Oxidative Stress and the Deep Evolutionary Roots of Cancer
There is a growing realization of the importance of oxygen in understanding cancer, combined with a serious effort to trace the evolutionary roots of cancer back to the dawn of multicellularity, and perhaps even to the dawn of oxygenic metabolism. Many tumor cells are hypoxic, and use glycolysis in favor of oxy-phosphorylation to metabolise. Whether this altered metabolism is a cause or consequence of cancer remains disputed. The way that healthy and cancer cells cope with reactive oxygen species (ROS) as well as the response of cells to radiation damage, is also integral to the understanding cancer. By bringing together experts from cancer biology, astrobiology and evolutionary biology, we hope to develop a new line of inquiry in cancer research.
Audio Interviews and Transcripts from the Workshop
- Interview with Thomas Seyfried, a Professor of Biology at Boston College who has written a book ‘Cancer as a Metabolic Disease’. He spoke about his presentation at the workshop.
Learn More about Thomas Seyfried | Interview Transcript
- Interview with Theodore DeWeese, is Chairman of the Department of Radiation Oncology and Molecular Radiation Science and Professor of Oncology and Urology at Johns Hopkins Medical Institutions. He treats men with prostate cancer and he has also runs a molecular biology lab doing cancer research for almost 20 years.
Learn More about Theodore DeWeese | Interview Transcript
- Interview with Philip James is from the University of Dundee in Scotland. He was a hospital physician and taught in the university’s medical school for 34 years, specializing in industrial medicine – in particular, in the use of hyperbaric oxygen treatment.
Learn More about Phillip James | Interview Transcript
- />Interview with Tomas Hode is a scientist and businessman whose company is hoping to develop new anti-cancer drugs.
Learn More about Tomas Hode | Interview Transcript
- Interview with Chris McKay is an astrobiologist from NASA’s Ames Research Center is a co-organizer of the meeting.
Learn More about Chris McKay | Interview Transcript
- Interview with Charles Cockell is Professor of Astrobiology in the School of Physics and Astronomy at the University of Edinburgh in Scotland. His research takes place in the world’s 3rd deepest mine which is also the first permanent deep astrobiology facility and one of the few permanent microbiology labs far below the earth’s surface.
Learn More about Charles Cockell | Interview Transcript
- Interview with Sally Dunwoodie is an embryologist at the Victor Chang Cardiac Research Institute in Sydney, Australia. She looks at how changes in oxygen levels affect developing embryos. | Interview Transcript
Interview with Thomas Seyfried
Thomas Seyfried: The issue of course is whether cancer is a nuclear genetic disease or whether cancer is a mitochondrial metabolic disease. What I did was I presented evidence from the old literature and newer experiments showing that nuclear genetic damage cannot be the origin of cancer. There are a number of experiments that were done conceptually as well as by experiment showing that if the nucleus of the tumor cell is implanted into a normal cytoplasm containing normal mitochondria, the tumorogenic phenotype is suppressed, despite the continued presence of the so called tumor associated mutations. These observations indicate that genetic mutations are not sufficient for driving the nature of the disease. What the mutations seem to do is abort development, but do not cause tumors. The other experiment is if you transplant a normal nucleus into a cancer cytoplasm where the mitochondria are defective, you do not get normal cells but you get either dead cells or tumor cells. What these findings indicate is that the normal nucleus cannot reprogram a cancer cytoplasm, but a normal cytoplasm can suppress any genetic abnormality associated with the origin or progression of cancer. These findings viewed together from a variety, a broad range of independent studies, indicate that cancer is not a gene-only driven process, and that the mitochondria play a major role, an extra-nuclear epigenetic system plays a role in the origin of this disease.
Pauline Davies: But could it be the case that if you have nuclear damage, that impacts somehow on the mitochondria in the cell causes them to become defective and therefore leads to cancer?
Thomas Seyfried: Well the mitochondria are the first organelles that are damaged. So, what happens is the integrity, the fidelity of DNA repair and the fidelity of nuclear mitotic division is under the control of mitochondrial function through calcium currents in the cytoplasm linked to the proton motive gradient of the mitochondria. What happens in cancer progression is you get aneuploidy, and nuclear gene mutations, genomic instability. At some point the genomic instability will impede or prevent a return to normal behavior. So it facilitates progression. It’s not the cause of progression, but it prevents the return to a metabolic normalcy. So the accumulated mutations and broken chromosomes reach a point where, a threshold is reached where the cancer cells can no longer be returned to a normal metabolism.
Pauline Davies: And that leads to cancer.
Thomas Seyfried: Well, you know, it’s all part of the same process, you know, the inflammation in the microenvironment is part of cancer. You know, that’s there because the cells are fermenting, it’s an unhealed wound, the persistent inflammation leads to further genomic instability because of the respiration. One of the more important issues is that this is not a Darwinian evolutionary process, it’s a Lamarckian process. It’s the inheritance of acquired characteristics, use and disuse. With each division, mitochondrial respiration becomes less used because of damage and primitive glycolytic function, fermentation increases, so this is what Lamarck said. And then there is horizontal gene transfer, and the formation of metastasis, where cells of the immune system, leukocytes, macrophages, these kinds of cells, will fuse with other cells in the microenvironment to lead to hybridization and metastatic spread.
Davies: Well this is fascinating, and I know that you spoke to me before, after a previous workshop, and you had a lot of feedback from members of the public.
