Linda Goodman: Stealing secrets from sleepy squirrels
Image courtesy of Linda Goodman
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To start us off, I sat down with Dr Linda Goodman, co-founder and chief technology officer of FaunaBio, a startup developing new therapies for humans inspired by disease resistance in animals. They’re looking at the genomes from a whole host of animal species to see which genes are associated with some of the amazing adaptations that could possibly be harnessed in medicine. But of course, these are genes from completely different species to us; how applicable are they to humans?
Linda: By and large, we're talking about the same genes that they have, and you and I have. They're just using them in a different way. They're turning them on and off in a manner that makes it less likely for them to get a disease or turning them on and off to reverse a disease. And humans do not currently have that ability for many of the common diseases, but some animals do, and that's what we're diving into.
Sally: So when you've got the entire animal kingdom to draw from, how do you decide where to start? Because that's a hell of a lot of species.
Linda: There are a lot of species! At Fauna Bio, we've started by focusing on the 13 lined ground squirrel, just because they have so many adaptations that could be applicable to human disease.
Linda: They're really a treasure trove and we realised that we could approach many different disease pathologies by looking at the ground squirrel.
Sleepy squirrels
13-lined ground squirrels go through a similar event to the human heart attack 25 times during their hibernation.
Image courtesy of Linda Goodman.
Sally: What is a 13 lined ground squirrel? I've not seen one. Where do they live? What do they look like? Do they have exactly 13 lines?
Linda: They do! They have 13 little stripes on their back. That's how they got that name. Yep. They live in the Midwest. You can actually hold them in your hand while they're hibernating and it's kind of creepy. They feel ice cold, but they're alive.
Sally: So when they're hibernating, I mean, we should start with: what is hibernation? I think most people have a rough idea of going to sleep for winter. But is there more to it than that?
Linda: Yes so real hibernation would be a drastic decrease in your metabolic rate for more than 24 hours. Many people think of hibernation as bears that kind of sleep for half the year. But when you're talking about small animal hibernators, it's actually a really dynamic process.
Linda: So the ground squirrel goes down to four degrees Celsius. Their heart rate also goes down to three to five beats per minute, and they stay there for one to two weeks. And then they come out of it, back to normal body temperature, and they do this cycle around 25 times throughout the winter. So they're constantly going in and out of this deep toper state, and this creates an effect that's very similar to a heart attack or a stroke, because all of a sudden their tissues didn't have very much blood or oxygen and all of a sudden they get reperfused with a rush of oxygen and blood.
Linda: And oftentimes this can cause systemic tissue damage if this were to happen in a person. But the ground squirrels are adapted to deal with this.
Sally: So how do you study these animals? Do you have ground squirrels in a lab? Do you go out and catch them at different points in the winter? What does the research look like?
Linda: So it's both of those. So we have a collaboration with the University Wisconsin at Oshkosh, and we have this colony of 13 lined ground squirrels out there. We also go on trips where we catch 13 lined ground squirrels to then bring into the colony because you don't wanna get a really inbred colony, that can really affect some of your results as well.
Sally: I've got to ask, how do you catch a squirrel?
Linda: It's an interesting process...
Sally: You're not running around with a net?
Linda: Oh, you kinda are!
Sally: Are you?
Linda: So one of the places that we go, it's kind of creepy. You have to go to a graveyard. They love that kind of environment because it doesn't get a whole lot of traffic. It's pretty quiet. It's a flat area, it has grass. And those are great places for them to burrow.
Linda: And essentially what you do is - you're not gonna coax them out of their burrows easily, but you can put a little bit of water in and then that kind of makes them nervous like it's raining. And oftentimes they'll run out and right into your net.
Sally: Oh, very smart! And you say that they go from being in this very low oxygen state, back up to a bit more of a normal one around 20, 25 times a winter. Why do they do that? Is that just the temperature warms up on one day and they think it's spring and then they get it wrong and go back to sleep?
Linda: You know, it's interesting, I think to the hibernation community, why exactly they're doing that is not completely understood. But it's thought that some of it has to do with the fact that your body needs periodic repair to keep from shutting down. So they're turning back on some of those repair enzymes and doing some amount of tissue repair before they go back into hibernation.
Sally: So we know that these amazing little ground squirrels - and there will be pictures on our website cause they are adorable - we know that they can survive these incredibly low oxygen environments, and I suppose it's more the fluctuation in oxygen that is what interests you when it comes to looking at human heart attacks.
