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26 Nov, 2021 06:46

Autophagy shields a person from infection – neurogeneticist

The human body is wise, it knows how to regulate itself. But like every mechanism, even the most perfect ones, it needs a reset button. We talked to David Rubinsztein, professor of molecular neurogenetics at Cambridge University, about the mysterious phenomenon of autophagy.

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Sophie Shevardnadze: David, so great to have you on our program today. So autophagy is like THE topic. Everyone's talking about it. Lots of myths surround it. So we figured we'll just ask you straight away what is all the fuss about. From what I understand, so correct me if I'm wrong, autophagy is like a process where cells deprived of nutrients, they sort of get rid of damaged structures and develop new ones. Is this a correct explanation?

David Rubinsztein: Can I clarify a bit?

SS: Absolutely.

DR: So it's a process that occurs inside cells. And it occurs outside the nucleus, so in the cytoplasm, and it's a process where cells form these double-membrane structures, which are like sacks which capture portions of the cytoplasm, and then deliver them to what are the incinerators of the cell, the lysosome, for degradation. So that's what autophagy is, as a process. The idea that it's stimulated by starvation is something that is conserved from yeast to people. But it's not always induced by starvation. There are other ways of switching it on as well.

SS: All right, so let's clarify, how do we make the cells go into the autophagy stage?

DR: So the number of signals that can make a cell go into that type of process… One is if you deprive it of nutrients, and it can happen with different types of nutrients, so if you deprive cells of amino acids, they can go into this type of process. If you deprive them of glucose, it can go into this process. If you deprive them of energy, it can go into this type of process. But it can also go into this type of process, if you switch on some genes that might be involved in cancer, for instance. So it is not restricted. The signals are not restricted to all those cell stresses caused by some nutrient deprivation, but they include them.

SS: In like a very common language, what would you say is a sure way to actually kick-start that process in a human body? Like if I'm sitting at home, and I decide, I want to try this because autophagy supposedly is very good for my organism, it’s prevention, it cures all sorts of diseases. So I want to try, what should I do?

DR: So I don't think that we know enough about that in humans to do the experiment. If you gave me a mouse, and ought to do to the mouse, if I starve the mouse for long enough, I can induce autophagy in many different tissues and many labs have assessed how long you might need to do it to get into the liver versus the brain, for instance, in a mouse. In a human, the data aren’t so clear. So there's one study I'm aware of where they've looked in different cells in the blood. And in only one of the cell types that they studied, after 24 hours starvation, could they see a change in autophagy. Now, they so they couldn't see it in the other cell types that they analysed in the blood. I suspect the same is occurring and many other cells in the body as well. So some cells might respond after 24 hours, but many others might not. And so those are unknowns in the field. And I say if you want to really kick-start autophagy, you could do with the certain drugs that might do so. But they're probably not drugs that you want to take without a prescription or you couldn't get without it.

SS: So we'll get to the drugs part for sure. But, for instance, Professor Yoshinori Ohsumi who actually got a Nobel Prize for describing the phenomenon, he told me recently, from what I could understand that it only can take up to 30 minutes for your cells to go into autophagy:

< Yoshinori Ohsumi: If we starve the yeast cell, so suddenly there start the signals that you can see morphologically, you can see autophagy start there within 30 minutes or something.>

DR: Well, Professor Ohsumi, he's been a pioneer working on the process but he's really studied yeast case. So if you study yeast or you study cells in tissue culture, so you study them in a very artificial environment, then if you starve them, you can see effects after 30 minutes or an hour. But when you starve a cell in tissue culture, you’re putting the cells virtually in nothing. And you’re putting them with water with a little bit of salt. If I did that to your body it would fall apart so that your body, of course, when you starve, it's a much longer adaptation to the starvation. If you starve for 30 minutes, your body doesn't know about it at all. You’ve got to starve for a long time. And you still have all the constituents of the blood and the serum and the bodily fluids, which are not like salt water. So I think it's moving from an artificial context in the laboratory isolated cells and culture to a whole organism. And that's why the 30 minutes is clearly not sufficient.

SS: – doesn’t make sense. I don't suppose it’s worth asking you if you practice autophagy?

DR: Does it look like it?

SS: Probably it doesn’t always have to be about losing weight.

DR: So I think you know, there are two parallel discussions. The one discussion is whether some degree of caloric restriction is beneficial for people. And the second is whether those benefits are primarily mediated through autophagy. And I don't think the answer to either is known, certainly model organisms like mice, there are some data. And there's some data in humans actually, that alternate-day fasting, for instance, improves various medical parameters of interest. But it's unclear whether those effects in mammals are primarily mediated through autophagy.

SS: It's just mind-boggling to me that you're telling me since the very beginning of this chat, that we don't know the exact results on people. And on the other hand, we have this whole movement for autophagy. And people are promoting it, and there are basically books coming out and saying how amazing this is for you. And this is like the answer to practically being immortal.

