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Ep #27 Transcript | George Church: Genomics, CRISPR, Synthetic Biology, Biotech Startups, & Dyslexia

Full episode transcript (beware of typos!) below:

Nick Jikomes

Professor George Church, thank you for joining me. My pleasure. Great to be here. I'm going to do an intro. But can you very briefly and concisely tell people who you are and what you're known for.

George Church 3:16

I'm George Church, Professor of genetics at Harvard, also at MIT, and I work on technology development, for biotech in general, but reading and writing, and editing DNA is probably our most commonly referred to, and applying it to developmental biology, all the way through recoding genomes. And I want to start out by talking about genome sequencing and personal genomics. I'm wondering if you can start out by painting a picture a general picture for people of where we've gone since the human genome project in the 80s to the present in terms of the cost and level of effort, say, in sequencing a human genome, and what your general involvement was in the biotech underlying that progress. Right. Well, so I've been kind of a sequencing technology junkie since the 70s, where it started by typing in all the DNA sequence that was known at the at the time in 1974. And that just immediately I saw how powerful that could be, I could fold up molecules from sequence. And so around 76 ish, I heard about the beginnings of new DNA sequencing method from Fred Sanger and Wally Gilbert. And so I started graduate school with wall eight, with that specifically in mind, the Genome Project, so I immediately want to do what's now called multiplex sequencing, and did it during my rotation meeting before I actually joined the lab in graduate school, and felt that that we should sequence everybody on the planet, possibly every organism as well. And that was, I think, that was kind of the naive musings of a teenager. But it it pretty rapidly, you could see start to I didn't know about exponentials at time and not read Gordon Moore's paper. But it looked like it was going to go faster than people expected. So So I helped start the Genome Project, the last year of my thesis was in in three meetings, in 1984 8586 84, was Department of Energy. And that's really where it started. So and then fast forwarding to your question is, it really kind of finished in 2004? Temporarily, it's kind of a pause, where it was still a draft. And in many people's opinion, there were lots of parts missing, it finally, finally finished a single genome, human genome this year. But even that, well, isn't clinically useful. So the thing that we did in 2004, was a very poor genome, both because it wasn't complete and wasn't clinically useful. So the methodology was used for that was immediately thrown out the window and replaced by what's now called next gen sequencing, I was involved in almost all the methods of doing next gen sequencing, including two different nanopore methods are actually a few different nanopore methods. Fluorescence by singer by hybridization, ligation and, and synthesis of polymerase and so forth. But anyone that quickly displaced it brought the price down from about $3 billion for a poor quality genome to now $300 for excellent quality diploid, meaning both your mother and your father's genome is represented. So there's twice as much information at least. And, at first, so $300 for a clinical grade genome that we now have today, and it's probably getting close to, well, certainly millions of genomes are being done per year, different granularity different qualities and, and goals. Probably the biggest clinical use right now is non invasive prenatal testing. But there's an awful lot that's done for cancer diagnosis, and, and, and you name it.

