George Church: Synthetic biology, Woolly Mammoth, Longevity- Learning with Lowell – 165 – YouTube
Interview links
https://www.learningwithlowell.com/george-church-biomanufacturing-1-million-cell-editswoolly-mammoth-learning-with-lowell-164/
https://www.youtube.com/watch?v=yNplpykf0B4
Summary
The transcript is of an interview between host Lowell and synthetic biologist George Church. Lowell asks George about the pressures of his work and how often he takes a step back to think about the impact of his work. A fan question is asked about whether we have a whole picture of biology and if there are still unknowns to be discovered, to which George responds that there are still big surprises to come, particularly in synthetic biology. Lowell asks George if there is anything in particular that he is excited about working on, to which he responds that he tends to stay away from incremental work and is excited about all of his current projects. They also discuss the biggest unknown in biology being extraterrestrial life.
Transcript:
(00:00) all right welcome everybody today to the learner little show I’m your host Lowell as many of you know we talked to expert scientists and artists every week uh today we’re joined with stroke Church which is interesting in particular because this marks when this episode is going to go up in uh the beginning of March it will Mark the beginning of my fifth year doing the podcast and George was there during the first year so I just want to I think that’s pretty cool and George has a huge rap sheet that
(00:23) would probably take me an hour and a half just to say it um but and people should know it but I’ll have like a screen uh rolling down his his history and background but uh George welcome back to the show uh it’s great to be back thank you all yeah so first question is uh so I I was wondering what is it like to be you with all the things that you’re doing and all the the pressures that you have to do a great job even just the stuff you put on yourself and so I was wondering how often do you think and
(00:51) just like take a step back and think about how um you went from like just a regular scientist to the point where you are now where the measure of your impact is in millions if not billions of lives over the course of like 10 years 20 years like the impact of your work is just so significant and maybe that that maybe that’s the one of the purposes of humility is so you don’t think about that stuff too much uh I mean I certainly do feel a responsibility to to take you know whatever uh education and opportunities
(01:23) have been provided and turned them into something that’s you know pay it forward yeah um and then uh just I think that’s a great opportunity to jump in with a fan question um so I’ll just read this verbatim because I suck at a paraphrasing so George is involved in multiomics gene editing Gene therapies epigenetics AI delivery like I said you trap sheet uh do you think that we have the whole picture or a relative whole picture of biology or do you think they’re still unknowns to be discovered in terms of
(01:55) biology Rejuvenation that type of stuff well I’m guessing the question is about big unknowns so they’re obviously yeah millions of little unknowns to be known to that that will get people excited I mean the millions of things that will get the public excited even so so they’re not that little but really big things uh I I I I I would have to say that uh a lot of that will a lot of really big things in the future will be synthetic rather than analytic that is to say there’s a finite number of things to be discovered and we
(02:30) discover them kind of the in order of their importance like importance could be abundance of a species on the planet or uh pathological impact on humans that sort of thing and so so what happens it comes kind of a successful approximation where we’ve gotten everything but in terms of synthesis There’s No Limit I mean we you know until we know how to you know use synthetic biology to create new universes we’re not we’re not anywhere done anywhere near done so uh I think there’s a lot of big surprises in
(03:02) the future and some of them will will be reading and someone will be writing a lot of writing the uh there’s a great Neil deGrasse Tyson quote where it says like the more you know the more the surface area of your ignorance expands and so is there is there an area in particular that you feel that negative way but like ignorant of like you’re like wow you know like there’s so much I don’t know about it in terms of like you know biology and synthetic biology [Music] um yeah I mean there’s there there
(03:32) my uh ignorant surface area is expanding at the speed of light I think it’s uh I think the biggest thing we don’t know anything about is and that includes me it is uh extraterrestrial life it it has the biggest Delta between there may be zero to there may be hundreds of billions of uh of Life uh planets that planets with life like ours and not like ours so I think that’s the probably the biggest unknown I don’t think we would be completely shocked to find that it’s zero or completely shocked to find out
