Science Friday - CRISPR-Based Sickle Cell Treatment | Pain Tolerance From Neanderthals

Episode Date: November 3, 2023

If given final approval by the FDA, this sickle-cell treatment would be the first to use gene-editing CRISPR technology on humans. Also, gene variants inherited from Neanderthals can impact pain tolerance in modern humans.  FDA Panel Clears Way For CRISPR-Based Sickle Cell TreatmentAn FDA committee cleared the way for a revolutionary cure for sickle cell disease this week. If given final approval, the treatment would be the first to use CRISPR gene editing in humans. Sickle cell disease is caused by a genetic mutation that causes blood cells to develop into crescent or “sickle” shapes. The extremely painful and often deadly disease disproportionately affects Black and African American people.Ira talks with Vox staff writer Umair Irfan about the new sickle cell treatment and other top science news of the week, including the link between the auto worker strike and a clean energy transition; new evidence about the moon’s origin; and why starfish don’t have arms. Your Pain Tolerance May Have Been Passed Down from NeanderthalsThere’s a little bit of Neanderthal in most of us. Neanderthals and Homo sapiens had a long history of intermingling, before the former went extinct about 40,000 years ago. That mixing means most modern humans have some amount of Neanderthal DNA—and it accounts for up to 3% of the genome in some people.While these genetic remnants don’t have much impact on our day-to-day lives, they may be responsible for one surprising effect: pain tolerance. Recent research shows that people with Neanderthal variants in the gene SCN9A have a lower pain tolerance than people without the gene.This isn’t the only Neanderthal remnant that’s been passed down. A study from earlier this year pinpointed a certain genome region that impacts nose shape. Taller, wider noses were passed down from our Neanderthal ancestors who lived in colder climates. A larger nose warmed air before it hit the sensitive lungs.Ira speaks with Dr. Kaustubh Adhikari, assistant professor of statistics at the Open University in the United Kingdom, who worked on both of these studies.  To stay updated on all things science, sign up for Science Friday's newsletters. Transcripts for each segment will be available the week after the show airs on sciencefriday.com.  Subscribe to this podcast. Plus, to stay updated on all things science, sign up for Science Friday's newsletters.

Your level of pain tolerance may have been passed down from non-human ancestors. We all have some ancestry from ancient human cousins called Neanderthals and also another related family called Denisovans. It's Friday, November 3rd, and hey, would you look at that? It's Science Friday. I'm SciFri producer Kathleen Davis. Most people have somewhere between 1 and 3% of Neanderthal DNA. The more we learn about the... the human genome, the more we find out how these Neanderthal remnants may still impact us today. One surprising effect that has recently been discovered is your level of pain tolerance. We'll get to that story in just a moment, but first, Ira and guest, Umair Irfan, talk about

the biggest science stories of the week. This week, an FDA committee cleared the way for a potentially revolutionary cure for sickle cell disease. Yes, a potential cure for sickle cell. If given final approval, the treatment could be the first to use CRISPR gene editing in humans. Joining me now to give us more details on this new treatment. Another top science news of the week is Umerer Fahn. Staff writer for Vox based in Washington, D.C. Welcome back, Omer. Hi, Ira. Thanks for having me. Let's get right into this story about sickle cell. Give me some details here. Right. This is a treatment called X-C-C-Cell. And as you mentioned, it's based on CRISPR, the gene editing technique. The thing to know about sickle cell

disease is that it's caused by a genetic mutation of just one letter. And scientists have long reasoned that if they could swap and correct that typo, they could potentially cure this disease. That one letter mutation, it causes the red blood cells to shrivel up into these sickle or crescent shapes, and that causes the cells to clog up blood vessels. That leads to a lot of other problems, things like strokes, organ damage, and even excruciating pain. And so that makes sickle cell a pretty debilitating disease. So this is pretty exciting that they've developed, not just a therapy, not just a treatment, but a cure.

