Hacking the Genetic Code with Dr Nessa Carey

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Hacking the Genetic Code with Dr Nessa Carey

We can alter the human genome, but is that really a good idea? In this brave new world, biohacking, a new system called CRISPR and gene editing may possibly be rewriting our futures.

In today's episode, we talk to Dr Nessa Carey about the complex world of genetics and epigenetics, including discussions on the true purpose of so-called “junk DNA”. We also discuss how viruses may alter our genetic code, as well as the future of genetic and epigenetic editing and the moral dilemma surrounding this technology.

Covered in this episode

[00:27] Welcoming Dr Nessa Carey
[01:14] Discussing junk DNA
[06:44] Retroviruses in human DNA
[13:02] How do cells know what genes to express?
[17:56] Environmental influences and genetic expression
[20:07] Methylation and genetic expression
[25:14] Mechanisms of epigenetic changes
[29:02] DNA of the microbiome 
[33:25] Changing epigenetic expression
[37:32] Are we focusing too much on SNPs?
[43:54] The future of treatment based on epigenetic testing
[47:40] CRISPR and genetic editing
[54:26] Women in science


Mark: Hi, everyone and welcome. Today we're talking with Dr Nessa Carey, molecular biologist, virologist and author of three fantastic books on genetics. She's a translational science advocate bringing really complex information to the public and to professionals to make it understandable. Hi, Nessa. How are you?

Nessa: Hi, I'm fine. Thanks so much. I'm so glad to be talking to you.

Mark: It is great to be talking. I've been looking through your books. I have to admit that I haven't read them yet, but they’re somewhat iconic. "Junk DNA" and "Epigenetics" and now "Hacking the Code." Boy, you, as a molecular biologist, this has got to be the most interesting time to be around ever.

Nessa: Ah. It's a fantastic time to be working on anything DNA-related. It's just ridiculous how fast everything is moving now.

Mark: It is, isn't it? So in the mid-2000s, we were sitting there thinking, "Wow, we're gonna uncover the DNA,” and then there were just too few genes. There was only, what, 22,000. And broccoli 10 times as many, and we were thinking, "No, we can't be that simple.” How is it…

Nessa: Absolutely.

Mark: How is it that 22,000 genes can make a human? It just doesn't seem enough bits, you know, in information concepts. How does that happen?

Nessa: There's two things to bear in mind. One is that those 22,000, genes, you can actually use them to make lots of variants of the same protein. So although we have 22,000 genes, those 22,000 can code for different versions of different proteins so we can make lots of subtly different proteins. But the other thing that's most important is that actually 98% of our DNA that doesn't code for proteins, that we don't think of as traditional genes, a large amount of that is actually really important in controlling gene expression, controlling how cells behave, and we just used to call it junk DNA. And it was a classic example of we didn't know what something did so we assumed it did nothing. But now we recognise that our genome is packed full of these other weird bits of DNA and that actually those are probably vital for creating organisms as complicated as humans.

Mark: There seems to be a bit of a battle going on about, you know, the 22,000, they're the protein expression, so they're the genes coding for proteins. That's 2% of the DNA. But the argument, I think, is and you've been, I think even part of the battle within code is the Darwinian dogma of there's only those genes, they're the only important ones, versus 80% is the estimate of what's active in the genome. It's a big difference between the protein code as in what's active. All that other DNA, that junk, is doing stuff. How far have we uncovered that? How much do we know about it?

Nessa: We actually know a lot more than we used to know. We know that a lot of that junk DNA now controls the expression of the protein-coding genes, and we know that that junk DNA, often it codes for things that are really important for controlling cell processes. So for example, we know that there are things that come from the so-called junk DNA which are vitally important in the development of certain cancers, for example. And we find that drug companies are now starting to develop ways of influencing the junk DNA…

Mark: Wow.

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Nessa: …in order to try to do things like control cancer. So it's moving very quickly. I think it's becoming impossible for most sensible people to say that those other parts of our genome are not important. They are important, but they do have quite different things in the protein-coding parts.

Mark: Right. My memory may be flawed on this, we have these apocryphal stories, but, was the junk DNA, didn't someone buy it? I mean, as part of the genome project, it was the discardable stuff, and some organisation or individual turned up to actually pay for the rights for exploitation of the so-called junk?

Nessa: There was actually a really big battle when DNA sequencing took off, not just about the junk DNA, but about any DNA. 

Mark: Right.

Nessa: And that was an idea that companies could create...find a DNA sequence and then patent it, and then anybody who used that sequence could end up having to pay them a fee. 

Mark: Right.

Nessa: But ultimately, the patent offices all threw out those kinds of claims, because they failed one of the critical tests, which is that the people who identified those sequences, they didn't actually invent anything. 

Mark: Right.

Nessa: They just found something that was already there in nature. They did nothing clever with it, It would be a bit like turning over a rock, finding a spider and saying, "I claim a patent on that spider." You're not allowed to do that.

Mark: And yet we have patents. I mean, there are lots of patents. The, cancer genetics is full of different groups that have effectively patented genes. So how...where does that stand now? We have $5,000 tests for breast cancer patients to tell them whether or not chemotherapy will work defined by certain genetics. 

Nessa: Yes.

Mark: And as far as I can tell, those genes are owned by companies that exclusively wrought everybody.

Nessa: So what is owned by those companies is, broadly speaking, the use of that sequence of DNA as a diagnostic tool that then allows you to say target chemotherapy. 

Mark: Right.

Nessa: What isn't allowed by the patent offices is just to find a whole random set of DNA sequences and patent those without any understanding of what they do. So if you can show that a particular DNA sequence is associated with a cancer risk and that that cancer can be better treated with some drugs than others, you can patent that finding and you can patent a diagnostic based around it.

Mark: Okay. So there the protein expression genes that you can patent if you find a use for them. How about the junk DNA, the epigenetics, everything?

Nessa: Yeah, you could patent the junk DNA if you could find a use for it…

Mark: Right.

