EEB 122: Principles of Evolution, Ecology and Behavior?

Lecture?21. Evolutionary Medicine

https://oyc.yale.edu/ecology-and-evolutionary-biology/eeb-122/lecture-21

Today we're going to talk about evolutionary medicine.?The range of issues in evolutionary medicine is really quite large.?

• We contain traces of our evolutionary history and they bias our responses in significant medical issues. So there's the hygiene hypothesis about autoimmune disease. There is our genetic variation for resistance and drug response. There are traces of the selection that illnesses, that diseases, have written on our genome.

• Then there are issues in reproductive medicine. You know something about genetic conflicts, imprinting and mental disease, because I talked about that earlier. Then there are the issues of ovacytic atresia and selective abortions and mate choice, which are an interesting part of reproductive medicine.

• A big part of evolutionary medicine has to do with the evolution and ecology of disease. And diseases have adaptive strategies. They have their own agendas. They have developed ways of avoiding our immune responses, of manipulating hosts. Some of them manipulate us; that's what coughing and sneezing is about. That's also what making us extremely tired and lying down is about, in malaria. Their virulence evolves, they evolve drug resistance rapidly, and those are very significant medical issues.

• Then there's all the information that's coming in now from evolutionary genetics and genomics about where viruses originated. So, for example, the detective work necessary to determine that the sooty mangabey was the ancestor of HIV-2 is done with molecular phylogenetics, and that the chimpanzee is the ancestor of HIV-1; that the SIV living in the chimpanzee is the ancestor of HIV-1 is done that way.

• Then there are very significant differences between different kinds of bacteria, in terms of their genetics and their population biology, particularly in how readily they can do horizontal gene transfer. So that if a bacterium in one species evolves resistance to a certain drug, how likely is it that that resistance gene will get into another species? It depends on the particular kind of evolutionary genetics that that bacterium has; and they vary in this respect.

• Then there are all of the issues about under what conditions do new diseases emerge? And that itself is quite a growing field. Then there's all about the degenerative diseases.?How did aging evolve? And given that we have an evolutionary theory of aging, what can we expect to be the characteristics of the aging organism? Are they going to be simple or complex; and if we fix one thing, will another thing break?

I'm going to talk about thrifty phenotypes, and parasites and autoimmune disease; and then about how pathogens have their own agendas and evolve rapidly. It's?a small portion of the subject matter of evolutionary medicine. But these are arguably important themes.

The point about thrifty phenotypes is this: Early life events are failing to predict late life environments. Perhaps they used to be good predictors, or perhaps those early life events were correlated well with the environment in the Pleistocene?for ten or fifteen years.?If you nutritionally stress a mother and infant, the fetuses and infants will have increased risk of obesity, diabetes and cardiovascular disease fifty or sixty years later. And the initial data that demonstrated this came from the Dutch Hungry Winter.?

• The idea is that stress early in life is switching the individual into a physiology that's very effective at conserving energy, but it is inappropriate if there's an adequate diet. So the muscle cells become insulin resistant, fat becomes concentrated in special depots. And we now have a lot of data indicating that this is the case in humans. So they come from the Dutch Hungry Winter of '44/'45, when the Nazis basically cut off the food supply to Amsterdam, and actually to much of Holland.

• The fact that you can reproduce it in a model system is quite important, because it means that for whatever reason that thing evolved, that kind of reason must also have been there for something as short-lived as a rat.

If we look around the world, about 20% of American adults are obese. Interestingly, in rural Mexico, 60 to 70% are obese. That's not something you'd necessarily expect.?The incidence of diabetes is exploding; so late-onset diabetes is exploding.

• The least obese nation is Japan, and a lot of the European countries kind of have low levels. But the ones that have very high levels of obesity are the U.S., U.K., and Germany, Australia. These are not necessarily the ones in which this kind of nutritional stress early in life would be very frequent.

• Countries like India and China,?in?Africa and Mexico, go through the demographic transition, and go through the economic transition into developing countries, so that they have a parental generation that was more food stressed, and an offspring generation which is more well fed, and more exposed to junk food.

The argument is that it was?adaptive in the Pleistocene environment, because if you could switch the offspring into a thrifty phenotype, it would have a higher probability of surviving the dangerous childhood years and making it perhaps to its first reproductive event. And, in that environment, what was going on at age fifty or sixty was probably irrelevant because most of the population was dead by then anyway.?

This is a hypothesis that is in the category of things where humans are mismatched to modernity.?We would always have worms and bacteria in our bodies. When modern hygiene--so basically good clean water systems--and antibiotics take out the worms and bacteria, our immune systems respond inappropriately. We can see that autoimmune diseases are actually exploding. So asthma, allergy, Type-1 diabetes, multiple sclerosis, other auto--Crohn's disease--other autoimmune diseases are increasing very rapidly. And as the infectious diseases have gone down, the autoimmune diseases have gone up.

