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Show Notes
This is another episode in our series on the great figures in developmental bioelectricity. We interview (~1 hour) Mustafa Djamgoz, who has made pivotal discoveries about the role of bioelectricity in the problem of cancer and its eventual solution.
Mustafa's book: https://www.goodreads.com/book/show/17612801-beat-cancer
Mustafa's papers: https://profiles.imperial.ac.uk/m.djamgoz/publications
Mustafa and I are co-editors of the new journal Bioelectricity: https://home.liebertpub.com/publications/bioelectricity/647
CHAPTERS:
(00:00) From Radios To Cancer
(04:24) Following Instincts In Science
(08:56) From Physics To Cancer
(17:49) Ion Channels Drive Metastasis
(28:40) Targeting Cancer Sodium Channels
(50:13) Living Longer With Cancer
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Transcript
This transcript is automatically generated; we strive for accuracy, but errors in wording or speaker identification may occur. Please verify key details when needed.
[00:00] Aastha Jain Simes: Thank you again, Mustafa, for taking time. We're really excited to talk to you. I think your work on cancer and bioelectricity is really fascinating, which we'd love to chat about, but taking a step back, why don't you tell us a bit about your background and how you even got interested in bioelectricity? I believe it was when you were a kid playing with radios and getting electric shocks, but we'd love to hear the story.
[00:26] Mustafa Djamgoz: Story has been around a while. It indeed started when I was about 17, and I built a radio transmitter from old valves and things. This is where I was born and grew up in Cyprus. I built this kit on my mother's mincing board. It had a nice shiny surface, but everything was out in the open. We were dealing with live electricity. I got the electric shock several times. I can tell you, I don't know if you or Mike, you must have had the old shock, Mike, in your time. I was absolutely fascinated, and also scared by this force going through your body that could kill you. After several times, I decided to turn it into, ultimately, a profession. It did work, by the way. I haven't turned it on for a while, but I was transmitting in the neighborhood. It was a crazy time. It was meant to work with just a Morse key. Then I found a microphone, connected to a microphone, and it worked with voice as well. It was incredible. At some point after I had my own lab and started recruiting graduate students, on a couple of occasions I said to my incoming students, "Look, if you really want to understand what bioelectricity is, you should go and put your finger in an electric socket. And then you will know what your PhD is all about." Well, this didn't go down too well at the time. But this has stayed with me. It's been a fascinating journey. I'm sure same from Mike, we live with this something between a dream and a reality. In cancer, we do believe we have generated a whole new vision of the cancer process, in fact, the metastatic process, and all because of bioelectricity, which of course not many clinicians, with all respect, quite understand. This was one of the early problems when I started sending papers to Nature, and they just couldn't hack it. The biologists couldn't hack the electricity or the bit of physics. The point came when I had to almost educate oncologists from bottom up, go down to basics and tell them about ion channels and remind them of Hodgkin and Huxley and all these things. And the rest is history. Here we are running a journal on bioelectricity. The field has established itself all around the world. It's going through changes, developments, novelties all the time, even today. I was just talking with Mike a minute ago. There's a paper in one of the cell journals talking about action potentials in glioblastomas. These aggressive cancers are electrically excited. The big question now is, what is this activity, what are these signals doing in driving the cancer process. We're beginning to form some ideas. So very exciting times.
[04:24] Aastha Jain Simes: Mike, go ahead.
[04:25] Michael Levin: Before we get into the background-wise, what would you say, in all of the courses, classes, all the education that you've had until now, were some of the most useful or the most essential things that have helped you make breakthroughs in this field? You're a leading figure in the bioelectricity of cancer in modern times. People ask me a lot, young people ask me a lot, what should I be studying? I have my own opinions, but I'd love to know from you, what did you feel was the most important for you?
