You know the expression, it’s what’s on the inside that matters. It turns out for that cells including cancer cells, the outside matters a whole lot too.
Specifically, the interactions between the extracellular matrix in the micro environment, the connections between the outside of the cell and the inside is central to how that cell behaves and for cancer cells, how they might grow, spread or most importantly be stopped.
It’s hard to overestimate the magnitude of this breakthrough for biology, cancer research and importantly breast cancer research. This singular discovery rewrote decades of scientific understanding and redirected vast amounts of future research and success. It occurred because of what’s been called the controversial insistence of Dr. Mina Bissell, a BCRF investigator since 2012.
Dr. Bissell is a distinguished scientist at the Lawrence Berkeley National Laboratory at UC Berkeley. She’s also one of the most honored scientists in the world. Among her many awards, Dr. Bissell received the E.B. Wilson Medal, the highest honor the American Society of Cell Biology bestows. She also received the Ernest Orlando Lawrence Award and Medal, the US Department of Energy’s highest scientific honor and the American Cancer Society’s Medal of Honor. There’s even an award named after her, truly, the Bissell Award. She’s a member of the American Academy of Arts and Sciences and the Institute of Medicine. Earned an honorary degree from the Pierre and Marie Curie University in Paris, among other universities and in 2010 was elected to the National Academy of Sciences. Dr. Bissell, thanks for joining me. You realize that we’re going to have to do a separate podcast simply to cover all of the honors and special elections and degrees you’ve earned in your career. I mean, how many people are members of both the Philosophical Society and the Royal Society of Chemistry? That Venn diagram’s got to be really small.
Chris Riback: I want to talk to you of course about the science and the research and the impact that your research has made on breast cancer research and cancer research generally. But I know and I believe that any conversation with you has to start with the idea of inspiration. You are as likely to quote the poet Yeats as you are to quote a Nobel scientist. You compare cell formations to images from space of water reaching the beach. I don’t know if the question is why do you find inspiration or how do you find inspiration? Both of them, I guess the why and the how do you take inspiration from so many different areas of life?
Dr. Bissell: Well, I believe that this is something probably I was born with. I have always been very curious. I have always had passion to know. I love nature and I must say that in college, I debated between becoming a chemistry major or actually doing English literature. I used the Venn’s. I love people. I just have a joy for life. But most importantly, a joy for science. Science is all encompassing and includes the universe if you will. I find analogy in many things in order to be able to reach people and tell them about the discoveries we do and why we are so excited about it.
Chris Riback: When you think about dance, when you think about literature, how does that … Does that enable you to see connections in science? I mean, part of me just thought that you think differently and the ability to think differently maybe gave you the ability to ask questions that maybe other people just weren’t thinking to ask. Does that make sense to you?
Dr. Bissell: People always say how did you do it? What happened? How did you even think of these things so many years before the proof came? In all honesty, I don’t know. But I have to tell you that if you read the essay that I now have written for molecular biology of the cell which is the journal for American Society of Cell Biology, I think you and your listeners would understand a lot more about my background, where I came from, how I developed the way I did. Chris, it is all a product of the micro environment.
Chris Riback: Yes, of course. It is in that which is the central to your research. That fascinated me as well. I mean, your research. Let’s get into the science a little bit. The micro environment and the relationship between the outside of a cell and the inside in the physical context. Before you made that discovery, people hadn’t thought very much about the connection between the outside of the cell and what was going on inside, had they?
Dr. Bissell: Well, people knew a lot about the nucleus of course. People knew a lot about the cytoplasm. People knew a lot about the cell. People also knew about extracellular matrix. There was a big group of people who were doing the chemical and biochemical analysis of extracellular matrix. But these molecules are huge. They are really huge and they’re insoluble. People had always assumed that it is just to keep the shape of the cell or to keep shape of the tissue that these things existed. What had not occurred to them was that actually these things are there for a reason, there is a wisdom in extracellular matrix. I mean, there is wisdom in, in fact, everything that nature does and which has lead to the way we think and we look and we act and we function and all the rest of it. Would you like me to give you a little bit of the history of how I began to think that these molecules may actually signal and they may signal to the nucleus and the nucleus may signal back?
