S6.25: 2023 Unzipped

Hello, and welcome to Genetics Unzipped - the Genetics Society podcast, with me, Dr Sally Le Page. It’s the final episode of 2023 so we’re sharing a Mendelian medley of unaired clips from some of our favourite interviews this year.

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Every year, Kat and I have the pleasure of interviewing some of the best and brightest in the field of genetics. Chatting with scientists about the ideas that get them out of bed in the morning is honestly my favourite part of this job, and so it’s always a little disheartening when we have to cut out whole conversations in the interest of time, or ‘kill your darlings’ as they say in the biz.

But lucky for you, we’ve wrapped up these conversational crackers into a scientific smorgasbord, an allelic amuse-bouche, a genetic gallimaufry, if you will, into this bonus episode.

Turi King: “Go for around the ears!”

Starting us off, we’re going to hear from Professor Turi King from the University of Leicester who I spoke to in June. In the episode, we talked mostly about her role as a geneticist on the project that found Richard III buried underneath a car park, and the ethics of sequencing historical figures. But our conversation also took a more practical turn, so here’s more of a how-to guide if you happen to stumble across a skeleton when you’re digging up your delphiniums…

Sally: So if you've got a skull in a ditch covered with a load of soil, is there a special way you have to get it out of the ground if you know that you're going to then study the genetics of it afterwards? 

Turi: Yeah, I mean I have to say I haven't done any skulls in ditches. I've done them in trenches. But so the main thing that you have to worry about is that the DNA in the skeletal remains is going to be degraded and quite damaged.

Turi: So whilst we're alive, we've got really nice long strands of DNA. And there are things that come along kind of break it, but your body just knits them back together for you. After death, that's not happening anymore. So what happens is the DNA starts to degrade, it gets into shorter and shorter fragments and it gets chemical changes that means that the DNA is quite damaged.

Turi: And it's not really how long the remains have been in the ground, it's the burial conditions. Or for example, if you're going and getting samples that are in a museum, how have they been kept? Ideally, you want cold and dry. That's best for keeping DNA as intact as possible. You know, warm, wet: not good because that helps the DNA degrade even faster.

Turi: So if you were to breathe on these remains and touch them and stuff like that, you're depositing your own DNA all over them, and that's going to swamp out any signal of any ancient DNA. So what you want to do is you dig under what's known as "clean conditions" which I think is quite a sweet term because you're often in dirt whilst you're doing this, but you're in there like the full-on CSI gear, face mask, hair net, you know, gloves, this kind of thing.

Turi: All the time you're minimising the possibility that you might contaminate the remains with your own DNA. 

Sally: That is amazing because obviously if it's buried in the ground, like there's soil, there's so much DNA in the soil, it's physically dirty, but I suppose it doesn't really matter as long as it's not human DNA.

Sally: Like if you're in a cow field, it doesn't matter if there's a cow that's just weed on the site, because you can separate that out genetically.

Turi: Yeah, as long as you're not trying to look for cow DNA! 

Sally: Now you say that DNA degrades over time. How far back can we sequence human DNA? Is there a limit?

Turi: Well, so mammoths, they've gone back over two million years, because you get mammoths in permafrost. So Neanderthals, over 400, 000 years. Humans - anatomically modern humans - over 40, 000 years. So you can go back really quite far. It really depends on the burial conditions. 

Sally: So these oldest 40, 000 year old human DNA that's been sequenced, has that been trapped in ice for a long period of time?

Turi: So these are from caves. They're from caves in Bulgaria, and the Czech Republic are ones that they've done. So caves are quite good because they can often be quite cold and undisturbed. 

Sally: So yeah, drilling into... do you drill into the bones? 

Turi: You do, so there's various bits of the remains that are better than others in terms of being able to get ancient DNA out, so the petrous portion of the temporal bone is your kind of gold standard that you tend to want to go for. It's the hardest bone in the body.

Sally: Which bone is this? 

Turi: It's in the ear, so it's like around the ear canal. You know, for a long time, we didn't know about this, but in the last sort of 10 years or so, it's been found that that is the best bit of the body to get DNA out of from the individual. 