[04:58] Mustafa Djamgoz: Well, I have always followed my instincts. I get that question all the time. And I always say, follow your instincts. Do what it is that you want. Just like I myself did. I did go on record once saying I could have been a road sweeper somewhere. My roads would have been the cleanest in the neighborhood. So do what it is that you want to do, but do it well. Now, of course, with cancer you're dealing with a deadly, serious situation. So there is no leeway. There is no chance to get it wrong. I realized very early on because we made the initial discoveries on prostate cancer. Many of my friends, including some from the West Coast, said, Mustafa, what you should do is set up a whole series of rigs down this corridor and blast through all the cancers. I thought, yeah, this is a good idea, kind of world domination type thing. Then when I tried, I got a very firm message back from the British establishment saying, do not dabble around. Just stay where you are and dig deep. This is not a party game. Don't spread too thinly. We kept on prostate until curiosity had the better of us. One weekend, with one of my students, we had a go at breast. Prostate and breast share many properties and so do their cancers. One weekend we did some recordings from some breast cancer cells and there it was, the voltage-gated sodium channel. One of the best things I did was to nip up to Newcastle in the north of England and make a presentation to the Physiological Society. The abstracts of the presentations are published, so we had that abstract published. The following year, a friendly group published a full paper reporting the same phenomenon in breast. From there it grew. Different people worked on different cancers. Different nationalities seemed to pick up different cancers. In Mexico, they did cervical cancer. Cervical cancer is quite common in Mexico, so those groups focused on that. The standard way of diagnosing cervical cancer is with a smear test, so they ran a slide and collected some cancer cells, put the electrodes on top, and there it was, the sodium channel directly in human cancer cells. Japanese groups looked at gastric cancer because stomach cancer is common in Japan, and there it was again. The rest is history. The days have gone now when we would get excited, oh, another channel, another cancer and just forget it. These channels are everywhere. Cancer is like brain. All the channels are there doing their own thing, just like channels do in the nervous system. And not on their own. They huddle together. They form networks and drive the very complex process of cancer. We work mainly on metastatic disease, on metastasis, which is, of course, the main cause of death.
[08:56] Aastha Jain Simes: I'm still curious about one of your background questions. At the age of 17, when you said you got these electric shocks, what did you think of electricity back then? What was the progression from a 17-year-old playing with radios and getting electric shocks to starting your own lab and ending up in bioelectricity?
[09:23] Mustafa Djamgoz: That's a very good question, Aslad. The natural thing for me to do then was to study physics. I did my university exams, some of them in Cyprus, finished them off in the UK at boarding school. I entered Imperial College to study physics. One of the best things I did, actually, because what physics taught me is to understand the physical universe. That's what physics does. Everything from black holes to galaxies to quantum mechanics and electricity. Physics would explain all these things to you with equations, not just qualitative phenomena. This was very satisfying: the fact that you could write an equation and predict the outcome of your experiment and show that light is a wave or light is a particle, depending on how you look at it. That was my first step up from those electric shocks into turning what was a hobby towards a professional training. When it came to a PhD, I had somewhat against me studying in the UK as a foreign student at the time. Biophysics was just coming in. I should say that I'm now talking of the 70s on the back of the golden era of physics in the first half of the 20th century. These gods of quantum mechanics and relativity and uncertainty and all these things. It was incredibly satisfying. We really went home every day very happy, almost. But I worked very, very hard. So biophysics, bioelectricity, the natural place to then settle was neuroscience. I worked on several neural systems, but I was always driven by model systems. I think Mike does this as well. One of my scientific heroes are Hodgkin and Huxley, and what the giant axon of this squid did to our understanding of nerve excitation and conduction. They couldn't have done half those experiments if it wasn't for that model system. I thought that was very essential to understand complex phenomena. You really need to use appropriate model systems. So for me, at that time, the retina was the model and it's a beautiful system. You could peel it from the back of the eye. It was mainly fish at that time. A natural brain slice would survive in simple oxygen. You put the electrodes in. There's a type of cell in the retina called a horizontal cell, which can code color. Remember, I hadn't yet seen a resting potential in any nerve cell or muscle. Because you're poking the electrode into the retina in the dark and flashing light, you knew you entered the cell because you would get some kind of a drop and then the cell would respond to light.