Chris Riback: Yes, please.
Dr. Bissell: All right. As you know yourself, I came from a background of chemistry in undergraduate degree and then bacterial genetics. I really knew very little proper biology. I believe that one of the reasons I did some of the things I did is that I was naïve. My eyes were fresh. I was not, if you will, corrupted by the textbooks in the sense that people write textbooks of things that are known. They don’t write about things that are not known. When I came to do postdoctoral work at Berkeley, what fascinated me, and I was in a laboratory that we’re doing virology and it was the heyday of the excitement about the discovery of the so called oncogene, meaning cancer genes. People were just thinking about smaller and smaller and smaller that could cause cancer. They all were so excited because they would take cells say from chicken embryo or any kind of cells that grow and they would add oncogenic viruses on them and them make a little bump and that bump that would overgrow they would call malignant and the cells that were staying more or less flat on the surface, they were called normal.
I began to think about what that meant and why the normal doesn’t look like my skin or my nose or my eyes. The malignant didn’t quite look like a tumor. I did, for once in my life, a very huge search in the literature trying to find out what actually was out there when people took the cells and put them in culture. I realized that there are many studies that show that when you take a cell from a liver for example or you take it from a skin or you take it from a prostate or you take it from a mammary gland and you put them in culture, they appear to actually change. At that time, I also was not interested in doing what everybody else is doing. I was just trying to learn a little bit more about cancer, what was out there, why did people disagreed. My own curiosity and at the same time my own desire to bring peace, if you will, to the literature trying to find out why this person would say this and that person would say that.
When I began to read the literature, I realized that people were simply not repeating each other’s work. They were thinking they’re repeating each other’s work but the environment in which they were doing their studies were completely different. For example, people were interested in what is known as aerobic glycolysis which means that cancer used a lot of sugar. There was a guy called Otto Warburg who won the Nobel Prize in the 50’s probably. He was just being forgotten completely because he was dealing with sugar metabolism. Nobody wanted to deal with sugar or glucose, who cares? Everybody wanted to do oncogene. I began to look in the literature of that. I realized that the unit that people are defining are not the same. I think maybe that reasoning came from my analytical mind, maybe from chemistry and maybe from my background, et cetera.
I began to realize that the explanations that you’re getting does not make sense. A lot of, some of these things that is in the literature doesn’t make sense. There are concepts such as cell autonomous activity or constitutive gene expression meaning a gene that is always on. That meant that it’s not being regulated. Or a whole lot of other things wasn’t making sense to me. Now, the realization that we have trillions and trillions and trillions of cells in our body came later but in a way, I was thinking about this, you look at the mirror and we now know that the genes in your nose and the genes in your eyes and in the gene in your mouth and the genes in your elbow, meaning the cells in these tissues are all the same. Why do they do so many different things and why when you read the literature or when I did the experiments myself with my postdoc and we took mammary cells and that were making milk and put them in a tissue culture dish, they completely forgot where they came from.
What did that mean? That meant that the cells were changing their behavior because their environment or their micro environment was changed. We began to ask the question of how does the micro environment can come back? At that time, they were a couple of people who had done a kind of interesting experiment, one was on liver cells where they took collagen gel, these large collagen molecule that are all over your body and without that you would turn into Jell-O or you would have no form. They put cells on it and the cells pooled on the collagen and the gel got floated. When it got floated and changed and sort of the cells on it began to change, these cells began to remember a little bit of those functions they had in vivo, by that, I mean inside the subject or inside people. It occurred to me that in order for the cells to be able to remember, they have to change shape and they have to look like where they came from. I began to think, “Well, why does my nose look so different from my eyes?”
The conclusion that I give in all my current talks is that there’s wisdom in the architecture of your mammary gland. There is wisdom in the architecture of prostate or liver and that at the last analysis, it is the architecture more than anything else, more than growth, that actually determines why is cell remembers to be what it is. Now, I have given you a very long answer and I could go on but I’m going to pause for you to ask the questions.
