 Hello and thank you. So my presentation today will be on evolutionary mismatches and the development of cancer. So to understand this we have to first understand the evolutionary theory of cancer development. So I'll be touching on both topics today. So cancer will affect one in three individuals in the United States currently. Cancer is still classified as a disease of the elderly. It affects mainly predominantly people over 50 years of age. However each year those statistics get lower and lower. There's good news though because cancer treatments since 1991 cancer treatments has that's way better. Since 1991 cancer survival rates have increased by 26 percent. What that means is that we have people living longer after cancer treatment. Now that also means that there is individuals surviving that are at risk for development of secondary recurrences of cancers or primary occurrences of new cancers. So we have to look at how can evolutionary theory help influence influence this. And for one prevention prevent the development of cancer. And two you know one of the goals of evolutionary theory is to then turn cancer into a clinical clinically manageable disease preventing it from turning into like a stage three or four cancer. So this quote was by Dr. Mel Greaves. He's one of the pioneers and leaders in the field of the evolutionary theory of cancer. And this quote really inspired this presentation. So any engineer confronted with a recurring fault in a complex machine or plant would look not only at the immediate source and cause of the fault but its system design. It's compromises and limitations. The engineer will resort to a blueprint. We have evolutionary biology and currently that's not being used in cancer research. So to understand the evolutionary theory of cancer we have to understand Darwinian natural selection. So it's been found that we can take evolution population genetics and apply these to the tumor or clonal perforation of cancer cells. So there's some ground rules for Darwinian natural selection. Number one is survival of the fittest. So selection acts on phenotypes not genotypes. Genotypes are genes. Phenotypes are how they are expressed. So the most fit cell or organism will have a higher advanced or higher possibility of passing on its genes. Another tenant is reproduction above all else. So the goal is to reproduce and pass on your genes. That means that our bodies aren't inherently designed for health and longevity. They're designed for reproduction. And that also means that if we have a deleterious mutation that presents itself after we've reproduced there's not a strong selection pressure to get it out of the gene pool. And this also means that what works best today may not work tomorrow. What that means is that fitness is determined by environmental stressors. So if the environment changes what is fit in one environment may not be fit in another environment. And most of the species that were the fittest on the earth over evolution are now extinct. So basically up here we have a progenitor cell. It gives rise to daughter clones. Now these daughter clones due to carcinogens or just intrinsic variability and mutation rates gain genetic mutations. Now these mutations can be deleterious. They can be neutral or they can be positive. Positive mutations increase an organism's fitness and are passed on. Neutral may or may not and negative they're usually culled out of the gene pool. So this can be seen in cancer cell tumor clonal proliferation. The end result of this selection is the hallmarks of cancer. So what are the hallmarks of cancer? These are the phenotypic traits that all cancer cells express. Now different cancer cells have different mutations but due to shared selection pressures they usually come up with this group of things that are inherent to all cancer cells. So they can evade the immune system. They replicate indefinitely. They also have dysregulated cellular energetics which is known as the Warburg effect. So this is something that's common to all cancer cells. So this begs the question. What is acting to select? What is the unit and what is the unit of selection? So it's been found that cancer stem cells are the unit of selection. So cancer stem cells are just like normal stem cells. Like normal stem cells they can give rise to more cells. With cancer stem cells they have unlimited replicative potential but decreased ability to de-differentiate meaning they can really only just become more tumor cells. They also have a long lifespan meaning they have enough time and they survive long enough to gain deleterious mutations which can potentially become cancer. And they're also highly plastic meaning they can take on multiple different phenotypes that can survive in different environments. And then the tumor microenvironment acts as the selecting agent. So this is the environment that surrounds the cancer cells that puts selection pressures on cancer cells and depending on the phenotype these cancer cells can either survive and thrive or die off. So this diagram kind of sums it up. We have cancer stem cells and there's some intrinsic fallibility and chance which goes into genetic mutations. Those are relatively unchangeable but we'll touch on those in a few minutes. Then we have mismatches and lifestyle factors that can go into cause DNA damaging events cause mutations in those cancer stem cells. Darwinian selection takes place and that's where the tumor microenvironment selects for the fittest cells. And this leads to a cancer cell which then can lead to tumor perforation. Now one thing on the side here is time is a very important factor. Time needs to occur for these