[13:35] Mustafa Djamgoz: One of these cells, a horizontal cell, would hyperpolarize to green light and depolarize to red. I was fascinated by this. There is a cell, one step, one synapse beyond photoreceptors. It's already telling you milk is white, milk is black. Membrane potential is going in opposite directions, depending on the color of the stimulus. This was an incredibly powerful signaling and coding mechanism, the way visual information was being coded. But what was happening, we were now well into the 70s. Plasticity was being discussed. Everybody knew that the brain is plastic in early life. Depending on how you rear the child or an animal, the brain develops accordingly. The retina taught us that there is also significant plasticity in the adult central nervous system. That was a bit of a battle with editors to use the term "adult synaptic plasticity," which has become a reality now because we know it happens as a function of learning and memory. So that brought me: neuroscience, the brain, was like a biological universe. What I learned from physics, I brought into neuroscience: I could look at the neurons, the way neurons were responding to stimuli or talking to each other in the way that I had learned about physical entities in the physical universe doing as well. With plasticity, I got to learn a lot about a system's capacity for change, not just anatomical change but change as a functional requirement. Depending on whether the visual system was light-adapted or dark-adapted, these synaptic interactions would change. For example, that biphasic cell — red, green, depolarizing, hyperpolarizing — became monophasic under dark-adapted conditions. That kind of makes sense because we don't need color vision in the dark. The cell kept in step. That was my 25 years of neuroscience. I loved it. I eventually did an EMBO course on ion-selective electrodes, and I inserted an electrode into barnacle muscle, this giant muscle, and there it was — minus 70 resting potential, correlating directly with where the electrode was. When I became interested in cancer, that was pure curiosity. There was no emotional issue or any reason. I was just curious. To me, that came across as a pathological universe. Cancer is incredibly complex. That's why it's so hard to deal with, to manage. With the training from physics and neuroscience, I felt at home analyzing this complex world of tumors. Interestingly now, these two fields have merged. There is a whole new field of cancer neuroscience. It turns out tumors are innervated and tumors acquire neuronal properties as part of their behavior. This is what I meant earlier when I said we're not just kidding when I say these are exciting times. Everything is gelling. I'm sure you'll want to talk about how we're going to use bioelectricity in the clinic. But I think we are rapidly laying the groundwork for exploiting bioelectricity in oncology as well.
[17:49] Aastha Jain Simes: I know you've already touched upon it, but perhaps if you can explain it more simply in terms of you had a 1995 paper, which was your first paper on connecting ion channels and cancer. How did you start connecting the two together? And then what would you say is the role of ion channels in cancer and bioelectricity in cancer?
[18:16] Mustafa Djamgoz: Right. So again, we wanted to adopt a comparative approach, we were convinced that ion channels would play a role in cancer. At that time, I asked two questions. This is how we were trained in physics. Always ask viable questions. Being able to ask a good question is much more difficult than finding the answer. If the question is good, there's a chance that you'll find an answer. If the question is bad, you'll be stuck. First, do cancer cells generate electrical signals? And this is now me thinking like an oncologist, what's bioelectricity got to do with cancer? This is cancer, this is not neuro, this is not muscle, it doesn't twitch, it doesn't buzz. That was indeed a very naive question because we now know every cell in the body has some kind of bioelectricity. Even red blood cells, which do not have any genetic material, still have a small membrane potential. So it seems you can survive without genes, without a nucleus, but you still need some kind of bioelectricity. So the second question was, do these signals differ between strongly metastatic cells, cells that are capable of invasion and aggression and spreading around and ultimately killing you, versus those cancers that are benign. They sit there, they're a tumor, but they're not aggressive, they don't invade. And for that, I adopted a rat model for prostate cancer. It's a beautiful model, the so-called Dunning cell model. This is a set of prostate cancer cells with varying metastatic ability, all derived from the same original tumor. So they're isogenic. So we're really comparing lemons with limes as opposed to lemons with oranges. And so when we did those experiments, immediately we discovered we expected something to do with calcium. Everything, calcium is everywhere, isn't it? So we thought we were going to get locked down in some calcium signaling and try and sort that out. In fact, what we found was the expression of a voltage-gated sodium channel specifically in those strongly metastatic cells. There are lots of ion channels, lots of different types of ion channels.