Chris Riback: Just one question? Because I’ve got about 75 for you. I can bring it down to just one. This concept of how environment matters and environment in the sense is everything. I think about how I am who I am and yet I may feel differently or even act differently depending on where I’m at. If I’m at my kid’s school, if I’m out with friends, if I’m in France as opposed to here in the US. That sense that environment matters-
Dr. Bissell: Yes, I in fact talk about that also in my talks. In the sense that the context is literally everything and that the ability of the cells to remember what to do and all these myriads of functions is always context dependent. That’s when I began to think about these floating collagen gels and the fact that one of the students who later became my postdoc, her name was Joanne Immerman, and she brought in the idea that if she took this idea of floating collagen gel and put the cells on them then the cells could make a little bit of milk. But it was not clear at all why and it was not at all clear whether the milk proteins that one could look at is because they just were left over and didn’t get degraded or whether the cell get a new message to which it was responding that, “Hey, you’re a mammary gland. You’re supposed to make milk.” Yeah, go ahead.
Chris Riback: Tell me about that science, the understanding … For the cell to understand its context, for it to be, in a sense, reintroduced to an environment or as well as the exterior wall. How did that science, how does that science work? Why does it matter? Why is it particularly important for people who worry about cancer or breast cancer?
Dr. Bissell: The model that I came up with to explain how your trillions of cells at any given time know what they’re supposed to be doing was that there has to be integration of signals that the cell receive which gives them, if you will, positional information. In other words, the cells says, “Hey, I am here and I look like that and I’m within this micro environment therefore I’m a mammary gland and therefore I would make milk.” The chromatin which is the DNA is wrapped with proteins within the nucleus and not every single gene is being expressed all the time. The chromatin reorganizes depending on the context. If you are within a mammary gland, the chromatin is one position. Of course, we have now more data on this and I know this to be true and it’s quite exciting.
But it was part of my hypothesis that in order for cells to be able to do what they do, they had to have a particular balance of a whole lot of signals that they were receiving. Their micro environment was making them behave correctly. They would remember what to do because of the signals that they were receiving from this unique composition of extracellular matrix material of which collagen is one and that, in fact, these molecules could have function and they could signal and the signal would be transmitted to nucleus and nucleus would react depending on the shape and the milieu that they found themselves. Now, this concept maybe difficult for people to imagine but imagine that you have now people think 30 trillion but they have said 10 trillion or 70 trillion but imagine how many cells that is. They all have to know at any given time that you are talking to me, your cells are doing what they’re supposed to do. How do they do it? Because they have the same genes, right?
Chris Riback: Yeah.
Dr. Bissell: The model that I proposed in 19 … published in January 1982 but actually had began to think of it in the late 70’s and had the manuscript done in 1980 and it took me a while to get it out but it was that a model of dynamic and reciprocal interaction between the outside and inside, in other words, of action and reaction. Sometimes when I give talks and I see somebody looking at their cellphone or somebody’s falling asleep, I actually make a comment and I say, “Look, how do you expect me to the passionate when I see that you’re falling asleep or you’re looking at your cellphone? Listen. Look up.”
Chris Riback: I cannot imagine. I cannot imagine someone sits in one of your lectures and falls asleep. Now I know you’re telling me stories. That’s not true.
Dr. Bissell: Well, come to my Wilson mega lectures, December 6th in San Francisco.
Chris Riback: I would love to. I would love to. You had this hypothesis but it hadn’t been proven, obviously, until you prove it. Tell me about the skepticism that you face around the hypothesis and tell me about what did that feel like, the sentiment when you saw, “Wait a minute, Bissell, you know what, you were right.”