Nick Jikomes 7:43

So, you know, over a period of a couple of decades, things not only got much better in terms of the quality of the technology, and how well, and how thoroughly, we could sequence the genome and fill in all the gaps. But it also got much, much cheaper and faster to actually do that. Correct. So we some people have said that we're now in the era of personal genomics. So if it's about 300 bucks as the cost of sequencing one Human diploid genome, you've got a bunch of new companies sprouting up that are taking advantage of this and allowing people to actually get their own genome sequence and learn stuff about their own genome sequence. Broadly speaking, how would you define personal genomics? And why should Why should at all, an ordinary person care about their own genomic data? Well, a lot of the placeholder enthusiasm, I call it that because it was, it was very pragmatic about price, people just were not willing to pay much more than $200 for a partial genome. And so it was very partial. Initially, it was like a millionth of the genome. But it could tell you a lot about ancestry and a little bit about health. Whole genome sequencing is getting pretty close to telling you everything, you might imagine that it would, I mean, it's not gonna tell you everything about everything, but it's gonna, you know, there's even complex diseases you can get prediction of, but multifactorial, predictive cancer, day to day changes. Sorry, in risk and you know, circulating DNA from cancer cells, immune changes, and so forth, all of that has decreased by roughly 20 million fold in the in the raw sequencing costs. Wow. So what, um, so people are probably familiar with things like 23andme. That's maybe the most common product out there that at least does a partial genome sequence. I know that many of your students and postdocs have gone on to do biotech startups of different kinds based on the research that they did with you. You in your lab or or in labs you've collaborated with one of those is nebula genomics, I've actually used this one could you describe nebula genomics and what they're doing and maybe how it's similar to or different than something like 23andme? Right, so I was an advisor to 23andme basis before they started, I've been very much a advocate, because they, they were very good at educating, educating and getting the word out that they and really helped establish DNA ancestry, and got us up into the 20 million sort of people worldwide. Now, we obviously want to get to a billion. So even their heroic efforts have just to start, but in terms of what you get medically, is you can think of there's a kind of a gradient of medical information. So they do, say, a million single nucleotide polymorphisms. So they're the polymorphisms means that the most common source of variation, and common variants tend not to be predictive of serious disease, they tend to be kind of loosely associated, mostly with the less serious diseases. And as you get more and more serious, it becomes randomly distributed on the on top of common alleles. Nevertheless, there are enough that you can add that to the ancestry and it adds value. The next step up is exomes, which means the protein coding parts of your genome is about 1%. So you've gone from a tiny fraction of a percent, maybe a millionth of the genome to now 1%. And in it, it works. Many, many of the most serious diseases are in the protein coding exome. But to illustrate what is missing is, if you chuck the gene in the middle and say invert it, all, all the exomes are still intact, nothing has changed with respect to the exome sequence wouldn't expect it to and it doesn't change, but it's completely non functional gene. So you can be really off in that regard. And so. So I think that when you get to medical diagnosis, you don't want to be depend on luck. If if the cost is the same, and the cost is, has been converging, so for a while, exomes, were about 1000 times cheaper than whole genomes. And now they're about the same price. They're both sort of in the 200 to $300. range.

And, and probably will drop, consider, you know, considerably in the next few years. So I think for any serious medicine, we should be doing whole genome sequencing. Where you actually haplotype, which means you can tell all the things that are on your mother's chromosome in your father's chromosome, not just the composition, but the exact sequence. And that's routine as well. And it shouldn't be even $300, it should be free because the the amount of money that you save, on average, not any individual, but it is way more than $300, it's probably 10s of 1000s of dollars, because it's it's a million dollars is a typical treatment for a rare disease, so called Rare, they're collectively about 3% of firsts. They're individually like one and 100,000. But collectively, they're about 3%. And so if each of those costs a million or $2 million, then it's clearly to society's advantage to make it free to everybody that wants it. So that's the base. Sorry, we're very close to that happening. Oh, wow. So the basic idea is if everyone sort of had their own personal genome sequence handy, and they were bringing it to the doctor, every time they went for a checkup, the amount of time and the amount you would save in terms of testing for diagnostics, would go way, way down. Because you'd have that rich set of genomic information that can essentially tell you things that would otherwise require a bunch of expensive testing. That's one way you save, and that's a big way. It also saves you know, morbidity and mortality premature, which has huge costs associated with trying to deal with somebody who went through an unnecessary medical procedure or got exposed to a disease that you know it ranging from bad reaction to anesthesia to inherited disease that could be avoided by genetic counseling. That is probably a trillion dollars a year that's that's, that could be saved by just just A few of these things which are on very firm ground right now, it's not like we don't need to do a lot of research. To get this going, it's already going, we just need to figure out how to communicate to people that even though they may not, they may be lucky 98% They don't know that in advance. And for the benefit of the public, it's kind of like the same argument for seatbelts and, and vaccines and all the rest is, you may be lucky, but you don't know that. And so why don't you just help the public health effort by participating and not smoking and wearing seatbelts and vaccines, there's a couple things, I want to talk to that branch off this. So one is sort of the personal data privacy issue. And the other is the integration of using personal genomics and data like this with just the general practice of physicians in interacting with your doctor. So for example, I, I have a nebula genomics report, but I have never brought it in to the doctor when I go in for a checkup. And I feel like even if I did today, they wouldn't really be able to do anything with it. So how do you think about bridging that gap between having a lot of this data today wanting to get more but also creating a medical system in which the physicians are actually equipped to utilize that data? Well, I actually think they are currently equipped, it is true that your average primary care physician cannot read a genome report. And when we didn't have time or or necessarily the interest, it is also true that your report and my report probably don't have much, that even if they were genome literate, there wasn't that much that they could do about it, because 98% of us really are not going to benefit from the genome as much as the 2%. Well, so what we're doing is we're trying to search for that 2% that are almost immediately actionable. And that actionability can win to sit at that extreme level, where it is where it is clear sciences sciences querying is nothing vague about it, that can can be committed, communicated to the primary care physician easily enough that they can then refer to a specialist. So for example, if you have,