[21:43] Mustafa Djamgoz: We focused on voltage-gated ion channels. Why? Because, Mike, we knew what the membrane potential, what voltage can do with proteins, including ion channel proteins. And that minus 70 resting potential that we take for granted, if you express that as a voltage gradient, it's equivalent to something like 10 million volts per meter. This is a huge force. And every protein in the cell membrane is subject to this force. So we thought, we're going to go with voltage-gated ion channels. We'll deal with ligand-gated and mechanosensitive channels on a different day. The other thing that we did was to focus on carcinomas. Now earlier we've just been talking about gliomas, these are brain tumors, but we said to ourselves, look, brain is already full of ion channels. We go in there and look at some brain tumor, then we'll have our God knows how difficult a job we're going to have sorting out the ion channels to do with the tumor versus those channels that are already there because it's brain. Whilst carcinomas being derived from epithelia, we thought would have a cleaner baseline. So we would have a better understanding of what was happening specifically in metastatic cells. And thirdly, we focused on metastasis because it is indeed, as we said before, a major cause of death from cancer. Those were the three prerequisites that we adopted. So when we looked at those cells, there it was. The sodium channel popped up and then the non-metastatic or very weakly metastatic cells didn't have this. Now, a lot of people at that time said this is an epiphenomenon. So we said the beauty of working with ion channels is the availability of good pharmacology. Neuroscience has come a long way, and we're spoiled for the ways in which we can analyze ion channels using drugs, using natural toxins. Of course, nowadays we can do all the gene silencing and so on. For sodium channels, the beauty is tetrodotoxin, the pufferfish toxin, nature's most specific agents, deadly. So we use it. It's quite difficult to get hold of TTX now because it's associated with terrorism, but we saw early on in the game that we could get it and use it, and there it was, this is a TTX-sensitive current, you remove sodium, it disappears, you can bring it back. And then came the point of proving that it's not an epiphenomenon. It actually contributes directly to the metastatic process. And for that, we did invasion assays.
[25:10] Mustafa Djamgoz: So we could put the cells into micropore filters, coat it with Matrigel. Matrigel mimics the basement membrane in cells, put the cells on top, and the metastatic cells digest the Matrigel and then go from one side of the filter to the other. So we did all those things with and without TTX. We could show that we could block the invasiveness, not 100%, about 50%. You're dealing with the percentages all the time. I sent that paper to Nature; it came back saying, "Well, yeah, interesting. If you do something in vivo and if you look at this and the other..." We adopted a bottom-up approach. The paper you just referred to came out in Peps Letters, quite a respectable journal, and we built up from there. It's been absolutely fascinating. So this is the phenomenon. The other thing I should note is whilst this voltage-gated certain channel was being expressed in the strongly metastatic cells, their outward currents driven by voltage-gated potassium currents were reduced. So it looked like the cells were trying to become excitable. Years later, using microelectrode arrays, we could show that these cells indeed generate firing action potentials. They are truly excited. So I call this the Cellex model. Cellex stands for cellular excitability. I hope you'll agree that even my mother understood this when I explained to her that to make cancer spread or to make cancer invasive, if it's going to kill you, what do you do? You make it excited, you make it excitable, get it out of control, make it twitch, make it destructive, invade its surroundings. How do you do that? You put some ion channels in there, turn it into a bit like an epileptic brain. The whole thing is twitching away. Cancer can be deadly and difficult to handle, but there are certain aspects that are actually quite inefficient and rely on chance. As these cells are twitching under the influence of action potentials, all they need to do is by chance bump into a capillary, get into the circulation, and then could end up anywhere in the body. Of those cells, only one in about 10,000 survive. It's not as if every cancer cell that goes into circulation will get to its destination. There's a lot of inefficiency and redundancy along the way, but if it gets to the wrong place, it could be very, very problematic.