And this is the first time they're using CRISPR and people. Is that right? Well, it's the first time we're going to have an actual approved therapy or an actual treatment that's going to be approved by regulators. You know, CRISPR has been getting a lot of hype. There's a lot of potential that we've been hearing about for a few years. but this is very likely to be the first one that's going to enter the real world that might actually make a difference in people's lives. And just how expensive is this treatment because they're always looking out for these due treatments.

Sometimes they go through the roof. Well, right. And also because we're in the United States and because of our health care system, everything has a price tag. We don't have a specific tag for this, but some estimates are that this is going to be costing about millions of dollars per patient. Now, the rationale is that, one, this is a complicated treatment to administer, and also that this is a cure, not just a treatment. So this will be a one-and-done-type deal. And also the pharmaceutical companies, they have to recoup their costs among a small handful of patients. This is not a very common disease. And so that means per patient, it's going to be very expensive. The question then is how much insurers and the government will pick up the tab to help people who need this treatment close the gap. Okay, so give us a bit of the timeline here when we might find out if the FDA does give final approval. Well, the advisors this week, as you noted, voted to give this drug the go-ahead. And the FDA usually accepts their advice and they're meeting again on December 8th. And so very likely in early December we'll get a final verdict.

Okay, let's move on to this next story, which is a little bit less optimistic. and that is for the first time in 20 years, infant mortality rates have increased in the U.S. That is not very good news, is it? How big an increase are we seeing? It's an increase from about 5.44 infant deaths per every 1,000 birth in 2021 to 5.6 in 2022. That may seem small, but one, it is statistically significant, and it is notable because it's an increase because for a long time, infant mortality was decreasing in the United States. Now, in the U.S., we've been kind of grim when it comes to these infant mortality statistics. The U.S. infant mortality rate is roughly double compared to other wealthy countries in our peer group.

And also, the U.S. has an abnormally high maternal mortality rate. So moms giving birth also have a fairly high mortality rate. But the trends were moving in the right direction until the past couple of years. And what do we think is causing this uptick? Well, you may recall in the past couple of years, we did have the COVID-19 pandemic. The infections were part of it, but the researchers that were looking at this said that it was probably the wider societal disruptions as well. It wasn't simply the people getting sick from COVID, but it was also people who were not getting regular health appointments, but also things like

inflation and the increase in the cost of living. That's making, you know, moms and parents basically choose between paying for necessities like rent and paying for things like preventative health care, and that means that they're not catching complications early, which in turn leads to more problems with birth delivery and in infancy. The next story you brought us is about the auto industry. This week, the United Auto Workers, the UAW reached tentative agreements with automakers ending the strike. You reported on the impact of these agreements on the shift to making electric vehicles. Why is that important? Well, it's important because the workers and the social component of the shift towards clean energy

is turning out to be a much bigger impediment to that transition than simply the technology. It's not simply about making better batteries or cheaper electric cars, but addressing the needs of the workers that make them. This was the conclusion of the National Academies. They put out a report last week looking at the things that we need to do in the United States to transition and to accelerate the shift to decarbonizing the economy. And one of the things that they wore, about was that the U.S. social safety net is really weak, and there aren't a lot of great worker protections. The UAW strikes kind of reflected that because among the issues that they were trying to get better agreements on were things like making sure that workers in electric

vehicle plants and in battery manufacturing were covered by contracts, but also that workers that lost their jobs making conventional vehicles also had some leverage in getting things like severance and training for new jobs. Yeah, because this is something we have to. prepare for and be ready for as we shift to an electric car economy. Right. And it's not just electric cars, but it's things like transmission lines, it's power lines, it's being able to install insulation and highly efficient appliances. There's a whole cadre of workers that are desperately needed. And the clean energy sector of the economy is growing. There's a lot of demand for workers, but very few workers in the fossil fuel sector or in the

traditionally dirty sectors are making that jump. If you look at the past 20 years, it's been less than 1%. And so one of the more urgent challenges for our economy going forward is how do you help people make that jump? Rather than simply dislocating people having layoffs in one area and jobs and jobs, how do you make sure that the people who are losing jobs can get some of the new ones and reap some of the benefits? That's going to be the big challenge going forward. Yeah, yeah, that certainly is. Let's stick, Romare, within the energy sector here a bit longer because there's big news in nuclear fusion this week. The largest fusion operating in the world went online this week in Japan.