Dr. Bissell: Well, these things don’t happen in a eureka moment because this is life. Although I was so excited when somewhere wiggly in my head, I was formulating this and I was thinking ho else can I sit there and explain tissue specificity or organ specificity, meaning, the fact that the cells not only make a nose and say a finger or an elbow and then remember that they are an elbow and a nose. You don’t get up one morning and have one thing turn into another. But from the experiments in Dolly, the sheep, we know that they made a whole sheep out of a cell from the mammary gland. Imagine, frozen piece of mammary gland sitting in the freezer, the guys figured out, they took some cells, they did a little changes, et cetera, but they didn’t introduce any genes, they didn’t do any of that and they put it in a blastocyst of a sheep that could become pregnant and lo and behold, what do you get? You get a clone of that sheep.
It says that the information to make the entire sheep is present in many, many, many, many of your cells and up to that point people would have thought that the mammary gland in fact was bipotent meaning it only could make two different kind of cells that are part of the mammary gland but not the entire subject. But you and I don’t get up in the morning and have two heads or have a clone or have something else grown. Why? Something must prevent the chaos that could ensue if the cells forgot that it’s part of a given tissue and that’s exactly what cancer is about. It is precisely when a cell doesn’t know to be nose or a skin or a mammary, that is it starts moving elsewhere, piles up, those really crazy things. But it takes with it part of the memory of that context. That’s why breast cancer is different from liver cancer. People just treat it as if cancer is one single disease. It’s not like that at all. The disease of the skin is one thing, the disease of the kidney is another, the disease of the prostate is another.
Organ dictate not only organ specificity but also when they become cancerous means they have lost that ability to interact with their micro environment and rather than remembering that, “Hey, I’m the prostate. I’m piece of a skin. I’m the tip of a finger.” They start becoming radical and piling up and growing and growing elsewhere and I still argue that when they go elsewhere, they don’t become completely something else, they have still the memory of that particular issue. That’s why … I’m sorry, go ahead.
Chris Riback: No, go ahead please.
Dr. Bissell: That’s why I think people have to really remember that to cure cancer, including breast cancer, they not only have to think about the cancer cells, but they also have to think about the environment that the cancer finds itself. If we take the tumor out, something else in that place of the tumor or some of the cells that have escaped already and gone elsewhere, they find a different environment and they start doing some other crazy stuff. That’s called metastasis. In my scientific career, we only not developed this concept that you have to put the cells back into the right architecture and the minute we did that with this gelatinous material that people isolate actually even from a tumor of a subject but we can also make it very clean by taking the components of a gel meaning molecule that is really my heroine if you will and it’s called laminin. There are many different kinds of laminin, but laminin 111 is one of the very first important laminin that was discovered.
This thing is part of this extracellular matrix which goes on glandular tissues and it’s called a basement membrane. This molecule is so versatile and is so important that the different parts of this molecule gives different signals to the cells. Once you actually have this molecule in tact as part of extracellular matrix, the cells are fine. You’re hoping, you’re doing the right thing. But once things start degrading, if there is inflammation, if there is aging, aging is the biggest risk factor for cancer, logarithmically, it goes up. Why? My hypothesis, which now a lot of people seem to be coming on, indicated that if the good extracellular matrix, in tact extracellular matrix, is giving you so many of the good signals, once it starts growing, you see these wrinkles that we get are the extracellular matrix that has gone degraded. We use elastin, we use collagen, we lose collagen. Things start, enzymes come up and start chewing it up. We get reacted oxygen species that then cause havoc.
The signal between the outside and the inside is not the right signal. Little by little by little, the micro environment also becomes reactive and the whole thing is what gives rise to cancer. Very quickly to tell you and your audience is that we have shown in a paper in 2013, in journal of clinical investigation, that if we take away the sugar in the medium, the glucose in the medium, the cells can revert the way you saw in my TED talk. They think they’re normal even though the genome is a mess. If you take the sugar away, they reorganize and they make a perfectly good looking unit of the mammary gland. If we give too much sugar by introducing the transporter or something to the normal cells or nonmalignant cells, they lose structure. Sugar is evil.