Sally: So how do you go from, okay, here's an animal with a really cool adaptation to here's a drug that we can use for humans based off it.
Linda: So a lot of it has to do with combining many, many different data sets. The primary one that we use from the ground squirrels is understanding the genes that are turning on and turning off at some of these critical time points.
Linda: What are the genes that are coming on as these tissues are all being reperfused, blood oxygen is all coming in, and they really need to protect their tissues from reactive oxygen species. What are the genes that are coming on precisely at that time point?
Linda: And then what we do is bring it back to humans and we would take a data set, say from individuals who've recently had a heart attack, and compare what's going on in these animals. One of these animals has had something very akin to a heart attack but was protected and did well, and the human had a heart attack and obviously took on a lot of damage.
Linda: And so we can compare the genes that are turning on and off between those two species to try to really hone in on this is the group of genes that we think matters.
Sally: And in the case of their heart being able to cope with these massive changes, what are the genes that you've found that they're using? What do they do?
Linda: They actually start to turn on a lot of the collagen genes that are required for repair, but then they turn them off very rapidly and their heart actually repairs itself at a much slower rate than mine or yours would if we had had a heart attack.
Linda: But when they've completed their repair, their heart looks great. It doesn't have all of the fibrotic tissue that we would, so we repair it fast and we do a bad job. The squirrels repair it very slowly, but do a great job.
Sally: We've been talking about how you've been looking at one species at a time, the ground squirrel, for example, and how that is amazing. But you've also just published data looking at a whole range of animal species all at the same time. Can you tell me more about that?
Linda: Yes. So this is work that began at the Broad Institute with Dr. Elinor Karlsson and Dr. Kerstin Lindblad-Toh, and also the University of Uppsala in Sweden. And the idea is that, If we look across 240 mammal genomes and we look for specific base pairs that have not mutated, and really we're talking about a hundred million years of evolution that separates these animals, if this base pair hasn't changed in that length of time. It's doing something really important. So if you had a mutation there, you were a dead mammal.
Linda: And that's how we know that these are really key base pairs to focus on, not only for mammals in general, but specifically for human health. So we can overlay the base pairs that we know that are conserved in these mammals with human disease data sets and really hone in on the specific mutations that matter for human disease.
Sally: And how many of these conserved regions are there? What sort of scale are we talking?
Linda: It's around 11% of the genome that is conserved.
Sally: 10, 11%, that's still quite a lot. So then how do you narrow that down further?
Linda: Yes. So we do that by linking these genomes back to specific traits. So we could then examine animals that have a trait and don't have a trait. Let's say, really long-lived species versus short-lived species, animals with big brains and little brains, and animals that can hibernate and not hibernate.
Linda: And then we can look at a different pattern of conservation and say, what are the genes that are highly conserved in hibernators? They're not mutating in hibernators, but they can accumulate a few bad mutations in non-hibernators and it won't matter.
Sally: But that means that when you're separating your 240 mammals into hibernators and non-hibernators, those hibernators aren't especially related to each other. And there can be species in there that are more closely related to them that aren't hibernators.
Linda: Correct, yes.
Sally: So you're now looking at like, okay, this gene has been conserved in these very disparate, very unrelated species that hasn't been conserved in their sibling species. So that's really powerful evidence to say it's something to do with the hibernation that forces this gene to be conserved.
Linda: Exactly. You have it exactly right. So we compare the 13 lined ground squirrel against other ground squirrels that live in more temperate climates where they don't need to hibernate. And we look at those genomes and then we also look at bats that will hibernate and not hibernate. And we could go in and say, well, what is consistent about all of the different hibernating species? Which of their genes has clearly been constrained over the past a hundred million years?
Sally: And how many of these genes have you found?
Linda: So I would say my list is around 20 that I feel confident about.
Sally: That's super manageable! Normally when people say we've identified targets, they're like, "Oh yeah, we've got it down to 2000!" and you're like, okay, good luck getting through that list, but 20 sounds super manageable. So what are the next steps?
Linda: So one of the great things that you can do with this is then compare to the gene regulation signatures. And what's amazing about this is these are completely independent data sets, right? One is genomics data, comparing 240 mammal species. The other is gene expression data from one specific hibernator.
Linda: And so we overlap those two data sets and say, do we see the genes that are conserved in hibernators also drastically changing their regulation throughout the course of hibernation? And that's how we hone in on really core hibernation genes.
That was Linda Goodman, and the papers she was talking about were published just last week in Science.