Turi: So you're right, there's DNA in the soil and all sorts of stuff, and it depends on what you're interested in. But if you're interested in DNA from the remains, a lot of the DNA that's in there is actually going to be from, you know, bacteria and stuff you're not necessarily interested in . So if you're interested in the DNA from the individual, you want to go for the petrous portion of the temporal bone because it has kind of the most amount of what's known as endogenous - so from the individual - DNA per kind of square inch.

Turi: Then next best thing to go for is teeth. And then after that, sort of the really kind of dense portions of long bones and you work your way down the scale of, you know, if I can choose, I'd go for petrous and then tooth and then so on down through the kind of the hierarchy of bones to go for.

Sally: But the ears are the best. 

Turi: Yeah, round the ear, really, really hard. It looks almost like quartz. It's really interesting when you're drilling around it, you can usually see when you've hit that bit because it's very, very dense. And the drill, it feels different on the drill when you're drilling.

Sally: Well, good to know if anyone's going out into their garden, go for the ears. 

Turi: Go for around the ears.

That was Professor Turi King, and you can listen to the rest of our conversation in episode 13: Kings, car parks and consent: should we sequence DNA from human remains?

Christian Ottensmeier: “Many of us will have developed incipient cancers that never make it to become proper cancers.”

Next up on our CRISPR cuts, we’ve got Christian Ottensmeier, a professor of immuno-oncology from the University of Liverpool. Kat spoke with him back in August about using vaccines to train the immune system to fight cancer. But why do our immune systems even need training in the first place?

Kat: Why normally doesn't our immune system recognise cancer? 

Christian: We see the results of failure. So the cancers that are potentially developing that our immune system can see get mopped up and removed before they become visible to us. I think that many of us will have developed incipient cancers that never make it to become proper cancers that we are sick from, because our immune system has actually done its job. So what we are seeing is the failure of the immune attack. 

Christian: Even in cancers that have developed, there is evidence that the immune system is still trying. And the more it tries, the better for the patient. So you get a spectrum from 'the cancer is prevented in the first place' to 'the cancer has happened but isn't really very bad' to 'the cancer has happened and kills you'.

Christian: And that is really a key knowledge that has been gained in the last perhaps 25 or so years, where we've begun to recognise that the immune system continues to try and the better it is at doing that, the better for the patient. 

Kat: One of the things I do know about cancer is that every person's cancer is a unique evolutionary journey. It picks up its own mutations, it goes on its own genetic journey as it grows and develops. And one of the issues with things like cell therapy for cancer is this genetic diversity. 

Kat: So when we're talking about therapeutic cancer vaccines, are we going to need to have a personalised vaccine for every individual, like the cell therapy for prostate cancer?

Kat: Or do you think that we will get to a point where there could be sort of a universal or a per-cancer-type or a per-general-genetic-flavour-of-someone's-cancer kind of cancer vaccine? 

Christian: I don't know the answer. So the problem with personalised cancer vaccines is that the tissue that you use to make the vaccine has a bias.

Christian: So let's assume you have 10 metastases and you take one sample from one place, then you sample what is representative of that one site and you hope that it's also representative of all the other stuff that is making the patient sick. That may not be the case. 

Christian: And it is unclear therefore to me whether the personalised vaccines will always be a step behind the development of the cancer cells.

Christian: So I think in the end we will only find out by looking at how often this kind of approach actually works. It is much easier in patients whose cancer has been removed because there, the heterogeneity will be much, much smaller, and essentially restricted to single cells or small clusters of cells. And that's why I think it is so exciting to see the Moderna personalised cancer vaccine in melanoma patients.

Christian: What will happen in more advanced disease, we just genuinely don't know. 

Christian: The alternative approach is to not make the vaccine very special to that individual, but make a vaccine that is very broad and can capture any kind of variant if you wish, or at least any kind of protein that you think might be characteristic for lung cancer or breast cancer, prostate cancer...

Christian: And so I think the concepts are: make it very specific - they are the personalised cancer vaccines - make it very broad and make it capture as many possible targets, and then sort of a halfway house along that spectrum.