Nessa: …and if you could show that you've had some benefit. What's much harder, actually, in this field is it's relatively easy to patent something if you have data that shows that it can help with diagnosis, it's a lot harder to make money from that patent. Lots of companies tried and lots of them failed.

Mark: Right. Now, there's one thing that absolutely amazes me because I'm involved in an area of chronic fatigue syndrome and a lot of the genetic stuff has... There's been these reports of human endogenous retroviruses, it's almost like old enemies that somehow got into our DNA, transgenerational not just, you know, infection of individuals. And in my particular field, there's lots of papers for and against. But it almost seems like there is evidence of a rise of the expression of the old viruses, that they've been silent for centuries, millennia, or however long. And now we're seeing paper after paper say, "Well, there is an expression of the old retroviruses. They're not actually as dead as we thought and not just junk. And nearly 10% of our DNA is these old viruses, sections of old viruses." Have you any ideas about what may be going on there?

Nessa: Yeah. I mean, a lot of our DNA, as you say, is these old dead viruses. And, yeah, there is one version of dead virus, we have nearly a million copies of it in our DNA. 

Mark: Oh.

Nessa: So they take up a huge amount of our DNA. One of the things that is really difficult now is that sequencing and analysing what sequences are being expressed in the cell has become incredibly sensitive. And so you can pick up expression at very low levels of things like, for example, reactivated viruses. The problem is that you can't necessarily show that they are having an effect.

Mark: Right.

Nessa: It could be that it's just that whole area of the genome is some reason being switched on really aggressively, and that a few of those viral sequences have managed to reactivate. It's very difficult to demonstrate that that's been driving the pathology. 

Mark: Aha.

Nessa: So it's a really controversial field.

Mark: The idea that these are the viruses that we should be paying attention to clinically really doesn't hold up in those circumstances, does it? It may be that there is an expression of this part of the genome that is just an epiphenomenon of something else going on in a sick person.

Nessa: Yeah, that's exactly what might be happening. I mean, it might be they play a role, but the jury is very much out at the moment.

Mark: Right. Okay.

Nessa: It's frustrating how long it's taken to make progress with chronic fatigue syndrome.

Mark: Do you have any thoughts about how they get there? I mean, to get into our DNA transgenerational they have to have got into the germ-line somewhere along the line. And...

Nessa: They do, and it seems to be a very common phenomenon in mammals. Most mammalian species have lots of these in here. It's almost certainly, that what happened was way back in the evolution, a virus sort of infected the cell, and the viral DNA will have got integrated into our DNA. And then at various points during evolution, that bit of our DNA has just been copied and reinserted over and over again. So it's a bit like a copy and paste function that's gonna a bit rogue…

Mark: Okay.

Nessa: …and so we end up with thousands of copies.

Mark: So then the question arises, in nature generally, nature tends to be fairly efficient by virtue of natural selection and things not needed, things not, without a purpose, tend to fade away. Or do they? Right? If 98% of our genome is not expressing for proteins, is it just an accumulation of junk that we end up with, you know, 3 billion base pairs and most of it does probably nothing? Why would, in evolutionary of biology terms, why would there not be a selection that would just say, "Look, if it's useless and it's taking up space, then it's not providing an evolutionary advantage and it would disappear over time?"

Nessa: Well, one of the things in my mind is that actually one of the greatest indicators of evolution is the fact that most things are not perfect.

Mark: Not perfect. That's true.

Nessa: Yes, they are written for other reasons, and they haven't done any harm and evolution's just hung on to them. There's an argument that actually having a huge amount of junk DNA can actually make your genome safer. Because, all around us, we're exposed to things that might change our DNA. They might cause mutation, so things like ultraviolet radiation or irradiation from certain rocks and chemicals, etc. If we can package the most important parts and the protein-coding gene it's really important they don't change their sequence. If you could package those in lots and lots of filler, and when there's a mutation stimulus, the chances are it's gonna hit the filler and not the protein-coding gene. So it might be that there was an evolutionary advantage to having a lot of this junk.

Mark: Like, packing material, bubble wrap.

Nessa: Yeah, absolutely, exactly like bubble wrap. And so it might be that that's where a lot of the junk originated, and that's why it was maintained. And some of it either always had a second purpose or it's been repurposed as we've evolved.

Mark: Yes. That happens in even the protein expression, the genes have multiple inputs, and they can express in different tissues in different ways. So genetics is far more interesting. It was originally thought of as "Here's the blueprint, you're stuck with it," and it seems more like a kind of menu now that here's the 22,000 things on the menu but mix and match as you see fit. You can't eat it all, so each cell just takes what it needs. And you choose from the menu…

Nessa: Yes.

Mark: …that’s the limits of what you can do, but how you express it is an entirely different story, isn't it?

Nessa: Entirely. I mean, we have 70 trillion cells in the human body.

Mark: Yes.

Nessa: And they behave in an extraordinary number of ways. And that all happens from the same DNA script. So it is, you know, I always think of it is, I liked your menu idea. I also think that as it's like a script, and you can kind of, you know, you can skip certain scenes in the play, if you like, or you can cut certain lines. And you can get completely different productions from the same play, you know. If you go to the theatre and see "The Merchant of Venice" one year, and then you see a different production 20 years later.

Mark: Yes.

Nessa: Yeah, they use the same script, but they're very different experiences.

Mark: Which brings us on to epigenetic expression. I am still not clear on how one menu, one pack of DNA, so rapidly can coordinate itself into shutting off almost all the genes as it breaks out into different organ systems. So every cell in the body has the same menu, recipe, or play. How do cells know what to do? Literally, how do they switch off the things they don't need and do the things they do?

Nessa: We still have a lot of gaps to fill in on that question. But what we do know is that as organisms develop, you know, it's like if it's one cell, then it's two and four to eight, 16, 32, 64, etc. those cells, certain cells start becoming specialised. And we have still extraordinary gaps in our knowledge about how that happens. Some of it is possibly just that as a cell divides, it's very unlikely that each of the two daughter cells gets exactly 50% of everything else. So when a cell divides, the nucleus divides with all the genetic material and that does get split 50/50 between the daughter cells. But you've got all the other stuff around in the cell. You've got things in the cytoplasm. And it's likely that as the cell divides, those don't get split 50/50. There's just randomly, that one cell gets a bit more of some of those molecules in the cytoplasm than the other. And it's possible that what happens is that then pushes the cell down to another level of development. But we have enormous gaps in our knowledge on this. We know that it works…

Mark: Right.

