Bowhead whales can live for more than 200 years – this protein might be why

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Blight so far. Like it sounds so simple. They had no idea. But now the data's... I find this not only refreshing, but at some level astounding.

Welcome back to The Nature Podcast. This time, how bowhead whales manage to live so long. And the search for a universal snakebite antivenom. I'm Sharmini Bandel. And I'm Nick Pertridge-Hall. First up this week, researchers have uncovered a key protein that could help prevent ageing by looking at a particularly long-lived animal, the bowhead whale. A bowhead whale is really...

remarkable animal. This is Vera Gorbanova, one of the team behind the new work that's been published this week in Nature. It is the longest-lived mammal. It can live more than 200 years. And it is the only mammal that lives longer than human. And of course, that makes it extremely interesting to understand the mechanisms, how it can live so long and stay healthy.

Whale is also very large. It's one of the largest whales. And with being large comes other challenges. One of them, how not to get cancer. Because cancer risk is proportional to the number of cells. Whales have a lot of cells in them, but yet they don't develop cancer more frequently. And that's another puzzle.

This puzzle is known as Pitot's paradox, named after the statistician Richard Pitot, who first observed that if the probability of a cell becoming cancerous was constant, then you'd expect those animals with lots of cells... like whales, to get cancer a lot. This isn't really the case, and not just for bowhead whales. Other animals, like elephants and humans, get far less cancer than the number of cells they have might suggest.

A couple of ideas have been proposed to explain this discrepancy. It could be that animals with lots of cells have lots of tumour suppression pathways. This seems to help explain why elephants don't get as much cancer as you'd think. These can work, for example, by increasing the number of cells that undergo cell death apoptosis. By getting rid of more cells with potentially cancerous mutations, you can end up with less cancer.

Alternatively, big animals could have better DNA repair, which could help remove damaged DNA and prevent mutations. To understand how the whales are so long-lived and so cancer-free, researchers have sequenced its genome, which has shown some changes to a range of genes that may help explain it. Ones involved in DNA repair, cancer.

and cell regulation. But the genome doesn't tell entire stories. So understanding really the cell biology is the next step. And our work is one of the first in that direction. Severa and the team looked at fibroblast cells, cells that help form connective tissue. They initially hypothesized that, similar to elephants, bowhead whales may have more layers of tumour suppression. so they tested how many mutations would be needed to cause cancer in these cells.

We had a hypothesis, and it turned out to be wrong, which is probably the most interesting, because if all your hypotheses are right, it would be boring. In human fibroblasts, you need to mutate, introduce five hits. like remove five barriers before you make a tumor. So our hypothesis was that in the whale, we would need to remove even more barriers, maybe six, maybe seven. And that...

how we were hoping we would find additional tumor suppressors. But against our expectation, we only had to remove four barriers, which is one less than in human. And that's where really the most interesting part started. How come they don't get cancer? How come? They seem to be less protected. So Vera and the team turned their attention.

to DNA repair. And this is where we found that they actually maintain their DNA repair much better, so they don't let things... They just maintain it, not remove cells once it's too late, but actually keep it in order from the beginning. The team showed that the whale cells were particularly adept at repair of DNA double strand breaks. These are where both strands of the DNA are disrupted and can be particularly problematic.

as they can lead to cell death if not repaired, and they've been linked with ageing and cancer. So Vera and the team next looked at how it is that whale cells are dealing with this particularly problematic kind of DNA damage. And we turned to... proteomics and transcriptomics and we looked at are there any genes or proteins that the whale cell produces at higher abundance and

There were quite a few that were different. You can imagine you compare a whale to other species, there will be many small differences. But one that really stood out was the protein named cold-induced RNA binding protein. or CRBP. So the CRBP was present in the whale and 100 times greater. amount than in other species so like you can't ignore it there is like so much you can barely see it in human cells and tissues

It's not entirely clear how it is that this cold-induced RNA binding protein, CIRBP, helps fix these double-stranded breaks. But through a few experiments, the team were able to come up with some ideas. Fairly short, very well-conserved protein. And it has this what's named disorder domain. So it can form a protective bubble.

around DNA break. So our hypothesis is that in the whale, because they have so much of it, so it really forms a very good bubble and it protects the ends from degrading while... Other enzymes are repairing the brakes. They were also able to show that the protein helped get nucleic acids that you'd need to repair brakes to collect.