That was Christian Ottensmeier, and you can listen to more from him in episode 17: Vax to the future: The science of DNA and RNA vaccines.

Antony Dodd: “Plants can’t see… but plants perceive different colours.”

Our next Christmas contribution rescued from the cutting room floor comes from my chat with Professor Antony Dodd as part of our episode on circadian rhythms. You may have heard him talk about how clock genes affect when’s the best time to apply fertiliser to crops, or how they could be hijacked to weaken malaria. But those aren’t the only unexpected places he’s found circadian rhythms…

Sally: It would make a lot of sense that things that aren't exposed to daylight, so they can't tell the difference between night and day, wouldn't be so closely tied to a day-night rhythm, a circadian rhythm. But then I saw that there's recently been some work in soil bacteria having a circadian rhythm. Isn't it dark in the soil? How do they know when it's daytime? 

Antony: So it might be dark in the soil, but there's temperature fluctuations in the soil. So in soil bacteria for example, the soil bacterium that has recently been reported to have a circadian rhythm is Bacillus subtilis, which is a soil bacterium that also associates with the roots of plants. But it's exposed to 24 hour cycles in temperature conditions in the soil and also in a variety of other environmental factors, so perhaps the availability of moisture in the soil fluctuates with a 24 hour cycle. Or perhaps the availability of certain nutrients in the soil fluctuates with a 24 hour cycle.

Antony: And in some circumstances it might be nearer to the surface of the soil where it would be exposed to some light. And indeed the work that I was involved with that investigated the clock in Bacillus and how it responds to different environmental signals found that it also responds to the presence of light and that that can entrain the clock. And it can respond to different colours of light in the environment as well.

Antony: It seems that what's happening is that it's integrating a variety of different types of environmental signals and using that information to align its biology with the 24 hour cycle. And that may depend on where it's positioned within the soil or whether it's not close to the root of a plant or in some kind of association with another organism.

Sally: You mentioned colours of light. I know that for humans they say that blue light is super important, my computer monitor I have it so that it goes yellowy orange towards the end of the day so that it's not waking me up. Is that the same kind of thing that you're talking about where some wavelengths have more of an effect than others?

Antony: Different wavelengths have different strengths in what we call entraining the clock. So entrainment of the clock is the process whereby the phase of the clock, so the timing of the clock, is adjusted by an environmental stimulus. And different environmental stimuli have different entrainment strengths, depending on their intensity, depending on the time of day that they occur, and also depending on the nature of the entrainment cue.

Antony: Light and temperature can have different effects, and different colours of light can have different effects. So in humans, blue light is a particularly strong entrainment cue. And in plants, plants can perceive blue light and red light. And in the study that we published, focusing on Bacillus subtilis, we found also that Bacillus can respond to both red and blue light.

Antony: Often, light of different colours is detected by something that we call photoreceptors. And photoreceptors are molecules or proteins that are found inside organisms that are modified by light, and that enables them to then communicate information inside the cell in response to the light. In the case of Bacillus, it's known that it has a photoreceptor for blue light and in our experiments we also found an entrainment response to red light but we know less about how it perceives and responds to red light at the moment.

Sally: And those different photoreceptors, I suppose that's the equivalent to like our RGB when you've got people who are colourblind, they're missing one of those, aren't they? 

Antony: It's actually possible to make mutants of photoreceptors in organisms to study the effect of those photoreceptors on circadian rhythms. In the case of circadian rhythms in plants for example, plants have a suite of different photoreceptors that perceive red light, blue light, and UV light.

Antony: And by specifically deleting individual photoreceptors, it's possible to find out the role of each of those in transmitting information into the clock. But you can imagine that when you have a situation where there's different photoreceptors that are tuned to receive different colours of light and to perceive different intensities of light, it provides a mechanism whereby the organism can conduct surveillance of its environment continuously in order to align processes including the clock with the 24 hour cycle.

Sally: So in a very tangential way are you saying that plants can see in colour? Or they can respond to colour, maybe not see because they don't have eyes or brains. 

