Science Friday - An AI for Smell, Heat and Agricultural Workers, Golden Lion Tamarin, Y Chromosome. Sept 1, 2023, Part 2

Episode Date: September 1, 2023

What’s That Smell? An AI Nose KnowsIf you want to predict the color of something, you can talk about wavelengths of light. Light with a wavelength of around 460 nanometers is going to look blue. If you want to predict what something sounds like, frequencies can be a guide—a frequency of around 261 Hertz should sound like the musical note middle C.Predicting smells is more difficult. While we know that many sulfur-containing molecules tend to fall somewhere in the ‘rotten egg’ or ‘skunky’ category, predicting other aromas based solely on a chemical structure is hard. Molecules with a similar chemical structure may smell quite different—while two molecules with very different chemical structures can smell the same.This week in the journal Science, researchers describe developing an AI model that,  given the structure of a chemical compound, can roughly predict where it’s likely to fall on a map of odors. For example, is it grassy? Or more meaty? Perhaps floral?Dr. Joel Mainland is one of the authors of that report. He’s a member of the Monell Chemical Senses Center and an adjunct associate professor in the department of neuroscience at the University of Pennsylvania in Philadelphia. Mainland joins Ira to talk about the mystery of odor, and his hope that odor maps like the one developed by the AI model could bring scientists closer to identifying the odor equivalent of the three primary colors—base notes that could be mixed and blended to create all other smells.  As Temperatures Rise, Farmworkers Are UnprotectedJuan Peña, 28, has worked in the fields since childhood, often exposing his body to extreme heat like the wave that hit the Midwest last week.The heat can cause such deep pain in his whole body that he just wants to lie down, he said, as his body tells him he can’t take another day on the job. On those days, his only motivation to get out of bed is to earn dollars to send to his 10-month-old baby in Mexico.To read more, visit sciencefriday.com. The Golden Lion Tamarin Rebounds From The Brink Of ExtinctionThe Golden Lion Tamarin is a small, charismatic monkey with a mane of red fur that’s a local celebrity in Brazil’s Atlantic Forest. This pint-sized primate was on the brink of extinction back in the 1970s, with only about 200 left in the wild.After decades of concentrated conservation efforts, an estimated 4,800 golden lion tamarins are now living in the wild. The multi-pronged effort involved reconnecting parts of the forest that had disappeared due to deforestation, vaccinating monkeys against yellow fever, and reintroducing zoo-bred primates to the wild.Ira speaks to Carlos Ruiz Miranda, associate professor of conservation and behavior at Northern Rio de Janeiro State University in Campos dos Goytacazes, Brazil. Dr. Ruiz Miranda has worked on restoring golden lion tamarin populations for decades, and was involved in every facet of this effort.  Unraveling the Mysteries Of The Y ChromosomeLast week, we briefly mentioned the sequencing and analysis of the human Y chromosome, which was recently reported in the journal Nature. It’s an important achievement—the small Y chromosome is filled with repeated segments of genetic code that make reconstructing the full sequence difficult. Think of trying to put together a jigsaw puzzle—the unique parts of the picture are easy, but areas with repeated colors, like sky or waves, are more challenging.    In addition to the complete sequence of one individual’s Y, other researchers compared the Y chromosomes of 43 different individuals—and found that the structure of the chromosome can vary widely from one person to another.The Y chromosome plays a key role in sex determination and sperm production, making it of interest to fertility researchers. It’s also linked to some diseases and health conditions.Adam Phillippy, a senior investigator in the computational and statistical genomics branch of the National Human Genome Research Institute at the National Institutes of Health, and Kateryna Makova, a professor of biology at Penn State University, join Ira to talk about the challenges of sequencing the Y chromosome, and what doing so might mean for medical research. 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.

This is Science Friday. I'm Ira Flato. Later in the hour, work to preserve the golden lion tamarin and unraveling the mysteries of the Y chromosome. But first, if you want to predict a color, you can talk about wavelengths of light, right? Around 460 nanometers, it's going to look blue. If you want to predict what something sounds like, you can talk about frequencies, 261 hertz. That sounds like middle C. but is there a way to tell what something is going to smell like? One way might be to look at a molecule and say that should smell like dirty socks,

or this molecule should smell like roses. Well, this week in the journal Science, researchers describe developing an AI model that if you give it the structure of a chemical compound, can predict where it's likely to fall on a map of odors. For instance, is it more grassy, more meaty, more fernic, more floral. Dr. Joel Mainland is one of the authors of that report. He's a member of the Monale Chemical Census Center and an adjunct associate professor in the Department of Neuroscience at