Finally, to get an idea if this protein was really contributing to the bowhead whale's longevity, they modified Drosophila flies to produce a whole lot of it and examined what happened. So that was a very ambitious experiment. We did it in collaboration with Mary Simons, who is a drosophila geneticist. And he found that flies started living longer and they were also much better at repairing DNA damage.

Subjected flies to x-rays and flies die, but those that had the whale protein were surviving better. This protein is also present in humans, although at much lower levels than in whales. and the team were able to show that they could enhance DNA repair with this protein in human cells.

So it does raise the possibility that eventually this process could be harnessed to help humans defend against cancer and potentially even ageing. So one, of course, a very direct way would be... to have some cold exposure because production of this protein is induced by cold. Of course, it's not that I recommend people to go swim in cold water. We don't know exactly what type of exposure would be enough and safe to induce it.

expression of this protein in humans and like in the living human. We know that if we take human cells and put them at a lower temperature for a couple of hours, we see that this protein is induced, not to the same level as in the whale. But it is induced. So now important question is like, OK, if you go and take a cold shower for five minutes, is it enough?

because prolonged hypothermia is not healthy so we don't recommend it. Alternatively, there could be some way to use a drug to induce the protein in humans. This is all some way off though, and right now Vera and the team want to understand more about how this protein works. Ivana Biedov, a biologist who works on ageing and wasn't associated with this new study, was pretty positive about these results. I'm very excited whenever there is a new way.

where you can come around and boost DNA repair high fidelity. Because ultimately, it doesn't matter how many insults your DNA is getting. The important thing is how you deal with it. So I'm always excited when there is a new hypothesis, new ways how to repair your DNA accurately. Ivana does note, though, that this repair will only be really accurate...

also known as high fidelity, if the DNA is broken cleanly. So if your DNA break is messy, it has to be processed and then the joining of the two breaks cannot be high fidelity repair. I think if I would have to protect my DNA, I would also try to prevent the damage as well as making the repair high fidelity as is shown in this paper.

It's likely as well that the whales have several different mechanisms that lead to their long lives. The other caveat that Vera and the team note is that this work was done in fibroblasts. Whereas in humans, cancer mostly starts in epithelial cells, the cells that cover and protect our organs and skin. Although Vera does think that because these DNA repair mechanisms are well conserved, it's likely it would work in these cells too. There's a lot more to be understood here.

but Vera is excited about what her team's discovery could mean for ageing research, as enhancing DNA repair has so far. Proven tricky. One important take-home message from this study is that it is possible to improve our DNA repair because many people say, oh, well... We already have DNA repair. We can't really make it any better, but the whale teaches us that it is possible. That was Vera Gobanova from the University of Rochester in the US.

You also heard from Ivana Biedov from University College London here in the UK. For more on that story, check out the show notes for some links.

Coming up, defending against snake bites may be a little easier as researchers have developed a way to make more universal antivenoms. Right now, though, it's time for the research highlights with Dan Fox. Researchers have developed a new way to grow crystals, using lasers. Many everyday technologies rely on the unique properties of crystals, but growing those crystals can be unpredictable.