This one is of the Tokomak design different than the last big news we got. Tell us about that. Right. You may recall earlier this year, we got the news from Lawrence Livermore Lab that they achieved more energy out of a fusion reactor than they put in. That reactor uses lasers to compress fusion fuel. They call that inertial confinement. The Takamak design that you described here is actually kind of like a giant magnetic donut. It's a donut shaped chamber surrounded by powerful magnets and it heats up the fuel into really high temperatures until it forms a plasma.

And the idea is if the fuel is moving really hot and really fast, that increases the chances of atoms colliding with each other and sticking to each other and triggering fusion reactions. This reactor in Japan is called JT60SA. It's now going to be the largest version of these devices. but it's still not quite big enough to be a reactor and that this design will be helped to be used to design a more commercially viable machine. And there is a bigger one under development, is there not? Right. This machine is called Eater.

It's currently under construction in southern France. And so this new reactor that's being fired up in Japan, what they learn from there is going to be used to help design and implement the fusion reaction there that they're building in France. And from there, they hope to, eventually build a machine that will actually put electrons on the power grid. Yeah, there's still one big knit in this story in that even though the energy you need to put in the whole technology is still a lot more than you get out. I mean, what you have to take off the

grid is still far above anything you've made. Right. And especially with the Takamax, you know, you're heating up this fuel to temperatures hotter than the sun. You need to get it moving really, really fast in a very confined space. And that requires a lot of energy to get started. So yes, you can trigger the fusion reaction, but the critical balancing act that you have to do is to get more energy out than you put in. And right now, they haven't quite gotten there with the Takamak design. Yeah. All right. Your next bit of news is actually from about four and a half billion years ago. Scientists have uncovered some intriguing evidence about the origins of our moon. This is really very interesting, has been interesting for years, about where did the moon come from, but now some new evidence for that. That's right. You know, one of the most popular theories for how the moon originated was that a proto planet called Faya collided with Earth and it caused a whole bunch of disruption and then eventually it, once the dust settled and they cooled off, we had the Earth and the Moon.

That made a lot of sense, but there wasn't a lot of forensic evidence for it, that we weren't able to find the debris or just some of the marks of it. But it turns out that some of the scars from that collision may be deep inside the Earth. There was a new study. this week that looked at the layer between the mantle and the Earth's core, about 1,800 miles below the surface, and they found these blobs that were basically kind of consistent, or they thought consistent with something that might have been left over from this collision. The scientists, they did some computer simulations, and they found that that actually did line up, that essentially that these blobs in the Earth's deep inside the Earth were perhaps, you know, left over residue from that collision that formed the moon. That is really cool. The moon is certainly still mysterious for a lot of us. Yeah, and I think kind of what's interesting is that about 10% of Thaya, this proto-planet, may actually still be deep inside the Earth. So we still have a significant amount of that

collision inside our own planet. Okay, that is cool. Let's finally move on to a story that falls into the category of very weird animal facts. It turns out that starfish, now known as sea stars, they don't have arms? What do they have if they're not arms? They're basically giant heads. Well, one of the scientists described them as a disembodied head walking on the seafloor on its lips. And so the reason they came to that conclusion is that, yeah, you know, you look at a starfish, and it doesn't seem very analogous to us as humans, but we try to draw those connections anyway. But it turns out that's kind of flawed.

When they looked at the genetics of starfish, particularly in development and they attached markers to their cells, they found out that. the cells that were distributed throughout the starfish's body were mainly cells associated with what they would consider a head rather than arms. And so from the embryo to the full-grown adult, it looks like most of its body basically fits within the description of what they would consider a head region rather than things that would be more considered limbs. And so it's forcing scientists to kind of reconsider how these animals plan their bodies. That is really, really cool. I'm not going to be walking on my lips, but using him to thank you and say goodbye. Amerifon's staff writer at Vox based in Washington, D.C. Thanks for joining us.