DR: Yeah, I don't think someone wants to be immortal. I think that there's a fairly good literature and … this work… But there's a sizable literature that argues in model organisms that if you can switch on autophagy, in general, it has beneficial effects. So that's the one argument. There's also literature suggesting in model organisms if you calorie-restrict, that's beneficial. And there's also a literature saying that if you calorie-restrict a mouse for long enough, you will induce autophagy. But those are all individual strands and the causal links between those strands have often not been tested in a rigorous way. So I would say that we need to learn more and do more experiments to try to understand if that's the case, but you can do that in a mouse, we can do it in a zebrafish or a worm, it's very difficult to switch off autophagy in a whole person's body to do a rigorous experiment, you can't actually do the rigorous experiments in people and so… Experiments on people are restricted in that way.

SS: From what we know so far, let's go through what benefits autophagy could have on humans. From what we know so far. I understand that we don't have a complete research. I tried to ask this question to Professor Ohsumi and he was very evasive, to say the least. So maybe I can get some answers from you. For instance, I have a colleague who is crazy about autophagy and she is actually adamant at telling me that her teeth got completely healthy after she started practising autophagy. Is something like this possible or would you say it's more psychosomatic?

DR: Well, autophagy influences many different systems in the body. So its roles are to protect against starvation. Its roles are to prevent the growth of certain organisms in tissues, so it has certain anti-infective properties. It can reduce inflammation, it might be relevant to your friend’s teeth. It protects against certain neurodegenerative diseases by stopping the accumulation of proteins that tend to clamp in the brain that cause various dementias. It can affect certain autoimmune diseases by reducing inflammation. It can be protective in heart disease. So it has a wide range of benefits if you can induce it in model organisms’ systems. And if you impede it in mice, for instance, then you can create a whole lot of manifestations or make many of these disease models worse.

SS: Do I understand correctly, primarily it is because it's anti-inflammatory?

DR: No, that's one of its properties. I think it’s possible that the anti-inflammatory properties might have much more widespread implications across a range of diseases than some of the other more specific roles. But I think they are quite good data, for instance, in neurodegenerative disease models, that if you switch on autophagy or you amplify it, then you can protect against certain diseases.

SS: Like Alzheimer’s, Parkinson?

DR: There is data with those types, or it’s types of those types of diseases. I think, yeah.

SS: I've heard somewhere also that it could help things like bone fragility? Is this a myth?

DR: No, some of the autophagy machinery can affect the bone fragility. And I think those were older studies, and it's not clear today, whether they are specific to autophagy or just part of the machinery.

SS: David, what about the brain itself? I'm not talking about degenerative diseases like Alzheimer's or Parkinson or dementia, but how does it affect our brain if it could be practiсed on a human body?

DR: So there's a literature which suggests that autophagy might be important in a whole lot of neuronal functions. It can remove various toxic proteins, as we've discussed, it can also help remodeling, so it can change our capacity to remember potentially. There's also literature that suggests that it might impact various psychiatric diseases, although the literature will then need more work. So I would say that these suggestions need further work to validate, so I think it might affect a wide range of different cognitive as well as emotional functions.

SS: And I'm thinking cancer because you're saying one of the functions is to anti-inflammatory function. So what can it do for cancer?

DR: So the cancer literature is complicated, and it likely plays different roles at different stages of cancer. So if you have an organism, which has a lack of autophagy, then it is more prone to the initiation of a primary cancer. But what happens and what frequently kills patients not the initial primary cancer, it's after it spreads to other sites, it's called a metastasis. And when you've got metastatic cancer, then it is believed that autophagy protects the cancerous cells from dying. So then you want to inhibit autophagy.

SS: Okay.

DR: So that's sort of a slightly simplistic view of the situation. But it's meant to illustrate that at different stages of the cancer, and potentially from one cancer to another, it has kind of different effects. So it plays roles, but I think they’re complicated.

SS: You said something about a human organism that has less autophagy or more autophagy... And that's very interesting to me because in our talk with Professor Ohsumi, he also said something about it, that autophagy is governed by genes –

DR: Yes.

SS: – and that it's part of our design:

<Yoshinori Ohsumi: If you have the ATG gene that means your cells have those kinds of machine to turn off their own proteins.>

SS: So what like if I have wrong genes I can't trigger autophagy?

DR: It's very interesting. So there are some very rare cases, very unlucky people who have mutations in core autophagy genes, so they have very little autophagy. And they have an early-onset brain disease, a neurodegenerative disease. So it is governed by genes and when there's severe dysfunction, you get those types of diseases. It is possible that there are variants which have very small effects, which we don't understand in terms of their population impact.

SS: Does the lack or the opposite of autophagy in one's body has anything to do with the immune system?

DR: Yes, I think it does, and particularly in terms of the inflammatory process, but there are other immune functions that are also quite tightly regulated by autophagy.

SS: And at some point, someday, if we learn how to trigger autophagy in our bodies and actually, you know, exercise autophagy to better ourselves, does autophagy level in your body grow with time, with exercise, like muscles grow when you exercise in a gym, or your brain cells?

DR: Do you have a memory for it in a sense?

SS: Basically.

DR: I'm not sure if anybody's really looked at it. That's quite an interesting idea whether you could sort of, in a sense, prime yourself to respond better to – So I don't think anybody's looked at that. I'm not aware of that, let’s put it that way.

SS: Here's a tip, you should look at it.