University of Pennsylvania in Philadelphia. Welcome to Science Friday. Thanks for having me. Nice to have you. Okay, before we start on this new work, let's get a refresher on smell biology 101. I was always taught that it's sort of a lock and a key situation in your nose with smell molecules fitting into like lock receptors. Is that right? Yeah. So I think that's a good analogy at the basic level and gets most of the things we care about correct. We have a more subtle understanding of that now as people have developed molecular docking tools and gotten sort of a finer grain understanding of having electronegative and electropositive interactions and things like that. So your team developed this AI model. How do you train a computer to smell things? The way to do

is to collect a lot of data. So a lot of these machine learning algorithms are very skilled at solving complicated problems, but they're very data hungry. So previous work, the sort of standard in the field used about 500 molecules to develop a model. And this work started with 5,000. We trained the model using these 5,000 odors. And we used a new type of architecture called a graph neural network that is very skilled at looking at molecular structure in a more specific way than previous models and allowed us to match those two things up. Do you have like a panel of smell testers to help them train? Yeah, so we created our own panel. So we took some people in Philadelphia and trained them for about four hours to be panelists for us. And that training basically consists of us

handing them a kit that has 55 different vials in it. And each of those vials corresponds to a particular smell. So we have a vial in there for grassy. We have a vial in there for animal. And they learn what those labels mean by actually smelling those. So we train them over the course of four hours, and then the panel would smell the 400 molecules for us. And so then because you know what the molecules smell like, you tell the AI this is what this smell looks like molecularly. That's right. And then we do pattern matching. So the model will look for molecular patterns that match up to various smells that all have the same percent. Now, I'm thinking of these people who can taste a wine and come up with this huge list of descriptions. Were some people better than others? Yes, some people are better than others.

And we definitely screened out some people who were not very good at this. Some default people that are untrained are terrible at this. And some people we have difficulty training. We had a couple panelists who were better than others, but I would say we did not have a real set of standouts there. At the end of this, after we had collected all the data and tested the model, we brought in a master perfumer. So Christoph Lotomiel came in as our ex-examination. expert. And he also smelled all these molecules looking for ones that were particularly interesting for industrial applications, for example. And he had very different description of these than the panel did. So one example, our panel smelled a molecule and rated it as sharp, sweet,

roasted, and buttery. And the master perfumer smelled it. And he said, that smells like a ski lodge or a fireplace without a fire. Now, you know, I know what that smells like now. That's a really good description. That's right. And if you think about sort of an ashy smell of old ash versus an ash of a fireplace that, you know, recently had a fire, those are different smells. And the perfumer was able to sort of pin this down very precisely. And are you able to train the AI to know that difference? Right now we are not able to. So the data we collected is sort of a lower resolution. We sort of think of it, you know, akin to eight-bit graphics. We have some rough idea of what these things smell like, but we don't have the level of resolution to get to what the master

perfumers doing. So it can get close to what you think it is, but not really hit it exactly. That's right. It gets in the neighborhood. And we would love to have 15 master perfumers smell 400 molecules for us, but unfortunately, that's a lot more difficult to pull off. Is it better at some kind of smell than another? Yeah. So the model is very good at things like garlic and fishy. And part of the reason it's good at those is that there are lots of examples of molecules in our training data that have a garlic or fishy odor. It's much worse at things like musk. And musk is actually a well-known problem in the field where you have many different molecules that have distinct structures, and all those structures, even though they're very different, all have this musk

character. Yeah, I would imagine musk smells a lot different to a lot of different people and certainly to the AI. So musk is sort of a tricky term. Untrained subjects will often relate it to sort of a body odor smell. But the way that perfumers use the word musk is this sweet powdery smell. And we know that some people don't smell certain musks. And indeed, the industry to sort of deal with this will often include multiple musks of different structures in formulation so that they know that everybody will smell at least one of the musks. I love it. I love it. Now, some AI models are kind of a black box, right? Can you look at what your model is doing and try to figure out why certain molecules smell the way they do? We can a little bit. There's still parts of the model that are very much a black box.

But what was interesting here was that we have a neural network, and the neural network first takes this molecular structure and tries to learn as much as possible about how molecular structure relates to perception, and it sort of culminates in this sort of next-to-last layer. And then out of that layer, it makes predictions for how cheesy something is or how grassy something is in different ways. So that next-to-last layer has all the information about all the different odor properties, and we can take a look at that, so we can essentially plot that out as a map,

of coordinates, and we can see which molecules fall close to each other in that map. And so that lets us understand sort of the logic of why the model is able to learn this better than previous models. Does this tell you anything about what's going on inside the brain or why we smell things the way we do? I think a lot of the field typically thinks about olfaction from the perspective of chemist. So we look at a molecule, and if two molecules have the same number of carbons and they both have a particular sulfur group in them, then people think that those are structurally similar molecules. And the brain has a slightly different take on this.