One of the reasons that the rate of cancer is so much higher in people who are obese or people who don’t exercise, this one of my things, mentoring thing in my lectures, exercise because exercise keeps your extracellular matrix and your muscles in harmony. Don’t take so much sugar in between meals. But all these things in excess cause loss of balance, loss of integration. Your tissues have to integrate signals in order to be able to be doing that. Cancer is loss of integration.
Chris Riback: Well, I will certainly follow that advise. I will do a little bit more exercising. I will do a lot a bit less sugar. I might add that I hope where you’re going with some of this research is that you’re going to solve this aging thing and if you could do that, Dr. Bissell, I mean then we really could find an award for you. I mean, that would really-
Dr. Bissell: Well, Chris, I always say that people who say we can eradicate cancer are smoking. They don’t know what they’re talking about. Cancer is a problem of aging. I mean, admittedly you can have babies with cancer and that’s a completely mechanism that what I’m describing because they get a really important genetic defect and as an embryo, they start developing where their architecture of their body is not quite right. You see, they have, if you will, those parts of the body that don’t have the right structure itself becoming, sooner or later, becoming cancers. But the point is that we will not eradicate cancer until we understand aging or we eradicate aging. Since that’s not easily in the cards and let me tell you that I think that’s a good thing because we have only one planet and if people didn’t die, I mean, imagine what havoc would ensue. I just say to people, relax about that, it’s part of life. It’s one of those things that sooner or later happens. It’s like seasons. Enjoy everyday and do the right thing, balance, balance your life.
Chris Riback: That makes sense. I absolutely want to do everything I can for the environment but you’ll forgive me if I don’t seek to immediately contribute in that way. In the short term, I’ll recycle. You’re talking about the human part. You’re talking now about the people. Obviously so many people live with cancer and breast cancer in particular. Do you get to interact with them?
Dr. Bissell: Yes.
Chris Riback: Do you feel the connection between the work you do and the work your lab has done and the therapies they maybe following to extend their lives or even beat cancer in those therapies that some of which, many of which may have come off of your research and discoveries that you’ve made?
Dr. Bissell: They have. They have. Actually, one of the … Of course, there’s a complete connection. I do as much as I can. First of all, I interact with a lot of advocates when I write grants, et cetera. We try to invite them to our group meeting. We talk about a lot of these things. I send my students and postdocs all over the world to good careers and they’re all passionate and they’re all doing very well. The most important other message that I give, Chris, as you again having listened to my TED talk when I blurted out that the most important thing for scientists to be able to solve all these important problems is not to become arrogant because have a culture of arrogance in higher echelon of scientists and specially in the US. It’s a little bit less in Europe. In fact, it’s a lot less in Europe. But they’re catching up.
This business of scientists becoming entrepreneur and pushing their favorite molecule and making companies and making millions and billions dollar really gets to me because I have always refused even after now that 3D has become a big, big thing. If you open up anything. Micro environment is a big thing. 3D is a big thing. All these thing and early on people wanted me to help them open a company or do whatever and I said, “Look, I can advise but I will never open a company because it corrupts you, because you are selling a product and the science you cannot sell, you can tell, you can discover, but you shouldn’t be selling.”
It is important to keep an open eye. I tell you that we think that if a lot of people get to a place where we can have more drugs and more additional … it doesn’t need to just be a chemical drug, it could be all sorts of other things, aspirin which inhibits inflammation could be the most important drug for patients only sad thing is we cannot give them it to them because when we are operating, they would bleed to death if they had aspirin. Why aren’t the big pharma finding anti-inflammatory agents that actually would not do that? I suggest that if you inhibit inflammation, if you inhibit this slow nastiness that all these horrible things we put in our body and get from the air but most importantly we do it to ourselves with obesity, with lack of activity, with too much drugs, with too much drinking, too much this and that is that we are actually messing up the balance. It is not as much the big environment, that it is the micro environment.