[28:40] Aastha Jain Simes: That's fascinating. Did you see the voltage-gated sodium channel uptake in all types of cancer?
[28:47] Mustafa Djamgoz: We, not we now, it's royal we, but we did in my lab, we did prostate, we did breast, we also did colon. There was a lovely paper that published on colon cancer from Georgetown University showing that the sodium channel is there. We call it sodium channel. Physicists are very precise. So it's strictly voltage-gated sodium channel because there are sodium channels that are non-voltage-gated. But anyway, for simplicity's sake, we call it sodium channel today. Those guys showed that these human colon cancer cells indeed express the sodium channel. They also asked a very good penetrating question: where does the sodium channel fit in this invasion mechanism or network? So what they did, they knocked out the sodium channel. They knew the subtype, NAV1.5, and they looked at all the genes known to be associated with colon cancer invasiveness, and the sodium channel turned out to be the first domino in the network. So it is an early mechanism in the metastatic process, driving these other major mechanisms of invasiveness, including MAP kinase and Wnt signalling, calcium, proteases and secretory mechanisms and so on. That really was also very important because what everyone wants in cancer is early detection. Early detection saves lives. So the sodium channel is indeed an early event in the metastatic process. People have even said that expression of the sodium channel is necessary and sufficient for cancer cells to become invasive. This is a term that we used to use a lot in my physics days, necessary and sufficient. It's a very powerful way of giving a message. This statement was made because those guys, this is the lab of Eric Bennett, expressed sodium channels in non-metastatic human prostate cancer cells, and it became invasive. The only thing they did was to put in a sodium channel and the cells became invasive. So it was necessary and sufficient. This excitability phenomenon, the way the sodium channels and the potassium channels combine, in our estimation, has been seen in several cancers. But the sodium channel itself has been seen in almost every carcinoma I looked at. The only exception in our hands has been pancreas. Pancreatic cancer is very difficult and deadly. I had a special PhD student working on this, and we really struggled to detect the sodium channel in pancreatic cells. We don't know why. In fact, we did form some ideas ultimately as to why not. But it's something we did not pursue. Maybe we'll go back to it one day. There's so much to do. Harvey Carton said to me at the time, "Mustafa, just put all these bricks down the corridor and just blast your way through before the world woke up. You would have done it all." I should say, going back to the 1990s, the five papers. As soon as we discovered the sodium channel and showed that it is a driver of invasiveness and metastasis, and then in vivo evidence came and so on, for it to become clinically viable, it had to be somehow different from the body's other sodium channels.