• Type-1 diabetes,?an autoimmune disease, is?common?in Europe and in Australia, and it's also fairly common in Saudi Arabia. And if you look at where worms and leprosy are common, where countries that have a fairly high incidence of these different worm infections, those are pretty much across the Tropics.

• And if you look at Type-1 diabetes against tuberculosis, you see where there's a lot of Type-1 diabetes there's not very much tuberculosis, and where there's a lot of tuberculosis there's not very much Type-1 diabetes.?So that's a negative spatial correlation.

• In Germany, and in other European countries, farm children have fewer allergies than city children. The kids with schistosomiasis don't have so many allergies, and they don't have a reaction to dust mites. Adults with less asthma are more likely to be infected with nematodes. In the Tropics, you almost never see autoimmune disease.?

People?are experiencing a disease which is caused?by our historical shift into a civilized state. It runs like this:?our?immune?system coevolved with worms and bacteria.?

• Worms are big, multicellular parasites and?have to live in our bodies a long time to reproduce successfully. When they send their eggs out, to get into another host, those eggs are going into an extremely risky environment, and it's not very likely that any single individual egg is going to make it. So the worms have evolved ways of living in our bodies, for a long time, without being knocked out by our immune systems.

• They are interfering with signaling pathways that also happen to be the pathways that elicit allergies and asthma. But we have an immune system that wants to react to them with a big inflammatory response, but it's not going to be able to get rid of them, because the worms have out-foxed us.

• So we have to make the best of a bad deal. We?have to down-regulate our inflammatory response, in the presence of worms, so that we don't damage ourselves; because inflammatory responses turn out to be one of the most damaging parts of degenerative disease.?That's what's going on in arteriosclerosis. That's what's going on in rheumatoid arthritis.

• The parasites have been removed, that actively down-regulate the immune response. That leaves inappropriate responses of our anti-worm machinery, and that anti-worm machinery lacks proper targets and is fooled by inappropriate targets.?

Imagine your body having come to evolutional equilibrium with worm infections. So the worms are down-regulating your immune system, and your immune system?has a lot of other things to deal with besides worms.

• The?immune system?producing a range of cells that can react to different kinds of invaders. And it has a screening apparatus, which is in your spleen and in your thymus glands, to screen out any molecule or any population of cells that is recruited by your immune system to attack your own tissue.

• Then you pull the worms out. The immune system is no longer down-regulating because of the presence of worms; the immune system cranks up, and it throws a lot of stuff at that screening apparatus. But the screening apparatus didn't evolve to deal with that much stuff. So it's kind of leaky,?letting through more cells that might react with your own tissue.?

That's a hypothesis; that's not a demonstrated fact. But what I'm trying to do is I'm trying to indicate to you that this issue of autoimmune diseases arises logically, either at the points where the worms had been manipulating signaling in the immune system, and then that has been withdrawn, or it is operating on the screening mechanisms that are built in for the immune system; both could be going on.?

Now, what kind of data have we got? We have?a knockout mouse that simulates Type-1 diabetes. So it's a model mouse; people have genetically constructed a model mouse, to make it like Type-1 diabetes in humans. And then they have infected it with various kinds of worms to see whether or not it is changing the T-cell bias in a way that would be plausible to basically down-regulate autoimmune disease. And these are things that prevent Type-1 diabetes in knockout mice.?

• Schistosoma will do it, Heligmosomoides will do it, Trichinella will do it. Mycobacterium--that's TB and TB's relatives--will do. Salmonella will do it. Basically infectious agents are antagonists of Type-1 diabetes in model mice.

• There's some evidence in animal model systems that this works.?We've got Schistosoma,?Trichinella, Trichuris and so forth. These things will prevent colitis, inflammatory bowel disease, collagen-inducted arthritis, Graves' thyroiditis, and so forth, in model systems.

• If you decided that you wanted to do therapy on humans?using these nasty worms, which have a big yuck factor, which one would you choose? Well you would want to have a worm that doesn't really?cause much pathogenic problem or?to multiply in the human. You'd want to be able to regulate the dose. You?wouldn't want it to alter the behavior in patients that have depressed immunity. You wouldn't want to be affected by common medications like aspirin.?

• It turns out this?pig whipworm?has these characteristics. Patients with Crohn's disease and ulcerative colitis improved after ingesting 2500 pig whipworm eggs.?People with Crohn's disease who got a fairly prolonged treatment with this stuff responded well. Patients with ulcerative colitis, in a double-blind, placebo controlled trial--which is another step up in rigor--did better on worm eggs than they did on placebos.