Actually, some of these people get sometimes mad at me because I say, “You can do a lot about keeping your micro environment healthy and that will help you a lot.” If I had time, I would have told you a lot more about how these cells that become dormant, the cancer cells that become dormant, how I think that at some point, the people who get over their cancer, they could still have a lot of dormant cells meaning sleeping cancer cells, but again that’s because of their micro environment. These cells go somewhere and they sit and they’re quiet. I think we can bring in the idea that we can have cancers that can be treated the way diabetes, in other words a chronic disease, where we can keep the patient healthy enough and these cells sleeping enough so that they won’t wake up. Of course, that’s not the cure, if you will, but we will be working on that area as well. A lot of my former students of whom I’m so proud are working in these different areas. I think, collectively, this field is going to help.
One molecule that we worked on very early and that’s called a Beta-1 integrin which is one of the sub-units of a receptor of how the extracellular matrix talks to the cell and sends the signal in is becoming an antibody. That is being developed by a company. I sit on the board. It was one of our patents. It is looking very good. I am very happy because it has very little toxicity and we think that if it’s given in conjunction with some of those really hammer type drugs we give to the patients, they’re going to need a lot less and therefore toxicity would be a lot less and that’s the way to try and go to reduce toxicity and increase potency.
Chris Riback: Well, I certainly wish that you did have more time because we would go on and I could ask you about that. This concept of treating cancer as a chronic disease, I would ask you about that. Also, I keep thinking this mix that you present between these macro views that you have and the balance of life and the connections of all these big aspects of who we are and where we are in your visions and using pictures from space and all of these big stuff and then yet you focus on the micro environment and that it’s the down to this and that, that interaction in your mind and how you connect the macro view and how that macro view affects the study of the micro. I could talk to you about that for hours as well I think.
Dr. Bissell: Well, maybe we’ll have another opportunity to talk because we have a couple of really, really exciting papers that are about to go out and once we publish them, they’ll be really big. They explain probably part of the mystery that we are still missing about how exactly a molecule in the basement membrane or in the extracellular matrix under a given condition can give the signal for the cell to stop growing and why is that signal lost in cancer and how can we bring it back. It may not be as complicated as people think but on the other hand, to get the complete balance, it is very, very difficult because the pathways that balance your prostate are going to be different from the pathways that balance your liver. They may be the same pathways but they regulate very differently. There is not going to be a single golden molecule that is going to cure cancer.
There is a whole lot of things that have to do, also if you will, with how you as an organism keep balance in your own life and how everything in the last analysis, the unit of function in humans is the organism itself, the connection of brain to the stomach, the connection of the stomach to the muscle, the muscle that does whatever. One has to get a holistic view but one has to get to the molecular mechanism. That combination is hard to find in very many people. It also has a lot to do with the way we give grants and with the way scientists think and that’s why Breast Cancer Research Foundation is such an unusually amazing organization. They choose the individual rather than what are the words of your grant in a single molecule.
Forever, I’ll be indebted to them because I lost a couple of very big grants for … one of them had to do with the budget of the government and another one had to do with shortsightedness of some of our leaders and people like Larry Norton and the Breast Cancer Foundation came to the rescue and I cannot tell you enough how much good this organization does.
Chris Riback: Well, those are very, very kind words. I’m sure that the impact, I’m sure that anyone is simply happy to help advance the impact that you have made and that you will make. In fact, I find myself thinking, “Please go hurry up and publish these darn papers so that we can talk again.”
Dr. Bissell: But it has to go through the review and the reviewers don’t seem to get it. (laughter) It is a lot of education on that too. That’s why at my old age I keep traveling and talking to young people. I’m all over. I’m just about to go to Germany and in one week I’m talking in three different parts between Germany and Switzerland and then I’ll give a talk in France and then I … I mean, that’s at the end of September I went to three keynote talks to the one day that the students celebrate whatever it is and it’s exhausting. But the passion of wanting to teach and mentor drives me. It’s a pleasure to talk to you.
Chris Riback: Thank you. It certainly does sound that it does drive you. Thank you so much for the time. Dr. Mina Bissell joining us today. I’m Chris Riback. This is BCRF Conversations. To learn more about Breast Cancer Research or to subscribe to our podcast, go to bcrfcure.org/podcast.
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