Antony: Plants can't see because they don't have eyes, brains or a nervous system, but plants can perceive different colours and they use that to obtain information about their environment.

Antony: For example, it's really important for plants to know whether they're adjacent to plants that will compete with them and take their light. So in order to do that, what they do is they monitor the spectrum of light that they're receiving. And if they have competing plants nearby, they're receiving more far red light because plants absorb red light, but far red light gets through.

Antony: It leads them to respond by changing their development so that they can grow faster and try to out compete their competitors. So plants use the spectrum of light that they're exposed to as a source of information so that they can understand and respond to competitive threats that might exist to give them the best chance of reproducing.

That was Antony Dodd from the John Innes Centre, and you can find out more about clock genes in episode 21: Time of your life: how circadian rhythms shape the world.

Kira Dineen: “The Genetic Information Nondiscrimination Act... I’m very glad that that’s in place - but there’s exclusions to it.”

This year we’ve talked quite a bit not just about the science of genetics but also the ethics of genetics and its impact on society, whether it’s making decisions about genetic modification, sequencing ancestral DNA or public understanding during the Covid pandemic. Back in April, I chatted with genetic counsellor Kira Dineen about direct-to-consumer genetic testing, such as the ones you get from companies like 23andMe or Ancestry DNA. You might even have been given one of these kits for Christmas where you spit in a tube, pop it in the post and then find out what percentage Neanderthal you are or whether you are genetically predisposed to like coffee. But, as Kira pointed out, these tests could have much bigger consequences…

Sally: I know that in the States, health insurance is... a thing.

Kira: Oh, it's a thing.

Sally: We do also have private health insurers in the UK. One of the biggest ones, Bupa, they actually offer their own DNA test, Bupa SmartDNA. And I can totally imagine a situation where someone gets their genetic test done, they find out that they're at a much higher risk for some very costly disease that requires lots of hospital interventions.

Sally: If I was an unscrupulous health insurer, I would say, "Right, I've got that information, you're going to cost me more in the long run, so I'm going to charge you higher premiums."

Sally: Is that a thing? I imagine if it has happened, it would have happened in the States. Is that a thing? Are there laws about it?

Kira: Yes. So there is a law that was put in place in 2008. Well, it went into effect in 2009, and it's called GINA. So that stands for Genetic Information Nondiscrimination Act. And again, this is in the US. And it protects two aspects.

Kira: So it protects, as you said, like insurance, like healthcare coverage - that. It also affects employment, where your employer can never use genetic information to make employment decisions - hiring, firing, stuff like that.

Kira: But focusing on the healthcare side, health insurers cannot use genetic information to determine if someone's eligible for insurance or to make coverage, underwriting, or premium setting decisions. So as you said, yeah, if I had a genetic result that increases my risk for a certain condition that they know is going to be costly, they can't change how much they're charging me. So I think that's really important.

Kira: I'm surprised that this went into effect in 2009? Like, that's relatively recently, right?

Sally: Oh, I was thinking that's quite early compared to the history of direct to consumer tests as well. Because - particularly thinking about relatives - I could imagine if I got a test, if I had to then declare my blood relatives' genetic tests and that then affected how much I paid for health insurance if I was in the US, that would be awful! Someone else's decision to have a Christmas present is now costing me thousands of dollars a year because of what they did. So it's good to know that that's not the case for now in the US.

Kira: Yeah, at least in the US. I have to do my homework for the UK. But it's also important to know like, okay, you're protected in that sense and that's great because otherwise then we'd be deciding, is it worth it to do the genetic test? What if this costs you money? Right?

Kira: So I'm very, very glad that that's in place, but there's exclusions to it. So it excludes long term care insurance, life insurance, and disability insurance which basically means this Act - the GINA Act - means if you have genetic testing that elevates your risk for something, insurance companies see that. There's no law protecting you for those companies, they could just say, "You're not eligible for life insurance, or it's going to cost you way more. You can't get disability insurance, you can't get long term care insurance."

Kira: I don't know of any cases where this has actually happened. Maybe there are and I'm just not aware which is quite possible, but I think it's important to realise this isn't covering everything.