DR: And should do more experiments on that.

SS: You should get a Nobel Prize for that. So you said except for the calorie reduction, there are other ways to trigger autophagy. Can exercise trigger autophagy?

DR: Exercise can trigger in certain circumstances, certain types of exercise – in the muscle, for instance. I think you can, again, if you make mice do certain types of exercise, it can trigger autophagy. And I suspect in people if you do certain types of exercise you’ll trigger autophagy. But when one reviews the literature, again, it's a little bit mixed. And I think the reasons why it might be mixed – if you’re healthy or if you’re sick, the type of exercise. And then many of these studies haven't been done in people, they've been done in mice. And so you know, translating what you got in a mouse to what you've got in a person needs a different type of experiment, it's worth having another look.

SS: Here's what I understand: from what we understand about autophagy now, it can be an answer to a lot of things, cure many diseases or prevention, at least. By the way, do you think it's more prevention or curing?

DR: I think it's often more prevention, I think delaying the onset, you've got a better chance with diseases. It's possible, you might be able to – it’s very difficult to cure diseases, there might be some infectious diseases, for instance, which might be amenable to autophagy, as one among a number of agents, maybe in combination, can help in to cure but many cases it is protective prevention.

SS: So back to my thought. What I don't understand is that you have this goldmine theoretically,  that we're sitting on – autophagy that hasn't been fully examined or practiced on humans, but it could be an answer to a lot of things, right? You're saying on mice, we know what happens. On humans – we don't because it's very hard to practice or experiment on humans. So there's this gap between mice and humans and what are we gonna do with it? I mean, are there any plans or any methods to actually do experiments on humans? Or are we just going to sit there forever and talk about literature?

DR: No. Look, it’s a fairly new field. I think, you know, when I started working on it, at the turn of the century, we knew very little about the genes in mammalian systems. So in 20 years, we've got a fairly good idea about the genes. You know, we and others are starting to try to look at ways that we're able to assess, even if it's indirectly, what is going on autophagy in different tissues in humans. So already people are looking in their blood. And I think we will have to start looking in other tissues or correlates in other tissues that will be informative in order to answer those very important questions.

SS: So you just think it's a question of time until we actually have –?

DR: It’s a question time and it's a question of money. But I think people are going to be looking at it more and more in future because exactly what you said that it's a process that has potential for impacting many different diseases and potentially healthier ageing. So I think we do need to understand these processes in humans.

SS: How would a human actually know that he has triggered autophagy? Is there a way of knowing?

DR: I don’t think the human would know. I think one would need to biopsy something. So in the blood, you can just take blood. If you wanted to see what was going on in muscle you'd have to do a muscle biopsy probably. Or you'd have to find a marker, which gave you an indication that autophagy was happening in the muscle, so something less invasive, but you'd have to measure it in some type of formal sense.

SS: Do you know a lot of big pharma are actually starting to look for a drug or create a drug that would artificially trigger autophagy in the human body? I don't know if you've heard about that.

DR: I know.

SS: So I can't figure out, is it a good thing, or do you think it should happen naturally?

DR: I think it's probably a good thing, we are interested in that area. And the reason is that, I think, you'll be able to, probably, it depends which tissue, for instance – So if you want to induce autophagy in the brain, you probably have to starve for a very long time, the brain takes a long time to respond to starving.

SS: Like how long?

DR: We don't know. In the mice, you probably need to starve for close to 24 hours, but you'd have to do it much longer in a human. And so there might be ways that you can activate autophagy in specific tissues much more effectively with the drug, and potentially with much better targeting. So you might be able to induce autophagy in certain places, without affecting other cells as well. So I think that is what people are trying to do. And I think it's because of the magnitude of the effect, as well as the potential to restrict the effect to certain tissues.

SS: So if you look generally at our cells, processes in our cells is what defines our health. Do you think we can ever hope to harness those processes and actually, maybe steer them where we would like them to?

DR: I think that more and more medicine is relying on what we call rational drug discovery. And that is based on the understanding of what's going on in cells. And so if we understand better how cells work, then we can identify pinch points that we can attack in order to switch processes up or down with much better control. And so you have to do right, we need to understand the fundamentals of cell biology.

SS: Are you like in a team of those people who are actually saying, yes, medicine and biology is entering this new breakthrough, this is like an epochal verge and everything is going to be completely incredible, nothing's going to be same again, when we're talking about heart transplants, and drugs for AIDS and cloning, genetic engineering? Are you as enthusiastic as many, or do you think –?

DR: Yes. I mean, it's the way, the tools for understanding biology have evolved in the last 25 years. It's just remarkable. I mean, it's truly remarkable. And, you know, when I was a student, nobody could dream of the prospects of taking human cells and removing every single gene one at a time to see how it affected a particular process. And now those types of approaches are becoming almost routine. And so that gives us the prospect of really understanding the way human cells and the human body works much better than ever before. And we really have technology at our fingertips that would be considered a dream 25 years ago.

SS: Well, David, thank you very much for this interview. Thanks for clearing up lots of myths about autophagy and hope you get that money soon to actually, finance all your research so we can start practising.

DR: Thank you very much.