Thomas Seyfried: Well, that talk and also the book that I’ve written have generated considerable interest in alternative approaches to management of the disease. Once the disease is recognized as a metabolic disease then we can begin to entertain metabolic solutions. Many of these solutions are very cost effective and nontoxic and quite effective in reducing or managing the disease. We don’t like to use the term cure because we haven’t used these therapies long enough to determine whether anyone would be cured from the disease. We do know, that we can get significant regression by targeting the metabolic fuels for the cell, for the cancer cell, and transitioning normal cells to a fuel that the tumor cells can’t use, which is an oxidizable keytone. You can then reduce inflammation, you can kill cancer cells by apoptosis programmed cell death, and you can enhance the health and vitality of the surrounding tissues. So reducing of inflammation, specifically killing cancer cells without harming the microenvironment, reducing the vasculature, all of these together is a therapy that can be realized, and it’s a little inconvenient because there’s some food restriction, but it’s not as bad as the adverse effects of the current standards of care.
Pauline Davies: And then did you go on to say that you would actually try and increase the oxygen pressure as well?
Thomas Seyfried: Yeah, this is very important, cancer cells can protect themselves from reactive oxygen damage through their high level of fermentation and the use of glucose through both glycolysis and the pentose phosphate pathway. These two processes will protect the cancer cells from a number of different drugs. The high fermentation and pentose phosphate pathway are actually the pathways that protect the tumor cells from a lot of different therapies. Our approach lowers the fuel for those pathways, that is basically glucose and glutamine together will then make those cells vulnerable to a whole spectrum of nontoxic, relatively inexpensive drugs which then can be used to manage cancer for a long term period.
Pauline Davies: Is there any update that you’ve got to tell me since we spoke last time or not?
Thomas Seyfried: If what I’m saying is right, then we should be able to target and destroy systemically metastatic cells. And we are seeing this in the models that show systemic metastasis in a natural syngeneic host. In other words, you should use the most natural form of the disease to test the hypothesis of how this is going to work in the human. And we’re beginning to see very good response in the natural hosts to these therapies. Once you realize that this is not a genetic disease, it’s a metabolic disease, then all of a sudden the whole view of the disease changes, and not only that, the therapy then changes. It’s just one of those things that’s going to take time. It make a take a whole generation, or maybe two generations, but eventually I think our species is smart enough to recognize at some point that this is the way it is. Or I hope that’s (true). Otherwise there’s no major advances.
Pauline Davies: What have you got out of this meeting?
Thomas Seyfried: Well I think that, the issue here is that, it’s good to have a broad of individuals present information on diverse topics, and then it begins to allow me to more clearly solidify what I know about the origin of cancer, and I also know how controversial and muddled some of the areas of cancer can be, leading to significant confusion on many aspects. It’s a disease that has created a great deal of controversy in many different areas, and it’s troubling that we are unable to pursue those particular approaches that may have the greatest benefit and impact because of restrictions by the field on the nature of the design of experiments. You know why in cancer are we pursuing the same kinds of therapies over and over again, with no significant impact on patient health? The numbers of people dying per day for cancer have not changed in 15 years. And the incidence of cancer is increasing at the same rate as the NCI cancer budget. The more money the NCI spends, the more cancer cases we get. It’s just a correlation, there’s no causality here, but isn’t it interesting that the more we spend on cancer, the more cancer we get, and the more people are dying from it. It’s really difficult and I’m wondering at what point, how many more years will we need to examine these figures before someone says we need to do something different than what is currently being done.
Interview with Theodore DeWeese
Ted DeWeese: I have the fortune or [misfortune] to be attending a lot of professional meetings, but this one is unique in that it’s meant to be wide ranging, it’s meant to be freewheeling, free ideas and exchange of those even when controversial and that is what academic thought is meant to do, to make you change your perspective or to at least to augment what you believe, and this is the kind of right form for that. It’s been one of the more exciting things that I’ve done in a couple years, so, it’s been fantastic.
Pauline Davies: Now you mentioned changed perspective. In what way has it affected you personally?
Ted DeWeese: Well, I’ve had the opportunity to now think about from a physicist’s perspective, and I’m in good fortune that in the kind of the field I do, I work with physicists every day, but that’s a little bit different in that they’re medical physicists thinking about the distribution of radiation or drugs in a patient. This is giving a more theoretic perspective, a more perhaps mathematic, a more quantitative, may be even a better way to phrase that, perspective on the way I would present data. They need to hear it differently, and that makes me think about how I have to provide the data, which means I have to understand it in a different way and that’s I think both for good parties, they need to hear data that they’re not used to hearing, but I need to be able to articulate it in a way that I haven’t [done before], which means I have to understand it on a deeper level, so it’s been great.
Pauline Davies: Ok, so you mean bridging that communication gap makes you think more deeply about what you yourself are doing?
Ted DeWeese: Indeed it does, and because the physicists tend to ask different types of questions. They may hear the same data as perhaps my physician, or more molecular biology colleagues, who of course have a framework in which to think about it, the physicists are going to hear the same data and ask a different kind of question, so it makes me think about, a little more deeply, some of the suppositions that are at play so I can try to answer those questions and sometimes you can’t.
Pauline Davies: And is there any idea that maybe you’ve heard for the first time, or a new perspective that’s made you think more carefully about developing your own ideas, not just in how you present them to the world, but changing fundamentally or did you know it all already?