(04:13) that it’s trillions of stars planets um but the details will will probably surprise us uh you know yeah I feel like the weirdest thing is if we were to go out into space and like and it’s not like so far where you uh I think like mathematically like if you go up far enough you start seeing the same things as ourselves or something like how the math works but uh if we go like the next chart system and like everyone looks like same as us that’d be so weird it’s like we must have been like seated
(04:39) somewhere or something yeah well panspermia is uh yeah is a likely mechanism uh we know that there’ve been you know many thousands of rocks that have passed between Earth and Mars uh over time some of those may have contained early life forms some of which may have survived but but yeah if we go far enough away uh the chances of contact are extraordinarily small and so they’d be independent and then um so you have many different projects that we you know I’ve alluded to is there something that you’re working on right
(05:16) now that you’re particularly excited about like you have so much on your plate but at the same time um like not not even like yeah is there something in particular that you’re working on that you’re like wow this is really cool like you’re like really like you know the difference between like I’m like you know checking boxes versus like you’re really excited about developing something yeah I have a tendency to stay away from checking boxes and incremental stuff if I possibly can uh yeah every now and then you’re you know
(05:44) a previous Revolution either from my lab or some other one just demands uh applications or incremental you know big incremental things uh and and in fact some of our biggest incremental our sort of our biggest changes have been you know the product of lots of increments you know for example a reduction in cost of sequencing by 20 million fold was the product of a bunch of twofolds uh maybe came in every few weeks or months um but to your question about what it’s a it’s a popular question is like which
(06:19) of your kids do you like the best um I I would say probably the one that is most impactful is you know when the genie gives you one wish you ask for more wishes and so the equivalent for science is uh asking for more years of research more youthful healthy years uh and and so we have a number of related projects both in my lab and in my uh alumni uh companies that are aimed at at um you know longer healthier years so that’s that’s one another one that very that I’ve been excited about for decades is
(07:05) um is recoding organ you know Multiplex editing and recoding of genomes so that we can from among other things make organisms a resistant to all viruses and that finally paid off this year we have the first example of an organism that we think is resistant to all viruses um and and uh and we tested this by doing you know field work getting a bunch of new you know thousands of new phages and and having very sensitive assays for for replication and and found none so um so that’s another one uh and they’re plenty of plenty more uh you
(07:47) know the getting a code for differentiation in other words the code that tells us how to get to any place in development both young and old backwards and forwards I think we’re making progress on that so that’s very exciting sequencing everybody on the planet is another one uh I’ll stop there yeah how um with the improvements and uh sequencing what would be the cost of sequencing 8 billion people like is it is that actually like doable uh it’s uh it’s totally doable and the the the the the cost
(08:25) uh let’s say that let’s say the the cost of an item depends on how much you get back right so it’s like yeah you get you get a uh um Kickback or something like that or you get you have an investment and then you get a return on an investment and my estimate right now is the the app the the genomes are about three hundred dollars each now for very high quality diploid genome which is not the original Genome Project uh which is not diploid uh anyways it’s about 300 it’ll probably be a hundred dollars within a year or two
(08:59) um but the return on that investment is on the order of ten thousand dollars or more on average so for some people you’ll get nothing back for other people you get million dollars back uh in savings uh for the for the Health Care System whether that’s a government system or Insurance system or some combination that’s the return on investment so actually it wouldn’t cost anything the sequence everybody on the planet it would it would it would result in a net gain is you know and I think there’s a lot
(09:30) there’s a lot there’s a growing amount of economic modeling that supports that yeah it sounds like the the Appellate program where people always say like oh we’ve put a lot of money into it but we the return on investment was like for every one dollar we got like 12 or 13 back like that’s a great deal just like you don’t notice it in the moment because people are like what about Islam about everything yeah I mean yeah so that even though we haven’t gone back to the moon and you could say well you know