• Well there was a case control study done recently in Argentina that showed that the progress of multiple sclerosis is a lot slower in the patients that are infected with parasitic worms.?So the data there was convincing enough to persuade the NIH to begin a clinical trial in Iowa in which MS patients are being treated with the eggs of pig whipworms.?

Humans evolve more slowly than their cultures, and therefore we are mismatched to modern life. We evolved to a diet and an ecology and a social life and a degree of cleanliness that was characteristic of a Pleistocene hunter-gatherer group, and that that's now changed radically and we haven't caught up yet; our bodies have not yet adjusted.?

The other thing that I want to tell you about basically is about how pathogens evolve. And they evolve very rapidly in response to things that we do to them, both to antibiotics and to vaccines. So the antibiotic resistance story is in large part a story about hospitals, because that's where most intense use of antibiotics is. Virulence also evolves.

So a little bit about antibiotics first.

• Almost all of the bacterial genes that allow them to process the drugs that we use, and deal with those drugs, that provide them with resistance, evolved before the human drug industry existed. And that's because bacteria have been engaged in?chemical warfare, with each other and with fungi, for hundreds of millions of years.?They have developed a large spectrum of synthetic capacity, and it's out there naturally in nature.

• drug resistance evolves in the soil and in wild animals. So if you go out and just take out samples of spore-forming bacteria from soil, that's not near a hospital,?every single one of 480 strains of bacteria was multiply resistant, and there was no existing class of drug that was effective against all strains. That's just natural variation that's out there.?That is the downside of biodiversity.

• There's a lot of evolutionary potential in natural bacteria. If you go around the outback, in Australia, and you sample enteric bacteria, that is gut bacteria, by?collecting feces?from various Australian mammals. What you find is that they have multiply resistant strains of bacteria; and they have never been close to a city, or to human beings that are taking antibiotics.

The agricultural use of antibiotics is quite important. The reason that farmers use antibiotics is that by reducing the amount of energy that their pigs, cattle and chickens have to put into resisting disease, their pigs, cattle and chickens grow more rapidly. So it pays them. If they use antibiotics, they increase their production.?

• One antibiotic that's actually quite critical is vancomycin. Vancomycin has been the last line of defense against multiply resistant staphylococcus aureus for about twenty years. You don't want resistance to evolve to vancomycin. If it does evolve to vancomycin, it becomes very hard to do surgery in hospitals.?

• Danish farmers were using vancomycin, and the Danish government noticed that and banned it. So we have a before/after comparison of how frequently do you pick up vancomycin resistant enterococci bacteria in Copenhagen. It dropped from 12% to 3%. There was a 9% rate drop in the rate at which doctors picked up vancomycin resistant bacteria in the city, when they stopped using it out there on the farms.

The other place where there's really a lot of antibiotic use is in the hospital.?

• The Center for Disease Control estimated that?in 2003?there were 90,000 residents of the United States that went into the hospital for some other reason, picked up a resistant bacterium, and died of a bacterial infection that they didn't have when they entered?the hospital.

• The bacteria that live in hospitals are almost all either resistant or multiply resistant, because that's where so many antibiotics are used. And it's a good thing to use antibiotics in hospitals?to increase?the?probability of survival, if they have to have a major operation.

• But the consequence of that, which is of benefit for the individual, is a cost for the population. And resistant strains are much more expensive to cure.?

In this context of the ecology of hospitals and nursing homes, there's been some fairly sophisticated thought given to how should we manage the use of antibiotics.?

• The kind of simple-minded way, which has often been used, is to?cycle the antibiotics. We'll use Antibiotic A for three weeks in the hospital, and then we'll replace it with Antibiotic B; and that way every time they start to evolve resistance to Antibiotic A, they get hit with Antibiotic B. It turns out that produces a selection regime which is extremely effective at causing the rapid evolution of multiple resistance.

• Turns out the best way to really screw up the bacteria is to assign antibiotics at random, to individual patients within the hospital, and change them about every two days. That's the most effective method?but?just hard to manage.

If we apply that to chemotherapy, many of?oncologists aren't aware that a cancer is a genetically heterogeneous population of cells.?

• The whole thing that gets a cancer going is an optimum mutation rate, and those cells continue to mutate?so they become quite genetically heterogeneous. It takes seven to nine mutations to turn a stably differentiated cell into a cancer cell.?The mutations that do it are often mutations to the DNA repair apparatus.?If you start prescribing one chemotherapy, and wait until it fails, and then start another one, you are applying a selection pressure that very effectively selects for resistance to chemotherapy.

• If a more sophisticated strategy were used, it's been calculated that the lifespan of cancer patients might be prolonged by several times. This is a place where evolutionary models can actually really help to better manage the use of antibiotics.?

Now virulence. Now I've used Ebola, HIV and malaria to symbolize the three different stages in the evolution of virulence when a disease emerges and moves into the human population, and then starts to become adapted to it.?

