The Art of Daily Genetic Tikkun

Alex Braver: I am lucky to have next to me Dr. Robert Shalwitz, founder of Invirsa, Inc., who’s going to be speaking both about – and we’ve had the pleasure of chatting with you about this on and off for the last couple of weeks, and also a couple of months – both the sort of scientific, I think – your expertise is the scientific background behind how our DNA repairs itself over time, which as we talked about it, I was like, I had no idea. “Your DNA is messed up, you’re in big trouble.” And also a little bit of sort of how that connects to your spiritual life and the idea of tikkun in Jewish life. So I’ll let you do most of the talking, but I’m very glad to be having you close out our Scientists in Synagogues series.

Robert Shalwitz: I’m Bob Shalwitz. I happen to be a pediatric endocrinologist. For those of you who don’t know what an endocrinologist is, I studied hormones, and I took care of young children with things like diabetes, thyroid diseases, adrenal problems, things like that. But then, amazingly, in 1995, I decided to take a job with Abbot Labs here, and I became a drug developer. So I actually developed drugs, pharmaceuticals, for good purposes. I have a couple pharmaceuticals that probably one of you, or maybe more of you, have taken. And I’m very proud of that work. And I’ve remained in this space of working on it.

But when I was there at Abbot, my team discovered a really exciting compound. And at that time, we started getting very involved with thinking about things related to DNA injury, because of how the compound worked. And that’s kind of motivated a lot of my career since about the late 1990’s. I’ve been working on this for way too long.

So, that’s me. I’m fortunate to be here with my principal consultant, who happens to be my wife. Paula’s here, and she’ll interrupt in case I go far astray.

Let’s start with some questions. Here are four questions. Take a look. I’m just going to give you two seconds to think about it before I go to the answers. Think about all the things you’ve learned about DNA. What exactly happens to a cell when DNA gets injured? And does this happen often? Is this something that really happens every day? And by the way, is the cell always successful in repairing its DNA? Tough question.

What is the purpose of DNA? You’ve all learned about DNA in school. DNA is the essence of why we are able to be a multi-celled organism. Without this, you don’t age, you don’t replicate, your cells don’t replicate. You cannot become this incredible multicellular organism that you are. But whether you’re a two-cell organism or not, you need to have a way to provide information beyond. Cells without DNA, which include some things that don’t have DNA, which really have a rough time, and really cannot build in terms of their ability to build as an organism. So, it’s the key to having multicellular organisms – the key to being human.

DNA Injury

What happens to a cell when the DNA gets injured? What things can happen? You all know that DNA is a double helix. You all learned about that, probably, in school, or maybe you didn’t. But in any case, there’s a double helix, and that contains all this amazing information for every protein that’s in your body, how it’s structured. And so, what happens?

“Can I ask what you mean by the term ‘injured’?”

Injured? Oh, let’s say it gets broken apart. That’s called a double-strand break. And can it come back together? Interestingly enough, when you break apart DNA – DNA has all these codes in it. And these codes, if you double-strand break it, which happens with radiation, which happens in the case of certain types of chemicals, which can just happen spontaneously, because of all sorts of oxidative injury – you could lose huge amounts. So when it puts that helix back together, what if you lose all that information? What if it’s gone? Will the cell keep going?

Well, it turns out the cell will keep going. And this happens, actually, not infrequently. So we’ll keep going. So DNA can get injured – it happens all the time – and the cell will attempt to repair that DNA.

By the way, if you ask your typical doctor what happens when the DNA gets injured in a cell, that doctor, most commonly, will say that the cell dies. But how often does DNA get injured in a given day?

So, this is the average one cell. How many cells do you have? You have 3 trillion cells in your body, not including the bacteria in your body. You also have, by the way, about 4 trillion bacteria. So, 20,000 events – this is for a typical cell in the body. It turns out that some of your cells have much more. Your eyes – there are a lot more events in your eye, particularly the front of your eye, because of course, the eye is exposed to ultraviolet radiation. So in fact, your DNA gets injured all the time in your eyes, and it has to be really good at repairing it. In fact, it is very good. And thank goodness, because in your skin – you can shed skin, because you know your top layers of skin are already dead. They’re just there. They’re contiguous, but they’re already dead. And they have to absorb the punishment from outside. All the stuff that you run into – physical injury, chemical injury, radiation injury, all those things. But in fact, the eye doesn’t have that luxury. Could you imagine if the cells of your eye were always being shed off of the cornea, off the front of your eye? You wouldn’t be able to see a thing.