[33:04] Mustafa Djamgoz: Sodium channels are a multi-gene family. They are in our excitable tissues as well as in some other tissues. What was different about the cancer sodium channel that we could exploit clinically? Very early on, we looked at molecular biology. I should say, when I say we, the lives of people like mine are spoiled by our students. I had a string of brilliant students and Jimmy had the idea that this sodium channel in breast by that time was an embryonic splice variant. He knew which exon would be spliced and what that splicing would affect. We went there, sequenced it, and there it was. The sodium channel in breast and in colon is indeed an embryonic splice variant. Since then, we've gone on to make a monoclonal antibody for that so we can target it. ADCs, antibody drug conjugates, are the new favored drugs in oncology. For the channel, we had one major clue for its clinical applicability. The other was something I had criticism for. Repeatedly, at public meetings, people would get up and say these things. Those two criticisms. One was that, as Mike will know, cancer cells have very depolarized resting potentials. Most resting cells sit at minus 60, 65, 70. These tumor cells sit at minus 20, 25, 30 at the most. Under those circumstances, the sodium channels ought to be inactivated. The fact remains that these channels are active because when you put TTX on we know exactly where TTX binds. It blocks the open channel, and because it blocks the open channel, for it to work the channels must be open or opening all the time. We suspected that what we measure as the resting potential isn't actually a static phenomenon. It could be undergoing some kind of oscillation. Recently with my bioengineer colleagues at Ariel, we used voltage-sensitive dyes, avoiding viralizing the cells with micropipettes and things, and we showed that cancer cell resting potential is very dynamic. They start from minus 20 or 30 and then they go through what I call hyperpolarizing voltage transients. I think that's another chapter in this world: what those transients do. Going back to clinical potential, the other criticism I kept getting is the sodium channel, the way it opens and closes over a millisecond, wouldn't bring in enough sodium to impact the cell. Everyone knows that cancer cells are loaded with sodium and sodium MRIs have shown that tumors are loaded with sodium. Where is this sodium coming from? This is something I put together like a jigsaw puzzle. The answer came from the fact that under hypoxic conditions, these sodium channels do not open and close over a time scale of milliseconds. The channels actually stay open for seconds. We call this the persistent current. That was the immediate thought: everyone knows growing tumors are hypoxic because once tumors grow, the inside starts lacking in oxygen.
[37:21] Mustafa Djamgoz: So why not? Maybe our channel undergoes this persistent current under hypoxic conditions. Do the electrophysiology, put the nitrogen in instead of oxygen. There it is. They develop a persistent current. And the beauty is there is a drug that blocks selectively the persistent current. This is Ranolazine. It is an anti-anginal drug because the same phenomenon occurs in heart muscle during irregular heartbeat, arrhythmia or angina, when oxygen doesn't flow effectively and hypoxia develops. Hypoxia, of course, is lack of oxygen. The sodium channel again stays open, sodium rushes in, and that disrupts calcium homeostasis and pH, and you end up with heartburn. Ranolazine blocks that component selectively. And that is beautiful because that is what we wanted. We couldn't afford to block the whole sodium channel. It would give people heart attacks, the nerves would seize up and muscles would freeze. We needed to somehow tease apart either the sodium channel or some particular property of it so as to not affect the primary function, which is the transient current generating our heartbeat and action potentials. And we've gone on to patenting that drug on the basis of secondary medical indication. Ranolazine is now in preparation for clinical trials. Now, there is a bit of a twist to this because Ranolazine is off patent. It's an old drug. I like old drugs. Mike knows much more about electroceuticals than I do. But I like golden oldies that have stood the test of time. Ranolazine is a beauty, but it is off patent and hence subject to generic substitution. And when I wrote about this first time, one of the referees picked this up. The paper was in a journal called Recent Patents in Cancer Research. This reviewer said, look, the kind of drugs that Djamgoz is talking about are likely to be cheap. Is this going to be a hindrance to their commercial development? And by that time, I had a company, I was talking to big companies, and Michael will know sometimes we like to push reviewers' comments to one side and to skirt around them. And my first tendency was not to get into this discussion. And I thought, actually, it is an ethical issue. I must address this. And I wrote in the final concluding paragraph that the kind of drug that would work on sodium channels in cancer, in oncology would be likely to be cheap, cheaper than existing cancer drugs, and we hope that this wouldn't be a hindrance to their adoption clinically. So there we are. I got to a point in my life now where I'm truly motivated about getting to patients, getting these non-toxic drugs that have significant potential tested. And I hope that one of them will work.