you know, BRCA one risk factor, the 1000s of them, some of them more common than others, but they're quite highly predictive. And you what is that BRCA one is a breast cancer risk factor. And it's, it's fairly common, especially in certain ethnic, or ancestral backgrounds. And even if it's not, no matter where you what your background is, you can you can go to a cancer genomics specialists, you can be referred to your primary care physician, all they need to know is this is very reliable data and should be referred to a specialist, and you go to an oncologist that has some genomic training, and, and, and you and you decide whether you're going to be monitoring whether you're going to have a child and then have bilateral mastectomy and over activities and that sort of thing. But that's just an example there plenty of things like that. There's things that you can do preconception and premarital, which are very low impact and very high predictability, but they don't even have to be high predictability because the, the negative consequences or low consequences of of having surgery, when you don't need it as high as high. So you want to have a very low false positive rate. But if you're doing, you know, pre conception premarital counseling, there's really not much at stake. I see. So basically, what you're saying is with the existing technology today, we could cheaply give everyone a personal genome sequence. And most physicians alive today in the US would have all the knowledge already that they need to take action on that rare but very important, very expensive one or two or three people out of 100 that have a key risk factor like that breast cancer gene, they would, it would be easy to get them up to speed just via the report, they don't have to go to school. It's just the report itself can get them up to speed and they'll know who to send to to either a genetic counselor or to oncologist, genomic psychologist now. Now in your case, presumably if you had something serious in your genome, they would have told you, right, and so the reason that you're not being referred to your primary back to your primary care physician is because your life Most of us, there's nothing, there's no alarm going off. That is possible that many years from now, we'll get even better at the genome. And so there's something for everybody. But I would say right now there's something for 2% of us. It's just that 100% of us need to find out whether one of the two percenters. Interesting. So the other side of this that is maybe worth unpacking a little bit. It's just questions around data privacy, and people's willingness to actually give their data to someone, even if it's not sort of being sold to the highest bidder. So that, you know, the question arises, you know, if I get my genome sequenced, who's holding on to that data and giving access to my doctor? And who else might they be giving access to? And should we be concerned? So I think we should always be concerned, especially with new technology, because there's even if there are rules that apply, if we haven't had practice applying those rules, so that, you know, there's rules like the, you know, the FDA has rules, the there's all kinds of soup over over sight. But saying, well, you should be concerned, there are good computational methods that can protect privacy still allow sharing of whatever the minimum is you need to share. So let's say, you know, in my genome that I have a compound heterozygote for alpha one antitrypsin serpina one, and that could affect my respiratory system, COPD, COVID-19, and so forth. This is something I could share with physician just by saying, like I have with you, and they don't need to see my genome, they can refer me to someone who could do appropriate Advanced Functional diagnostics, or I could share the genome, but in such a way that they can only ask about the you know, exactly what allele it is, and exactly, you know, what other modifier alleles. And, and, and, and they never own the genome, they never possess the genome, I am the owner of it, and only I can, in fact, it can even be made their computer methods you can make, so even I can't decrypt it. So let's say, you know,