So it’s a really remarkable system. We continuously repair the DNA so that we can continue and go on, and still replicate and age. Is the cell always successful? Well, of course, you know, the answer to that is no – because one, we don’t live forever. That’s number one. Number two, we know people get cancers; we know that, eventually, mutations can occur. The other thing is, we all know that we age. And the principal cause of the aging, actually, is accumulated DNA injury. We’re going to talk mostly about that today.

But these are the kind of basic concepts you have to start with, because I have to tell you, most people have never thought about this. Why would you? “What happens to my DNA?” Oh, my God. But anything you can think of can happen to your DNA. And when you lose those signals, then all of a sudden, whatever it’s encoding is no longer encoding correctly. So, the issue of DNA repair is very, very important.

Single and Double-Strand Breaks

Just to give you an example, this is out of an amazing paper that I sent to my whole team recently, and I don’t expect you to understand it, but there are some very cool things here, on this curious slide – just to back up my comment – this was just published, looking at a whole series of things about DNA injury. So, SSB stands for “single-strand break.” That’s over out on the right side. And then on the left side, you see double-strand breaks.

So, you see, thankfully, that double-strand breaks don’t happen very often. Single-strand breaks you can repair, right? It’s just broken. You have a template there. That’s the beauty of it being double-stranded. There’s a template – you can repair to the template. But double-strand breaks are broken apart, and then you have to go back and compare to the other chromosome, the other gene, that’s on the other chroma. Remember, we all have pairs of chromosomes. So, very complicated.

There are lots of things on there. I just wanted to show you all the different names, things that can happen to all those base pairs and things like that. One of the things that’s on there is this very inconspicuous-looking one called 8-oxo-G. This stands for “oxidation injury.” You all talked about, everyone talks about eating antioxidants, right, like vitamin E? Well, actually, vitamin E and lots of antioxidants are very important for minimizing the number of 8-oxo-g events that occur. These can be incredibly destabilizing for the chromosome, for the genes.

So it’s just an interesting array of stuff. Photodimers from sunlight – why do people tell you to wear sunglasses? It’s to prevent against this type of injury in your eyes when you’re outside, and lots of other things. This is something that’s happening all the time. And you’ll notice, by the way, that these are all with superscripts. So 10³ stands for [a number] in the thousands. And so you can just see how many. And for depurination, which is another interesting form of this, and single strand breaks for your typical cell at the right, those are 10⁴, that’s 10,000. It could be 100,000 per day. A complicated space – but I’m dwelling too long, so I’ll keep going.

So what happens with all this? Remember, I said that DNA injury is, in fact, probably the major cause of aging. So it seems a little unlikely. You would think, “Aging, gee, I’m just getting older. My cells are getting older, so they’re not working so well,” right. But why aren’t they working so well? We all want to wonder, why is my hearing no good? Why is this something else? The major reason for that is that, even as good as your cells are at repairing, you start to accumulate injury within your whole DNA substructure. And if this becomes too much, then in fact it’s not working as well, and you accumulate problems. So DNA damage is a major cause of things.

And you can see on there, on the slide, it says “cellular senescence.” That means the cells stop replicating. So, think about muscles. If they don’t replicate the cells, you can’t repair them. You can’t get enough cells. If you go and hit it, you can’t repair it, because you can’t replicate it anymore. Or your whole energy system may not work. So particularly, diabetes is related to DNA damage and a lot of other things. So, complicated space that you’re not typically thinking of. Everybody just thinks, “Well, we just age, right? We just get older.” No, you don’t just get older. You get older for a reason.

So, this kind of helps you to understand it. My idea was to give you pictures of what’s going on, because to get into the really deep, dark science of DNA repair is a tough space – it’s very complicated. I will have a slide on very single detail you ever wanted to know. I won’t take you through it. But it’s the idea: you accumulate DNA damage, and you want to avoid that. And the way you can avoid that is by DNA repair. So you see that aging – there’s this little green arrow. You want to repair DNA damage. You see the red bar there? That’s the idea that if you have good DNA repair mechanisms, you can repair that damage, and your cell can go on. It can replicate, and it can go on to produce another good-quality cell, and it can continue to perform its job.

