Dr Karissa Sanbonmatsu

Karissa is a structural biologist and an expert in epigenetics. Karissa leads the Sanbonmatsu team at the Los Alamost National Laboratory and has shared her research in a TED Talk on the biology of gender and TEDx talk on epigenetics and love.

Caitlin Morrissey

How do you see the science of DNA applying to the evolution of cities? Does that make any sense from your perspective?


Karissa Sanbonmatsu

It does make sense. And so I think, you know, sort of an older view of DNA from, say, the 1950s or so, was that, you know, people have genes, and they're inherited and passed down from generation to generation. And you can have a random mutation here and there, and then due to survival of the fittest, you know, those random mutations can be more successful. And then likewise, in a city, you could have traditions and so forth passed down from generation to generation, even structures and highways and so forth.


Greg Clark

Karissa, if you're happy for me to jump in and out, then I will do that because what you've just said is absolutely fascinating and very important for us. And so the kind of shock that could produce these new environmental molecules that then alter the genetic makeup of the city, this could be a physical shock. Could it also be an economic shock or a social shock, the arrival of a new population that wasn't there before, the change in the industrial structure of a city? Obviously, we're talking here at a level of metaphor. And I want to come back in a minute and ask you, actually, is this only a metaphor. Is there such a thing as the collective DNA of a group of people living together in the same place? But does that make sense to you then, that what you're saying is that in this epigenetic understanding, all sorts of things could be these molecules that come in from the external environment; it's not just a physical change.


Karissa Sanbonmatsu

Yeah, absolutely. And I think there are three levels to your question. So the first level, from the biology point of view, just to be clear, we call them sort of environmental perturbations on the DNA material. The DNA material is called your chromosome or chromatin and that consists of the DNA plus different proteins, and there are many different ways to influence the structure or folding of that chromosome. So you can have an environmental toxin or cigarette smoking, especially during pregnancy, for example. 


But also, there are many studies showing that when the baby is undergoing-- in animal studies in rodents, such as mice and rats, for example, when the babies are pups, have a very stressful upbringing - for example, they get no nurturing from their mother - this alters their stress response at the molecular level, and it can impair their stress response throughout their life and that can be passed down to their kids and grandkids. So it's kind of a mix between nature and nurture. It's like a social event that happens but that creates a hormone response that can affect how the DNA is organised, actually. And then there are many, many other events like that. There are positive events too. Oxytocin, the sort of falling-in-love chemical can alter the structure. Going on diets, exercising, all this stuff. So that was at the biological level.


Greg Clark

But that's a very interesting answer, if I may say, Karissa, as well. I'm going to ask one more thing, if I may, and then we should get back to the questions that Caitlin set. But I suppose-- and forgive me that some of these questions are ignorant. I'm an urbanist and not a geneticist. But are these kinds of changes to DNA, changes to chromosome that happen as a result of these environmental factors-- are they always permanent, or are there processes through which, as it were, the original DNA pattern can be recovered?


Karissa Sanbonmatsu

Yeah, that's a great question. And no, they're not always permanent. There's a whole spectrum of some are permanent, some are semi-permanent, some are very transient, not permanent at all. And it's this whole kind of language. And in fact, I think there's over 200 different kinds of modifications, and people have really just stuck to studying 5 or 10, and that's what most of the literature is about. But there's a whole zoology of different modifications that haven't even been studied yet, and there's a whole spectrum on if they're permanent or non-permanent.


Greg Clark

When these changes are non-permanent, is it sometimes because of intentional therapeutic activity, or is it nearly always accidental?


Karissa Sanbonmatsu

Absolutely. And so there's a race now in Big Pharma to uncover drugs that can reverse these epigenetic modifications. There are some on the market that-- there are different kinds. It's a very, very-- I'm giving you a very overly simplistic view of how things work, but to go into just a little more detail, these changes happen to the DNA, but something makes those changes. So usually-- for example, if you have an oestrogen hormone, that may come in and bind to an oestrogen receptor, and then there may be a complex taking that to the DNA. So there's often hundreds of different kinds of protein molecules involved. And they have-- and they call them readers and writers where some read the epigenetic programme, and some write the epigenetic programme and edit it. And so they've targeted sort of the readers and writers of this messaging system that are kind of across the body-wide. So it's very a crude way of doing drugs nowadays for epigenetics, but they're trying to refine it to get more and more specific to actually reverse specific epigenetic modifications, yeah.