Nessa: …because that's why we all survive and that's why we live, but we don't really know all the key steps. We don't understand a lot about how you start from this one cell and end up with all these different types of cells. But as cells start to change and as their gene expression patterns start to change, you get some sort of feedback loop. So that as the gene expression patterns started to change we can use a system called, or the cell uses a system called epigenetics to start reinforcing those changes and making it easier for the cell to continue with the same patterns of gene expression. But you can tell by the fact I'm having to use very vague statements that there are just huge mechanistic gaps in our understanding about this.

Mark: Which is amazing because there's a kind of an intelligence of the cells at the blastocyst stage as they start to expand, that voluntarily, that I understand there's even a concept of almost up and down, you know, left and right in the cells that there is spatial orientation, that cells are...

Nessa: Oh, yes, they'll definitely have polarity even very, very early in development.

Mark: And that sets their destiny for a particular cell line. So, I know this from the mitochondrial disorders, that the unequal division of mitochondria, some of which may be more damaged, can lead to mitochondrial diseases in say muscle or brain but not in bone. 

Nessa: Yes.

Mark: But there are those, as you say, the cellular components are unevenly divided, and that can set a sequence very early on in life that moves us on to diseases, really well known mitochondrial diseases. But you're saying, other cytoplasmic components, the same kind of thing happens. So is it, I thought it was just mitochondria, is what I'm saying.

Nessa: Yeah. It almost certainly happens with other things, and it happens with the distribution of proteins…

Mark: Right.

Nessa: …in the cytoplasm. And probably as the nucleus divides, there's differences in the proteins that present in each of the two nuclei. And the difficulty is that we've never really been able to interrogate that because we've never had the technology that's sensitive enough to do that very well, and we still don't. 

Mark: Right.

Nessa: It’s so much easier to look at DNA than it is to look at proteins.

Mark: There was a famous cartoon many years ago, of a set of equations on the left and the outcomes on the right, and the middle term said, "Then a miracle happens."

Nessa: Absolutely. I've used that cartoon so many times, it's brilliant. And it's certainly far more true of biology than it is of mathematics. 

Mark: Yes.

Nessa: That’s absolutely true.

Mark: Yes. I come back to that every time because, in medicine, our listeners are mainly practitioners, we get that question,"And why would that happen?" And we know the data gap, but we make up a story that fulfills whatever the person needs to hear at that time.

Nessa: Absolutely. And I always warn students that in biology, one of the things that we do if we don't understand something is we give it a really fancy name...

Mark: Yes.

Nessa: ...so that it sounds like we understand it, but…

Mark: You're talking to a doctor there.

Nessa: Yeah, absolutely.

Mark: We turn everything to Latin.

Nessa: Yeah, there you go. So you're even more of the field. That's what we do. We do it all the time. And it means we pretend that we have an explanation when actually all we have is a description.

Mark: Right.

Nessa: And we do it constantly.

Mark: So tell us about genetic expression. I mean, from our listener's perspective, we are told all the time about how diet can influence the genetics and how it can do so very, very rapidly, that external influences have profound changes on the way genetics are expressed, which seems to be almost Lamarckism, but it's not, is it?

Nessa: No, it really isn't. During our lifetime, we're subjected to so many variations in our environment. And those don't have to be dramatic ones like climate change, they can just be that we start eating differently or we do more exercise or whatever. And we've always known that how people indeed and the organism turns out is a combination of what we used to call nature and nurture. And then we kind of redefined that as DNA and the environment, it was genes and environment. But if we know it's a combination, then it means that there has to be some way that those two things interact. You know, how does an environmental stimulus change the expression of a gene? And in some cases, change it for a very long time. 

And this is where the field of epigenetics comes in. Epigenetics refers to another level of information which occurs on DNA. And we do understand the molecular basis for this, we understand that its differences, tiny differences that get added to the DNA and the proteins the DNA associates with. And these are called epigenetic modifications. And what they do is they never change what the gene codes for, but they change the way that it's expressed. So they can drive up the expression of the gene or drive it down or in extreme circumstances, switch it off for your entire lifetime. And when a cell divides, those epigenetic modifications get passed on, so the daughter cell does the same. And this is, those epigenetic modifications, that's why we end up with different cell types because our cell types get different epigenetic modifications that basically allow a cell to become a fair skin cell…

Mark: Right.

Nessa: …or a kidney cell, or a brain cell. But once that cell set is established, then the environment can also influence some of the epigenetic changes as well.

Mark: Is this in the area of methylation of genes and the histones? Is that what's the, transfers across generations of cells? It seems like methylation, just adding a carbon and three hydrogens, it doesn't seem plausible that that could influence or change the replication of DNA, and yet those and histones seem to have a life to them, which extends way beyond the microseconds that I would have imagined are necessary for, you know, they'd be cleared out very quickly. Why are they not cleared? Why does a cell when it divides not just drop all that and then start the whole thing again?

Nessa: So DNA...direct modification to DNA is almost always methylation. It is, as you say, one carbon and three hydrogens. And that's an incredibly stable bond when it's added to DNA. It takes a cell a huge effort to remove that modification.

Mark: Wow.

Nessa: Yeah. It's a really hard modification to remove, and in fact, cells can't remove it, they just changed it to something else. But that modification, when DNA divides, there is a machinery in the cells that when the DNA divides and is copied and is passed on to daughter cells, because each daughter cell gets one of the original strands of DNA, which may have methylation on it, there's a mechanism in the cell that means enzymes come along and can see that there's a methylation mark and they make sure it's reestablished on both strands of DNA.

Mark: Aha.