Ted DeWeese: I hope I’m never arrogant enough to think I know it all already, and if you just talk to my wife you’ll know that is for sure. I think the principles that several of the physicists have brought together, the concept that there’s a reawakening, let me use that phrase, of some of the more ancient types of signaling pathways, other kinds of pathways that were present in more ancient species that still are inherent in our genome, in our DNA, that when cancer is evolving, perhaps those earlier mechanisms, processes, pathways are engaged, we’ve thought about that but I didn’t quite have some of the detailed perspective that some of the physicists brought to that, so that’s actually changed my mind about how I think about genetic alterations and what that might mean to uncover other things that I hadn’t thought about, some deeper level of genetic alterations that may have other meanings than I had contemplated. So yes, while I had known about it, I didn’t have the deeper appreciation of it.
Pauline Davies: And I’ve noticed that there’s quite a bit of argument and discussion at this meeting, very varied perspectives.
Ted DeWeese: Very, and that’s a good thing. When people can come together and hear the same data and then bring their own expertise and experiences to it, and even if they’re clashing, if they don’t necessarily agree that’s ok. As long as people try to do that in some respectful manner both parties will come out of that in some deeper level of at least belief that someone else is working on the same problem, might not agree with how they’re doing it, but at least they’re attacking the same problem to get to the goal of ultimately trying doing something for patients, that’s the bottom line.
Pauline Davies: And what do you think about all that hyperbaric work that we’ve been hearing about?
Ted DeWeese: I think it’s fascinating because as Philip, the person who presented that data suggested, that most, and he named physicians but I would argue indeed most scientists as well think about oxygen mostly as just sort of what’s the percent of oxygen that people are exposed to. No, it’s the barometric pressure, it’s the pressure the oxygen is under that is the most important, and I think that’s fascinating because it suggests that you can drive more oxygen into the blood and that the cells are capable of using very high levels of oxygen that here to fore I frankly didn’t think occurred, and he proved then in very good data, as far back as the 1960’s to show that in fact that is true, that high levels of oxygen can be used by cells which is very important for diminishing some of the nasty effects that cancer can cause.
Pauline Davies: What sort of patients do you treat in your hospital practice?
Ted DeWeese: Well I personally focus my practice, exclusively, or essentially exclusively on prostate cancer. I have done so for well, since I became a faculty member at Johns Hopkins, and that has led my research to primarily be focused around prostate cancer. That said, things I’ll be presenting here today really aren’t all therapeutic or prostate cancer centered, they’re more about how cells might be using different genetic mechanisms to deal with mutations that arise, and if the injury to a cell is occurring at a particular rate over time, that perhaps the cell doesn’t want to deal with at all and just die so it won’t mutate, because as soon as it tries to repair injury there’s a risk that it could mutate, which could lead to a cancer. So, I’m hoping to get a lot of input by my newfound colleagues who will help enlighten me on how I should think about this differently because I’m sort of stuck in a paradigm right now.
Pauline Davies: Right, how do you treat your cancer patients? Do you have a particular technique that you use?
Ted DeWeese: Yeah, indeed. I’m a radiation oncologist so therefore the bulk of my work is on a daily basis with those patients is using radiation of various sorts, but primarily ionizing radiation. The portions of my research that are more translational primarily have revolved around how do you modify DNA repair, specific in cancer cells that would lead us to be able to use far less radiation to treat cancer patients because of course any of the standard treatments we have today like radiation and chemotherapy while perhaps killing cancer cells have the risk of also injuring other cells. So we’ve just come up with a way to use two RNA molecules that can be fused in what we call a chimera, which can only attack prostate cancer cells, and then diminish the ability for those cells to repair and you can use about fifty percent less radiation.
Pauline Davies: And you’re using this in the clinic now?
Ted DeWeese: So we have gone all the way up to starting our toxicologic work, so that’s all been as we would say preclinical work both in vitra or in the culture dish as well in animals, we’ve also done it on tissues removed from patients so we know that it will work, so now before we get an FDA approval to do the clinical trial we have to finish the toxicology in both dogs and in mice, so that’s ongoing right now but then we will have the clinical trial rolling.
Pauline Davies: And what about the phototherapy that we were hearing about today where light basically seems to be able to kill tumor cells?
Ted DeWeese: I have no deep thought on that yet because it was so new to me to think about light that is otherwise not ionizing, it’s not UV, can drive profound changes in the mitochondria in particular that all of a sudden would have some important either deleterious effect on the cancer cell or frankly at a different wavelength might have very important healing components to injured cells to reducing inflammation. So I’m absolutely fascinated and I’m fascinated if I think about my own practice because as I just mentioned our standard cancer therapies whether, again radiation, surgery, chemotherapy, might be beneficial to patients and thank goodness they can be, but they have risks of side effects. Can something as relatively straightforward as this sort of phototherapy that seems to be healing other diseases also help to minimize the risks of side effects from cancer patients that I might be inducing today. I’m absolutely fascinated so now I’ve had a new friend in Mike Hamblin that I’m going to try to think about how we could extrapolate this into a model system to at least test the concept.
Pauline Davies: Right, sounds like a new collaboration is about to begin.
Ted DeWeese: I think so, and several others have occurred here as well so I’m quite happy to have been able to attend this.
Pauline Davies: Thank you very much.
Ted DeWeese: Oh my pleasure, my pleasure.
Interview with Philip James
Philip James: My particular discipline within that specialty is hyperbaric medicine and diving medicine and obviously hyperbaric oxygen treatment, and I’m more interested in inflammatory conditions particularly those that involve the brain because brain inflammation can be triggered by nothing more than a head injury.
Pauline Davies: So how is it that changing the oxygen concentration can affect the disease?