mutations to happen to form cancer. That's why we see cancer in the elderly and that's why cancer stem cells long longevity is kind of hypothesized that they're the initial progenitor of cancer. So this is a diagram of the tumor microenvironment. It's very complex. It's basically an ecosystem. You can think of the cancer cell as a seed and the tumor microenvironment as a soil. For the seed to grow and flourish it means the appropriate microenvironment. Now tumor microenvironments are usually classified by hypoxia, inflammation and acidosis. And there's a whole network of cells within here that cancer cells can co-op. They grow their own blood vessels. They recruit immune cells. Then you can think of each different area of this as a different niche within a tumor. These different niches can be populated by different tumor cells and those tumor cells can only survive in those niches. So one thing that Daryl Edwards touched on yesterday and I'll talk about today are tumors are heterogeneous masses of cells. Meaning that you may think that tumors are just one population of cells that grow and divide but due to evolution and the selection pressures of the different microenvironments within the tumor they actually have different populations of tumor cells within a single tumor. Now what this means is that I initially said that tumor cells or most tumor cells had all the phenotype, the hallmarks of cancer. What's actually been being found is that a tumor, the sum of the parts actually needs to display the hallmarks of cancer. So that means that different aspects and different tumor populations within a tumor can actually say provide immunosurveillance. It can actually grow blood vessels. And it's been found that heterogeneous tumor like so one of the main, one of the initial areas where this started was glioblastomas and they are one of the most aggressive forms of cancer. They're also one of the most heterogeneous forms of cancer. They have multiple different cell lines in them. So heterogeneity actually increases aggressiveness of tumor types. And these cells we can use ecological theory to model this where they can compete and cooperate with one another for resources and benefit the whole. What that also means is that so when they're competing with one another they can actually more resistant cells can inhibit the growth of more aggressive cells. And these cells may also construct their own niches as I said in the tumor micro environment which they can also, so tumor cells can secrete factors called cytokines which are inflammatory growth signals and they can basically prepare the way for their metastasis. So, you know, with breast cancer it may metastasize the lung, liver, bones or brain. And those cytokines may prepare the way altering the soil for the seed to flourish. And you can think of metastasis as the pinnacle of evolution. So when it comes to tumors and treatment evolutionary mechanics may be responsible for most treatment failures. So in this diagram we see we have a heterogeneous tumor cell population and one therapy may take care of the main tumor block. That's the main goal of therapy currently is to debalk the tumor decreasing the greatest number of cells. So it can get rid of a large number of cells but due to the heterogeneity of the tumor there may be resistant cells in that population. And these resistant cells are usually more aggressive. They can go on to form, you know, a new tumor which is usually more aggressive and more metastatic. And I was going to touch on some theories that could, you know, evolutionary theory could influence and how we could use these to influence cancer treatment. But there's actually going to be a talk on that tomorrow so I recommend everyone here go watch that. But the implications of this is that there may never be a magic bullet. We never may find one therapy to cure cancer based on the evolutionary dynamics of cancer cells and tumors. So this diagram here basically could sum up this entire presentation but basically we have stressors and these stressors are both internal and external. We can think of external stressors as evolutionary mismatches. So stressors act to increase the heterogeneity basically the different tumor cell populations and change the genetics of these tumors. And heterogeneity can work back and increase the stress of a system which basically leads to the clonal selection of cancer cells. And right now research doesn't look at any of this. There's some evolutionary researchers looking at cancer but we basically look at each individual portion of this and try to target therapies towards that. And so the goal of evolutionary mismatches, the goal of evolutionary theory is to decrease system stress to limit the heterogeneity of these cells. So this brings us to mismatches in cancer. So cancer is not a modern disease. So a paper published in June of 2018 found that there's 274 incidents of cancer in the fossil record dating back to up to 2 million years ago. So we know that cancer is not modern but the cancer rates continue to climb in the 20th century. So we have to change something or look at our past to dictate our future because we know that hunter gatherer populations had lower incidences of cancer. The problem when looking at mismatches is that we have qualitative not quantitative information. What that means is we know that something like immunosuppression or inflammation or they can cause cancer but we don't know the dose and duration needed to cause carcinogenesis or progression or anything like that. So we have to turn to evolutionary theory and look at our ancestors to make some assumptions. So as I said, cancer rates have increased. Humans