There are lots of cases where we have very similar structures that are perceived very differently or very different structures that are perceived very similarly. And when we looked at this map, we saw that it solved several of these problems in a way that was better than previous models. And we hypothesized about why that might be. And our guess is that what it's doing is looking at this from a metabolic perspective. So if you can think about smell as being important for us to find nutrients in certain foods, you could imagine that there's an essential amino acid in a food that has no odor.

And that essential amino acid, even though it's odorless, can be broken down into smaller molecules that do have an odor. And so you can imagine this amino acid is split in two, and those two halves don't look the same, but both of them are signals for the same source nutrient. So the olfactory system would like to link those back and say those have the same smell, but a chemist would not think that those were structurally similar. Very interesting. You know, with colors, we have the three primary colors.

You can mix and match them to make all the other colors. Are their primary smells? We think that there are primary smells, and we're now playing around to try to figure that out. So this paper really was focused on understanding single molecules and how to make predictions about those, but in reality, almost everything that you smell is a complex mixture. And so the next phase of what we want to do with this research is understand how you can take two molecules A and B, where you know what they smell like, and then predict when you mix them what the mixture will smell like. And if we can tie those two things together, we can go sort of forward and take any recipe

and predict what it smells like, or we can go backwards and look at the universe of smells and try to identify these primary odors that would allow us to use them as sort of simplified building blocks to make a wide variety of odors. You know, our tongues have taste buds on them that are sort of dedicated to certain tastes. Does our nose have sort of smell buds that are dedicated to certain smells? There's some debate about this. I think there are a couple of cases where you have a specific receptor that's tied to a specific percept that we would sort of cognitively think of as a category, but there are also other cases where you look at these receptors and they respond across a wide variety of categories. So that's still an unsettled question in the field as to how

these actually match up to a specific percept. That's cool. Do we all smell things the same way? Like we can all agree on what blue is, but can we all agree on how something smells? Yeah. So in some cases that we know very specifically, that's not true. So one example here is and drosthenone. And about a third of the population when they smell this molecule, don't smell anything at all, myself included. A third of the population when they smell it, smell it as this sort of sweet sandalwood odor. And then another third of people will smell it

and find it to be a very intense urine odor. So we've linked this to genetics. Certain people have a receptor that responds to this molecule, and that changes your perception of this. And we find that if you look at, you know, one individual and another individual, you'll have these areas of disagreement. But once you put panels together

and you get those panels to be large enough, around sort of 12 to 15 people, you can smooth out that very, variation. And at that point, we find that really the differences among smells is really similar to the sort of level of noise or differences in vision. So even though we think of vision as sort of this truth that you can put in an RGB number and everybody will think that that number is exactly the same color, in reality, there's variation there too. And so we have this variation in vision and yet these visual maps have been really profoundly useful. Similarly, we have variation

in smell and but we think that smell maps will also be extremely useful. That is cool. Now, once you have this model, you used it to predict chemicals that haven't been smelled before. Something new that we have never smelled? That's right. So, in fact, we tried to pick 400 molecules that had never been smelled before for the study. In fact, industry has done this previously. There's a sort of famous example of a molecule that smelled like the ocean that was used in the sort of late 80s and a lot of different fragrances. So prior to that time, perfumers had no access to that particular smell. They discovered a molecule that let them now create lots of things that smell that way. And it resulted in this big boom of that particular type of fragrance. As we wrap up, what are your big goals? What would you really love to be able to get out of your research?

I think really the big goal here is to figure out primary odors. I think that right now, if you think about what you can do with your phone in terms of sharing and recording images or sounds and storing them and archiving them and bringing them back up without destroying them, we can't do that with odors right now. And the ability to digitize them, find primary odors will really explode the possibilities for what we can do with smell.

Wow, sounds cool. Thank you for taking time to be with us today. Thanks for having me. Dr. Joel Mainland, member of the Monel Chemical Census Center, an adjunct associate professor in the Department of Neuroscience at University of Pennsylvania in Philadelphia.

We have to take a break, and when we come back, deadly heat waves are for agricultural workers. We'll be right back after this break. This is Science Friday. I'm Ira Flato. And now it's time to check in on the state of science. This is KERNO. St. Louis Public Radio News. Iowa Public Radio News. Local science stories of national significance. Being a farm worker in America is very hard and it's dangerous. Hundreds of millions of us have experience the heat wave this summer, but for people working out in the fields to grow and harvest our

food, that heat may be deadly. My next guest reported on their struggle for harvest public media investigate Midwest and the Mississippi River Basin, Ag, and Water Desk. Eva Tesfai is a reporter for KCUR and Harvest Public Media based in Kansas City, Missouri. She reported this story with Monica Cordero at Investigate Midwest. Welcome back to Science Friday. Thanks for having me back. Nice to have you. Okay, you know, a lot of people have experienced the oppressive heat just walking around, but what makes agricultural workers so vulnerable to the heat? Yeah, I mean, obviously a lot of them are working outside. It's quite hard physical labor, depending on what you're doing. But yeah, usually it is. And, you know,

because of that, they're 35 times more likely to die from the heat. That statistics comes from the National Institute of Health. Another reason that they're particularly vulnerable is a lot of them are often paid by how much they pick. So if they're picking apples, they'll be paid by how much they get that day. So that can incentivize them to work harder to keep going, even if they're feeling the effects of the heat in negative ways. And I heard that a lot of them don't really feel like they have a choice. Like I spoke to one farm worker, his name was Santiago. He wanted to not share his full name for privacy reasons, but this is what he said. You know, you got to support your family no matter what.