For a minute, we should stop and think about the brain. The brain doesn’t replicate much. If your cells were constantly replicating, you wouldn’t remember. It does replicate some. It’s very slow. There are lots of actual places in your body where cells don’t replicate much. The brain is very protective. It’s in the crazy head of yours, which is a lot protected. There’s no sun coming in. The only sun that’s coming in is through your eyes, and that only gets to the retina. But the brain is well-protected, and that’s great. It’s also very protected from chemical injury because of the way the bloodstream is designed. And thank goodness for this, because if our brain had so much DNA injury – which, it still has some, particularly, let’s say if you become hypoxic or you get knocked out, like a car accident or playing with football, many other things – then it’s actually pretty tough on the brain, because you don’t have lots of extra cells to bolster the response.

So, the brain is very good about this, so its number of injuries per day is probably quite a bit lower. And there are other places in the body where it’s quite a bit lower too. But anyway, if we can improve our DNA repair mechanisms, we could age better, we could live longer, and we could have less problems while we’re aging – maybe less cancer or maybe less infection, because we know how to fight off infection better. That would be the benefit if we could do it better.

Damage to the Body

So where would in the body would the most damage happen?

Well, actually, the eyes are the worst, because there’s no physical protection. The next worst – the skin, actually, is quite bad, because ultraviolet radiation penetrates right through those dead cells and goes right to the actual living cells. You’ve only got a few layers to protect them. The radiation goes right through.

And then the gut is hugely impacted. But the gut can turn over cells. The gut is really good at getting rid of cells, so it actually gets rid of cells very aggressively. A lot of what’s in your poop is cells that have died, because there’s a huge amount of turnover.

And then everything else depends. The heart, by the way, does have quite a bit. Particularly as you get older, your ability to pump blood is not as good. The lung is another place that has a fair amount. You are inhaling lots of stuff. The second largest killer in the world right now is respiratory disease, and lung disease is huge across the whole globe, because of increased pollution and lots of other things that are going on related to plastics and a lot of other things around the globe. So, DNA injury comes from all sorts of stuff – things you wouldn’t expect. Thankfully, the brain has not gone. The heart, though, is tough – it’s a big place.

So, are there things you can do? So, yes, you can get online and you can read about a zillion things that you might be able to do. And I will tell you, just to be honest with you, the data is not good in terms of “Does diet improve it?” Yes, there are certain little unique elements in diet that are really important – certain micronutrients, some other things. The problem is, it’s hard to do those studies because these are 20- and 30- and 40-year studies, so the data is not going to be overly compelling. But in the lab, the data actually is pretty good for a lot of very good elements. So, yes, you should really eat your vegetables, by the way. It’s really important. And you really should stay up on what you’re doing, and you should stay well-hydrated, and you should do things to avoid getting cardiac disease, because what does the cardiac system do? It protects the whole body from oxidative injury and things like that.

And the data on exercise is actually the best. It’s better than the data on diet, because it’s really hard to control people’s diets over 30 years to really do this type of study, but exercise is actually better. So good, consistent, moderate levels of exercise – there’s actually very nice data showing that you can age better. Not super-severe exercise – marathon runners are a whole nother world, and that’s not really where the great data is.

But in the end, you’ve still got to have that DNA repair. So this is one thing – can we do it better? This is a beautiful article, by the way, from the British Medical Journal, just the other day.

So, I’m going to now walk you through the entire details of doing DNA repair. No, I am not. One of the cool things about DNA repair that I discovered, which I thought was so great, was that it’s amazing how many different ways you can repair DNA. Every little thing that can go wrong with your DNA can be repaired. It’s actually pretty incredible.

I was feeling lousy, but now I’m feeling better!

You should! Because you are feeling better because you keep going and doing this stuff. So the body is really incredible. It’s developed multiple systems in order to repair your DNA. And there is no “but” – I mean, it’s just a great thing, but it’s not a perfect system. And the most difficult one, in the right corner, these double-strand-break repairs, where essentially the systems have to go and compare to that other chromosome so it can rebuild the whole latticework of the DNA. And this can happen, but it’s very energy-intensive. One of the big things that your body does in terms of – everybody thinks of just pumping blood, that’s where you mostly spend your energy, and thinking. But in fact, one of the biggest things you do is DNA repair. It’s a huge consumer of energy that allows you to keep going on a day-to-day basis. So, you should really feel good that it’s possible to repair your DNA, and that you can keep going.

