous if we want to be able to determine the fate of the patient, the fate of the tumor and the patient. We have to sample from many places and in the face of heterogeneity, we couldn't do better than looking at single cells from the cancer. And that's where the idea of doing single cells came from. It was to get an idea of in some sense the scope of cells that make up the cancer. Some might be fairly benign that they're sort of on the sideline sort of watching things happen and some of the cells in the cancer might be very very aggressive and that's aggressive ones that we wanted to be able to see. So they could be hidden by a preponderance of the benign looking cells and the way to reveal them was by looking at many many hundreds of cells.
And so a lot of our technology then turned to learning how to do that. So we set ourselves a goal for doing that and around 2008, so only two years later we had our first successes in doing that and that was based in part on DNA sequencing. DNA sequencing became an economically efficient way to gather information about the genome and we worked out methods so that we could do it from even a single cell. And we had the help of some other methods, technology that's been developed I think for bacteria, and they worked when we applied them to human cells. So we published the first papers on tumor heterogeneity seen from a point of view of single cells and that was I think eventually published in maybe 2010 because it always takes years to writing a paper. So that's the history of that. I mean, we've evolved much beyond that since that time.
Chris Riback: Tell me about that. Tell me about the evolution and tell me what you are working on now. How are you translating that? Are you focused on? ... At the beginning of this conversation you outlined kind of the clinical versus the genetic? Is your focus now on the genetic or what's next in terms of the technology?"
Dr. Michael Wigler: Anybody who knows my lab knows that focus is a word that is not well applied. We do many many things. We're still trying to find a niche for the single cell analysis for prostate cancer. We develop technology that makes it increasingly cheap and increasingly more friendly so that it's easier for other people to do. We also started to think about single cells in the blood and one of my colleagues was one of the first to show that there are often single cells from a cancer in the blood system. There were two labs to demonstrate that and that was again from prostate cancer, but I think we know that it's also true for some breast cancers. And so that started our thinking about what can we tell from looking at the blood of a person.?
And that became a very productive field that emanated from many quarters not around. People became finding signals for the tumor in DNA in the blood as well as in cells in the blood. And we have been developing techniques aimed at achieving two goals in that arena. The first goal is if a person has a cancer to be able to determine how much of that cancer load they still carry after treatment. So for example, suppose that somebody had a tumor removed, then they should be very little signal for that cancer in their blood because the cancer hopefully is gone. But if we had very sensitive methods we might be able to see that the cancer maybe after a year or two years or even five or ten has reappeared.
And we want to know that at the earliest possible time because often what happens is the patient has been in remission, has been clear of cancer and then some years later they start developing symptoms and by the time they're showing symptoms the cancer has spread to many sites in the body and it's too late to do anything. But we theorized that if one had an early detection system, maybe we could see the earliest signs of the cancer returning. And even though you might not know where it is in the body, you might be able to treat it with this or that chemotherapy and then be able to measure the decline again. That is one of the goals of looking for the traces of the tumor in the blood system and when need to system that is relatively non invasive so that a patient would come in every six months, have their blood drawn and then we would look for signs that the cancer is still sort of a controlled, contained.
The second goal is far more ambitious although that's an extremely ambitious goal and one that I think is going to be achieved. There's no question in my mind that we will achieve that. We are the people who will achieve that. There are already a host of a very good ideas out there that show promise. Goal number two fixes cancer before the patient or the physician could know it's there with a blood test. And there's a lot of money that's been invested in that arena, hundreds of millions of dollars in the commercial arena and we're sort of a small player in that field but we have very very good ideas about how to do it and that's the other active area of our research and we think there's promise on that front as well. And the future there will be a little bit like a colonoscopy but less invasive.
We're wanted to find evidence somebody's got a neoplasm we would be able to tell where that neoplasm is taking place, whether it's breast or liver or renal and hopefully with a high specificity so that nobody comes alarmed. We only get positive signal when there's something really to look for and we could tell the radiologist where to look for it and that one would then be able, I'm combining ideas, to say, "Oh yes, in this organ there is a growth and it's at the dangerous kind." And then one would be able to intervene early and we would reduce death by cancer. So that's the second of our goals.
Chris Riback: And they really do align with what you noted earlier in early detection system and it's detecting, it sounds like you're simultaneously potentially focusing on existence, severity, location, some combination of those.
Dr. Michael Wigler: Right. A lot of the early detection doesn't evaluate severity, which bothers me. So you have the situation, prostate cancer, that's the situation prostate cancer, very good at detection, they report severity.
Chris Riback: Then you've left yourself something to do otherwise you would have accomplished everything already.
Dr. Michael Wigler: What if we reach our goals?
Chris Riback: Yes.
Dr. Michael Wigler: Yeah I'm 70, I'd like to get some of them.