• The first phase, which would be Ebola, Lyme disease, bird flu, SARS, rabies,?it's an accidental infection. It's coming in from another species and?not adapted to us yet, and sometimes these things are just incredibly virulent but?not always the case.?We probably don't even notice the thousands that come into us and never take root and die off quickly, because they simply pass without having caused any major disease.

• The reason that small proportion?are highly virulent is that they've never had any evolutionary experience in humans, and they're not adapted to the level of virulence that's best for them. They kill us too quick; they kill us so quickly they can't get out. Ebola is essentially a self-snuffing disease. It won't spread out of one village, because everybody's dead too quickly for it to transmit.

• Phase Two would be one in which the parasite's been established, but it's still far away from its optimal virulence. This is probably the case with HIV. The virulence of HIV is probably still evolving. And the Myxoma virus that was used on rabbits in Australia. So it evolved its virulence downward in Australia, because it was killing rabbits too fast.

• Then in Phase Three you're dealing with a parasite that's well established, it's been in that host for a very long time. It's probably at its optimal level of virulence. It will kill some people, but it doesn't kill them too fast. It kills them at a rate where most of it can still get out and get into another individual, before the first host dies. And that's probably the case with malaria and tuberculosis.?

Let's take something which is in Phase Two where?virulence evolution actually becomes part of a medical technology.?

• Microbiologists have been using serial passage to produce attenuated vaccines for a long time. And what an attenuated vaccine is, is a pathogen that would cause a serious disease, but it's been evolutionarily changed, so that it's attenuated. It will infect you but it won't make you sick, and it will therefore elicit a very strong immune response, which is also effective against the unattenuated relatives.

• That's been used to produce the Sabin oral polio vaccine; the measles, mumps, rubella, yellow fever and chickenpox vaccines; one flu vaccine; and a TB vaccine and a typhoid vaccine. It shows?that rapid evolution of virulence is a medical technology, and has been now for fifty years. The reason it works is that pathogens evolve rapidly.

• The results demonstrate that there really are widespread tradeoffs in performance on different hosts. This tradeoff, that you do well on one host and poorly on another,?limits host range and constrains the emergence of new diseases.?

You get a nice genetically homogenous mouse, which is not going to be any kind of a genetic challenge to the parasite.?You inject it with parasite; parasite grows exponentially, and while it's still in exponential growth phase, you take some of it out.

• You remove its transmission costs. You take away any tradeoff it might have had with transmission. So it's going to become really bad at transmission, but it gets good at growing. You extract it, you re-inject it, and you let it go through exponential phase--you just keep it in exponential phase the whole time.?

• Polio?is?passaging?through cell culture. So it's really good at living in cell culture. It's getting really lousy at living in monkeys, and the longer it lives in cell culture, the fewer monkeys it kills, until after 50 passages in cell culture it isn't deadly at all, in monkeys; and at that point they began a clinical trial and put it into humans.?

There are a number of points in that whole story about manipulating virulence. One is, virulence can evolve really quick.?

• Virulence has been manipulated by medical technology, for the last fifty years, to produce some of the most successful vaccines on the planet.?That itself is an impressive confirmation of this hypothesis, that in order to do really well on one host, you have to give up the ability to infect others.

• If you want to produce a vaccine that's a live, attenuated vaccine, that infects a human, you take it out of the human, you put it into something else; you make it really good at killing that other thing; it becomes lousy at killing humans, and when it gets lousy enough at killing humans, you can use it as a live vaccine.

Whether virulence will evolve in response to vaccines? I've already introduced you to the virulence transmission tradeoff. If you're too virulent, you won't transmit, because you will have killed your host before you can get out.?

• Now what happens when you make an imperfect vaccine? It does pretty well, but it doesn't kill all of the pathogens in all of the hosts. That's why we call it imperfect. That imperfect vaccine will reduce the cost of virulence by making likely that some hosts will survive in the presence of virulent strains. So you're getting a partial immune response. The pathogen can persist in the body, a longer period of time.

• But then if the virulent strains are the more competitive ones, and you've got multiple infection, then the virulent strains are the ones that are going to be surviving the longest in the bodies of people that have an imperfect response to the vaccine.?So it turns out that this actually happens in mice with malaria; you can demonstrate with mouse malaria that this is the case.

It?creates an ethical or public health dilemma, which is rather similar to antibiotic resistance. It's going to be really good for the individual human being to be vaccinated against malaria. Hundreds of millions of lives would probably be saved. But, as an unfortunate byproduct of this wonderful thing, we are probably going to have a situation in which the surviving disease becomes more virulent, and a few people are then hit by a really nasty strain of malaria.?

It's not a recommendation that you don't vaccinate, it's a recommendation that you understand the consequences of vaccination, which are evolutionary, and be prepared to deal with them.?