And most of the DNA repair goes on at night, when you’re sleeping. And the reason is because there are certain things that help with the cycling of sleep. And actually, one of the proteins we’re going to talk about, which is this protein called p53 – which is my baby, that I think about all day long – works in cycles, and it actually matches up. So, at night, it actually stimulates your DNA to repair the most.

The Best-case Scenario for DNA Repair

So what are we trying to achieve? What is your DNA trying to achieve in your DNA repair? It’s trying to achieve this kind of beautiful match of a healthy lifespan – so you live to be 80, hopefully, although, can you live to be 80 and feel good about where you are at 80? And, yes, some things eventually will break down, but that you’re not just aging with pain, or you’re not just aging by losing: “Well, I lost my brain, but I’m still aging.” That’s not a high quality of life, right? So it’s maintaining an optimal lifespan, which, in humans, as you know, the average lifespan right now is about 82, 83 years old, which is actually a long time – not as long as turtles. It doesn’t give me much. But we take what we get, and we try to do our best.

The other big killer is tumors. So, I thought I’d talk a little about tumors. And why do people get cancer? Who here has heard about BRCA? Everybody’s heard about BRCA. BRCA is Breast-Related Antigen 1, or BRCA-2. So when you get inherit BRCA, if you happen to be unlucky, what are you inheriting? You’re inheriting a mutated BRCA, not a normal BRCA. By the way, BRCA is critical for double-strand break repairs. That’s what BRCA does every day for all of us, all the time. But people who have an abnormal BRCA are usually only missing one. They have a mutated BRCA, and it just doesn’t work very well.

So in any case, with tumors, when you get a tumor, does it happen because you just have a BRCA gene, or does something else happen?

So here’s a quiz. If you were to go look up online any tumor, how many mutations do you think you would see in the typical tumor cell line that you would see online? How many do you think you’d see? Thousands, typically, but they’re usually in the range of 20, okay? And these are 20 major mutations. And those mutations didn’t happen at the start. They were acquired. So what happens is that if you’re a BRCA and you don’t repair your double-strand break so well, you can get a new mutation, and that’s what often will cause it. And one of the more common things that gets mutated is p53. And so you’re not able to actually repair your DNA as well. And that’s how you get tumors.

And tumors happen for lots of reasons, but it’s mostly because the DNA gets injured. And on top of your predisposition, sometimes, of getting a tumor, then you get additional genes that get damaged, and then you’re not able to stop a tumor from happening.

p53, the Guardian of the Genome

Okay, so I just thought we’d take a break on that because everybody worries about this. And so I just want to make it easy for you to understand about tumors. Right now you know everything. So p53’s job is to be the “guardian of the genome.” It’s an amazing compound protein that we are fortunate to have at least one pair of. There are other types of animals that have more than one p53. And it balances the whole phenomenon of health span, tumor suppression, and then minimizing aging acceleration. You want to get the right blend so that we don’t all die of – you’ve all heard of that disease that causes you to age very fast, progeria disease. But there’s a specific gene there that causes you to age quickly. So we want to age reasonably slowly, with high-quality function and not getting tumors, so that we can continue to be.

And that’s the job of this thing called p53. And p53 strikes this amazing balance. So when a cell – it strikes the balance of getting the gene repaired. But if it’s really bad in a cell and it can afford to get rid of that cell, then it gets rid of that cell. It says, “I’m going to give it a signal to commit suicide.” And cells commit suicide all the time, just so you know. This is something called apoptosis, that they just do, and they’re doing it for the benefit of the good, for the benefit of the body. So, in your gut, that’s a place of apoptosis all over the place. And there are other parts of the body which have very high levels of apoptosis. So, it’s a beautiful part of trying to balance this whole thing.

At night, you ought to think about this: when you meditate, just before going to bed, just say, “Gee, you want to give good –”, give whatever your view is, karma or something like that (that would be a non-Jewish approach), but whatever way you want to think about that. You want to think about high-quality DNA repair because it helps to achieve that benefit.

Are you saying if you think about it it might happen? There’s no conclusion, but if you sleep better, it will happen better.