Do you have like two or three kids? You've got to work harder. And you're talking about the kind of jobs they're working at. These are really difficult backbreaking jobs, right? Yes. So, you know, typically we see these farm workers working in specialty crops. So that's like picking fruits and vegetables. The farm workers I talked to in Missouri, they picked apples.

and you can imagine those get really heavy after you collect more and more. So you're carrying that, and then you're also climbing up a ladder to get the apples, which is, you know, dangerous if you're feeling faint from the heat. And you're also, you know, you're out there all day in the heat, looking up at the sun because you're looking up to get the apples. So, you know, a lot of them use eye drops and things like that. I've also here in the Midwest, we see a lot of farm workers doing detasseling, which is a job that, you know,

know, typically used to be done by like high schoolers on their summer break, but now we're seeing more farm workers come from Central America through the H2A program. People can come over to the U.S. and work for the summer. Those are kind of the two places that I've seen farm workers working in the Midwest, but obviously, you know, on the coast, it's definitely more of those specialty crops. I mentioned that this was a deadly kind of heat. How many deaths are we talking about here? Yeah, so we found Monica Cordero, my colleague found, that there were 121 deaths related to heat, and that was from OSHA data from 2017 to 2022. That number is probably undercounted just because it is hard to classify a death as related to heat.

Usually heat does aggravate conditions that the body might already have. A lot of people who have died from heat-related causes die from cardiac arrest. And also that this is just OSHA data. This is just data where OSHA went and inspected these fatalities. So it likely is more. Are there any regulations there for farm workers when it comes to heat waves? Yeah. So there's no specific regulations when it comes to heat federally.

Only four states have regulations when it comes to outdoor workers in heat. And that's California, Oregon, Washington, and Colorado. But OSHA is saying that under the general duty clause, employers do have a duty to protect their employees from the heat. But, you know, some of the advocates for farm workers I talked to said that's not enough. The onus is still on the employers to try to protect from the heat. And it would be better if there were some sort of standards. Yeah, we know there's a huge percentage of farm workers who are undocumented.

How does this play into this issue? Part of it is it makes it a really hard issue to research. Like I said, those deaths were probably undercounted. We don't really know the population size of farm workers in the U.S. because many of them are undocumented. So it makes it hard to know the amount of heat illness cases, how to know the amount of heat-related deaths, things like that. And on the regulation side, it makes it harder, especially if OSHA's, you know, regulating on the general duty clause. You know, they have a system where you can submit complaints about this under their national emphasis program on heat.

But many farm workers who are undocumented may not want the federal government getting involved, may not feel comfortable enough to report any complaints about the working conditions or even complain to it about to their medical providers or anything like that for fear of losing their jobs. It's a very vulnerable population for sure. That's amazing. You know, we know that our climate crisis is intensifying. So I can imagine we can expect that this will get worse for the workers. Yeah, we're definitely seeing, you know, more climate extremes across the U.S. We had a really bad heat wave that covered a lot of the Midwest and the South last week. Some parts of the Midwest here where I am had heated index temperatures of over 120 degrees.

And one thing we're definitely noticing about the central part of the country is that the heat index is getting higher. So heat index is the calculation that includes humidity and temperature. so it often is described as like the feels-like temperature. And it's important to consider humidity in this story because humidity can really exacerbate the risks that heat poses because it makes it harder for your body to self-regulate by sweating. So one thing that we found working with Climate Central, they found that a large part of the central U.S.,

so the Mississippi River Basin had an average of six degrees increase. in heat index since 1950s. So it's definitely getting hotter, more humid. I did talk to some farm workers who had worked there for longer and they said, you know, every year is different, but overall some of them said that it does feel like it's getting worse. And especially with humidity, they do describe, you know, not feeling like they're not able to breathe. Some of them even said, like, that working in Missouri where it's super humid is worse sometimes than working in places like Florida and Texas where it's not humid, but it's really, really hot. Could we see some kind of standardization for worker protections on the federal level?