the forest government comes in and orders it, you know, orders at gunpoint, the my physician that turn it over, orders me to turn it over, they can't decrypt it, because I even I can't, all they could do is, you know, with the appropriate medical know, how they could ask very specific questions. I see. So basically, encryption technology can be used to regulate, who gets to see what, or sort of portion out like, I could give permission to a physician to see only this part of my chromosome 13, where there's a gene that's relevant, right, and this is what Nebula has pioneered. I mean, Nebula is not the first personal genomics company that I've helped make. But it's really the first one, I think, we got really serious about the privacy aspect. And my understanding, it's been a while since I've sort of checked on this is that one of the things that Nebula has done or plans to do is actually allow people to use their genome sequence that they get through nebula to do to actually monetize it, and or help facilitate research. So for example, if nebula sequences my genome, and I've got some sort of rare mutation that's under studied, that, that scientists want to study, I could actually decide if I want to, to give them access to my genome for study, and actually be compensated for that. Correct. And it's entirely in your control. So it's not like nebulas going to, you know, chain, you know, get sold to somebody else. And then they can change their policy, you can do it in a way that no matter who has access to the encrypted form, they can't do anything with it. So even if nebula goes under or gets acquired or something like that, they can't suddenly change their mind. So that's, that's good effect even you can't change your mind. So if you put really strict upfront restrictions on it, and then you later change your mind and you really, your option is re sequencing. But the good news is it's cheap enough that you can re sequence it and and give it a different set of rules. But the point is this in a computer science, since this is finally feasible to do, and, and people should avail themselves of it. If there's various reasons why you would want to do research, for example, if you've got a family disease, and you participate in research, that means your family kind of goes to the front of the queue. If you're there, it's more likely that a cure will be developed, that's good for your family. If your family is involved in the research, I mean, that's a promise. That's just a, that's just a possibility. Interesting. So, we've talked so far about genome sequencing, basically, reading the genome and figuring out what it says. The other thing that people have probably heard about at this point is the writing side, we now actually have the ability to change and edit in at least semi arbitrary ways, the genome, the big technology there, that is been has been talked about lately is CRISPR. So can you just explain for people in a non technical way, what CRISPR is and how it works at a basic level. So CRISPR is one of many ways of editing the genome and mana one. And editing the genome is one of many ways of doing gene therapy. You could include gene therapy as a subset of editing, it's, I think it's more reasonable to consider editing a subset of gene therapy. So I would say you can add genes, you can subtract gene functionality, you could precisely change it like you want to change white one base fare and a to a G. And then you can do what's called epigenetic therapies, we're changing the way the genes work without changing the genes themselves. So adding genes is kind of classic gene therapy. Many people that have a genetic disease, they're missing both copies their mothers and their fathers copy of a gene. And so they, they, they need to get it added back in. And that's most of the of the gene therapies that are in clinical trials right now are of that type adding. So that's not editing, in my opinion. Editing and most editing that is moving its way towards clinical trials is also not precise editing, when you change an ad to a G, it's subtracting, it's your editing, you make a mess in the gene, and it doesn't function anymore. And there are not that many genetic diseases that are fixed by that. But that's changing the precise editing is something that we're getting better at and and that will, that's the

big category. But there are plenty of these gene therapies and even editing that's making it into the clinic and having impact already this is not far off. This is already happening. And this includes cancer, retinal diseases, and hemoglobin. Apathy is like sickle cell anemia. Interesting. So CRISPR allows you to edit the genome in principle, you can change individual basis, but in practice, we're not quite at that level of fidelity. Yeah, the the topic of editing is actually undergone a form of grade inflation. So when I, when my lab started editing in the 80s, late 70s, we met precise editing we met you, you dream something up in the computer, and you make it. And actually there was a Nobel Prize awarded long before the much deserved one to Doudna and sharpen ta it was to Capeci and Smithies for work that we did in the 80s for precise editing. But that the great inflation has resulted in almost anything you do to a gene is that they? Even if it's imprecisely knocking it out, I see just fine. And on this side of the technology, I think there's another startup that you help see called a Ditas or Editas. And they're using CRISPR technology. Can you talk a little bit about the types of things they're working on with that technology. So at atoss was arguably the first CRISPR company, Jennifer Doudna, and I co founded it along with three others, Fung Zang, Keith young, and David Liu, all of them have gone on to be pioneers in all aspects of gene therapy and editing. Edit thoughts was, was the first but it was quickly joined by two other good companies all within a few blocks of each other in Cambridge, Massachusetts, very amusing. And people would ask me, you know, you know, are is this is competition a problem? I said, No, this is actually not enough. Three, the companies are not gonna be enough to handle the 1000s of genetic diseases that are rare, plus many that are common plus aging reversal, which is also kind of a genetic disease. And so I felt that wasn't an in and we've we're continuing to form new gene therapy companies as needed, but at atoss specifically went after diseases that would benefit from removing a copy of a gene variant that was dominant, let's say something that where one copy could make it work. or where you could change a regulatory sequence and express a new a related party. So, so for example, what? There are two ways of dealing with sickle cell at least two ways. One of them is to express fetal version of the hemoglobin and the other is to actually correct the the adult copy. And anyway, I think at a tosses has gotten the first in vivo gene editing CRISPR editing in a retinal disease LCA 10. So that's, and they've also helped with the Carty technology, which is, I would say is one of the most promising anti cancer because you're basically using a engineered part of the immune system that T cells to go after a particular subset of blood cancers like B cell leukemias and lymphomas. So for the retinal thing, are we essentially talking about a potential cure for certain forms of blindness? Correct. So so the there there have been gene non editing gene therapies for blindness. And now there is an in vivo meaning you inject directly into the retina, adeno associated virus, a cap of protein capsid, surrounding the CRISPR, editing, genetic components. So you mentioned that there was these two other CRISPR based startups, and that this was a good thing, because there's actually so many applications here, that this won't even be nearly enough to tackle them all. So it sounds like we, you know, shouldn't think of this as you know, a classic, zero sum startup war, but there's so many diseases that could benefit from this type of research. And so many therapies that can be developed that, you know, all of all of these three startups could each make breakthroughs and completely separate diseases using the same basic technology, right?