That’s what I wanted to ask.

Does this repair mostly go on when you’re in REM sleep?

No, it’s not just that. It’s just that other energy is now not being used for other things as much, so you actually can channel your energy toward DNA repair, particularly when you’re sleeping. In somebody who doesn’t sleep well – it does not go as well. You don’t just get as much of it.

But it’s very cyclic. p53 goes in 12-hour cycles. It’s not just a single 24-hour cycle. We have lots of proteins in our body that go in cycles. Proteins just don’t stay all the time at one level, they’re constantly moving. Why do you think that proteins particularly cycle all of the time? It’s to allow them to sense what’s going on. If the protein is always at one level, it can’t sense what’s happening in your cell. So by going up and down, your body’s able to do that. There are proteins that go in six-hour cycles, 12-hour cycles, 24-hour cycles. There’s even stuff that probably goes in seven-day, weekly cycles or more. So it’s very cool – your body is a very cool space.

So, this is what the p53 is doing. And this is the thing that I actually study, which is p53, because I want to see – can we help to do this better, and particularly in the eye, which suffers from a lot of DNA injury?

And just to kind of walk you through one last way the key of DNA repair is to age gracefully: so you’re really trying to help the cell make the right decisions. Your body is trying to help the cell make the right decision to protect against cancer, to not lose too many cells, to only lose enough cells so that you can replace them. And then what you also want to do is retain functionality of the cells that you want to keep, which is most of your cells. You want to keep them at the highest- functioning level. That’s the job of the whole DNA repair system.

There are some other things that go on here that p53 controls, and one of the most interesting parts that it controls is not just the DNA repair, but there’s a curious thing that has to happen when you’re going to repair DNA. If you’re repairing your DNA, is that a time you want to replicate the cell and make a new one? Any guesses? No, you want to wait, right?

So the same thing, this p53, controls that cell cycle, so it’ll actually slow down your cell cycle. So that gives it time to repair, because the repair process doesn’t happen just instantaneously. And particularly if you have a big break, a double-strand break, you need time to do it, so it takes more than just a couple of seconds – in fact, it takes minutes. It takes a lot more than a few minutes in order to achieve that, if you have a bad break in your DNA. The other thing is [that it] gives time for the p53 to survey your entire genome. So p53 teams up with a whole bunch of other p53s – in fact, three others – and it produces this quaternary p53 that actually surveys your genome for breaks. It’s a very cool process. And this is just going on all the time, to really make sure you’re in an optimal state.

What Can We Learn from Elephants?

Remember I said we could do it – it’s possible that we could do well, maybe that little extra boost of p53 might do it. In fact, there were a whole bunch of experiments in mice to try to produce super-p53 mice. And they did achieve it, in fact. But when they first did it, they just got more of the protein to be around, without all the control elements for p53. In fact, those animals did not do well. But when they got all the control elements in place and were able to implant super- p53 mice, in fact, they aged normally. So they don’t necessarily age longer. But what they did is [they] aged better. They were more tumor-resistant, and they were more resistant to infections. And in fact, there’s an animal –  one of my favorite animals in the world – that does this all the time. Elephants, in fact, have twenty p53s. They’re slightly different from each other, but they have 20 of them – so elephants, by the way, get almost zero cancer, so they age longer. They’re very big.

Well, if they’re not poached and killed, in fact, the elephant lifespan is as long or longer than a human’s. But they’re living in a very different environment, typically, so it’s pretty hard to judge elephant lifespan length. But they’re really in the 75-85 zone, generally, in the wild. So it’s pretty incredible. So, they actually have 20 of these genes, and it’s very cool that they can essentially do that. And they also are very resistant to viral infections. And that’s because viruses manipulate the DNA, and they also manipulate p53 in lots of ways. You may have heard about this theory of COVID causing excessive aging – one of the theories is because COVID actually suppresses p53, and that may be one of the reasons why COVID causes this late COVID syndrome that people are calling kind of an excessive aging. And that may be one of the major reasons for that. But in any case – we’re not going to talk COVID today. That’s not the goal. But it was just to give you a very recent example.