My pleasure, Ira. Thanks for having me. There's a little bit of Neanderthal in most of us. Neanderthals and Homo sapiens had a long history of intermingling until the former went extinct about 40,000 years ago. That mixing has led to some modern people having up to three percent. of Neanderthal DNA. And while these genetic remnants don't have a lot of impact on our day-to-day life, it may have one surprising effect, pain tolerance. Joining me now to talk about new research in this field is my guest, Dr. Kostobadakari, assistant professor of statistics at the Open University and the United Kingdom.

Welcome to Science Friday. Hi, Ina. Thanks so much for having me. Nice, thank you. So there is some Neanderthal in most of us? It is indeed. So most people in what we call Eurasia and the Native Americans, we all have some ancestry from ancient human cousins called Mian D'Ethals and also another related family called Denise Oven's. That is cool. Let's get right into your study. There are different kinds of pain, right? The pain I feel when I stub my toe, it's like different from chronic back pain, for example. What kind of pain were you looking at in this study? Yeah, exactly.

So we were looking at normal pain sensitivity or pain perception. And as you said, if we end up touching a hot pan while cooking, we want to feel that pain because that then keeps us sick, not burning our hand. And that is very different from chronic pain, which is not so good for us. And it is, in fact, something that healthcare systems spend billions trying to manage and treat. So we were looking at the first kind of pain, which is the normal pain perception, and that would vary a little bit between people to people. So that's what we were studying.

And for the people who have these Neanderthal genetic variants, just how much of a difference in pain tolerance was there? It wasn't a lot. So because we are talking about normal pain perception, so for example, if we touch a plate, that's our body temperature, we won't feel pain. But if we start increase the temperature slightly, at a certain point, I will say that it's starting to feel hot and that we will stop that experiment. So it's that kind of sensitivity we are talking about. That's one particular kind of pain perception or pain sensitivity we are measuring.

And that would vary between people say you may feel that at 40 degrees Celsius. I may feel that at 42 degrees Celsius. So it's a relatively small variation. And correspondingly, the near-and-earthal contribution we saw. where at this relatively moderate amount as well. But that is noticeable enough once you study a large enough group of people. So the Neanderthals had a lower pain threshold. Do we have any idea why that would be?

That is a very interesting research question, which unfortunately we haven't figured out yet. And that's part of the next step in our research. So it certainly did something because we see that particular bit of gene that we inherited it was under positive natural selection. So it certainly gave us some sort of advantage, but we don't know exactly what it was. If Neanderthals had a lower pain threshold,

would they have to be a little more cautious in how they live their lives? Well, that's a good question. Might have been. So we don't exactly know what would the ramifications be in people's daily lives. As I said, it's a relatively small variation. And essentially, every gene our body does a lot of different things. So it's not necessarily that pain was the

ultimate outcome characteristic that was influencing this natural selection. It could have been some other function of this team. So it's a very interesting question. We don't know the answer yet, I'm afraid. Do you think that because we humans survived with a little more pain tolerance, it increased natural selection toward us? That is possible. There are hypotheses that even between different groups of modern humans, there are variations in pain tolerance. And that might have some advantages. So a common example is malaria, for example, that there are selective advantages of people having malaria protective genes in certain parts of the world, and that might have been helpful.

Right. So something similar could have happened. So we know that these Neanderth people lived at colder climates, and they had various adaptations that help them survive in these colder conditions. So we also know that they passed some of those genes that conferred these evolutionary advantage to modern people living in those areas. So it might have been the same story with these paintings that something like that happened, but we exactly don't know yet.

Very interesting. A few months ago, you found that nose shape is dictated by Neanderthal genetic variations. Tell me about that. What you found there? So that was studied with the same group of people. What we do is that that's how we found that there were certain changes in certain genes that modified our nose shape within, of course, the range of normal human variation. And when we did that, we found certain genetic changes in certain genes.