To see whether they could standardize the process, this team tested an alternative method of propagation. Instead of using a small seed crystal to attract molecules from a solution, they aimed lasers at nanometer scale gold particles. and found that they could control exactly where and when the nanoparticles organised into a crystal structure. Next, they want to use multiple lasers at a time to carve out more intricate structures and perhaps

create new materials. They also hope to test how their laboratory-grown crystals hold up when used in electronic devices. If that research has grown on you, you can read it in full in ACS Nano. Some female stink bugs grow fungi from an organ on their hind legs and use the microorganisms to protect their eggs from wasp attacks.

found only on the hind legs of females in a small family of stink bugs, was previously thought to be used for hearing, because of its apparent similarity to sensory structures found on other insects. But when researchers took a closer look, They did not find the membranous structure expected for an ear-like organ. Instead, they saw pores that connect to secretory cells. These pores act as a nursery for fungi, which the bugs smear on their eggs.

Experiments showed that this fungal coating forms a physical barrier that helps to prevent parasitic wasps from laying their own eggs in the stink bug eggs. Without this fungal cover, newly hatched wasp larvae could eat the stink bug eggs. from the inside. You can find that paper in science.

written by a venomous snake, your chances of avoiding serious injury or even death depend on getting the right antivenom. If delivered in time, anti-venoms can be life-saving, but they usually only work against venoms from a narrow set of snakes. Now a team of researchers writing in Nature describe how they may be one step closer to producing a universal antivenom against snake bites.

Reporter Anand Jagatir spoke to author Andreas Haugau-Lauston-Keel about the work and started by asking him about the impact of snake bites worldwide. So everyone is aware that snakes exist and that snake bites are a medical emergency and very dangerous. But very few people are aware that it has a very huge impact on global health.

estimated that around 5 million people are bitten by venomous snakes. Many of these suffer quite grave consequences, and around 100,000 and 150,000 people die each year. and around three times that are left with permanent damages, such as amputation of a limb or massive tissue damage. Are there particular species of snakes that are most relevant when we're talking about these numbers? It's more than 200 different species of venomous snakes that are...

considered medically important for humans. But among those, the so-called vipers and the so-called elapids are responsible for the majority of all the bites and deaths amongst humans. Vipers It's perhaps the largest group, and that includes rattlesnakes. And the other group, the lapids, includes the copras, the mambas, the coral snakes, and the sea snakes. And what is it about the venom from these snake species that makes them so dangerous?

The vipers often cause a lot of tissue damage, hemorrhage, and interference with your blood's ability to coagulate. If you look at the elapids, many of them have neurotoxins that go in and block your muscles' ability to move. This will paralyze the person or prey. So when you dig into what venoms are composed of, it becomes a very complex picture with probably several thousand.

medically relevant toxins for mammals and therefore also for humans. So the fact that you've got all of these different species of snakes that have... different kinds of venom and within each venom you've got you know all of these different toxins that acts in different ways that presumably means creating an anti-venom that is going to work across many different types of bite is going to be very challenging.

Exactly. Until later years, the prevailing view in my field has been that constructing... Broad spectrum covering many species of snakes, antivenom will just be too complex an endeavor. It will require too many components. Manufacturing will be too expensive and challenging, and it just won't be feasible.

And part of that also has to do with the way that antivenoms are currently made, which if people aren't aware of, I think they might find a bit surprising. I certainly did. Could you walk us through the way that we currently do things? The antivenoms that are currently... you could say on the market or in the clinic, they are without exception all based on antibodies that come from the blood plasma of immunized animals, which is typically horses or in some cases sheep.

You take several different venoms and you give increasing doses, but start very low so you don't hurt the animal. But the animal's immune system will see these toxins from the venoms coming in and recognize them as foreign. And that will provoke the animal's immune system to make an antibody response.

And ultimately, you end with that mix of antibodies isolated from the plasma. And the good thing about this is it works. It can neutralize snake venoms. And it was a breakthrough technology when it was invented 130 years ago. However... We are also 130 years later in history. Yeah, I mean, it does sound like quite an elaborate and complex process. What are some of the downsides of the antivenoms that you make in this way? Yes, so some of the downsides with them is, of course, that...