Yeah. So in 2021, OSHA announced that it's going to work on specific regulations for heat. They're working on a national standard for heat. The problem is that process could take years. We kind of have no idea when that is going to come. But yeah, they are working on that. Yeah, yeah. You know how. Slowly bureaucracy moves, right? Is there concern that any OSHA rules, for example, would come into practice just too late for these people? Yes, there is concern, and, you know, there are calls from different people to speed up this process. Like United Farm Workers just reissued its call for a national heat standard. Last year, a bill called the Assumcion-Valdivia Heat Stress, Injury, Illness and Death Prevention Act was

introduced and that would force OSHA to issue a heat center much faster than the normal process. That bill didn't make it anywhere last year, but it has been reintroduced by Democrats this year. So there is this concern. There is this push to try to get this happening faster. Like I said, there was a really bad heat wave last week. And people are waiting for for these regulations. But at the same time, I think there's also an awareness that once it is there, It might not be, you know, implemented entirely well. There is worry about the amount of inspectors OSHA has to implement these things. But everyone I talked to who advocates for farm workers basically said it's better to have this than nothing.

And states are moving too slow on this. Like I said, there was only four states that had actual regulations. And we're not really seeing a push for it on the state level. So they are just waiting for the federal government. Well, Eva, we hope that your great reporting might speed this stuff up. Thank you for taking time to be with us today. Thank you. Eva Tesfai is a reporter for K-CUR and Harvest Public Media based in Kansas City, Missouri.

She reported this story with Monica Cordero at Investigate Midwest. And now we're going to head to Brazil for some good conservation news. The Golden Lion Tamarin is a small charismatic monkey with a main of red fur. It's a local celebrity in Brazil's Atlantic Forest, but this pine-sized primate was on the brink of extinction back in the 1970s, only about 200 of them lived in the wild. After decades of concentrated conservation efforts, an estimated 4,800 golden lion tamarins are now living in the wild. They are still endangered, but those who work on this project say it's a really good sign that the population is turning around. Joining me to talk about this is my guest, Carlos Ruiz, Miranda,

Associate Professor of Conservation and Behavior at Northern Rio de Janeiro State University in Kapos dos Goit Kazes in Brazil. Welcome to Science Friday. Hello, thank you. Nice to have you. These golden lion tamarins, they're so cute and they are so charming, and I understand these monkeys are certainly beloved in their native habitat, aren't they? Yes, they are. They are. symbol and people just really like to watch them and see them in their backyards when they can. One of the districts that we work, even the public phone booths, are in the shape of the golden land towering. No kidding.

Now, I understand that you have a personal history with these monkeys also, that you say they've saved your life. Tell me about that. Twice, actually, I was standing, both cases. I was standing next to a venomous snake and I hadn't seen it. I was just observing the monkeys. And the monkeys approached me, making all kinds of noises and calls. And I was very worried.

I thought they were attacking me. But then I realized they were pointing to the snake. Wow. That was about a foot away from me. Yes, I have to say that they saved my life twice. Wow. So you have a really vested interest in liking them even more. I know.

I'm in debt. You're in debt. They are so special to you and to the community. What is their family structure like? So, yes, the tamarins live in an extended family structure. You know, the male and the female and their kids from previous birth. The female, mostly time, 90% of the time, is birth to twins, sometimes triplet. They are very heavy for the mother, so everybody helps take care of the baby.

So the father carries them on his back, and then the older siblings, bring food and also carry them on their bike. So they have a very tight family unit. Sounds like they're very similar to the people's family structure. Yes, yes, they are. Now, take us back in time. I mentioned at the beginning that there weren't very many of them, not so long ago.

Why did their population drop so drastically? So mostly the loss of their habitat. I mean, these monkeys live about 80 kilometers north of the city of Rio. and, you know, this is where people live and work. They're in the coastal plain, which was always used for a sugar cane or coffee cycle. So they were in a very active area. There was a lot of deforestation. You know, the Atlantic forest lost about 90% of its forests in the previous centuries.

So what kind of work does it take, you and your conservation scientists, to restore this population? Yes, this is the work is to restore people. population by restoring the habitat, we even reintroduced monkeys from zoos all over the United States and Europe. Wow. And how do you do that when you say restore the habitat? What do you have to restore exactly? Connect the patches of forest that were left that are unconnected. And most of them are private lands. So that's restoration and connecting forests. And it requires the help of the local community. This is Science Friday from WNYC Studios. Now, I understand there was a yellow fever outbreak in these monkeys. Tell me about the vaccination campaign you helped with. Yes, 2017, there was a yellow

fever outbreak in Brazil, and it has been a long time since we have seen yellow fever in this part of Brazil. And it was very swift, and hit the monkeys very hard, and we lost about a third of the population. So we used the human vaccine, but we had to kind of adapt it to the monkeys. So we tested it and we looked like it was safe. And so we started a

vaccination campaign. And for two reasons, once to protect the monkeys from the next outbreak, which usually this outbreak is coming in like 10 year cycle. There's a good expectation that there may be another outbreak in next two or three years. So we vaccinated the monkeys and

it's part of our what scientists call now the one health approach where you deal with human and animal health part of the same process. So two things that we did, vaccinate the monkeys and then make a big campaign for humans to get vaccinated. So next outbreak, it would be very subdued because we're going to have both the monkeys and people vaccinated. Did you actually have to go out and give individual shots to the monkeys?