Philip James: Well oxygen controls inflammation and when tissue is damaged, and it doesn’t matter whether its damaged by infection or by direct injury, the damage effects the capillaries within the tissue, and that means that they get swollen and they leak some agents from blood, which set up an inflammatory process. So the recovery from that is oxygen dependent. Obviously we get a specific dose from the air, but sometimes that’s not the optimum dose and we need some more.
Pauline Davies: So what do you do to give more?
Philip James: Ok well, obviously we can increase the amount of oxygen we breathe from 21% which is in air up to 100% whatever the prevailing biometric pressure is, but to give a higher dose we’ve got to use a pressure vessel, otherwise known as a hyperbaric chamber.
Pauline Davies: Now is that a common treatment for brain injury?
Philip James: Well it isn’t yet, but there are a lot of studies going on in the United States at the moment of using this for veterans from the wars in Afghanistan and Iraq. And treating their brain injury because many of these veterans get a chronic form of brain injury and the studies are now showing that this actually can benefit from being given more oxygen. Basically its extending the envelope of recovery. No one will deny that breathing is essential to getting better, obviously if you stop breathing you don’t exist, but we forget that breathing is necessary to get better when were sick, whether it be an infection or an injury. And so what we’re doing is actually improving that level of recovery by actually improving breathing.
Pauline Davies: Making sure that all cells wherever they are in the body get sufficient oxygen.
Philip James: Yes, to the best of our ability, and obviously the cells operate in a fairly narrow range of oxygen concentration, and unfortunately none of the disease processes result in any elevation of the oxygen levels they all reduce it. And so if we give more oxygen through the lungs then we can actually correct that deficit. We may not be able to if the blood supply and the effective tissue is damaged. In general we can actually optimize the delivery of oxygen to correct the deficit.
Pauline Davies: Now you showed a very horrific photography of a young woman who was injured when a plane exploded right above here and she was very badly burnt and she made what seemed to be a miraculous recovery within just a few days, tell me about that.
Philip James: Yes, it was near Christmas in 1985 and as you say a light aircraft crashed on a shopping mall, and obviously she was burnt by the cascading gasoline fuel, aviation fuel. So she sustained a second degree burn that looked as if it were likely to go to third degree, which means that the skin then sloughs off and that requires grafting. But the unit she was treated in actually had a hyperbaric chamber run by a college and friend Dr. Paul Cianci and he obviously allowed me permission to use his slides, and this is how burns should be managed. And so there are some units in the United States that do use oxygen in this way for burns patients, but the greatest problem is that we don’t teach this methodology in medical schools. That means that doctors can qualify without understanding how to use oxygen as a treatment. They will learn how to use oxygen as a supplement to insure that hemoglobin is saturated but they don’t learn how to extend that dimension to using oxygen as a treatment. If you say to a lay person, “Does the brain need oxygen”? Obviously they’ll look at you as if you were crazy, but if you say this patient has had an injury and an area of the brain doesn’t have enough oxygen what we need to give? And I think most people would say we need to give some more oxygen. And so that’s exactly the logic that underpins using this treatment. And of course we now have amazingly sophisticated imaging systems and I’ve showed the use of magnetic resonance spectroscopy to show ATP levels in a newborn infant.
Pauline Davies: So that baby was damaged at birth?
Philip James: Yes, the baby exhibited signs of neurologic problems, and so was followed up from birth and its ATP levels were still a third of what they should be, 35 days post delivery. And even though we’ve used this technology, and ATP of course is dependent on oxygen, nobody says can we do anything about it by actually improving oxygen delivery. And it’s because it’s not taught in medical school, and I explained in my talk how we overlook the fact that during delivery, with the compression of the head the blood flow through the brain can reduce and then when it’s restored we get this phenomenon called reperfusion injury. Reperfusion injury involves neutrophils and signaling of neutrophils to actually invade the area and unfortunately this is the signaling they use for infection. They release the same free radicals that they do for infection and so they exacerbate the damage. And reperfusion injury was first described in transplanted organs, particularly with the heart. It was found that if the period the heart was removed from the body extended beyond about three hours, or certainly four hours, when blood supply was reestablished in the recipient of the donor organ, they measured the blood coming out and found evidence of damage to the heart and a huge amount of research was done in the 1970’s and 80’s which implicated this phenomenon of reperfusion injury. And so the dependence of this, on oxygen and the need to give a very high dose of oxygen has now been very well established because it down-regulates the adhesion of neutrophils and prevents their sequestration into the tissue. And so if you can prevent the neutrophils invading the tissue you avoid reperfusion injury. And so we have a fundamental problem that we ignore barometric pressure and we ignore oxygen used as a treatment.
Pauline Davies: Well I guess that the oxygen story is the reason you were invited to this meeting.
Philip James: That’s perfectly true, as I explained in my first slide when I read the interview in the UK, a journalist interviewed Paul Davies, then I looked at the paper that he and Charley Lineweaver had written. It was a PDF file and I simply did a search for oxygen in that paper, and it wasn’t there. Then I did a search for hypoxia and that wasn’t there either, so I thought maybe it’s worth contacting then to say that this ancient cassette of genes is actually controlled by changing oxygen levels. That led obviously to eventually an invitation here.
Pauline Davies: And what have you been thinking about this meeting so far? Have you learned anything?