Chris Riback: I'm sure that you would love to. I know that you're joking and we know that you have and we all expect and hope that you will continue to. Just in listening to you and going through the history, I find myself curious even before the history that you've described already, you yourself, how did you get into this? Was it always, I mean going back to growing up for you personally, was it always science? What was it?
Dr. Michael Wigler: No. My first goal was to be middle heavyweight champion and that was when I was three and that's because I had an older brother and I used to hit him, he killed me with the idea to become heavyweight champion. My next goal was to be a rocket engineer, I wanted to build rockets, go to the planets. And then I got over that and I became interested in rocket propellants which got me interested in chemistry and the chemistry got me interested in mathematics and then I wanted to be a mathematician and I was already, I guess by seventh grade. And then somewhere along there I toyed with the idea of being a writer, but I ended up going back into mathematics which I pursued in college.
And then towards the end of college I became somewhat regretful that it wasn't doing something of social utility. So I decided to go to medical school. This was a radical departure for me and it was wrong headed but I didn't finish medical school. I went from medical school into sailing back to science because there was too much unknown in medicine. But I was in medical school really impressed by its need for science that medical science was in a fairly abysmal state. So when I went back to do research and I finally got my PhD degree in microbiology, it was with the intent of doing a kind of science that would be relevant to medical problems and the largest medical problem that I could see was cancer. So that's how I ended up being a cancer researcher.
Also one of the most interesting because the cell is turning against the body and how does the body ... The cell of the body is really a disciplined army of dedicated self. So the fact that the cell could lose that discipline seemed like that should be actually relatively easy thing to do so why aren't we all dying from cancer? So there was clearly tremendous amounts of interest in biology and cancer biology. So not only was it an important medical problem, but it was also going to be interesting. And one of the things that I try to do in life is to have fun while giving help to others. I think if you can have fun while helping others, you really can't maximize lots more than that. In that same lecture which was titled Fighting Cancer One cell At A Time, I started that lecture with a joke. Do you know the joke?
Chris Riback: Tell me the joke.
Dr. Michael Wigler: Okay. The joke is, I have to remember it, what does philanthropy [..]
Dr. Michael Wigler: What they have in common is that you can have fun about giving pleasure to others. So they were at this lunch and they were all having a good time enjoying each other's company but they were giving money to the lab. So I was making an analogy between philanthropy, the pleasure that you have. You can give pleasure to others because the lab enjoyed getting money so it can do it's research while enjoying it yourself. So that's the thing it has in common. Maybe I don't remember the exact wording, but it's online, you can look for it online.
Chris Riback: I saw it online, it's there. If someone searches you YouTube does not forget, it's got all your greatest hits there I can vouch for that. Speaking of greatest hits, what role has BCRF played in your research?
Dr. Michael Wigler: BCRF support goes back to the late '90s when we were just beginning to shift to genome analysis of the cancer cell, and that's the area we are in now. We would not have been able to do it without the BCRF. So they were the source of funding that enabled us to pivot into this area. They gambled on us. There's no way I can overestimate their importance. We would not have gotten support to do what we have, the direction we took from the NIH and it determined our future. And all along the way, initially the BCRF was a large portion of our funding and by time its grown to be a smaller portion of the funding as more and more of our research have expanded in this area. But they always play a part at sort of the leading edge.
So right at the moment the BCRF is funding an area in what's called Spatial Transcript Comix, which is about as futuristic now as our early work was back then. And it would be a little bit difficult to explain just what that's about, but it is in effect an attempt to use DNA sequencing as a kind of microscope. So you get a full picture instead of getting the histo-pathology report of the cancer with all the cells in relationship to each other and to the blood vessels and to support strong inflammatory cells, you get a much more precise picture from the RNA and the DNA in those cells. So we're trying to basically convert DNA sequencing into a microscope. And we think that will maybe in the distant future be how one really gets the ultimate information about just what is cooking in your cancer.
Chris Riback: Another great title, just what is cooking in your cancer. Well that one's yours and you'll have to promise me that you'll come back and do another conversation once you're there on-
Dr. Michael Wigler: I'm happy to just about anything for BCRF, it's a great organization.
Chris Riback: And it's clear to me and to go back to maybe I think it was the seven year old you, it's clear that you're still reaching for the stars and it's interesting that at one point you were potentially interested in the cosmos. Your focus has gone down to the single cell level as we discussed but clearly in getting to talk with you, you are reaching for the stars. So thank you and thank you for the work that you've done.
Dr. Michael Wigler: Thanks for the compliment, it's been a pleasure.
Chris Riback: That was my conversation with Dr. Michael Wigler. My thanks to Dr. Wigler for joining and you for listening. To learn more about breast cancer research or to subscribe to our podcast, go to BCRF.org/podcasts.