Nessa: So we understand, it's an amazing machinery. It works fantastically well. And we understand how that works at the DNA level. What we don't understand is when cells divide, and the histone proteins gets split between the two daughter cells, we don't understand how the histone patterns get re-established or are maintained in the daughter cells. And those patterns are really complex because there's not just methylation, there's loads of other modifications that the cells can add. And it's another of those black box areas where we just don't get it and we don't know what happens.

Mark: We don't get it, and yet there's things as simple as diet and exercise seem to have profound effects in those areas. It's almost, again, like, you add something as complex as what the person eats and then you see clinical outcomes, which are clearly different expressions of genes that happen as a result of dietary change, translating into, you know, health or sickness in a human being. There are clearly mechanisms at the biochemical level which must be able to do mop up operations or change that. You can't control, for example, you know, ionising radiation, but you can control your diet. And if the diet is controlled, how does that feed into that whole system of genetic expression?

Nessa: Again, there's quite a lot of black box stuff there that we don't always know about. But we do know that there will be things such as if you change the level of sugar in your diet, that will change the amount of insulin that's produced, that will change how the cells respond to insulin. And the bit that we were always missing before with why that would lead to long-term changes in gene expression. 

Mark: Right.

Nessa: It looks now what happens is, as genes change their expression that influences how they become modified epigenetically. And so you end up with this reinforcement cycle. And eventually, you may get cells trapped in the wrong patterns of gene expression, as a consequence of, well, a dramatic change in diet. But it's important to remember that those changes happen over time. You know, one doughnut is not going to…

Mark: Right.

Nessa: …completely change your epigenetic information.

Mark: And it has to change over time with vast numbers of cells all responding in the same kind of way. So it's not like radiation where a single DNA strand can be broken and that can progress on in particular ways and cancer as a result of it. It can be one cell in those circumstances, whereas with diabetes, with calcium deposition, things are going wrong with trillions of cells…

Nessa: Yes.

Mark: …at the same time based on something in the environment.

Nessa: Yes. But probably what we see is a threshold effect.

Mark: Right.

Nessa: So probably what happens is you don't get any obvious difference until a certain percentage of the relevant cells have hit a certain percentage of abnormal gene expression. But we're not very clear on what that percentage is. And it will almost certainly vary for different people depending on their genetics, and it will vary depending on what the stimulus is that you're looking at. The trouble is that humans are a terrible experimental species. You can't really do this in humans.

Mark: If only we could breed them up and clone them all and put them in cages, it would be a lot easier to figure this biology up.

Nessa: I know. Life would be so much easier.

Mark: I've always thought that with my patients. So 35 years of patients that I think they are all in of one trial, every last one of them doesn't do what I tell them, but they don't do it in different ways.

Nessa: Yeah. Absolutely.

Mark: So how... I suppose the clinical question is, that threshold concept would make some sense to me. You know, as a clinician, you get a person to a point, they're doing their diet, they're doing things, and things don't seem to be moving at all, the body's going through the same, say, Type 2 diabetes, and then they're at a threshold point. At some point, it's almost like the body's doing enough to remember its old pattern and go back to a different pattern of expression. And that involves a coordination that we...oh, I have no concept of a mechanism for. How is it that you push and push and push and nothing happens? And then suddenly, people make a move, in the individual you see the blood sugar and the insulin change fairly rapidly with a dietary change that they've been doing for six months, 12 months, nothing happens and then it goes, right. 

Nessa: Yep.

Mark: So is that a plausible mechanism for that?

Nessa: I think one could argue that epigenetic changes are consistent with that mechanism. If we look on the basis that very few people develop Type 2 diabetes overnight. It's taken a long time for that gene expression…

Mark: Yes.

Nessa: …to become so abnormal. So I think we really have to expect that it will take a long time for it to normalise, again. Our cells seem to have some sort of internal, almost like a thermostat that they try to revert to because they're trying to maintain some level of homeostasis.

Mark: Right.

Nessa: They're trying to maintain stability. If they're...if that thermostat's got set at the wrong temperature…

Mark: Right.

Nessa: …as it were, you know, it's going to take a long time to persuade the cell that it needs to change that condition. So I think if we see something take years to develop, it's not surprising that it may take months at least to reverse it.

Mark: To reverse. Yeah, I mean, it does fit with what happens in practice that there is drug therapy, and the drugs are highly targeted to affect or you know, destabilise an enzyme, do something quickly. Whereas with lifestyle, environment, and diet especially, there needs to be a persistence of the same signal over a longer period of time to affect, I guess a more profound change than what a drug can achieve normally.

Nessa: I think that's absolutely right. And of course, that's such a problem from the point of view of health interventions, because as humans, we seem to adapt really well to doing the wrong thing quickly, and maintaining doing the wrong thing, but it's very disheartening for people when they're trying to change their diet, and then not really seeing benefits as quickly as they'd like to see. And so I think it's another thing that makes us give up.

Mark: Yeah, and the drugs become very attractive and the sugar is so addictive. So, and experiment fails and they drift in different directions. I always get the feeling that if doctors were better at accumulating data and actually following it through, we could have contributed a lot more to the science of this rather than have experimental rats suffering as on our behalf.

Nessa: But I think all healthcare professionals are working in an incredibly difficult environment. Certainly if it's anything like the UK at the moment where our politicians talk a really good game about preventative health care, but they just don't put enough money into it.

Mark: Yeah.

Nessa: Because, it's a long-term game, and our government through elected for five years. Nobody wants to make unpopular decisions. And lots of public health is initially unpopular.

Mark: Nearly all of it is because in some ways consumerism is bringing all of the advantages for the ones who are good at harvesting energy, who would have made it through all the droughts and all the famines. 

Nessa: Yep.

Mark: It’s now a dangerous world to be in because there's no famines in Woolworths, so.

Nessa: No, absolutely.

Mark: Then the question becomes, we've got, I want to just move sideways a little. We've got our 22,000 genes. The big area that has grown over the last few years, almost replacing the genome project, is the microbiome. 

Nessa: Yes.