have the highest rate of cancer of primates, Amanda of mammals in general. Wild animals have lower rates of cancer compared to domesticated and lab-bred animals and there's lower cancer rates in hunter gatherer populations. So this graph was looking at the Achi people of Paraguay. Now we see that in here they had long lives. It was documented that they lived into 65 and 70s. They had lower incidence of cancers and they died generally of infections and other diseases of old age. Now they even gave the benefit of the doubt and they looked at the cancer rate and kind of inflated it for potential cancers. And even then they found that the cancer rate was significantly lower than the average rate of cancer in the UK. So basically what it looks like is time allows us to accrue genetic mutations. Mismatches influence the microenvironment selective pressures to select for cancer cells. And then we have things like trade-offs which increase our intrinsic capabilities of developing cancer. And I'm going to touch on these in a few minutes. So these are some common mismatches that we should all really know about but they're not UV exposure and skin cancer. The one thing I want to note is that infections and cancer. Infections were originally the initial mutagen. They found over in the 1800s that infections lead to chronic inflammation which lead to increased cancer rates. So it was the original carcinogen. Now our ancestors had higher rates of infections and infection-related cancers. But a study published a few months ago by Dr. Greaves that I referenced. He looked at infants and we may have seen this paper in this community that he looked at infants with lack of microorganism interactions in their youth and found that they actually had higher levels of ALL and Hodgkin's lymphoma. Meaning that there's definitely a happy medium there where too much immune stimulation in youth lead to things like autoimmune disorder but too little could also predispose us to cancer because there's a training of the immune system that happens at youth. So I was going to talk about movement but Daryl Edwards had a whole presentation on it yesterday and I think he covered the area excellently. So if you haven't watched that presentation, please go do so. So one thing we like in this community is diet. So what happens when we look at diet and cancer? So we can start with macronutrients. We can look at carbohydrates, fat and protein. And many of us have probably looked online, looked at websites, blogs, papers, eat this, don't eat this and you can definitely limit cancer growth. But the fact remains that depending where you look and if you want a cherry pick basically every single macronutrient has been linked to cancer. The development of it, the progression of it. So it's really not a clear area of research yet looking at macronutrient ratios. So then we can look at hunter-gatherer populations in their diets and what they ate since they had lower rates of cancer. So compared to our modern ancestor we have increased processed foods, decreased fiber, increased exposure to toxins such as herbicides and pesticides, higher inflammatory rates due to omega-6 to omega-3 ratio. And then one thing is decreased vitamins, minerals and phytonutrients. Many of those phytonutrients have been found to be antioxidants, anticarcinogenics and affect cancer pathways in multiple different ways. And so the fact that those are decreased in our diet isn't a good thing either. One thing to know is that our hunter-gatherers actually, you know, Boyd Eaton and Lauren Crudain found that they actually ate more calories on average than modern humans because they had higher energetic inputs. So then we can look at diet quantity. So when it comes to obesity and cancer, obesity has been linked to 30 to 40% of all cancers. Obesity leads to chronic inflammation, increased circulating hormone levels, it depresses our immune system and, you know, influences our microbiome. So we can look at Japanese versus Okinawans. Japanese generally eat more calories than the Okinawans, and they have higher incidences of cancer. That's obviously correlation. But then we can look at a population like anorexics. Anorexics actually have lower incidences of cancer. Obviously they're, you know, predisposed to a lot more conditions, but it is striking that they do have lower incidences of cancer. So what the research actually looks like by a paper by Hursting's AL showed that caloric restriction is arguably the most potent, broadly acting dietary regimen for suppressing the carcinogenic process. So it looks like caloric restriction. So the mechanisms behind that is adipose tissue is generally very inflamed. That inflammation can cause genetic mutations. Obese individuals have higher circulating hormone levels, such as leptin, adiponectin, IGF1, glucose. All of these are growth-promoting factors for the development of cancer. So caloric restriction actually limits all of those, decreases inflammation. Now from the anorexia study, we know that prolonged caloric restriction leads to negative health outcomes. So that's where something like the fasting-mimicking diet that Dr. Walter Longo is looking at, or intermittent fasting come into play. So then we can look at the microbiota. Out of all primates, we have the least abundance and the least diversity of microorganisms. In the states, we have lower than those in Venezuela and Malawi. There's multiple factors leading to this, such as decreased fiber intake, antibiotic use. But an ultramicrobiota causes local and distal inflammation. So those microbiota-socrating cytokines that can actually cross the intestinal barrier go into the