So, elephants are cool – I think they’re really an amazing animal. And so Paula and I, and Isaiah, were out bathing elephants a few weeks ago. It was actually a pretty amazing experience, in Thailand, because we were doing a p53 study in Thailand with our drug. And we were at this elephant sanctuary. It was actually an amazing experience. I don’t know how many of you have been up right next to an elephant, bathing an elephant. It’s cool.

This is an Asian elephant, which is small. So his back only goes up to about 9 ft. You know, an African elephant would be in the 11-12-feet range. So, it was a very cool experience.

Bringing It Back to Tikkun

So, I wanted to get back to this. So that’s really the story about DNA repair. Obviously, I didn’t give you all the nitty-gritty details because I don’t think any of you want to know them, but it is an amazing idea. I think that whole concept of surveillance, and all the time, looking for the little things is, I think, a great way to think about tikkun and tikkun olam. It’s not necessarily how tikkun olam was particularly originally defined, but from a standpoint of this concept of constant surveillance and looking around, I think it’s something we really don’t even appreciate about our bodies, how constant it is that our body is always looking for problems and always trying to repair those problems. We do not wait for a catastrophe. Most people think of the catastrophe – “the leg is broken.” Oh, yes, that’s certainly a big-time repair that has to happen. But most of the repair that happens when you break a leg (I’ll just use a leg as an example) – what is most of that? Most of that is replicative repair. The only way you got to that replicative repair of your leg is because you had been repairing your DNA all along. If you had not, you would not be able to repair it. So, it’s a really cool concept that allows you to adapt to the moment of the catastrophic change by being in great shape so that you can actually deal with it.

So to me, that’s a very cool concept, and I think it’s really one that I like to think about as I try to approach my little space of humanity here. So that’s the only type of thing. I just thought now, after that little preaching, I thought I’d talk about my drug for two minutes. So we identified this drug back in around 1998 with my team at Ross, which is now called Abbott Nutrition. And we were interested in a compound that could help people getting radiation therapy to their mouth, because they were getting what’s called mantle of radiation for Hodgkin’s lymphoma, or something like that. So they would get all these horrible sores in their mouth. So, could we develop a nutritional product that could treat that problem?

And we did. We identified this compound – it’s a very specific compound – I could tell you what it is, by the way, because it’s called ADP, adenosine diphosphate ribose, which you can all go look up. But ADP ribose is fundamental. We didn’t know it at the time, that it’s totally fundamental to the whole process of DNA repair, in a very, very complicated way. But the cool thing was we were able to take some animals, and give them a little bit of radiation injury in their mouth – in fact, just literally put it on there topically. And in fact, sure enough, we were able to reduce the amount of radiation injury that those animals got. And it worked also for radiation on the skin, but unfortunately Abbott didn’t want to pursue it at that time, so that’s a whole nother matter.

So I licensed the rights and I decided, after I had had a few other day jobs for a little while, that I would come back to this and see if we could do something. So we didn’t understand how it worked. But what we learned over time was that by having this really great little feedback modulator – natural modulator – we could actually stimulate the pulses of p53. Not long-acting pulses, but short-acting. We only wanted short-acting pulses of p53, and that’s because if the p53 gets activated for too long, that’s actually the signal to tell your cell to commit suicide, to cause apoptosis. So we wanted to bolster the little blips to induce DNA repair. And that’s, in fact, what we do.

So we’re right now doing trials around the world with little drops of our little compound, called Inv-102, to actually improve eye repair – like from dry eye, which is mostly from ultraviolet radiation. And we’re going to be looking at other diseases, something called Fuchs’ Corneal Dystrophy, and infections of the eye, and things like that, to really see if we can help people recover from these types of problems. So that’s my drug, Inv-102. It’s a very cool thing.

Alex Braver: I think the connection to the model for Tikkun Olam – the mystics saw the human being as an olam katan, right – as a sort of small world within ourselves, and as a model for the broader world of the cosmos. And just on a basic sort of human level – I think I said this to you earlier – we have the traditional blessing of asher yatzar, that we thank God for making us with wisdom, and that if one little thing that were meant to be open were closed in the body, or one that was meant to be closed were open in the body, we would fall down flat. And it works both on any capillary or vein, and also any one gene or one protein or one compound in the wrong place at the wrong time, not functioning in the right way – it really fulfills the meaning of that blessing. And I think sort of getting to see how it all works, for me, helps to have a greater appreciation of the human body and the miracle that we’re even able to be here.