Mark: And the genetic expression of our microbes that not only, it's almost like another organ in the body, as separated individually. The microbiome has 1.5 or 2.5 million genes that seem to have interactions with some of our own cells, even if it's only mitochondria and the kind of the genes there. But there's an amazing interaction between almost the superbugs in the gut doing their own thing…

Nessa: Yes.

Mark: …and influencing and changing our expression. How do you think about that? Do you bring that into the issue of genetics for humans, or is that just too complicated to even consider?

Nessa: I think it's going to be a huge area. I think at the moment, the difficulty is we're only scratching the surface, and we're at that stage where as a scientific community we're generating a huge amount of data, but we can't quite convert that data into useful information at the moment. So we can tell that there's an enormous quantity of bacteria around the body, in the body. We know that really extreme changes for the bacteria seem to have a bad effect on our health. But trying then to tie that down to what kind of bacteria we ought to have is really, really difficult. And I think we're starting already to see an awful lot of hype…

Mark: Yes.

Nessa: …and a lot of things that really can't be supported. And I think one of the things that can be quite ironic is we will almost certainly end up getting to the stage where we understand the microbiome better, and as a consequence, we will give people health advice, which will basically be, eat more vegetables and the less saturated fat and less meat. We will understand why that's important, but it won't actually change the epidemiological advice.

Mark: I think it's one of those amazing things that after all the research we keep coming back to fill your stomach with vegetables.

Nessa: Absolutely.

Mark: And things work a lot better by magic once again. 

Nessa: Yes.

Mark: We have in Australia, one of the WHO advisors, saying it is time for us to remove stomachs here, is taking Australia is there are a million stomachs that need removal.

Nessa: Oh my God.

Mark: Why? Well not because we didn't need stomachs, but because now digestion is done in the supermarket before you even get the food, and the stomach is now like the appendix, a residual organ that is just a problem because we get all the nutrition out of that food. And so the idea is we take the stomachs out, don't change the diet. And that comes back to the politics of can you get people to do the right thing? Give them a choice and it almost seems written in law that they will do the wrong thing, even though it's a drive from the brain. The biology tells them "Grab the kilojoules, eat the food." 

Nessa: Yes.

Mark: There’s something about that biology that this is just the wrong time for a lot of people to be alive.

Nessa: No, it really is. I mean, we are clearly as a species and not adapted to having access to unfettered amounts of nutrition.

Mark: Yes.

Nessa: Or at least calories. Yeah, it's, we're are, for most of our evolutionary history it was a struggle to get enough food to survive, and our bodies seem to be designed to make the most of that, which was fine until somebody invented hamburgers and everyone had enough funds to buy them. It was just, it's just a bit of a perfect storm, unfortunately. And it's an incredible because more people on this planet are now suffering health consequences from obesity than from malnutrition.

Mark: And of course, as practitioners, we see the failures. There may be successes in that little group as well of people that would not be able to have survived except that there is easy availability of the kilojoules. We don't see those in our clinical practices so much. So almost by definition, what we used to call family history is now morphing into this idea of genetics. Things that we would ask people about what happened to mum, dad, brothers, sisters, cousins, and aunts…

Nessa: Yeah.

Mark: …we’re now doing DNA testing for it. I have my suspicions that that's not exactly the way that this is going to end up. 

But the questions about the DNA, if you're looking for bad news, DNA can always give you bad news. 

Nessa: Oh, yes.

Mark: If you're looking for what to do with it to make a person well, you're looking for how do we change that epigenetic expression? How do we change the trajectory of a person?

Nessa: Yes.

Mark: So is this what epigenetics can show us? Are we moving in a direction which for the clinician and practitioner will say, "Okay, here's the genetic story, but here's how you shift that in a particular direction?" Are we getting to an area where there's practical advice that can be given beyond “fill your tummy with vegetables?”

Nessa: We're getting to the stage where epigenetics is having a major impact on healthcare, but initially, it's going to be on conditions, which are certain types of cancer. We know that certain types of cancer, what's really going wrong is that the epigenetic mechanisms in the cell have gone a bit bananas. 

Mark: Right.

Nessa: And we know that we can use certain drugs to reverse that process. Epigenetics also have a lot of attractions in terms of treating chronic conditions. Because, if most people have chronic conditions, there's not really anything you can define as wrong with their DNA. 

Mark: Right.

Nessa: They might have certain variants of certain genes that make them a lot...a little bit more susceptible to certain conditions, but there's nothing fundamentally wrong with their DNA. What's quite possible in those people is that their DNA is locked in the wrong expression patterns because of abnormal epigenetic profiles sort of developed, maybe in response to the environment, but maybe perfectly randomly. And that's really encouraging because if that's the case, it's a lot easier to change the epigenetics in an individual than it is to change their genetics. So, we may find new routes into drug treatments for things that are chronic disorders such as Type 2 diabetes, but probably more impactfully in things such as rheumatoid arthritis and other immune conditions. And ultimately, we may even find that this has a role in neurodegeneration such as Alzheimer’s, but that's a very long shot at the moment. 

So we will start seeing certainly new drug therapies. I think what I suspect we might find epigenetics being used for is monitoring those people who are responding or not responding to healthcare interventions, such as a change in diet. It would be really great if you're trying to change your diet and it's not feeling like it's making that much difference to be able to give people feedback from their epigenetic system by looking at what's happening to their epigenetics and saying, "Look, you know, you're not feeling better yet, but everything is starting to go in the right direction."

Mark: Right. So then there's a practical application. Can you measure epigenetic expression? Is that simply seeing genes coming back to life that code for something else. Is there a practical way of clinicians seeing that?

Nessa: Yeah, you can do it that way, but you can actually directly analyse the epigenetic modifications that are present, particular genes. The problem is, often being sure that you're sampling the right tissue.

Mark: Right.

Nessa: So obviously, most of the time what practitioners do is to take blood samples and to analyse the blood sample. But there's a real question mark over that. If the condition is something such as Type 2 diabetes, we have to ask, is the blood really the right tissue to be sampling? Now, it might be because it might be that even though the blood isn't what's causing the condition, you get the same epigenetic changes in the blood as you would in the more relevant tissues such as the liver. But we don't know that for sure. So you have to do a lot of work to make sure that you're actually following the right changes. But I think that could be something that might empower patients quite well.