bloodstream, leading to inflammation systemically. They're also directly mutagenic and can lead to multiple forms of cancer and ultramicrobiome. A Western diet actually predisposes, it changes the bacteroides-fermicutes ratio into a more pathogenic kind of phenotype of our own overall microbiome. So then I'm going to take a little side and talk about life history trade-offs. This is a subspecialty of evolutionary theory. And basically, when organisms take in energy, they have to partition that energy into different aspects of fitness. Basically, the main goal is to take that energy and turn it into viable offspring. They need to offset this with things like somatic maintenance, growth, and then, so you can see here, you can either have cancer defense or reproduction. So in stags, larger horn size is correlated with more offspring. However, stags with larger antlers actually have higher rates of cancer. We can actually see this in humans as well, where in males, an average of three to four millimeters increase in leg length. Increases our cancer risk for over 80%. In females, larger breasts are associated with higher rates of breast cancer. And we're the only mammal with protruding breasts outside of lactation, so clearly there's a trade-off between increased fertility and decreased somatic maintenance, allowing cancer to, obviously, we're choosing reproduction over somatic maintenance. So then if we look at breast cancer as a model, so breast cancer is the most common cancer in western females. One in eight women will develop cancer. The risk of breast cancer development may be 10 to 100 times higher in industrialized society, Boyd Eaton found. So then we can look at the different aspects that go into play with this, the mismatches, the life history trade-offs. It looks like calories is one of the main factors, so we're going to make the assumption that calories lead to higher circulating estrogen levels, and circulating estrogens increase the risk of developing breast cancer. Basically, since we have abundant resources, we're channeling it in to reproduce. So obesity, children that are obese and increasing obesity rates, are implicated with early menarche. For every menstrual cycle you have, it increases your risk of breast cancer. So between western women and hunter-gatherers in Africa, western women on average have 400 menstrual cycles, whereas hunter-gatherers in Africa have around 100. We can look at the reproductive life history between hunter-gatherers and modern women. There's definite different patterns. So say in China, oh, and then one note of the early menarche, in Chinese populations, average menarche at 13 years old, versus 17 years old increases your breast cancer risk over 80% as well. So when looking at evolution or hunter-gatherer ancestors in tribes, they usually had, and this can be debated by studies, but they usually had menarche around 17, 18, had their first child around then, on average had five children and lactated for three years. So it looks like, and then there was a study in China showing that for every lactation cycle you have, it decreases your risk of developing breast cancer by 11%. So then there's other factors that go into this, hormone replacement theory and birth control pills, obviously increasing your levels of estrogen. Discontinuing those therapies reduces your risk of cancer in usually two to five years. Xenoestrogens in the environment also increase your risk, such as BPA, endocrine disruptors. And then you may think, well, there's obviously some genetic predisposition to cancer. So when looking at the BRCA2 mutation, it's been found that in 1920, women in Iceland with a BRCA2 mutation had an average risk of around 20% of developing breast cancer. Fast forward to 2002, and they had around a 70% risk of developing breast cancer. So there's definitely some environmental factors that go into play. Then looking at males and prostate cancers. So Western nations have a 6 to 10-volt higher incidence of prostate cancers increased, and that's been linked to increased testosterone levels. So we can, and when eastern populations move west, they begin to develop higher rates of prostate cancers. Incidentally enough, eastern populations have the same rate of small tumors, when you've probably heard that most elderly men, when they die in their biopsies, they have some form of prostate cancer. Well, in east versus west populations, they do have the same rate as ours, but we somehow, you know, the initiation isn't the problem. It's the promotion of the cancer growth. So between cultures, it looks like increased calories lead to higher testosterone levels. Higher testosterone levels, serum testosterone levels, lead to higher rates of prostate cancer. You may say, well, older gentlemen have the highest risk of developing prostate cancer, but they have the lowest circulating testosterone levels, but it looks like from this graph in other studies have shown that there may be a priming effect in youth where high circulating testosterone levels in youth predisposes prostate cancer growth and predisposes you to developing prostate cancer. Within cultures, calorie consumption, increased calories, increased circulating testosterone, increased prostate cancer. Within cultures, we can look since, you know, we're generally even on the caloric consumption, monogamy versus polygamy. Well, the Hadza versus the D'Toga tribe in Africa, the Hadza are monogamous. They pair bond with a female, reproduce, and then their testosterone levels decrease. In polygamy, the D'Toga society, they pair bond with a female, reproduce, and then they're looking for other mates. So their serum testosterone levels never