Greg Clark

Thank you so much. Back to Caitlin.


Caitlin Morrissey

Thank you so much, Karissa. This is truly fascinating. I just want to pick up on this point that you're making about epigenetics and I wonder if there are ways that our DNA changes for smaller or more incremental reasons? Moving away from the discussion just about large shocks. I'm thinking about the way that cities, old cities, for instance, like London might acquire different traits over time.


Karissa Sanbonmatsu

Yeah, absolutely. And so from my understanding, basically, the large shocks are the ones that get really imprinted and passed down to future generations and persist through your whole life. But throughout your life, this epigenetic programme is constantly being adjusted and tweaked and so forth. And the same when that the egg is developing into the baby, you know, everything's being tweaked all the time by all kinds of different effects.


Caitlin Morrissey

I'm thinking now about whether it's possible for people who live together in the same place to acquire sets of DNA and how that might work at neighbourhood levels or at different levels within a city?


Karissa Sanbonmatsu

Yeah. So basically, for epigenetics, there's sort of a stark boundary between the DNA sequence versus the shape of the DNA, and they can be related, but they're also fairly independent. So in terms of DNA sequence, this is your normal classical genetics where when people couple, they have babies and that gets passed on and so forth and that would be the way people would share DNA. Now, for epigenetics and the folding or the structure of the DNA, there, the environment can actually impact that. So if it's a group of people, even if they're not related at all but they're experiencing the same, like, toxin or something like that, they could definitely get similar signatures on their DNA in terms of the shape of the DNA.


Greg Clark

So maybe, Caitlin, it makes sense for us to ask Karissa the most challenging question that we're sort of dealing with. So, Karissa, we've been speaking to mathematicians, statisticians, architects, urban planners, economists, sociologists, and they all basically say to us, "This idea of the DNA of cities is a great idea. What a wonderful metaphor." And we've been asking ourselves the question, well, in what sense is this a metaphor; in what sense is this more than a metaphor? And in a sense, you're the person who's most likely to have an answer to that.


And what I think I hear you saying - and I want to check this with you - is that on one level, a city is a system of all sorts of things - it's a community of people for sure - but it's a system of infrastructure, it's a built environment, it's an inherited set of ideas, ways of working, industrial specialisations, cultural productions, all of that. And in our interviews, we asked people about the most unusual inventions that have come from certain cities. If you like, there's a metaphorical dimension in which we can say the city is like a human body. There's a genetic code that means this city can be more authentic to its genetic code or less so. And if you like, on the metaphorical level, we've got, you know, urban planning is a form of epigenetics which is designed to help the city be more like itself, right? So that's one level upon which this idea works, and I'm grateful for your comment on that.


But there's another level that you're talking to us about here as well which is that actually when a large group of people are living together in the same place, the environmental factors that they have in common can, in fact, on a biological level, alter their DNA through these epigenetic processes that you've described. So this can be for a group of people living in Amsterdam or living in Dublin or living in Albuquerque, that this can be a literal conversation about the DNA of a particular urban community or something similar. Did I get it right? And if so, is there a relationship between these two things that's obvious to you?


Karissa Sanbonmatsu

Yeah, I think that sounds like a fairly accurate assessment. And then I would say that these large events that happen, then I think you could-- I would really expect to see very common chromosome shape signatures or epigenetic signatures across a large segment of the population. For example, I'm not sure if people looked into this, but I would think the 9/11 survivors may certainly have common epigenetic modifications due to stress or all the toxins around there and so forth. But something like that, I think. And even if the whole city was going through a very stressful event, I think you might see something there as well, but I would think there may be a number of different things. It would be a good-- a great NIH proposal or something, I think, to do genome-wide sequencing for two different cities, for example, and look at the epigenetic aspects of the sequencing and see what you find. I think you would probably find something.


Greg Clark

And are the shocks that you're talking about here, Karissa, always things that, in a sense, create stress?


Karissa Sanbonmatsu

No, no. That's the stuff I know the most about, but there are many other examples besides stress. But this is kind of the more textbook example; this is what really put epigenetics on the map. Professor Meaney at McGill in Canada was one of the more famous people who pioneered these studies to show that these baby rodents that weren't nurtured by their mother, it really screwed up their stress response not only in them but in their kids and grandkids as well. And it also had implications for diabetes and a number of other disorders and so forth.