[41:37] Mustafa Djamgoz: The other thing that we did, according to CELEX, by blocking the sodium channel you'll get an antimerostatic effect. But we also brought in the outward currents because we knew that by opening the potassium channels we could generate inhibition in the cells. So it's a double whammy. We combined Thranolazine with a potassium channel opener like Minoxidil, and we could get much better effects. That was in vitro. A lot of work remains to be done in V1 and stuff. We are well positioned. The concept has consolidated and our colleagues around the world are beavering away. Drugs are coming along, antibodies are coming along, companies are coming along. I think it's just a matter of time before the things that we are doing, some of which we started, become reality. Maybe we can mention, Mike, that soon the NCI, National Cancer Institute, will be running a workshop on cancer bioelectricity. When people at NCI, NIH pick these things up, things become serious. That's another step up. I did say this to Cancer Research UK when I got money from them, and I want to say something about funding. We got money. Once we demonstrated the neonatal nature of the channel and wanted to make an antibody, I made an application to the technology arm of CRUK and got the money. I said to them, "I wish I started this work 20 years ago, so I could be 20 years ahead now." They said, "You wouldn't have got the money 20 years ago. The field had to be consolidated for us to believe you, and then you got the money." Talking about believing, this is one of my favorite experiences. Nature sent the paper back, but we're building up the story. I was applying for funds and not getting grants, but something did happen. I'll say two bits of experience in this regard. First, after we published the prostate story on those Danning styles, I had a surgeon who wanted to do his Master of Surgery in the lab. I was delighted. Medics are always fun to have in the lab, very interesting. I said to him, "You're a medic. You're going to work on human cells." The guy would operate in the morning, rush to the lab with his bits of prostate tumor. I think he snipped a little bit from the normal side as well. Trying to do the electrophysiology turned out to be quite hard. We did get some results, but then we eventually moved on to cell lines and demonstrated again that the sodium channel is there. Block it.
[45:54] Mustafa Djamgoz: suppress the invasive illness, basically showing in humans what we had already shown on the rat cells. This paper came out in the American Journal of Pathology. At that time, the Sunday Times, the major national weekend newspaper in the UK, telephoned Imperial and asked, "Is anything interesting going on at college that we can make news of?" The college gave a list and they picked our research. And so the headline was "Pufferfish toxin, new hope for prostate cancer." Look at how the journalists turn these things around. Because of the use of TTX and things like this, the contact was made midweek. By the weekend, a half-page article came out in the Sunday Times. I was very nervous as to what these journalists would write. I was a young academic working with these high-powered oncologists. I thought, my God, if they don't apportion the credit or they do something wrong; these are journalists, not scientists. In fact, this story was perfect. Monday morning, the telephone in the lab went red hot. People telephoning to offer money to support the research. I couldn't believe it. All those years I worked on the gratula, nobody offered me anything like that. After consultation with Imperial, we formed an internal research fund, which I eventually registered as an independent foundation, and that oversaw and enabled us to cross some critical bridges in building up the evidence with those little funds. The charity still exists; it's still semi-dormant, but I enjoy doing charity work. I really think people who do philanthropy in the right way and associate with those sort of people are special because you're doing something really purely for goodness. No expectations. Eventually I got a grant from the Medical Research Council for prostate cancer, which was surprising. As often happens, some of the people on the panel — one of them said to me, "Mustafa, we haven't known what to do with you." They could neither accept all the evidence that I was putting out, nor could they reject it because this was peer-reviewed publications and things. "Do you know why you got this grant?" I said, "Why, Colin?" He said, "Because you connected the sodium channel to epidermal growth factor, to a mainstream cancer mechanism." That was a big lesson to me. Since then, I spent a lot of time associating functionally these channels with mainstream cancer mechanisms, meaning growth factors, hormones, tumor suppressors, mechanisms of apoptosis and all these things. That really helped because people then started not believing anymore, but understanding. That helped us a lot in really firming up their foot in the field, as it were. So, a whole world of experiences.
[50:13] Michael Levin: Mustafa, I have a question. This comes up a lot and it's pretty heartbreaking. I get a lot of emails from patients, from people who have cancer, and they say, okay, I've been reading all your papers. I see it's all very exciting. What do I do? The hope is that someday we have something to tell them other than "hang around, we'll get it eventually." We want to have something. My question is: is there anything that you're aware of that you can tell people that's actionable beyond "talk to the best oncologist you can"?