Philip James: Oh very much so, yes, I mean there has been some fabulous presentations. The molecular aspects and the biochemistry are obviously very complex, but there have been a number of issues that have come up and of course one of the key ones is the role of neutrophils in metastasis of cancer. That’s particularly fascinating because it’s something I’d anticipated, on, I guess, theoretical grounds because they are unique cell because they can migrate within the vasculature with no connection, no actual physical connection to any other cell. So they actually have an independent existence within the circulation, and that’s very unique. You probably know that red blood cells don’t have a nucleolus and so they are not strictly a cell at all: they are a capsule containing hemoglobin. They have a lot of structures which are part of their formation but having extruded the nucleolus, red cells can’t reproduce. On the other hand, the neutrophil has all the compliments of a proper cell and so it’s very, very unique.
Pauline Davies: So you’ve enjoyed yourself?
Philip James: I have enjoyed it very much indeed; it’s been a delightful meeting with delightful people and a delightful environment.
Interview with Tomas Hode
Tomas Hode is the CEO and co-founder of a biotech company called Immunophotonics, which has developed a therapeutic cancer vaccine. Dr. Hode trained as a physicist and an astrobiologist and has worked in photomedicine and the medical laser devise industry. He is excited about testing some of the ideas he heard in the meeting.
Tomas Hode: Very much so, in fact, what I’m hoping to do and then it’s kind of [that] I think I might be in a relatively unique position in this group, is that I do believe that I have the ability to take this back to perform some studies based on the discussions that have come in this meeting and something that could further both the therapy that we have developed as well as essentially put to test some of these ideas.
Pauline Davies: So which ideas in particular?
Tomas Hode: Well I’m particularly interested in, obviously relating to the sort of metabolic issues or disease, if you will, with the cancer, and see if we can essentially starve the tumors to death while we also apply our therapeutic cancer vaccine to it as a combination therapy, and also something that might at some point become feasible to take through a regulatory process.
Pauline Davies: Right, so tell me about your cancer vaccine work.
Tomas Hode: So what we have developed is an autologous cancer vaccine where we are essentially using the patient’s own tumor to induce an immunity against that cancer, and the therapeutic vaccines in general, the autologous vaccine approach, is that you normally have to extract tumor tissue from the patient, ship it off to a lab, perform some procedures, send it back to the patient for reinjection of immunized cells. It’s a cumbersome process. So what we have done is used a similar approach, an adjuvant based approach, and essentially produced the vaccine inside the patient through a very simple procedure, takes about an hour, no toxic effects from what we have seen, the patient walks home, walks back to normal life after that.
Pauline Davies: Is it a big secret or can you tell me about it?
Tomas Hode: No I’m happy to tell you about it. The approach that we are applying a laser to any one accessible tumor, so with that we disrupt tumor cells locally that as they die they release their debris or tumor antigens and then in the same site where we applied the laser we inject our immunoadjuvant that we have developed and is proprietary. So with that we activate locally antigen presenting cells and specifically dendritic cells. These activated dendritic cells process the tumor antigens that were liberated by the laser, migrate to the lymph nodes, and then present the antigens to, for example CT8 cells, cytotoxic T cells, and we get a systemic immunity. And we have seen in investigative driven studies that were not sponsored by us, but we still get to share some of the data, that in very advanced cancer patients we have seen some quite extraordinary results, including in several patients complete resolution of metastatic disease. So these were patients that might have had three to six months to live, some with enormous tumor burden, and two years later, some of them are still alive and they are without any tumors.
Pauline Davies: And do they have a particular sort of cancer or does this work for all cancers?
Tomas Hode: We believe that it should work for pretty much any type of solid tumor cancer. What we have seen is primarily breast cancer and melanoma patients. The reason for that is simply because their tumors tend to be somewhat more accessible to the laser, so if you can palpate the tumor it’s easy to perform the treatment. You can perform the treatment on other patients or other types of cancers as well, it’s not too complicated, but the main issue with this therapy that, aside from apparently being effective or might be effective, is the fantastic practicality of it. It’s so easy to perform. You can perform it in outpatient clinics in rural areas in the Amazon if you want. So it’s very practical it’s easy to implement.
Pauline Davies: So I’ve heard about melanoma patients being treated by a vaccine with some remarkable successes.
Tomas Hode: The one that has been approved recently is Ipilimumab, or Yervoy (which is the tradename). And it’s a somewhat similar approach, you essentially try to make the T cells more effective in targeting the tumor. And we think that that might be a great combination ultimately with our therapy as well because what we do is essentially we educate the immune system to recognize the cancerous form, and a combination with therapy that makes that immune response more effective is something that certainly makes sense.
Pauline Davies: Now with these tumors, when you’ve got metastatic melanoma it goes not just to the surface, it’s internally as well, into various organs. How do you target those tumors with lasers?
Tomas Hode: Well this is the beauty of the method is that we really only need access to any one tumor. So if we have a patient with one accessible tumor and metastatic disease and lungs and liver and other places it’s the immune system that targets it. So what we have seen is that particularly lone mets seem to respond very well when the patient is responding. We have also seen some, sort of empirical evidence on brain tumors shrinking and in one case disappearing. Now some people ask, “What about the blood brain barrier? How can the drug penetrate that?” and the answer is that it’s not the drug that penetrates, it’s the immune system. The immune system has been educated to recognize this as foreign.
Pauline Davies: Have you actually tried your own technique on patients?
Tomas Hode: Yes. So we have seen in a couple of investigator driven trials, it’s about 30 patients that have been treated so far, and obviously the patient population is too small to draw any big conclusions from it, so I think that the most significant conclusion is that we in fact have patients, maybe 25 to 30 percent, again that number is very rough so it might change significantly, but in the small patient population we have seen 25 to 30 percent that show complete responses, and that means after the therapy maybe up to nine months afterwards we see no evidence of disease and also it seems to reduce recurrence potentially. Again, it’s a fairly new study so it’s hard to draw too much conclusion from it but the fact that patients have responded with complete resolution of tumors, I think that is the most significant thing.