Greg Clark

But would there be examples of things that are not so much stresses? So I'm trying to think a little bit laterally here. I'm wondering, for example, whether something beneficial occurs that's accidental in a certain place, and it leads to this amazing burst of optimism in a community. Can that also have an epigenetic process associated with it?


Karissa Sanbonmatsu

Yeah. In the field of epigenetics, the negative effects are the easiest ones to study, so that's what's been studied the most. But in the last five years, there have been a number of studies at more positive things such as exercise and diet, and I think many others. But I have read a few papers on exercise and diet showing that just after one year of exercise, you know, it changes some of your epigenetic modifications. So, yeah, I think there can be positive things as well, but these haven't been studied as thoroughly.


Greg Clark

OK, that's very interesting. The sort of things that are in the back of my mind is that we sometimes notice with cities that a positive event can occur that leads to a whole cycle of optimism, confidence, trust-building. For example, Barcelona hosts the Olympic Games in 1992, and it leads to a whole cycle of creativity amongst a population. Or, you know, the gold rush happens, and San Francisco then develops an attitude which is very open about shared prosperity or other things. Or maybe, you know, Kyoto hosts a world summit on the future of the planet, and it leads to a whole series of behaviour changes. 


So we notice that these kinds of events can trigger positive responses at a community-wide level in terms of behaviours. But what I haven't-- and attitudes. What I have never understood before was whether there was a-- that there might be an epigenetic basis to that. And that's in a sense, what you're saying.


Karissa Sanbonmatsu

Right, right, right.


Caitlin Morrissey

Karissa, I want to ask about when people understand more about their DNA, or the more that scientists know about DNA, how is it used? Because one of the questions that we're trying to understand is, once cities understand their DNA and their traits, how they might be able to use it?


What has the study of DNA revealed about humans, and how DNA is used, and how might we relate that to our study on cities?


Karissa Sanbonmatsu

Yeah, so the main way it's used would be in therapeutics and in drug discovery, I'd say. And so, right now, for cancer-- so basically, the epigenetic programming - we call it programming - means when the changes-- the DNA-- it's kind of complicated, but basically, your DNA has sequence, but you can chemically modify the DNA without changing the sequence and that will change how the DNA is kind of-- it's folded up. It looks like a ball of spaghetti basically, but it's a very specific ball of spaghetti. In fact, almost reproducible where you'll get the same kind of ball of spaghetti over and over.


Caitlin Morrissey

This is so fascinating. And there is another question that we have been asking the economists and the architects and all of the other urban experts which is about what understanding the concept of the DNA of cities might leave out about the way that cities evolve. 


And is there an analogy there for the way that plants and living things evolve that the DNA doesn't always explain?


Karissa Sanbonmatsu

Yeah, absolutely. So this is kind of the-- one of the main aspects of epigenetics is that, you know, the classical genetics is saying that your sequence is passed down to your future generations with the possible exception of sort of a fluke mutation that might occur due to errors in copying and so forth. But in epigenetics, you can have dramatic changes in the programming of the DNA that can be passed down, and these are not just fluke mutations but caused by a specific environmental effect or stressful social upbringing and so forth. So there's a lot more diversity in how things can be inherited when you take into account epigenetic effects.


Caitlin Morrissey

And this is a very simplistic follow-up question, but are all traits passed down, or are there stronger traits and weaker traits? 


Karissa Sanbonmatsu

This is a good-- yeah, this is not well understood at all in terms of epigenetics. So, you know, in terms of all the possible traits, there are only less than 1% have been studied. Really hardly anything's been studied in terms of the full gamut of different traits you can have. So we know that some can be passed down and most haven't been studied yet.


Greg Clark

And I suppose the point might be, Karissa - and I'm checking again with you here - that you might see different stress responses in different cities.


Karissa Sanbonmatsu

Yeah, absolutely.


Greg Clark

So let’s take an obvious example. Somewhere like Wuhan, which was the epicentre of the original infection, locked down in a certain way, but then recovers quickly as opposed to, let's say, a London or New York that goes through two, three, four waves.


Karissa Sanbonmatsu

Absolutely. This is a-- whole new fields are going to be created, are being created now, I would say, in terms of the science and the social-- like you're saying, this is a great idea that you just suggested for a new project like the time dependence of the epigenetic response and not only the time dependence but also like how long the lockdown lasted and how that plays out, like Wuhan versus New York City versus Los Angeles right now. You know, so, yeah, all kinds of fascinating things are going to come out of this.