They are based on undefined mixtures of antibodies coming from horse or sheep. So these components are also foreign in the human body, and our immune system will react to them. In some cases, they can elicit severe allergic reactions.

Then there's a limit to how much blood you can take out from a horse. So it is expensive to manufacture antimembs. You both need to have the snakes in captivity, milk them, and then you need to immunize many horses. And then the last thing is that given that you use these...

mixtures of venoms and you immunize a horse. Many of those venom components are maybe not medically relevant for humans. So you get a bit of an unbalanced composition of these antivenoms that yes, they work, but it's a low content of what you would call therapeutically relevant.

And that means that you need to give very high doses. So in the paper, you describe a different approach that gets around some of these issues. And rather than using a horse or a sheep, you actually used an alpaca and a llama. and that's because the antibodies that they produce are different to the antibodies that you see in most mammals, and they're called nanobodies. Could you explain what a nanobody is?

A nanobody can do many of the same things as an antibody. They're exceptionally stable, they are very cheap to manufacture, and they retain all the same binding capacity as a regular antibody. You know, that's maybe not enough for all types of diseases, but for something like snakebite, then a nanobody can do a very good job. So what was the process of getting the nanobodies that you wanted from...

the alpaca and the llama, and then turning that into an anti-venom that you could use against snake bite. We thought a lot about how best to mix the different venoms to encourage the llama and the alpaca's immune system to make as broadly. neutralizing nanobodies as possible. And then once they were immunized, we then isolated some of their white blood cells that produce antibodies. Then we can just work with the DNA and then we don't need any more llamas or alpacas.

Then they are pensioned, and I'm told that they go to a petting zoo somewhere and spend the rest of their llama life or alpaca life there. And then, of course, when we found the sequence that encodes the best nanobodies, then we can stick the gene into... A host cell and it spits it out in very high yields and you can grow it in a bioreactor and mix your different nanobodies so you get the most optimal ratio. And so with this process then, you were able to create this...

relatively simple cocktail of just eight molecules. How did you go about testing that and how well did it perform? We ended up... testing against all the 18 medically most important elapid venoms from Africa, tested them in vivo, so into mice. And not only did it work, it covered...

almost all the species. We need an extra component against one of the green mamba venoms, but it had exceptionally broad coverage. We did include an antivenom that's on the market, and at least in our tests here, it looked like it performed better.

And we also tested against dermal necrosis, so that's when the skin is destroyed by snake toxins, because that's typically one of the things that existing antivenoms have a hard time fighting. The nanobodies actually... more effectively neutralize the locally acting toxins.

So it sounds like you've been able to achieve a couple of different things in this paper. One is that you've been able to demonstrate you can actually make a broad spectrum antivenom that actually works. And the other thing is that your approach allows us to potentially move away from this.

This elaborate, complicated procedure of having herds of horses and, you know, a zoo of snakes that you have to milk. That sounds like a pretty big step forward from where I'm standing. I mean, how would you characterize the implications of this work? We don't expect that our mix is, you could say, completely perfect and optimal. But the difference here with our work is that here we actually make something that's kind of product ready. We haven't cherry picked species. We've actually taken...

the 18 species that it has to cover and developed it against that. I, of course, particularly hope that this work will pave the way for better treatments and therefore better snakebite management globally. This has immediate utility for antivenoms against all venomous animals. But I also hope that others will look at this and say this was neat. This was actually quite a useful way of developing complex biotherapeutics.

against complex disease targets in general. That was Anand Jagatia speaking to Andreas Haugau-Laustenkiel from the Technical University of Denmark. For more on that story, check out the show notes for some links. And that's all for this week. If you fancy keeping in touch, you can. We're on X and Blue Sky at Nature Podcast. Or you can send us an email to podcast at nature.com. And if you've enjoyed the show, why not let us know? You can leave a review or a comment on your podcast.

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