Yes. we capture the monkeys and we bring them to our field laboratory. And yes, we have to give them injections one by one. How many monkeys would you think you've done? A little bit over 400. It was slow at the beginning because we were testing. We were in the third stage of vaccine tests like we do with people. So we were testing them in the...

Right. A test in the population. So the first 150 monkeys we had to capture twice. We capture them, take blood out, vaccinate them, and release them, and we have to go about 45 days later and capture them again and take a sample of blood to see if the vaccine had not work. And it did really well, about 92% of the monkeys show that they were immunized. So now we just capture and vaccinate.

You continued to do that. Yes, we have an aim. It's going to be around 800 based on our goals of vaccination, which is going to be to vaccinate enough monkeys so that the population will never go down to a number that they would not be able to bounce back on their own. Well, you have fixed the habitat. You have gone out and vaccinated the monkeys

and will continue to do that. Is there still any other kind of work you have to do to make sure the populations continue to thrive? Yes, part of the connecting the habitat, the big thing now is, working with people, and we have been doing this from the beginning, so that we need to protect the forest area further, and even though they're in private lands,

people can do private reserves in their land. But also we're working with sustainable economic activities so that people, you know, this is a rural area, but people need to make a living and carry on with their lives. So the tamarings are part of it, but we foster like ecotourism and organic farming, So we work together with the community to find what the solutions, economic solutions are going to be. And it's going relatively well.

Wow. So you're hopeful. Yes, I am. Every hopeful and optimistic. Well, I'm glad to hear that. And I want to thank you for taking time to be with us today. You're welcome. You're welcome.

Thank you for the opportunity. Carlos Ruiz Miranda, Associate Professor of Conservation and Behavior at Northern Rio de Janeiro State University. Camposta Goite Causes in Brazil. We have to take a break, and when we come back, unraveling the mysteries of the Y chromosome, but scientists are learning about this genetic outlier. Stay with us. This is Science Friday. I am I. Refledo.

Last week, we briefly mentioned the sequencing of the Y chromosome recently reported in the journal Nature. It is an important achievement. The Y chromosome is a bit of a genetic outlier. It's tiny. But it also plays a key role in sex characteristics and some diseases. So this week, I'd like to dig a little deeper into that discovery with two of the people involved in sequencing and interpreting the structure of the human-wide chromosome. Adam Philippi is a senior investigator in the computational and statistical genomics branch of the National Human Genome Research Institute at NIH. Welcome back to Science Friday.

Thanks, Sarah. It's a pleasure to be here. Nice to have you. Dr. Katarina Makova is a professor of biology at Penn State University and State College, PA. Welcome to Science Friday. Thank you. I'm really glad to be here. Let me begin with you, Dr. Makova. Let's get situated, can we? Remind us of what the Y chromosome is and what it does. So the Y chromosome is one of the two sex chromosomes that our genomes harbor. The Y chromosome is specific, two males, and it is present only in one copy in males, unlike the other chromosomes that are present in two copies in males. One we get from the mother, another one we get from the father, but the white chromosome, the men get only from their father. And how is it different from other chromosomes?

First of all, it harbors the SRY gene, which is important for male determination. This is the main difference. It also harbors many other genes, important for spermatogenesis, and it also harbors many repeats. This is how it differs from the other chromosomes. And is it smaller than the other chromosomes? It is rather small, yes. It is only about 60 million bases long. And is that significant, too, the size? Yes, the size is significant. Because the Y chromosome has a counterpart, the X chromosome. And these two chromosomes evolved from a pair of just normal non-sex chromosomes about 170 million years ago. And originally, they were the same size.

However, the Y chromosome shrank in size, but the X chromosome stayed just the way it probably was originally. And why the Y chromosome shrank so much is a really interesting biological question. That is interesting. Dr. Philippi, when we last spoke, we were talking about the filling in the gaps in the human genome to get a complete sequence. Why did the Y chromosome take extra work? Yeah, it's these repeats that Katarina mentioned. And in that respect, the Y is very different than all of the other chromosomes, even different compared to the X. And it's this accumulation of these repeats of, you know, tandem variety where you have these head to tail repeating arrays.