Greg Clark

And I guess also the fact that we're using different vaccines as well. There wil be different different genetic effects from that.


Karissa Sanbonmatsu

Absolutely. Yeah, absolutely. So all kinds of things to look at. One thing I'm interested in is, you know, some people are resilient to infection and some people are not. Why is that? You know, they break it down very crudely, like if you have a compromised immune system, but I think if you go into more detail, you know, some people are surviving and unfortunately, some people are not. And why is that? You know, we think the answer may lie in epigenetics somewhere.


Greg Clark

What kind of answers would that be? Because the same question exists for cities, by the way. Why does one city survive deindustrialisation and prosper afterwards and why does another not?


Karissa Sanbonmatsu

Yeah, yeah, I have no idea. It's such a wide-open field. It's hard to, you know-- I think some people have a more robust immune response than others. I'm not an immunologist, so I couldn't really speak to that. But another topic is in 


Greg Clark

OK, you've given me an idea for a new section of the book which is to compare the immunity systems of cities.


Karissa Sanbonmatsu

Yeah, absolutely. Yeah.


Greg Clark

Yeah, yeah. Really helpful.


Caitlin Morrissey

And I think that links because Philadelphia and New York are examples of cities that deindustrialised and it left a really lasting impact, which we've already alluded to in the case studies that we've been writing. 


Karissa Sanbonmatsu

I mean, another thing is, right, Twitter and all the big tech allowed everyone to work at home permanently from now on till the end of their company. So I think this is going to change the-- you've probably been thinking about this. This is changing the city dynamics as we speak quite a bit, right?


Greg Clark

Absolutely. And if you like, this changes, in a sense, the morphology of cities. And it changes not just what we might call the spatial geography, but it also changes things like the network effects, the spaces, of flows, all sorts of things in the city. So we're predicting that all cities, in a sense, will move to some version of a new set of guiding principles which are more distributed, more networked, more localised, more hybrid. There's a whole series of ideas about how the city reorganises itself around this idea of trying to be pandemic resilient in the future. But also having tried and tested a higher level of digital activity during lockdown, it's the carried behaviour that then is taken over into the next cycle that becomes important.


Karissa Sanbonmatsu

And this is very analogous to epigenetics, going back to the metaphor, in that, you know, we're having a big impact event now (referring to Covid-19), and I think this is really going to persist probably throughout our lifetime, I would think, but for a long while. And in epigenetics, that's what happens. You have a big impact to your biological system. It restructures the DNA and that gets frozen in and it persists. So I think it's quite analogous.


Caitlin Morrissey

I was just going to ask, Karissa, you've been hearing us talk and ask you questions, which obviously reveal to you the level of our understanding of DNA, and is there anything that we're missing? Is there any key component that we haven't quite considered yet that would be useful for us to understand for our study of cities?


Karissa Sanbonmatsu

Yeah, yeah. There are a couple of ideas I wrote down. I was talking to one of my colleagues last night, and we came up with some interesting things. One was on horizontal gene transfer. I don't know if you've thought about this, but this is not in epigenetics but just in regular genetics. But in bacteria and other organisms, but certainly, in bacteria, you see a lot of-- they're called horizontal gene transfer, where the two bacteria kind of exchange DNA material, but they're not really reproducing in the traditional sense. And this has a way of kind of scrambling the genetic record. So it makes it pretty much impossible to trace back through the generations which bacteria is related to who. It makes it very, very difficult because everything gets kind of scrambled laterally across. So that's one thing.


Greg Clark

Both of those are spectacularly helpful, by the way, Karissa. If you just think about this second one, this kind of hijacking the machine or the hostile takeover, one version of this could be described as the financialisation of the real-estate systems of cities when, for example, housing is built to service the local population, but then it's acquired by foreign capital and taken out of the use of the local population because it's then being used just as a trophy asset to park capital. And that's one example.


Another example could be in a city where, you know, you had a tradition of a progressive government for 50 years and suddenly, a populist government gets in that decides to completely do away with all of the normal investment norms of the city. But you also get this idea of an extractive elite, that where certain kinds of companies or investors come in with the intention to sort of strip the assets of a city. It's a very-- so it's a kind of neo-colonialism actually in the way it's described. But all of those things could be in the space you're talking about here of the hostile takeover.