[50:49] Mustafa Djamgoz: As you can imagine, I get that question all the time. And what I say is roughly what you would say: We will get there, just be patient, just hang in there and so on. But I've gone a bit further than that. In part through my charity, I still see a lot of cancer patients. Sadly, they often come to me when they're desperate, they've been through the motions, nothing else to do, and then they think you and I have the magic wand. I have grown to appreciate integrative medicine, combining Western medication, chemotherapy, with natural agents and lifestyle. In this regard, what we were saying before, the fact that tumors turn out to be innervated now provides a physical mechanistic basis for the impact of brain on cancer. I'm not saying you can sit there and meditate and your cancer will disappear. These things help. There's a paper in Nature, it's been some years now, where people induced two types of tumor. One was melanoma, one was lung cancer. This is all in mice. Then they stimulated a part of the brain called the ventral tegmental area. A very small part of the brain — about 10,000 neurons — uses the neurotransmitter dopamine, the reward transmitter in the brain. What happened was these tumors shrank or their growth slowed down. This was evidence that brain activity does impact on tumorigenesis. I can't offer them magical solutions. But we can give them hope. I think there are some practical things. The first thing I tell them is stop salt, cut out salt. Dietary things, pH — I'm a strong believer in alkalinity. I looked into this and published, because physiologists would say the body's pH regulatory system is so strong it doesn't matter what you eat, pH will always be fixed. But it's not. If you drink bicarbonate and go and measure the pH of the urine first thing in the morning, you do see that it's gone alkaline. So you can overcome some of these things. I wrote a book which I need to update actually called Beat Cancer. It sells on Amazon. The last figure in that book is a balance, which I drew with my own hands. That's how I see cancer and cancer patients managing their cancer or living with their cancer and its progression. In our lives, there are factors that add to the plus sign, make the cancer worse. It could be your diet, it could be smoking, it could be obesity, all those things. On the other side of the balance are the things that you can do to counteract that. So it could be green tea and alkalinity and vitamin D. I tell patients, Mike, go to bed and ask yourself every night, what have I put on the minus side of this balance to keep it tilting away.
[54:55] Mustafa Djamgoz: This fits in with the title of the series: live longer — in this instance, live longer with cancer, because I want to see cancer become a chronic disease that we can live with. I think that is the first step. If we can manage this balance, it will give us hope to be able to live with cancer, certainly live longer with cancer. The old wives' tales about positive thinking now turn out to have a physical or mechanistic basis. We ought to take that seriously. I think cancer patients need management. For many years, we ran a drop-in centre for cancer patients in the north of England where people would come and get this advice. We would hold their hands and often accompany them on appointments and help them survive better. Of course, the sad thing is I used to teach medics. The day I got my first professorship, I said, I'm not going to teach medical students anymore. What medical students get on nutrition in five or six years of medical training is about half an hour. The old saying that we are what we eat is absolutely true. We are a biochemical engine. The difference between us and robots is our chemistry. And our chemistry originates from a diet. So it gives people hope. The other thing that gives people hope is that when we befriend them, when we sympathize or empathize with them, that also goes a long way. It's not just that you are supporting patients. Patient supporters also need support. We are in a little society in which we can make some difference. Can we make all the difference? Not always. Some cancers are almost curable and manageable, others not so much. But cancer for sure now is not a death sentence. We don't refer to it anymore as the big C. We use the word cancer quite easily. Let's hope that today we can live with it. I think we are. In my estimation, clinical oncology is coming around to this concept of living with cancer. Let's try and turn cancer into a chronic condition. There are lots of examples of this, like diabetes. We can live with diabetes. The big example is HIV and AIDS. Now HIV can be controlled and you can live with it without AIDS ever developing. From all the research and everything we have learned in this world of bioelectricity, in which neuroscience, biophysics and oncology all mix, from that mixture we can generate not just hope, but some practical reality.
[59:02] Michael Levin: It's a fabulous place to end on. Thank you so much, Mustafa.
[59:08] Mustafa Djamgoz: Thank you so much. Thank you, guys.