Yes, the other two are CRISPR, therapeutics and intellian. And as far as I know, all three companies are doing pretty well. They they have not interfered with each other. In fact, I've been been together with all three CEOs quite frequently, or representatives, all three companies at meetings, and they're, they're quite, they get along quite well. So I, I think it it's, there are plenty of industries like this, where there really just is not enough talent to go around. Now, that may change someday, but I think hopefully going to cure a lot of people before that, we get to saturation. And so on this general topic of human genome, engineering, you know, chain actually deciding and using technology to change human genomes, there is, there's a lot of promise and also a lot of concern. And so, you know, naturally, you sort of see a spectrum of opinions about how we should do this, or whether we should do this at all. One side of the spectrum, right is, you know, if you've got a serious disease, like an embryo that will give rise to a baby with a fatal, terrible disease, like Tay Sachs or something, almost everyone that I encountered would say, Yeah, we should be able to go in and fix that defective gene to prevent the death and suffering that will inevitably occur from a genetic disease like that. On the opposite side of the spectrum, you've got basically the idea of making designer humans, someone could pay, presumably a large amount of money in the future, go in and basically design their own baby that has the best of everything. And most people seem to react to that by saying, well, we shouldn't be able to do that. So obviously, what's tough about this is there's really no hard and fast line in between those two extremes, where you can easily say, Yes, we should be able to do these types of things. No, we shouldn't be able to do these other types of things. Do you have a general sort of framework that you use to think about the bioethics of something like this, that you might be able to share with people? Sure. I mean, I, I teach a course in bioethics every year. It's required by the NIH, or responsible conduct of science and, and, and I've co authored a lot of papers on these sorts of topics for this particular topic, which does come up quite a bit. I think there's you can break it down into various parts. I mean, first of all, there's there's very little medical need for germline, which is what, what you didn't explicitly say that but it's changing the, the reproductive part of the human so that every subsequent generation will inherit it. There's very little call for that. So far, it's a it's an imagined market. Even the even the designer baby is pretty hypothetical. Both because technically difficult and, and, and not medical, public health emergency of any sort. So if we're technically easy, as is most cosmetics, even cosmetic surgery but but but most of the things you would do this cosmetic you do with literally with changing your hair color your eye color with contacts, and, and so forth. That's problematic partly because it encourages bad relation with your body view it reinforces ancestral discrimination and so forth. The other spot, so I was I would say that that's a very low priority at best. The other aspect is the equitable distribution. So even the the somatic gene therapy, meaning that currently approved FDA approved gene therapies are very expensive, and they fall in the category of orphan drugs. And I think we're grateful that they're the Orphan Drug Act, I think. It allows us to, to, to not ignore these rare diseases. But it also creates a market for very expensive medicine. So million dollars a dose. So that's somatic, that has nothing to do with germline, it has only been passing on for generations generation, it is