drop and they have higher rates of prostate cancer versus the Hadza. So within cultures, we can look at socioeconomic factors and we can look at the challenge hypothesis showing that competition and challenge actually increase your testosterone levels because it primes you to reproduce, you know, increased testosterone for aggression. So individuals of low socioeconomic status actually have higher circulating testosterone levels and higher incidences of cancer. Then we can look at genetics where repeats in the androgen receptor making, you know, more receptive to androgens actually increase your fertility, but then it increases your risk of developing prostate cancer further. So there's definitely, you know, mismatches playing with some life history stuff, playing with things that we can and cannot change that lead to the development of cancer. So early exposure to adversity can increase the risk of developing cancer later in life. So children exposed to famine, war, the death of a mother, or abuse all have increased rates of cancer development. There's some debate in the literature whether stressors in adult life can lead to the development of cancer, but studies have found that job instability divorced in the death of a spouse can increase your cancer risk by two times. In fact, police officers who work for every 10 years on the force of police officer works, he's at a 67% increased risk of developing prostate cancer. And then when we look at what's the opposite of that, if we look at, so beta blockers, individuals on beta blockers actually have women with breast cancer on beta blockers actually have increased survival time. So there's a blunting of the stress response with beta blockers. And then if you have increased social networks of cancer, you actually have a 40% decrease risk of increased risk of survival and decreased risk of cancer occurrence. Now there's multiple different mechanisms why this happens. Stress inhibits the immune system, increases inflammation, alters the HP axis and changes DNA methylation patterns. This can all influence, once again, the microenvironment putting selection pressure on these cells to then develop into tumors. There's many confounding variables such as stressed individuals are more likely to abuse substances over E, not sleep. So in all of these studies and in all of these mismatches, there's many different factors and none of them are in isolation. So then we can look at something like sleeping cancer. So human sleep has been selected to be shorter in duration but deeper than other primates. But modern day humans has kind of taken that to the end degree and now we get less and less sleep. So women sleeping less than six hours a night have more aggressive forms of breast cancer we know that night shift workers have increased risk of developing cancer. So some mechanisms behind this, T cells actually move to the lymph nodes during sleep developing immunological memory. So we know that exposure to blue light and brightness dimming melatonin production. Melatonin is the sleep hormone but it also has potent anti-cancer mechanisms. So that could be a possible mechanism behind it. It promotes cancer cell death, inhibits apoptosis, inhibits blood vessel growth so it's a broad spectrum acting anti-cancer. So then with environmental carcinogens and cancer I just wanted to touch on this topic briefly in that there's many different carcinogens many of them we don't know what they do. We know with ionized radiation we know with now recently formaldehyde has been shown to be a carcinogen we know with asbestos all of these things are carcinogens and they have multiple different mechanisms such as DNA mutation, increasing inflammation, decreasing the immune system. But one interesting study showed that environmental carcinogens actually decrease the growth rate of normal cells. So what that means is you're decreasing the growth rate of your normal cells. Well, if there's a cell that has a mutation that allows it to survive and thrive in the microenvironment it can then take off and start dividing and that may be a common mechanism behind environmental carcinogens and cancers. So basically this framework here mismatches lead to genetic instability. They directly and indirectly modify the tumor microenvironment promoting cellular heterogeneity. We've already determined that heterogeneity is a bad thing because it can lead to more fit cells that can lead to development of cancer. And the tumor microenvironment can act as a cancer suppressor and a promoter. You can take a cancer cell and put it in a benign tumor microenvironment and it won't form a cancer. So all these factors go into modifying the microenvironment that lead to selecting for more aggressive cells. So this is Rudolf Virchow. He is the father of modern pathology. He was the first person to discover that chronic inflammation can lead to the development of cancer. And over 100 years ago he said, indeed a great deal of industrious work is being done and the microscope is extensively used, but someone should have another bright idea. And that bright idea I believe is using evolutionary theory of anti-cancer drug development and things like that and guide our lives on how we prevent cancer as well. So prevention is still the best cure. So avoiding mismatches, making those small adjustments in your life can really add up. But due to obviously trade-offs and inherent genetic instability, there's always going to be the risk of developing cancer. Standard of care is still the gold standard, but before during an after treatment there's a lot that can be done to kind of move the needle in your direction. So this is the