Pauline Davies: Did you know about Tom Seyfried’s work before this meeting, that’s the calorific restriction?
Tomas Hode: I have heard about it, but I did not actually know that it was his work, and I certainly did not know about how well founded it is. I didn’t know that it had so much research behind it and it certainly made sense to me. It made sense to me to such a degree that, as I said, I would like to try this, and that is the one of the things with these meetings is that I think they are fantastic brainstorming sessions, but it is also so that we must not forget the bottom line in this, and the bottom line is that patients are suffering and dying. And if there is anything that anybody can do to take this to patients, then I think that’s the most significant thing that can come out of this, and that’s what ultimately I would like to do with this.
Pauline Davies: And is there anything else you found particularly interesting in this meeting?
Tomas Hode: The other approach that I really found interesting in this is, of course relating to reactive oxygen species and oxygen, is the hyperbaric oxygen chamber approach which I have not seen or doesn’t seem to be as much data on it at this point, but it’s another one of those things that is very easy to test. And tested in a metastatic tumor model that you historically know what results to expect, you know within what time the animal should die, and you compare it. It’s a simple experiment that can be performed, and it is another thing that I’m going to bring back, I’m going to talk to my team, and hopefully we can do something about this.
Pauline Davies: Alright, sounds like quite a few collaborations coming out of this meeting for you.
Tomas Hode: For sure, and actually there’s another one, maybe less dramatically potentially impacting people, but sort of a side project that we’re doing with is we’re going and have been down to Tasmania to talk to researchers to see if there is anything we can do with our therapy to treat the Tasmanian Devil. And the Tasmanian Devil is a marsupial that is going extinct because of a contagious cancer. So, I’ve talked to a couple people in the group and we’re all enthusiastic about this and the possibility of maybe not necessarily saving human lives but maybe helping to prevent the extinction of a species on this planet.
Pauline Davies: Well that would be terrific, I mean it’s a national symbol of Australia really isn’t it? That and the kangaroo.
Tomas Hode: So obviously we have no idea if our therapy is going to work on the [Tasmanian] Devil, we don’t even know if it works on any marsupial, but I think that it’s worth an attempt, and if the researchers and the Australian collaborators agree to this I think it’s, again it’s an easy thing to test, I think that what we need to do is test a little bit more, try it out a little bit more, not be afraid of that, and maybe to round off, the idea with this series of workshops is to have physicists meet cancer researchers and so on, but my father is an old experimental physicist, and I tend to take an experimental approach to things, so I think that if we can join in with the experimental way of thinking, combine with the theoretical way of thinking from the other physicists in the group, I think that that can certainly lead to something that really is interesting in this. And I truly believe that this forum has the capacity to bring out and into practice new ideas that may not have been tested before.
Pauline Davies: I actually think it’s very interesting that you can go away and do these experiments, because I have found that people are very tied up with the experiments that they can do, and they have to justify what they’re going to do at a particular time. They can’t very easily just change their minds and do something different but is it because you’ve got your own privately funded lab that you can do this?
Tomas Hode: No, in fact we are working with the universities in both the United States and in other countries. One of the differences might be that ultimately I’m running a biotech organization, a company that ultimately is supposed to take this to market, and with that I think that we might be somewhat more practically oriented, because we can fund some of that research with the means that we have, pay our grants to universities to perform certain research, but with that it becomes a little bit of a different situation, I mean we’re a very tight group and we have a combination of the academic setting with animal labs, we have the practicality, or the forced practicality of running a company and seeing where can this actually lead, and we also have deep ties into sort of nonprofit aspects of this which ultimately is about, you know helping people. And I think that with this group that we have it might be one of the things that makes a difference, but I think that if you’re forced to be practical, I was in academia before and what forced me was the grants for my continued research, and obviously it’s good if it’s sexy or if it’s good if it’s popular or something along those lines. I’m similarly forced while running a company, but it’s different factors that govern this, and it has to be extremely practical, it has to have a potential to lead to a therapy that can go out to patients, and ultimately can both further growth in society and you know, help patients.
Interview with Chris McKay
Chris McKay: It’s been going very well. The focus on the meeting has been on oxygen, it’s history on earth, its effect on life, and its effect on cancer. And astrobiology, an astrobiologists like me, have always had a fascination with oxygen because of the key role it has played in evolution and its variation over time on the history of the earth. And so to see the connection between oxygen and cancer, really opens up a whole new dimension for me of appreciating the link between astrobiology and cancer research.
Pauline Davies: Now, is there anything in particular that has surprised you about this meeting so far?
Chris McKay: The thing that surprised me the most about this meeting so far is the complex way that life responds to oxygen. And that at very small levels, reactive oxygen, oxygen that is potentially dangerous, is actually useful to cells. It helps the cells build up their immunity, build up their strength for dealing with oxygen. Although at high levels the reactive oxygen can be damaging. The other curious thing is that it’s clear that cells, the body, developing embryos, use oxygen as a signaling molecule. So the presence of oxygen and reactive oxygen turns on certain proteins and turns off certain others. So the interaction of life with oxygen and cancer cells with oxygen is very complex and for us as astrobiologists, it’s now motivated us to look and see if that same kind of complexity is mirrored in the simple life forms that we find say in deserts where reactive oxygen species is also a major stress, but the organisms that live there are not human cells or mammalian cells but simple micro organisms, simple bacteria. Where going to go to the lab now, the field now and see if we can see the same mix of behaviors and responses to reactive oxygen
Pauline Davies: I’ve been talking to a lot of people at the meeting, and they say that they love it because it’s bringing together people from lots of different disciplines and they wouldn’t normally talk together. So that, in itself, sounds to me to be valuable.