of problematic bioethics, because it is not easily equitably distributed. Now that keep in mind that we are in an era where many technologies that are very expensive, let's let's say the $3 billion non clinical genome mutated into $300, high quality clinical genome in just I don't know, fraction of a decade, then maybe we could bring down that cost. So that's that's one way of addressing equitable, equitable issues. There's also normal ethics issues that are completely well established in the FDA, our safety and efficacy. Those I think we can trust the FDA will deal with except for the very long term, the FDA will approve things that pass short term toxicity. They're not really well equipped to deal with equitable distribution or invention nor possible long term consequences. So for example, if you get cancer chemotherapy, you're changing your you're mutating your germline, in a way that that really the benefits of the cancer chemotherapy outweigh the risks of subsequent generations has been the the argument. It's interesting that there, there tends to be more enthusiasm or more of a, we'll let this pass if it's perceived as random or natural than if it's intentional, which is kind of the opposite of the way it is in most other engineering fields. So if, if a bridge accidentally falls down, that's not a good thing. You want to intentionally design it, so they won't. But if you intentionally design a child, other you know, other than, say, education, and, and, you know, good nutrition and clothing, and so forth. So there's, there's all these kind of X exceptional isms and focusing on methods rather than on outcomes. I suspect that we will, that as we get closer and closer to these things, we will focus more and more on the outcomes. There is a concern about enhancement, where people forget that most of our technologies are enhancing, you know, vaccines have make it a superhuman relative to our ancestors, we can just calmly go through a ward full of people with serious infectious diseases not and not have to worry about it, while our ancestors would have been terrified if they if they understood, assuming they understood the risks. So enhancement isn't necessarily a bad thing, as long as it's equity distributed and safe in a long term sense, but it's hard to test long term. It's really hard to get paid to get Funding for very long term clinical studies. But it happens. One way or another, it happens in what's called phase four, if nothing else, one of the switching gears a little bit, one of the things that was so interesting to me, when I took my bioethics course, as a young PhD student, which you taught, was that you gave us an interesting disclaimer at the beginning of the class, which is that you actually suffered from narcolepsy. And it was possible that you would just suddenly fall asleep if you weren't completely engaged at any given moment. And you also shared that you have Dyslexia as well, I believe. And it was an interesting conversation, because these are two things that most people would say are debilitating, at least to some extent. And yet you lived with them for a long time and had a very interesting and successful career, despite these things. So could you talk a little bit about what it's been like for you to cope with both narcolepsy and dyslexia? And how you've sort of navigated how you conduct your work with those things? And whether or not you actually do you actually feel that they're disabilities? Or do they actually help you in certain ways that you've learned to appreciate? Well, let's start with in northwest, this dyslexia are the sort of things that make you have your your employment prospects are restricted? They're not, it's not. There are some jobs that are you. But if you're, in some countries, in some cultures, children are quickly shunted into different training, has different employment pass, even at a very young age, they take tests and, and you know, it's decided

that, that, you know, if you can't read, you're really not going to be qualified for most white collar, pink collar professions. And fortunately, your brain is capable of reprogramming itself. It's, it's hard. But you know, if you ever seen a stroke victim, for example, go from not being able to walk or talk to being almost normal again, you see the incredible power of rerouting also you doing things, often in a very different way than then your previous brain or what might be considered a neurotypical brain would operate. And I think that's what happened to me over the years as I figured work arounds. You're sort of desperate, you know, it's, it's, it's, it's not fun. It's not fun being freakish at all, when you know when you're going through elementary school, because everybody wants to make fun of whoever's not in the middle of the bell curve. It's also not fun to be classified as someone with it doesn't have much future because they can't stay awake and they can't read. But, you know, I, I kept getting classified as needing remedial reading classes. And I think it was like an eighth grade and in, in the my senior year, like transitioning into college. But that's, you know, they had figured out different ways to read in different ways of coping. I've I've visited and taught at the schools for Dyslexics, and I see all it's a much better era now if you if you're fortunate enough to make it to one of those schools and there's hundreds of them in the United States alone. You know, you you listen to books on audio. That's, that's a solution. You have book readers that will help you read they they're they're often quite bright. The Dyslexics I've met, there's even the ones that are more severely affected than I am. They were they haven't been able to learn really how to read the half to listen to spoken versions. But there's, you know, coping mechanisms for the narcolepsy that really hasn't improved much it got worse as I became a teenager. In fact, I might even be considered a teen onset. My daughter is affected as well. It varies a little bit with not just the adolescent hormone but with pregnancy hormones. So but the you know, the coping there is finding a job where you don't have to drive. Find a spouse that can help you drive or can drive with you instead of you. But that rolls out a whole lot of jobs. And then and then I think it's communicating with people so that they don't think that you're just bored with them or that you did you considered staying up late playing video games was more important than your your day job. It's sometimes a misperception of people who have daytime sleepiness as they're staying up all night doing things they shouldn't be doing. And then they don't do their they job properly. It also helps to be kind of be your own boss. Because then, I mean, you still have people judging you if you're not communicating, but at least they're not judging in a way that's fatal for your career. Anyway, you know, it's, it's all risks versus benefits. And I think that, that some, there are some benefits for being dyslexic and narcoleptic. early in life, you do look at things differently. And, and I think that some of the things I learned from the dream state and from having to deal with things visually a lot, when I would read books, I would read an encyclopedia. But I would mainly look at the pictures, which was both easier, but it helps you to make makes you think about things more visually and spatially. So, so so your brain was thought not better, that's different. I see. So So you had to take a more visually oriented strategy, as opposed to sort of internally verbalizing words to yourself because of your dyslexia. Um, I mean, I think, yeah, I, I did have trouble with the verbalization as well. And I had a reputation as late as Graduate School of saying three words a day.