That was Kira Dineen, and you can listen to the whole conversation in episode 7: Chris Hemsworth took a genetic test for Alzheimer’s. Should you?

Cordelia Langford: “ I didn't really have a role model… But I'm so glad to have the role that I have today.”

Part of the mission of this podcast is to inspire more people to be interested in genetics and potentially take up a career in the sciences. But what if you’re just not cut out for life in a lab? Well our next unaired appetiser talks about just that. In July, Kat spoke with Cordelia Langford, the Director of Scientific Operations at the Wellcome Sanger Institute about being a part of science without actually doing the experiments or writing the grants…

Kat: It's interesting from a career perspective because I did the very standard route into science. I did, you know, science A levels, I did a degree, I did my PhD and then realised I wasn't very good at science and went into science communications. But I think it's interesting from a career perspective that there's this whole world of jobs that are in and around the world of science but aren't being a scientist.

Kat: Do you think we should know more about scientific operations as a career avenue for people who love science but don't necessarily want to work in a lab?

Cordelia: I do believe that we should enable people to know more about these opportunities because the range of roles that are available that actually are contributing significantly towards science without necessarily being a researcher, they are plenty.

Cordelia: Your description is not so dissimilar from my own experience. I started my career feeling as though the only option I had to get along was to get a PhD. There was no question in my mind. It felt like it was the only way I was ever going to progress and I was quite ambitious. But it was during my PhD that I thought, "I love the science, I absolutely love this, but I love the technology and working with people more."

Cordelia: And it was serendipitous. In fact two of my PhD colleagues were very much wired - at the same time, we were doing our PhDs at the same time here at Sanger - they were very much wired to going off and writing grants. I perceived that the traditional researcher route - academic researcher route - was writing grants, spending ages writing manuscripts, getting rebuffed, writing again, and that just did not appeal to me.

Cordelia: And at the time that I was coming to the end of my PhD, a decision was made at Sanger to create a facility that was actually focused on microarray or DNA chip technology. This was a collaboration with some cancer research charities. And I remember thinking, "That is exactly the sort of thing that I feel like I want to do!"

Cordelia: And in fact, a number of people said, "Well, aren't you wasting the fact that you've done a PhD? Are you sure, is this the right direction?" It felt absolutely right for me because I realised that my skills lay much more in terms of building technology, solving problems, working with people, developing protocols. I was so delighted for that opportunity and that really was the foundation that enabled me to follow a path that meant that I perhaps took on more and more responsibility over time, perhaps for more numbers of labs and people up to where I am now.

Cordelia: I didn't really have a role model. And so I felt a little bit like I was picking my own way. But I'm so glad to have the role that I have today.

Cordelia: It's interesting that you said that you, I think you made a comment that you said something like, "Oh, I realised I'm not very good at science!"

Cordelia: And it's interesting, because in my brain, I just thought, "You're good at science. You're obviously good at communicating!"

Kat: I'm not good in the lab... And it's the same thing. It's like, I just didn't want to be on that treadmill of like grants and grants and grants and grants and... Also I think I'm a completer and a creator and I just couldn't stand that you could work for three years on something and it just goes nowhere. And I'm very clumsy as well so it's not good working with pre-implantation embryos if you're going to be clumsy...

That was Cordelia Langford, and you can hear the rest of her conversation with Kat in episode 15: Cordelia Langford: Making big science happen.

João Pedro de Magalhães: “There's been lots of interesting findings in these long lived disease-resistant species.”

And just as the year has almost come to an end, we’re almost at the end of this episode, but don’t worry, I won’t leave you with a lump of coal. The last - but certainly not least - of our Christmas cold cuts comes from back in May, when I spoke with João Pedro de Magalhães, a professor of molecular biogerontology at the University of Birmingham. The episode was all about what we could learn from the animal kingdom to improve our own health, and it seems like there’s a few species out there who could teach us a few things about getting older…

Sally: What would you say is the coolest adaptation or the quirkiest thing that you've found? Because you've studied loads of different species at this point. What's the animal that you're like, "Wow, they've really got this funky thing sussed out as to how to protect themselves from ageing?"