Mark: Okay. So we can, with the technologies available, we can peer into the epigenetic expression already. 

Nessa: Yes.

Mark: So what there's been a focus on mainly has been single nucleotide polymorphisms. The SNPs have become a very big issue, which are really just variants, so they're kind of nature's ability to do its own experiment, change an amino acid here, change a protein here…

Nessa: Yep.

Mark: …change a nucleotide there. That leads to a kind of almost negativity in practitioners. They say, "Oh, you've got a SNP. That means you have a problem. What can you do about it?" But these SNPs are just natural variants. These are the survivors of evolution, these are not mutations that are new that you have a cancer outcome from.

Nessa: Yes, absolutely.

Mark: Are we going the wrong way with SNPs? Are we over-interpreting the SNPs as if they are the genetics, the destiny of a person, and then making decisions that should be made mainly maybe by an epigenetic expression, rather than giving vast amounts of nutrients to counteract the SNP?

Nessa: Well, the SNPs question is very interesting because if you take somebody who has an abnormal SNP, what that suggests is that somewhere else in the universe there is a human with the perfect genome. 

Mark: Yes.

Nessa: And there is no such thing. Yeah, it will be lovely, but there isn't. Because...

Mark: The platonic version. We just need that platonic version we make everybody the same.

Nessa: Absolutely, yeah. The platonic genome would be just awesome, and then we could just change everyone to that.

Mark: We could use CRISPR for that. We can make a billion perfect humans. Exactly.

Nessa: Yes, there you go but it will all be fine you see. What we all have is just a range in our DNA. And there are certain changes in DNA, where we know with 100% certainty, if you have that change, you're going to be in deep trouble. 

Mark: Right.

Nessa: But those are what we always think of as the mutations, the disease-causing mutations, where a single change causes a devastating impact. But most of the variation that we see in the human genome doesn't have that impact. It might make you slightly more susceptible to something or slightly less susceptible to something under certain environmental conditions, but they're not really strong predictors for an individual of whether or not they're going to develop a condition. And one of the things that we've seen in the UK recently is huge concern over companies who will offer to take the genetic data that you've got by say, sending your DNA over to a company like 23andMe, and then saying, "We will take your data and we will tell you all the things that you're at risk of." 

Mark: Yes.

Nessa: And there's enormous concern that actually that's a huge over interpretation of the data, and really all it does is frighten people. It doesn't enable them. It doesn't make them...it doesn't give them any better healthcare opportunities. It just scares them for no real reason, because most of these variations account for perhaps 5% of risk of a particular condition at most.

Mark: Yes. And I think all of our listeners, all of the practitioners have experienced the heart sink of a person dumping a large wad of paper saying, "That's my genes. Is this why I'm feeling sick?"

Nessa: Yep. It must have been bad enough when people just turned up with something from a newspaper saying, "I think I have this condition." Yeah, somebody comes into, because you know, that can’t be from.  

Mark: No. Well, it's not really, not fun. I think humans have a negativity bias. You know, we're looking for bad news to stay safe all the time. 

Nessa: Yep.

Mark: And when a new signal comes out to say, "Here's a whole bunch of bad news," the problem is separating what's important from what's rubbish. 

Nessa: Yes.

Mark: And a lot of the SNP variants are simply, you know, nature's way of making sure there's always a survivor, no matter what, how bad the environment gets, that variation is important. 

Nessa: Yep.

Mark: The ability for people to switch that on and switch that off is built-in but invisible to us as practitioners. 

Nessa: Yep.

Mark: So we're forever looking for a bit of a help to say, "Okay, you've got those genes. And, you know, I could have told you from your family history that If dad had diabetes, mom has diabetes, they both got overweight, there's a fairly good chance I didn't even need genome analysis or anything like that." 

Nessa: Yes.

Mark: What we're looking for as practitioners, I think, is always what's something that is actionable that we can see? You know, if there is...if we're doing genetic tests, what if we find it is going to make a difference to the person in front of us? And it seems like epigenetics rather than the genome and the gene expression of the proteins, it seems like epigenetics has got all the potential, but it's difficult to translate what to do for an individual from the research that we see available at the moment. We know what can go wrong, what to do is coming back almost to basics of get your diet, get your exercise, do the things that the body interprets as health-promoting, and then watch and see what happens.

Nessa: I actually think that is basically what it comes down to. Because, if you think about the SNPs, it's bad enough trying to interpret what those will mean for an individual, an individual sitting in your consulting room. And the problem is, at least with the SNPs here, you're looking at a stable DNA variation that has been there since that person was born and is present in all of their cells. But if you start looking at the epigenetics around that SNP, for example, there's a vast array of epigenetic changes that could take place around that SNP. And then you have to try to incorporate all of that with all the other epigenetic changes taking place all over the rest of the genome.

Mark: Right.

Nessa: And then you have to take into account that will be different in different tissues. So, unfortunately, I think for the disorders which have a partial genetic component and a partial environmental component, it's going to be quite some time before we can actually say, "The combination of these five SNPs and the presence of those 20 epigenetic modifications, that's the bad combination." It's going to take quite a long time before we can get there. And the older I get, the more I just keep thinking, "Eat your veggies, cut down on the alcohol, go for a run,” that kind of thing. It really is the only thing that we know works.

Mark: Do you think it will become more specific over time? Do you think we're moving to a point where the tools, where we understand more precisely that you know, broccoli for this person is going to be a good thing? Are we going to ever move to that kind of level of detail for the individual or at the moment, it's a big data issue, you know?

Nessa: Yes.

Mark: Can you add enough correlations? Can the epidemiologists and the geneticists and the SNP variants, can they be worked into a fabric which is meaningful? But translating that to the individual is what each of us as practitioners have to do. It's so bloody difficult. Because, if you look far enough you see SNPs that have potential negative outcomes all over the place.

Nessa: Yes.