That may have been preference as much as aptitude and it's hard to say hard to disentangle them completely. But I was naturally attracted to fields like crystallography and microscopy, where, you know, the three dimensional image is is kind of the point. Interesting. One area that I wanted to ask you about, because I know we're short on time, is synthetic biology. So very broad questions, what is synthetic biology in broad terms? And what do you think is some of the most exciting stuff going on in this neck of the neck of the woods today? Well, synthetic biology is one of those umbrella terms that that means different things to different people, I think that's healthy, you can think of as the the biological equivalent of synthetic organic chemistry. Or you can think of it as the engineering sort of the engineering rigor brought to biology. Or you can think of it as various subfields different flavors of synthetic biology with the like, origins of life as a kind of synthetic biology or simulate doing some of the things that computers do. So, programming with biology, the various metaphors that go well beyond metaphors, they're using, you know, logic gates, and so forth. That's one another field Synthetic Genomics is another field where you're actually literally synthesizing or hyper edit, doing so many edits, you're changing the genome radically. That doesn't necessarily overlap the the other fields and, and the list of synthetic biology can include developmental biology and ecosystems, basically, anything that's biology, you can more than just observe it, which was kind of classic biology was the hunters and gatherers that would go out and observe nature and bring back stuff, podcasts and things. Now, we can change it, in that in medicine, that's therapeutics in agriculture is it's the basis of most agriculture and almost all agriculture is using genetically modified organisms, either by classical methods or by recombinant DNA, or even now CRISPR. Are there people working on creating life from scratch today in the lab? It's hard. I mean, there are people that would like to including myself, there are two things one is how do you really do it from scratch? I mean, the people probably closest that are the pre biotic researchers who are saying asking, Can we make it differently? Can we do it from scratch differently, the more different it is, the more you can argue this from scratch. But if you try to just synthesize a genome, you're already in, you're already cheating in so many levels. It's a good cheat. But, you know, you're, you're, you're you're accepting all of the evolutionary baggage. All the great evolutionary gifts. You're you're using the same polymer is the same enzymes, etc, etc. If you go back to pre biotic then you can say is that are there polymers other than DNA? Can you use, you know, different sugar rather than deoxy ribose or ribose? There are plenty of examples of those that you can use. Can you play around with the phosphate? Can you play around with the basis? The different? Can you do non Watson Crick base pairing? Can you even get rid of the hydrogen bonds completely that's been shown to work from Floyd Rome's Berg's work. And so forth. So, but going all the way to scratch is, is very challenging because most even the prebiotic there really, there's a heavy bias towards trying to figure out how it actually happened, rather than all the alternatives, but there's a healthy amount of each. Interesting. Going back to something you said earlier, you mentioned, let's assume that that most listeners will know that genes can encode proteins you actually mentioned earlier, when we're talking about the human genome, that's something like 1% of the genome actually encodes for protein. And although that's a very important 1%, it's only 1%. And there's been a lot of talk in popular press for many, many years now about so called junk DNA, I'm wondering if you could just unpack for people what that other 99% of the genome is, and maybe what some of the exciting things are, that we're learning about the non protein coding regions of the genome,