prescription. And overall, as I said before, reduced systemic stress is the main thing. If you reduce systemic stress you can reduce that heterogeneity. Questions? They don't really look at those studies, but it's looking at, you could look at say like a Caucasian population that lives in the east. They generally have the lower risk of cancer development. Any other questions? Oh, go. Okay, so you mentioned informally to me that breastfeeding your children does have maybe some protective effects. Can you elaborate on that at all? Yeah, so that was the study showing that between modern humans and traditional humans we generally have more men's C cycles. We have less children. And so the increase it's not necessarily the breastfeeding although there's probably some mechanisms there that reduce the risk. But it's the circulating hormones, breastfeeding. When you're breastfeeding you have increased levels of prolactin. Prolactin decreases the production of estrogens in the body. So generally when women are breastfeeding they're in a lower estrogenic state. So that's, you know, I'm not going to say 100%, but that's most likely the mechanism behind that. Okay, quick question. Great presentation by the way. I want to know you were talking about breast size increases risk for cancer. Would that, would either reduction in breast size or even augmentation cause any risks as well? Or would that play into it? I haven't looked at the data on that so I can't speak to that. But if we were to kind of hypothesize I believe just the larger breast means breast tissue just like with the aging theory of this presentation you have more time to develop genetic mutations as you age. With larger breasts you have more breast tissue for genetic mutations to accrue. That would probably be the mechanism behind it. So if we were to hypothesize would, you know, decreasing breast size, decrease the risk of cancer I think the only comparative studies we could look at were women who then decided with, you know, BRCA one or two mutation who decide to undergo a bilateral mastectomy because then they have no breast tissue and they do have reduced risk of cancer development. But, I mean on the positive side the presentation shows that although there's always going to be some genetic factors in there a lot we can reduce that risk exponentially with lifestyle factors. One more quick question. What can you talk, can you speak to HRT therapies with regard to cancers as well and the increase or even decreased risk for those? That's definitely a touchy subject with a lot of people and I mean there's definitely ah so HRT the study I looked at and some studies showed that it looked like estrogen plus progesterone therapy increased the risk of developing breast cancer while estrogen therapy alone didn't but I'm not, I don't do hormone replacement therapy. Dr. Ruiz Duaz and he would know a little better than me but there's definitely an increased risk when using HRT and I think a position paper came out last year what was it where they recommended it was the National Endocrinology Association that recommended that for women going through menopause who wants to do HRT they recommended to do HRT for the shortest amount of time possible with the most minimal dose so just like the recommendations there it looks like we probably want to mimic ancestral hormone levels and not go, I know a lot of we don't want to go super physiological in any of these things and we definitely want to if you're undergoing HRT get your hormone levels checked pretty regularly so can I just I would honestly need to do a deep dive into the research on that it's very conflicted there is not a consensus on this issue and that's it's complicated there's probably many modifiable risk factors that go into that nothing, especially the human physiology, we're not in an enclosed system so looking at these women, were they inflamed what were their diets like were they already predisposed to developing this and then you kind of just they had like I put in the prostate cancer slide, we had the initiation process which we all do I will add that we all at some point have cancer cells in our body so what is it that inhibits those cancer cells from growing and just like with HRT and breast tissue there might be an initiation there but HRT may promote the growth of it I just wanted to a quick remark about the number of children in ancestral populations, there's a lot of variation about that and actually some of the stuff I've been looking at with early modern societies so 16th to the beginning of the 19th century women were typically having about 10 children so I don't know it means you're rarely not that doesn't account but I wanted to know about those the fossil record cancers, are we talking about actual tissue samples or is it just DNA so the problem there's 274 documented cases, the problem with this is that 2 million years tissue doesn't survive so most cancers that form in individuals are epithelial based cancers, within 2 million years that tissue is gone so you would be looking at things like bone metastasis they're looking at so there's 274 documented cases of advanced cancers but that really doesn't negate the fact that there's probably much many more cases of cancers that affected individuals and then they passed away and then that tissue degraded it is a hard but we do know that there was cancer and basically as soon as we hit from unicellular organisms to multicellular organisms the genetic programs were in place for cancer cell development because basically it's looking at ecological and evolutionary theory it's going to promote cheaters and cheaters sometimes thrive in environments