Mark: 90% of which are utterly irrelevant to that person. And yet, it has big red dots on it on the gene report.

Nessa: No, definitely. And I'm not sure how long it's going to take before we can do this at the individual level. Everybody, of course, at the moment, it's all big data…

Mark: Yes.

Nessa: …and AI. And yes, we need all of that. And we can see how that will operate at the population level. I think there's going to be a lot of areas where it's still incredibly difficult at the individual level, and also the number of times where we're going to see changes at the individual level, and we still won't have a therapeutic approach we can use anyway, other than the basic public health things. So I think it's going to be incredibly challenging. We will understand it much better in cancer before anything else because cancer is just so unique. And I think we'll see big benefits to that. And I think it's going to be a long time before we can as an individual level integrate the genetic, epigenetic, and then the environmental to make a really good, genuinely personalised health recommendations.

Mark: Right.

Nessa: I think what will probably get much closer to is a refinement of the current situation where instead of, I don't know, trying eight different drugs for epilepsy, you only have to try four…

Mark: Right.

Nessa: …and there's a decent chance one of them will work, for example.

Mark: That even happens... We do the genetics of cancer cells. They seem to be able to adapt to chemotherapy extraordinarily quickly. It's almost like the environmental push of the chemotherapy directs the evolution of the cancer away from damage by the chemotherapy. And so in that particular area, we do see genetic changes, little or very little genetic changes in cancer over short periods of time measured in weeks or months…

Nessa: Yes.

Mark: …in order to change to a new drug. It just seems, chasing our tails. It seems like the wrong way to go when there is a different opportunity if we understand it of prevention and reducing the number of cancers we have to chase like that.

Nessa: Yeah, I mean, prevention is always going to be the best way my... Look…

Mark: Tell politicians that.

Nessa: Yes, I know. I know. They, just, it's just not fashionable for them. But prevention will always be the best thing. We also have to remember, of course, the reason so many people get cancer is because they're not dying of heart attacks anymore.

Mark: So if we could only kill them in some other more humane way, you think they'll...

Nessa: Yeah. I mean, it's really quite interesting, but, you know...

Mark: That's never going to be popular.

Nessa: ...I think, they just started saying that in the, I think in the UK, that now just dementia-type conditions are the biggest cause of death, which simply means that people aren't dying from cancer. 

Mark: Yeah.

Nessa: They’ve stopped dying from heart disease and now the cancer survival rates are better. But ultimately we all have to die of something. It's just a case of when and how horribly. So we have to remember that some of the medical problems we're seeing are actually a consequence of fantastic medical advances in the past.

Mark: Right. Well, talking about this, there's just two things I'd love to finish off with. One of them is something that scares the crap out of me to be honest, CRISPR-Cas9 and the gene editing. This idea that we have now tools that are cheap, effective, and we can run in, even at you the know, the blastocyst, even at the earlier stages of life, and make things better, this concept of a platonic ideal of the human. 

Nessa: Yeah

Mark: Is…should I be scared of that? Is that something that should bother me, or is it just another tool that will take its place?

Nessa: I think we absolutely should be incredibly measured and conservative about how we apply this technology in anything that might change the germ line. I think when we're talking about an adult or somebody who's already born, whose already ill, I think this will just become another tool in the therapeutic armoury.

Mark: Right.

Nessa: And we're starting to see that already. There are already trials ongoing using CRISPR-Cas9 approaches for sickle cell disease and thalassemia  and also for some eye diseases. And it's going to, it has potential to be really great there. I think we have to be much more conservative about making changes at an incredibly early stage of development that will be passed on to the next generation. But I think, I have one, of the things that I found most interesting was reading a particular article about this recently, and it was from a family who had a very extreme genetic condition. And for them, CRISPR-Cas9 gene editing could be great for future generations…

Mark: Right.

Nessa: …of that family because you could just wipe it out from the family. And one of the people in the family said something very interesting. He said, "All that we are asking the doctors to do is to change our gene to look the same as that gene in the other 7 billion people on this planet. 

Mark: Yes.

Nessa: “Why is that such a big deal?" And I thought, "That is actually an incredibly helpful way of looking at it."

Mark: It is, however, interestingly true that it's now at the point where we are the genetic selectors. Evolutionary biology... Evolution is, always sought to, well, you get rid of genes like that because, you know, there is a failure of procreation in, down the generation. And so medicine, the strangest thing about medicine as science is we believe in evolution yet we are at our core anti-evolutionary. It’s survival of the richest, if you can afford your gene editing. Survival of the richest is not survival of the fittest, and we now see ourselves capable of doing almost anything to keep a baby that would not have survived alive…

Nessa: Yes.

Mark: …and having to deal with the consequences that the brutality of evolution is something that we're trying to overcome. We are fighting against the very, what we believe to be the basis of life in all life on the planet. I have my concerns about it, but I don't know what to do as a doctor. We are fixing people, helping people one at a time, that's our job. 

Nessa: Yes.

Mark: But sometimes I just wonder if we have tried to bypass evolution and whether that will in the long-term, come back to bite us.

Nessa: Except evolution is always biting us anyway. 

Mark: Yes.

Nessa: If we think about, because diseases don't die out. Yet the recessive ones never die out for the reason you and I both know, which is probably carrier frequency remains the same.

Mark: Yes.

Nessa: But even dominant diseases don't die out because of new mutations. 

Mark: Right.

Nessa: So it's always going to be an issue. There will never, even if we felt that the world would be better without these conditions, and that's an incredibly complex ethical position.

Mark: Yes, it is, isn't it?

Nessa: It's never going to happen, you know. And if you think of something like to shed muscular dystrophy where the boys have this awful muscle-wasting disorder, that will suddenly crop up in new families because of new mutation. So we're never really going to make that difference from that point of view to evolution. 

Mark: Right.

Nessa: I mean, we've done it, it's what humans have always done, isn't it? I mean, and we could claim, say that antibiotics were anti-evolution.

Mark: Yeah, of course.

Nessa: Because, those people who wouldn't have survived a bacterial infection now do. But I'm still taking my penicillin when I need it, without a doubt.