João: Mmh, there's a couple of things that spring to mind.

João: I would say there is one adaptation, but it's not so much ageing related, that I've always found intriguing which is metabolic adaptations. So whales, because they're so massive, if they have the same metabolic rate per cell that we do, then they would have a lot more heat generated. So they need to have a different metabolic regulation to ours.

João: And one of the things we did find in a bowhead whale, and then we also observed in other whales, is that actually some of the mechanisms, in particular one protein called uncoupling protein which is involved in thermoregulation, is very different between the whales and other mammals. And so we think this is related to the metabolic adaptations, with the fact that, you know, the cells from the whale, they cannot generate as much heat as a human being. I think someone estimated, or anecdotally maybe said that if they generated the same heat as a human being, they will literally boil the water around them because it would generate so much heat. So that's one that springs to mind as quite interesting from a metabolic perspective.

João: I think in terms of ageing, we haven't really figured it out. There are great adaptations. I mean, Vera Gorbunova, for example, she found in naked mole rats that they secrete a particular kind of hyaluronic acid which is quite long in naked mole rats. And this hyaluronic acid contributes to the flexibility of tissues, because naked mole rats, they live underground and so because they live in subterranean tunnels, they have to go through the tunnels, and so they need to have very plastic skin, which you notice if you ever see them.

Sally: They look really wrinkly. They look incredibly wrinkly.

João: And the reason for that is because they don't have fat deposits under the skin. Their skin is very flexible, so you know, I can't move my skin very much, it's got fat that's attached to it. But naked mole rats, their skin is very, very flexible, because they live in tunnels.

João: And so one of the reasons as well is that they have the hyaluronic acid, and that hyaluronic acid also protects against cancer, which I think is quite an interesting adaptation, cancer-related. So yeah, there's been lots of interesting findings in this long lived disease-resistant species.

Sally: Hyaluronic acid, is that it?

João: Yes, hyaluronic acid.

Sally: That's the stuff in skin cream, right?

João: It is, and you can also do injections of hyaluronic acid.

Sally: And will it give us amazingly supple skin like a naked mole rat? I can't imagine any pharmaceutical or makeup company putting a picture of a naked mole rat on the box and saying, "Have our cream and you can look like this!"

João: That would be a good one, yes. But yes, hyaluronic acid is used already in humans. Well, I've had injections of hyaluronic acid on my knee, for instance, because I play football and I have knee problems, so it's used for quite a few things basically.

That was João Pedro de Magalhães and if you want to listen to the whole episode, it’s episode 9: Raiders of Noah’s Ark: Stealing genetic tricks from the animal kingdom.

That’s all for now and that’s all for 2023! Thank you to all our guests who have taken the time to chat with us over the year.

We’ll be back in January when Kat will be sitting down with Greg Radick, author of the new book Disputed Inheritance: The Battle over Mendel and the Future of Biology, to find out whether it's time to shake up the way we teach the science of heredity and finally retire the Grandfather of Genetics, Gregor Mendel, from the classroom.

For more information about this podcast including show notes, transcripts, links, references and everything else head over to geneticsunzipped.com You can find us on Twitter @geneticsunzip and please do take a moment to leave us a rating in the Spotify app or review us on Apple podcasts - it really makes a difference and helps more people discover the show.

And don’t forget, all I want for Christmas is…for you to fill out our listener survey at geneticsunzipped.com/survey where you can also enter for the chance to win a signed copy of Kat’s book, Rebel Cell. 

This episode of Genetics Unzipped was written, presented and produced by me, Sally Le Page. It’s a First Create the Media production for The Genetics Society - one of the oldest learned societies dedicated to promoting research, training, teaching and public engagement in all areas of genetics. You can find out more and apply to join at genetics.org.uk.  Our theme music was composed by Dan Pollard, the logo was designed by James Mayall and our executive producer is Kat Arney.

Thanks to the whole First Create the Media team who work on making this podcast happen, including additional research by Miyako Rogers, project management by Fergus Powell, and research, scripting, production and editing by our podcasting wizard, Emma Werner. Thanks for listening, and until next time and indeed next year, goodbye.