There's also a big enrichment of what we call palindromic repeats. And so just like you think of a palindrome in the English language, it reads the same forward and backwards. There's a lot of sequences in the Y that have this unique property that you really don't find anywhere else in the genome. And because of all of these interesting repletes and complex structures, it's made the Y incredibly difficult. call to solve as a puzzle. And that's what made it the last of the 24 for us to complete. So if you're trying to piece together fragments of DNA, that's what makes the Y harder to sequence than any random chunk of DNA? Yeah, it's exactly like a jigsaw puzzle when I use that analogy, that people always save the repetitive bits of the puzzle for last, you know, the repeating

buildings, the Waldo's, the grass, the sky. It's easy to do the unique bits. And luckily, 90% or so of the human genome is unique enough to put together. You have a lot of the edges in there already. Yep, the edges are easy. You can put the faces together. It's all the repetitive bits. And a lot of those live on the Y. And we think one of the reasons for that is because the Y is exposed to a lot of different evolutionary pressures. And so, for instance, as Katarina was saying, most of your autosomes or the non-sex chromosomes always come in pairs. You have two copies of one, two copies of two, et cetera, one from your mother, one from your father. The Y chromosome, it's only in 50% of the population, and those people only have one copy usually. And so there's

just fewer copies of this chromosome floating around in the population, and that exposes it to these different evolutionary pressures. And so it accumulates these repeats as a way of kind of adapting to this unique environment that it lives in. Okay, so walk us through a bit about how you go about a project like this. Where does the DNA come from? What happens? to it. The DNA from this individual came from a project actually that George Church started a number of years ago called the Personal Genomes Project. And that project was very innovative in its way of consenting individuals into research. And so it gave them a lot of extensive training on how they might envision their data being shared in the future, what risks might

come with that and so forth. And so everybody that bought into this project was fully aware that their genomic material would be made publicly available for the world to see, and they were highly educated on what that meant. And so that allows us now when we sequence genomes from these individuals to publicly release that data without any ethical concerns. And so this comes from an individual in that project. It's a male individual. We focused primarily on the Y chromosome here,

but we did sequence and assemble the whole genome. The issue now is that it's become so cheap and easy to do whole genome sequencing, that the analysis is the bottleneck. And so we sequenced the whole genome, and then we kind of isolated out the Y and spent a year or so really analyzing the composition and the characteristics of that one particular chromosome. Interesting. So Dr. Makovia, you have this sequence.

What does it tell you? So, first of all, we knew previously that the Y chromosome is very repetitive, but we just didn't know how repetitive it really is. So it is 85% composed of repeats compared to only about 54% repeat composition for other chromosomes. So there is a big difference here. And the repeats on the Y chromosome, they come in different flavors. Some of these repeats are transposable elements that jump from one location in the genome to another. Another group of repeats are satellites.

These are the tendibly repeated arrays of DNA, and some of them form centromeres, for example. And these are the structures on the chromosomes that are required for cell division to proceed. And some, as Adam already mentioned, are palindromes. So these are these inverted repeats of DNA sequence that actually allow pairing of DNA within the white chromosome. So the white chromosome is unique. is that it cannot exchange information with other chromosomes, like the X, for example, over most of its length, but it can exchange information with itself, within itself. And this allows it

to get rid of many deleterious mutations, as well as of some unwanted repeat, some of deleterious repeat such as transposable elements. So is it doing its own housekeeping, basically? Is that what you're you're saying? It looks this way to us. Yeah. I always like to think of it, you know, as keeping backup copies. And so in most of our cells, you have two copies of the rest of the genome. And if you have an error or mutation in one, say you spent too much time at the beach and you got some UV irradiation, that double-stranded break can be repaired by the homologous chromosome. The Y doesn't have that luxury. And so it kind of has to keep its own backup

copies. Let me move on to the second paper that was published in the same issue of nature that looks at the sequence of 43 different Ys. And they found that they're very different, Dr. Makova. What does that mean? First of all, this tells us that the Y chromosome evolves really fast, even within humans. And there is almost two-fold variation in size on the Y chromosome, even among humans, but most of this variation is outside of genes. Most of this variation is at repetitive sequences. But some of this variation exists in genes. In particular, the variation exists in the different copy number of the genes that are important

for spermogenesis. And we still have to wait and see what this means in terms of function, what this might mean in terms of fertility. Is this surprising to find this? This is surprising, but some of the work on the variation in copy number of genes was done before, and we know that if you take a look at 100 different men from around the world, they will differ in the copy number of these genes. Each one will have a unique combination of copy number of spermatogenesis genes

on the Y chromosome. So the variation is immense. But this variation in size has never been shown before. This is a totally new discovery. Interesting. That leads me to this other question you may have anticipated. If there's such variability in the Y from one person to another, do more samples from more people tell us anything more useful? Certainly. I think this discovery of this immense variation of the Y-Fromosome among different humans, among different men, is really a new starting point to start associate the Y-phromosome genetics with complex traits in humans, including susceptibility to diseases, but also potentially some xenotypic traits as well. Another point, you know, thinking about the evolution of these chromosomes, we like to think