Chris McKay: That’s right, having people from different disciplines focusing on the same problem allows us to look at the problem from many different angles. So my input in the discussion is mostly the perspective of studies of desert microorganisms and how they react to reactive oxygen and the perspective that that has on the mechanisms and how those mechanisms are different from the mechanisms that the cancer researchers are finding human cells reacting to oxygen. So it’s that comparison that I’ve been mostly been discussing in the breaks and in the discussion period, is here’s what were finding in bacteria in deserts, here’s what you’re finding in humans, isn’t this interesting to compare the two of them.
Pauline Davies: And do you find it interesting that NASA is very supportive of this initiative to bring cancer biologists and people from astrobiology together?
Chris McKay: I think it is interesting that NASA finds this an interesting connection. I think it’s partly because the culture of astrobiology within NASA is intrinsically an interdisciplinary one. It started as an interdisciplinary endeavor and it continues that way and those people with that kind of perspective naturally find it interesting and exciting to work in new areas and so when Paul’s workshops generated this idea of a link between astrobiology and cancer we had no trouble at all interesting astrobiologists in the topic and coming and being involved, that was very easy to do.
Interview with Charles Cockell
Charles Cockell: Well we are interested in a number of things, but one question we want to address is does background ionizing radiation have an effect on life and was it involved in causing the evolution of pathways to deal with reactive oxygen species? Now you might think from the name reactive oxygen species that would be reactive damaging chemicals produced by the presence of oxygen, but one of the mysteries of life is the fact that these pathways are very ancient and we also find them in microbes that live in anaerobic environments, places without any oxygen. So why have these very ancient organisms that live in anaerobic conditions evolved these pathways to deal with reactive oxygen species? One possible answer to that is that ionizing radiation causes the formation of these reactive chemicals even in environments where there is no oxygen in the atmosphere and we can test that hypothesis by taking away the background levels of ionizing radiation and seeing what the effect is on these reactive oxygen pathways.
Pauline Davies: And what do you expect to happen? I’m asking what do you expect because you haven’t done the experiment yet.
Charles Cockell: Well, what we would expect is that for aerobic microbes that live in environments where there is oxygen that background level of ionizing radiation might be a conditioning factor, might help them deal with reactive oxygen species. So when you take them deep underground and you cut out that background level of ionizing radiation. You might think that it’s detrimental to them, because now they don’t have this continuous background level of radiation that’s conditioning them to deal with reactive oxygen species from the presents of oxygen gas. But for anaerobic microbes, taking away that ionizing radiation might be a good thing because it would take away one of the few stresses that causes the production of these reactive toxic oxygen chemistries, and so the environment would end up being better for them.
Pauline Davies: Now you’ve been at a meeting here at Arizona State University, What have you got out of the meeting that you’ve just been attending?
Charles Cockell: Well this has been a really astonishing meeting for me because I thought about looking at these experiments that we have talked about and looking at life in low radiation environments, and I was vaguely aware that there was a connection between radiation and reactive oxygen species and cancer and the onset of cancer. But it’s not something that I ever thought of getting involved in just because it’s not my area of expertise. In the space of two days I’ve learned a vast amount about cancer and where this research might fit into looking at cancer research. So I came in two days ago thinking about growing microbes in the deep subsurface, and by 6 o’clock on the second day I’ve already agreed to grow stem cells in this lab deep underground, which is great! There is a collaboration now that we’ve set up in the last two hours to look at low radiation in stem cells, another group that are looking at making markers inside cells to look at reactive oxygen species with a view to applying this to cancer also now going to collaborate on this project. And I think it’s fantastic because now there’s a connection between astrobiology and deep subsurface biology and cancer research even if in a reasonably limited way to begin with. But the fact that I have formed collaboration with someone looking at stem cells and trying to understand the answer to cancer, I think this is really really exciting. And the reason why I find that exciting is because you know Mars exploration, earlier earth research, all this sort of stuff is fascinating and I think it’s really essential to understand how life evolved on early earth whether it can be somewhere, elsewhere it tells us a lot about ourselves. But cancer is such a visceral, tangible problem, and people suffer from this disease and it’s something that so many people have experience of. But I have never really come face to face with that research communities and to come away from a meeting thinking that you can apply thoughts about life on early earth and life on Mars and actually make a contribution to this and not to think about it come to research meeting where you’re talking about it but actually collaborating with someone and make a contribution. I think it’s really tremendously exciting I think that any of these sorts of workshops where you’ve got interdisciplinary thinking going on and where you can make these sorts of links is a wonderful thing to do.
Interview with Sally Dunwoodie
Sally Dunwoodie is an embryologist who works at the Victor Chang Cardiac Research Institute in Sydney, Australia. She appreciates the similarities between aspects of embryonic development and tumor growth.
Sally Dunwoodie: The meeting has been fantastic. It occurred to me and I guess it’s not a novel thought, but we become so specialized as researchers, and we work in our silos, and when we go to conferences, we join people who are working in the same silos, and so we’re very sort of isolated and very specialized. Coming here has made me realize that, Paul Davies made the comment that we’re really trying to join the dots, try and understand how we can do effective research into cancer, and I think bringing together people with such different interests, we’re finding commonalities and we’re being able to join those dots.