I actually did my thesis, sort of, it was a mixture of technology development for new sequencing technologies that we mentioned earlier. And it was on junk DNA. And the thesis was that I felt that some things that might appear to be junk DNA actually have functions. So it was functions of introns introns, were the just discovered. And, and I was working in two of the first introns discovered, and they had functions in them. So what's in there, so So first of all, the introns themselves are, are not do not find their way into the final proteins typically. And they're involved in regulation of, of RNA metabolism, RNA splicing, so forth. So and they can contain regulatory elements active DNA level like enhancers, so enhancers Can, can be in the original DNA. And they can act on nearby promoters to regulate the level and the what tissue type of RNAs are made. And they can either occur in the introns, which are later spliced out before you make the protein and coding RNA. Or they can be upstream in other kinds of so called junk DNA that is never transcribed into RNA. There's plenty of RNAs that stay RNAs and do their function as RNAs ranging from the key components of RNA splicing and protein synthesis ribosomes, T RNAs and so forth, to regulatory RNAs that will, that will bind to other proteins or to other RNAs or DNS. So there's a, there's no particular reason that we should think that the 1% that it goes proteins is particularly more useful other than the fact that ends simple organisms like bacteria, that the proteins constitute 9090 plus percent of the genome. And therefore, it seems at least for bacteria, you don't need that huge amount of other DNA. That's why. And also, you'll see variation even within animals, from say genomes, around 90 million base pairs to genomes that are hundreds of billions of base pairs. And so that so called C value paradox indicates that it might be junk because it it seems to change so rapidly in evolution compared to proteins. But that said, to be really junk to be something it would be that you can delete it and have no consequences. And, and by no consequences, I mean, less than a fraction of percent advantage in the wild. And so it's hard to prove the effect. Nobody has really pointed out to me, or in the literature. a bona fide example of this base pair is definitely junk that you could replace it with anything, and you'd have no consequences of the population genetic level. I think that's, that's hard to do. And it's probably unlikely. We know that there are certain sequences that if you pop them in just about anywhere, they're gonna be toxic. So that means that the sequence at that at any point in your genome is at least avoiding those toxic sequences. Right? So it's not completely neutral. Nothing is completely neutral. So I am not a you can tell I'm not a fan of the junk DNA hypothesis, putting it mildly. You know, in the interest of time, are there any final thoughts that you would leave people with generally regarding biotechnology and perhaps the general attitude that we should have? Or or at least that you have in terms of, you know, should we be optimistic about what the future is bringing? Or should we be skeptical and perhaps scared as a lot of people are? Well, I think they're not necessarily contradictory. I think we should be cautious about all new technology, not just biotechnology, anything that's new, we should have been more cautious about the internet, and maybe we would have avoided the level of hacking and viruses and identity fraud and so forth that we have, okay, so we should always be cautious. Safety should be like, number one priority.

But there's also we can be under optimistic, where we underestimate how quickly something will change, especially when you have an exponential where the technology, like sequencing technology has improved 20 30 million fold in less than a decade. If you underestimate that, then you're ill prepared both for the negative and positive consequences. So that so I think this is something where cautious optimism is definitely it could change everything, it's likely to change everything. And if we're pay attention, it will change everything in a very good way. And why I say that is it's not just restricted to medicine, or even to biology, agriculture, and so forth. Almost anything we currently manufacture could be probably made cheaper and better with bio nanotechnology. So the best nanotechnology in the world is bio nano this basically, biology makes things that are atomically precise. And by that I mean that every atom is in the right place, by the specification of the organism, and a fraction of an atom diameter matters. So there are enzymes where if you move things by over by a fraction of the bond length between two atoms, it changes the enzyme Khattab catalytic rate completely. So biology is really good at that. And we're going to exploit it probably from making everything from including

not limited to what we normally think of as biology, including information, storage, computing, new materials, all these things are going to be done and cheaply, because you can have an entire forest for full of this precise matter right now. And it's all free. Nobody orders up the primeval forests on a purchase order. So that those would be my parting shots is think about it as an incredible set of gifts. That that were a billion years of trial and error perfected all kinds of gizmos that were just beginning to appreciate things like CRISPR came out of junk DNA, it literally was classified as junk DNA, until we figured out what it could what we could do with it. And we're probably not even close to done with most of the things that we've discovered in the files here. And for non specialists, is there a good place or a good resource where they can follow either your research in particular, or just developments in the biotech world in general that you might recommend? Well, if they go to my website, we try to alert them to what's happening in general. So we're kind of not heavily specialized and work on many different technologies. So it's a it's a, it's a good resource, a book I wrote called Regenesis is, is still fairly relevant for synthetic biology. And they're, they're not, not that many books that are written about that the feet where the synthetic biology is going. So those are, those are two that happen to be quite familiar with. I think, increasingly, podcasts like this one, and and the popular science literature is getting better at following these fields. So that's kind of a really easy way to get into it. There's a slight bias towards certain topics that are more popular. But it's still whatever, whatever gets the pump Part THE PUBLIC excited enough about science in my era was you know, Moon landing on the moon, you know now it's it's things like you know, cancer therapies and you know, applying microbiology to ecological conservation and the extinction and things like that, that captures the imagination. And then they look at, hopefully look at adjacent Science and as its power to benefit them. Alright, well, Professor George Church, thank you for your time.


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