Mark: No, absolutely. But the concept of the science, what are we fiddling with something that kind of got us to this point over, you know, a couple of billion years, 3 billion years maybe. There is something that just sits a little bit uncomfortably with me that when we can get in and modify it, and we think, "Oh, we understand the future." I know how literally medicine, we understand the idea what a person needs. We keep on making that mistake over and over, that our smart brains can figure out what otherwise has been an evolutionary history.

Now, it's not that I would stop it, but it just gives me cause for concern that if we extend that and we start to think of abnormalities as not having blue eyes or not being tall enough. 

Nessa: Yes.

Mark: Or that we start on a different process where we have a monoculture of humans that are then ultimately, in evolutionary terms, the most susceptible group that are in the world.

Nessa: Yeah, I mean, it's partly the slippery slope argument. It's also we have to remember that we think things like sickle cell disease, is a terrible disease.

Mark: Yes.

Nessa: And it is a terrible disease. But we have to remember the reason that sickle cell disease has reached such high levels is because that mutation also gives you resistance to malaria. And you so it's very difficult always to say that a mutation is a negative thing.

Mark: Yeah.

Nessa: I think the thing to remember with editing humans, editing our DNA, is this will always be an incredibly specialist activity. Because CRISPR itself is extraordinarily easy to do, in vitro fertilisation is still very hard.

Mark: Right.

Nessa: And to edit humans in such a way that they passed it on that change to their offspring, you have to do that through in vitro fertilisation technology.

Mark: So there's a bottleneck elsewhere?

Nessa: Yes. Now that's not to say that won't have a significant impact. I mean, I'm old enough to remember the first test you baby being born, Louise Brown. And since Brown, there have been 4 million to 5 million babies born through in vitro fertilisation. So it's not that the numbers were originally small, but it's a percentage of the human race will probably remain very small.

Mark: And so the final thing, you being a woman in science, the DNA history, and the Nobel prizes to Watson and Crick, I know Rosalind Franklin's contribution, and she did die before the Nobel Prize. But I'm hoping because I have three daughters. I'm hoping that the openings in science are not so male-centric as they have been over the years. This is an area where Rosalind's contribution was enormous and yet, almost nobody knows Rosalind Franklin's name.

I say this for a reason. I think males are very good at given a task getting to the end of the task and you know, getting to the endpoint. And I think they lack a concept of wholeness of interactions if you like that. We are good at task-oriented stuff. I think it requires something more to understand whole systems and any, I certainly see this in the women that I see, if you've raised a baby, you can't be goal-oriented. You have to have had understood the variability, the demands, the kind of sloppiness that is essential to making a successful baby. And I see a world where good science has led us to the brink in so many areas that we are now threatening our planet. 

Nessa: Yes.

Mark: And it requires a different way of thinking, which I don't see happening from the goal-oriented approach. My hope is that there's a space for a different type of thinking and that maybe we're seeing that now, that the interact owns the concepts of wholeness and interacting systems is a whole new generation's approach. Where women are honoured and had to take their place in that process. Is that actually happening or is it still a men's game, science?

Nessa: I can only...I can speak to the UK where things are changing, but they're changing much more slowly than anyone would want. There have been very good initiatives in the UK we have this thing called the Athena SWAN Awards, which are awarded to universities. And they have to make a big effort in terms of making sure that their promotion criteria and selection criteria and so on are much more based on equality and diversity than they were. 

Mark: Right.

Nessa: But one of the most extraordinary statistics and there's a fantastic graphic that was put together by the journal "Nature" last year, it was a shockingly low number of women who have won the Nobel Prize. I mean, it's just ridiculous absolutely ridiculous. I think somebody calculated that more women have been in the group "Pussycat Dolls" or build allowed than have won the Nobel Prize in Physics, which is the, is a bit it's just that level of lunacy. In terms of the impact that has I don't know if it's a gender thing, but one thing that bothers me all the time is that we are constantly trying to science our way out of problems.

Mark: Yes.

Nessa: And yes, we need science, you know, the science has to pay huge...play a huge contribution to climate change and antibiotic resistance and a whole load of other things. But so often, I feel that we fall into the trap of there's a problem, and we try to solve it with science when actually, we do that rather than dealing with the root causes of the problem. And all we do is create another new problem as we go along. I mean, I love science. It’s a brilliant thing.

Mark: Me too.

Nessa:  Absolutely fantastic thing. But not everything should have a tech solution. Here we need much more engagement with the humanities and the social sciences, and we need to be thinking longer-term rather than just pushing that Doomsday moment a bit further away all the time. We need to step back, I think.

Mark: On that. I would love to finish this. Nessa Carey, it's been bloody delightful talking with you today. So much for that, I would like to pick your brains over that we've run out of time. 

Nessa: Yes, it’s been great.

Mark: It’s been a privilege to talk with you. I hope to do that again and maybe meet you someday I think I have a new hero now.

Nessa: That would be fantastic. I would love that but I am sorry that we are recording this at such an ungodly hour in the morning hour for you.

Mark: The world is a small place. It just has different time zones.

Nessa: That's true.

Mark: Nessa, thank you very much. It's been delightful.

Nessa: Absolute pleasure. Thank you so much.

Mark: This is FX Omics and I'm Dr. Mark Donohoe.


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Dr Nessa Carey

Nessa Carey has a PhD in virology from the University of Edinburgh and has had successful careers in both the university and commercial settings. She was a Senior Lecturer at Imperial College School of Medicine in London, where she led a research team investigating a genetic disorder that gets worse and worse as it passes down through the generations in an affected family. For nearly ten years she has worked in the biotech industry, trying to take basic science discoveries and turn them into new treatments for human diseases. Over the last four years she has been working with some of the world’s leading scientists in the exciting new field of epigenetics. Epigenetics is the biology that explains so many of the puzzling things around us – why identical twins get less identical with age; why childhood trauma can affect you for the next sixty years of your life; why our bodies change as we age; why we develop common diseases like arthritis and how we can start to treat them better – and her book explores all these and much more.