Pauline Davies: And what was your talk about?
Sally Dunwoodie: So my talk was about mammalian embryogenesis. How mammalian embryo develops, and how it responds normally to the low levels of oxygen in its developmental environment. We’re interested in how oxygen acts as a morphogen for normal embryonic development, and how when that oxygen level changes during gestation, how the cells in the embryo respond from proliferation to differentiation, and how that has a structural effect on the organs that are forming.
Pauline Davies: So you mean to say that the structure of the embryo is determined by the oxygen that they’re subjected to?
Sally Dunwoodie: Yes. Not oxygen alone, but rather that changing oxygen levels can then, so there are oxygen gradients in the developing embryo, and that gradient will turn on some genes for expression and produce proteins that will affect the way a group of cells will behave, and another group of cells that are receiving a different oxygen level will have a different molecular response, and so you will have a group of cells proliferating in one area, and others differentiating into a specialized tissue type basically laid out, or dictated to by the oxygen gradient to which they’re exposed.
Pauline Davies: And if something is different about that do you get abnormalities?
Sally Dunwoodie: You do indeed. So it’s been long known, well at least since the 1820’s, that if an embryo develops in a low oxygen environment that you will get developmental defects. So you know, the heart won’t form properly or the neural tube, the brain. And this was actually work done by a French scientist where he put shellac around a chicken egg, stopping the oxygen getting in and the embryo developed abnormally and had limb defects and heart defects and so on. We’ve been doing research in my laboratory showing that low oxygen or hypoxia, just a short exposure to it during embryonic development in the mouse, for example, can impact on the formation of somites, which are precursor tissues to the vertebral column or indeed can have detrimental effects on heart development, and recently we’ve been able to show that if mice have a genetic predisposition for a birth defect, and they get a secondary insult, a hypoxic shock that indeed they form heart and vertebral defects. So it’s a gene environment interaction between the predisposition and the low oxygen.
Pauline Davies: And what’s the connection to cancer?
Sally Dunwoodie: The connection to cancer is an interesting one. So, tumors grow and they don’t have an oxygen supply, and as they get larger they become low or hypoxic in oxygen in their center, and so what they do is they stabilize a protein called hypoxia inducible factor alpha and that protein is a transcription factor, and it turns on the expression of a growth factor called vascular endothelial growth factor, VEGF, and basically VEGF acts as a signal to surrounding blood vessels and calls them in, such that they will supply the tumor with a blood supply so it can get larger, and ultimately cancerous cells will go through the blood system and metastasize elsewhere in the body. So there are a lot of commonalities between tumor growth and hypoxia and the organization of blood vessels around it in the form of angiogenesis between tumors and between developing embryos.
Pauline Davies: So do you think that the two communities have got a lot to learn from each other?
Sally Dunwoodie: Yes I think we do, because we do think in slightly different ways, and it’s very interesting for me to have been here today to listen to the talks of the cancer biologists and understand the way they’re thinking about hypoxia and the effects that hypoxia has on cell survival and cell death and so I’m learning from them to think as a bit of a cancer biologist when I’m thinking about the role of hypoxia normally in embryonic development and under levels of less oxygen or hypoxia during embryonic development. And I think, I guess it goes the other way as well, I would suspect, I’ve had some comments from the cancer biologists that some of the work I presented today has given them some thought about how they too think about tumorous cells and how they respond to oxygen in a cancer scenario.
Pauline Davies: Do you think this might lead to a collaboration between you and a cancer biologist?
Sally Dunwoodie:Yes I do and in fact I think there are a couple of areas here. I’m keen to think more about the role of hypoxia and how it affects the metabolism of a cell and its survival with respect to embryonic development. So, I’m certainly going to start using some of the cancer biologists’ tools and their knowledge and I’m looking forward to exploring collaboration with them.
Pauline Davies: Have you heard anything today that has surprised you?
Sally Dunwoodie: I’ve been very much surprised by the research presented today about the role of high oxygen and the healing effects that high oxygen can have and how putting cancer patients in hyperbaric chambers can actually, in combination with choleric restriction kill tumor cells. I think that sounds absolutely fundamentally fantastic, and it would be very nice to see that work in the clinic.
Pauline Davies:What have you learned from this conference?
Sally Dunwoodie: I think what’s very interesting is when you step out of your sort of focused area of research, you realize how little you actually do know, because those who are listening to you are not experts in your area and so they ask you the most fundamental questions, and you often say, “Oh yes, well that’s known” but in fact when you think about it you don’t know why it’s known, and you go back, as I did the other night when I got back to my room, and when I was looking on the internet at papers and realizing that actually we don’t know some of the fundamentals that we assume we do know. And we get a lot of really good basic questions about well you’ve looked at something at a particular developmental time point during embryogenesis, what happened before that and what happened in other species and what happened a hundred million years ago. So, you get a whole lot more questions from an audience such as this who are not embryologists which really make you start questioning some of the fundamentals in your own area of research, and I think as we are usually surrounded by people who know the same as you, we all ignore those gaps or don’t even know that they’re there, so we don’t even ignore them, we don’t even know that they’re there, and it’s coming to a workshop such as this where you’re bringing together cosmologist, cancer researchers, bacteriologist, embryologists such as myself that the gaps are revealed and the uncertainties are revealed and I think that’s fantastic.