But we also looked at whether we could have inherited those genetic changes from Neander, or from Denisovans, the two ancient groups of humans we intermingled with. And when we did that, we saw that there was one particular gene which was influencing our nose height, which we seem to have inherited from the Neanderthals. And again, there was probably some evolutionary advantage of having that particular genetic change. And we hypothesized that because the Neanderthals started living in these colder northern climates, 400,000, 300,000 years ago, they were much better adapted to that climate already when modern humans started to move in. So it's quite possible that when we intermixed with them,

we said, oh, these genes are already giving you some advantage to living in these climates, we borrow them. And we did. And that's what we postulate in this paper. What kinds of noses were inherited from Neanderthals? I was looking up Neanderthals, and it seems they had longer, broader noses? Was that an advantage? What kind of advantage did that give them? So what we hypothesize, this is not something we can, you know, do an experiment and improve,

but what we hypothesized in our study and in several other studies by other research groups is that when you have a colder climate where the air temperature is much lower, you don't want that very cold air to reach your lungs directly. So what you want to do is heat up the air a little bit when it passes through your nose and you're breathing to you. So if you have a nose shape which gives you a bigger surface area inside, that helps to warm the air more. So that is what we think is the reason.

There was this other species, the Denisovans. There were also early hominids. Do we know if modern humans have their genetics too? Yeah, we definitely do. So we have recovered DNA from Denisovans, and when we compare that to worldwide populations of modern humans, several groups have them. So East stations, Southeast stations, Native Americans, there are certain parts of Southeast Asia, which have up to 8 or 10 percent of Genoven ancestry. So that's quite interesting. Wow, that is interesting. Is it possible that if you have Neanderthal or Denisovan genetic genetics, variance. If someone is curious about it, is there some testing panel? Can I get it tested to see if I have those genes? I don't think you can get it tested directly from the consumer genetic tests. So this is a slightly more sophisticated genetic analysis that we do. But I think it's possible.

So these testing companies might one day be able to implement these comparisons to the say at least overall what percentage of your DNA could be Neanderthal or could be denisophan. I think a couple of companies might do that already. But if you wanted to look at specific variants, whether those are inherited from Neanderthus or Denisovans, right now we know a fair amount about certain genetic variants. So these companies may one day decide to put those variants on the chip and then at that point you would be able to find out. Is it possible that there are more Neanderthal or Denisovian?

genetic variants out there than that we just don't know yet about? Yeah, there's certainly that possibility. So you know that globally there are many populations that are understudied and there have been research efforts to increase representation in genetics research. So if that happens and we study more and more groups of people around the world, we'll probably find out more about it. Yes, certainly. And as far as the pain threshold, there's no way.

that I could know just by, you know, maybe being more sensitive to pain that I have that Nandotol variant gene, could I? I mean, what you're saying is it's really not that striking a difference. No, you're completely right. It's not that striking a difference. So there are certain characteristics and certain genes which are linked in a very obvious way, for example, whether you are able to digest milk or not, usually in Europeans' populations, that's down to single change in a single gene which gives you the ability to digest lactose. So those are examples in which is very obvious. And if I see that you are able to digest lactose or not,

I'll be able to see if you have the genetic variance or not. It doesn't work that way for most of the other characteristics that we study, like height, like this shape, like pain. So there would be a lot of genetic changes in a lot of genes that each give you very small advantage or disadvantage, and therefore it is very difficult to say. I mean, the other thing, of course, is that there is a huge effect of environment as well. So, for example, when it's a colder climate and you stub your little finger on your feet, it feels worse.

So there would be, yeah, those kinds of variation. Or, for example, for height, you know, nutrition has a huge effect on height. So, of course, there would be, in general, a lot of difficulty in trying to link a specific characteristic to a specific gene. Right. Well, next time I stub my toe, I can't say, darn, those Neanderthal genes in me. Indeed. Fascinating. That's about all the time we have today. Thank you for taking time to be with us today. Thank you for having me on the show.

Dr. Costa Badakari, assistant professor of statistics at the Open University in the UK. And that's about all the time we have for today. A lot of people help make the show happen, including Ariel Zitch. Flores. Dee Petersmith. Full of Samares. And many more. On Monday, we'll talk about how one climatologist has spent his career warning us about nuclear winter.

We'll catch you then. But for now, I'm SciFRI producer Kathleen Davis. Have a great weekend.