And this kind of gene transfer and scrambling. Sometimes this idea is applied to cities where you've had a kind of-- a very high level of interracial sort of family creation without it necessarily being freely chosen. So, again, in colonial situations like, say, in Cape Town where you've got a large proportion of the population who are mixed race, but that mixed-race environment or that mixed-race population comes from colonial acts of violence. It doesn't actually come from freely chosen relationships between people. So you've got all of that. So very interesting.


Karissa Sanbonmatsu

Yeah, I think on the horizontal gene transfer, Lynn Margulis has a great book on, I think, what is life or about what life is. And she has a photo there where one bacteria is infecting another, and it has this kind of tube that extends out and is transferring its DNA through the tube into the other and then just snippets of it go into the neighbouring bacteria. So you can imagine just information going from one city to another city or one company to another just, you know, during the year. Not really-- this is not stuff that's being passed down; it's just sort of side to side. I think this happens quite a bit, but that would be an analogy in the genetics world.


Greg Clark

Well, again, that's really interesting. In human geography, we talk a lot about tacit information flows and this being a very important part of the benefits of cities, that there's not just the formal flows of information; there's all of the informal flows of information that are really critical to urban success.


I was going to ask you one other question, if I may. So another-- one of the other people we've interviewed has talked a lot about what we might call alternative medicine, so we've talked about homoeopathy, acupuncture. We've been talking a little bit about pressure points, acupressure. In other words, there's this idea that you can apply this thought that, you know, a small amount of pressure or a small dosage of some kind of ingredient placed into a system can have a catalytic effect that unleashes new energies, new flows. You know, I suppose you could call it the feng shui approach. Is there anything in genetics or epigenetics that really mirrors this, the idea of a very small particle having a large system effect in that way?


Karissa Sanbonmatsu

Yeah, I can't-- yeah, I can't think of anything off the top of my head. You know, in regular genetics, I would think a viral infection is a little like that where they're all quite small particles and then they replicate themselves to take over cells and destroy tissues, destroy your lungs, for example. But yeah, in epigenetics, I haven't come across anything like that, but I'd have to think more about it.


Greg Clark

OK.


Caitlin Morrissey

So the final question is, if we were to have asked you the right question, would there have been anything else that you would have wanted to tell us or to say about the DNA of cities or DNA that might be useful for us understanding whether or not cities have DNA?


Karissa Sanbonmatsu

Well, I think we covered it all, but, yeah, I would say the main thing is that in classical genetics, you know, you have the DNA being passed from mother to child and then to their kids and so forth. Whereas in epigenetics, you don't need to wait for that to happen. It can just be some kind of big, intense event that can restructure the DNA and then that can be passed down. So that's the main concept.


Caitlin Morrissey

Actually, that is an incredibly useful answer because I had been thinking all along, how far can this-- how far can this metaphor go when cities don't, in a human sense, have parents? But if we think about it in terms of epigenetics, that makes a lot of sense.


Karissa Sanbonmatsu

Yeah, yeah, yeah. In epigenetics, you don't even have to invoke having parents and kids because a lot of the stuff happens within one generation or over a few years or 10 years or something like that. You don't need the reproduction to still think about how these events are affecting the gene or gene programming and so forth.


Caitlin Morrissey

Well, thank you, I feel like I've learnt such a huge amount from you today, and we are so incredibly grateful for just spending time with us and giving us your insights.


Karissa Sanbonmatsu

Well, thank you as well. This has been a great conversation, and I look forward to checking out the book and seeing how things come out.


Greg Clark

And Karissa, is there anything of yours that you would really recommend us to read?


Karissa Sanbonmatsu

Yeah, absolutely. I started in epigenetics in like 2010 or 2011. And Nessa Carey has a book called Epigenetics Revolution. And this got me fully obsessed. I didn't know what epigenetics was. You know, I was just doing my thing with RNA molecules. And this got me fully obsessed, and I moved a lot of my research programme to epigenetics. And it's very well written, easy to read, and it goes through almost everything.


Greg Clark

So we should read her book, not your book?


Karissa Sanbonmatsu

Yeah, yeah, right.


Greg Clark

Well, we would like to read something that you've written as well because we'd like to cite it, too.


Karissa Sanbonmatsu

Sure, sure. Yeah, I have a paper called Rise of the RNA Machines, and these are all a bit technical. And then we have a new paper out in Journal of Computational Chemistry from 2019 where we did the world's biggest computer simulation, and it was the first simulation of a gene, so those might be two things to look at.