about things like natural selection happening at the level of the organism, right? Right? You know, the bear's weak. It dies in the forest. The better bears take the place. But it's happening at multiple levels. And so the individual sperm are also competing against each other in a winner take all battle. And so if one of those sperm cells get some type of mutation that makes it swim a little faster or live a little longer, it can out-compete its brothers in that race. And so this is what I'm talking about. And I talk about these different evolutionary pressures that the Y chromosome is exposed to. Because when those sperm are competing, It's really the Y chromosomes in there driving them that are also competing. When we talk about some diseases being sex-length, they travel along with the Y chromosome. Does this give us any insight into why or any route to help people with those conditions? This is certainly the work that we hope will be happening in the future, and we hope that this opens new avenues for research of sex-linked, genetic diseases because there are several types of cancer that are linked to the chromosome Y genetics

in particular. Promocin Y might have tumor suppression properties and having a copy of chromosome Y might mediate some cancer phenotypes. If the Y is generally inherited down the male line, Do all the Y chromosomes trace their way back to a single ancestor, Dr. Makova? Well, we do think so, yes. Just as we talk about the mitochondrial Eve, we are talking about the chromosome Y Adam. A different atom, I'll point out. It's a neat bookends, Ira, that the project that we launched to finish these last gaps in the genome, The first chromosome that we started with was the X chromosome.

And the last chromosome that we finished was the Y. And the X has some also interesting disease-linked genes for some of the same reasons we mentioned earlier, that in X-Y individuals, you only have one copy of both the X and the Y. So if you inherited from your mother a defective copy of a certain gene on the X-chromosome, you don't have a backup copy. And so there's certain X-linked diseases that are more frequent in males for that reason. And so the sex chromosomes definitely have interesting sex-linked disease associations.

That is fascinating. This is Science Friday from WNYC Studios, talking about the Y chromosome with Adam Philippi and Katrina Mikova. I know you're both working on a project to put the human Y into context with other primates Y chromosomes. Who wants to tell me about that? Yeah. So we are currently deciding the complete telomere to telomere sequences of the

Y chromosomes of our close relatives, chimpanzee, Bonobo, Gorilla, Orangutan, and Gibbon. We hope to talk more about this in the future with you, but our preliminary results suggest that the Y chromosome has evolved very rapidly in primates. Just to give you a preview, the proportion of genes that are shared between human and chimpanzee white chromosomes is as low as the proportion of genes shared between human and chicken outside of sex chromosomes. And we diverged from chimpanzee lineage about six million years ago, whereas human and chicken diverged 300 million years ago. Now that you have the sequence, where do you go from here? So first of all, the white chromosome carries segments of DNA that are important for male fertility.

So having the reference of the Y chromosome, the accurate reference of the Y chromosome, opens up studies of male fertility. It also opens up functional studies of repetitive elements, such as satellites and their role for the rest of the genome, not just for the Y chromosome. It opens up additional studies of white chromosomes. fibrosome variation in humans. And I think the most important one is that it allows scientists to

incorporate the white chromosome into studies of predisposition to genetic diseases. Dr. Philippi, do you have anything you'd like to add? Yeah, I find the sequencing of these non-human ape species both incredibly interesting and incredibly promising for our understanding of human health going forward. Because when we look at the non-human apes, so Katerina can correct me if I'm wrong, but if we're talking about the great apes, they share a common ancestor going back around 12 million years ago.

And we're talking about an evolution of a genome on these independent lineages for 12 million years. And evolution is very creative, and it will try all possibilities of mutations, have mutations and rearrangements and so forth. And so when we look at things in those genomes that have not changed, that tells us that they're incredibly important to the genome

and to the function of the individual. And so then if we're in a clinical setting and sequencing a new genome of, say, a newborn that has a rare disease, and we see a mutation in one of these regions that's incredibly conserved across all of our near relatives, we know that it's functionally very important. And so that can help disease detectives

kind of narrow in onto the mutations they're looking for when they're trying to diagnose an actual patient in the clinic with a rare disease. Wow, this is all fascinating stuff. We have run out of time. I want to thank both of you for taking time to be with us today. Adam Philippi is a senior investigator in the computational and statistical genomics branch of the National Human Genome Research Institute that's at NIH. And Katerina Makova, Professor of Biology at Penn State University. Thanks to both of you for joining us today. Thank you. Yeah, thank you, Ira. And that's it for this week. If you missed any part of the program or you would like to hear it again, subscribe to our podcasts or ask your smart speaker to play

Science Friday. You can find us all week on social media, Facebook, X, the former Twitter, or with our newsletters, sciencefri-dot com slash newsletters. Or you can reach out to us the old-fashioned way. SciFri at ScienceFriday.com. We'd love to hear from you. Have a great weekend. We'll see you next week. I'm Ira Flato.