(09:56) that was nothing that was a wash you know it was one of the most expensive projects uh in history uh right up there with the Manhattan Project but we did even though we didn’t go back to the Moon we got GPS satellites we got other satellites and uh um a you know variety the Telecommunications satellites so those three alone were some of the biggest uh ticket items uh in in return on investment so yeah yeah and then um the the making organisms so that they can’t be like virus perf is like how I summarize it um what was the organism I
(10:36) don’t think I read about this was it did you get any pigs it’s uh it’s a uh it’s a by archive preprint that will be a nature paper soon um accepted um it uh um uh the organisms E coli um which has a pretty a particularly severe virus problem they’re they’re a huge number of characterized and uncharacterized viruses in contrast to like the second favorite uh micro industrial microbe I would say is yeast baker’s yeast and Baker’s use has essentially no virus problem um I mean that’s just evolutionarily so
(11:21) so E coli has enormous one used as very little they’re both the top among the top two industrial microbes but I would say that most my industrial microbes fall into the Goliath category I mean they have virus problems so for example almost everything that’s in an air dairy industry yogurt cheese so forth all those microorganisms have virus problems in fact that’s one of the reasons one of the first applications of crispr was in the dairy industry um because it has such a big virus problem s dissolved but it was certainly it was
(11:57) a motivation yeah um I’m still waiting for them to put up uh the past year statue the giant milk thing that we talked about like five years ago on um because you’re on I think like the the road that’s near I hope this isn’t docking like where you where you work but like there’s like a road nearby called pasture Street or something like the pasteurization guy and I think like five years ago we’re talking about like we should get a giant like milk carton to like symbolize like history and everything
(12:22) um my address at Harvard uh medical school is Avenue Louis Pasteur um and we do have a giant melt carton not on Avenue Louis Pasteur but uh down in downtown Boston uh it’s it’s in some tourist section you know where they have a few museums the Children’s Museum and the computer Museum I’m not quite sure what the milk is all about I think it’s a place where you can get ice cream they should move it down to you’re you’re sure yeah and a giant uh wine bottle as well while they’re at it yeah and
(12:59) um for uh so a viruses how do we know that the virus is just like won’t see that as a potential food source and adapt to find it like how how can we certain that they won’t just make new viruses right so um the the way we did it is we for for two codons out of the 64 triplets um we swapped uh the amino acid from serine to leucine so normally these two would be serine and now they’re leucine and the the the host the E coli host was in on the game and so we we swapped them around so that the host is completely
(13:39) unaffected the virus was excluded from this normally there would be co-evolution where for every step that the bacteria would take the virus would take this you know a comp a complimentary step and would keep up with it but we took it offline and made uh thousands of changes about 20 000 changes and now the virus has every time it sees those two codons which is quite frequently Syrian these two serine codons are are common in every every protein that means every protein has a mixture of Syrian leucine at every place
(14:12) this occurs so that means every protein is broken in multiple ways and so the only way to get them back to where it’s at all functional would be that have some kind of uh way of editing all those sites kind of the same way the host was without intelligence and not edit all the other ones so it’s dead and that level of mutagenesis that you would need to get that level of editing would kill kill it in other places so it’s hard for it to escape now there is a possibility of making new viruses so viruses in a certain sense
(14:47) are as little as a polymerase that it got from The Host encapsulated in some way in proteins those lipids or plus or minus lipids and so that could happen um but uh I think it would take a long time uh we’d never I don’t think we’ve ever observed one going from scratch uh and uh you know if if one did arise then we would you know maybe there are things we can do that prevent the polymerases from being co-opted or um and we don’t we also don’t know how capsids form spontaneously but probably
(15:24) there’s all kinds of ways to aggregate proteins and they just become more and more symmetric um as time goes by yeah and then I think um like using a software analogy like potentially if there was something like that you could just offer like a software update to their biology like anyone who’s using that type of thing and then it would like you could always stay out of Step if there was a virus was like absolutely yeah um oh would you say something nope okay good I just always like to make sure I’m listening
(15:54) um when you develop technology like this I feel like there’s got to be like 100 companies that just kind of like follow you around and just like wait for it to come out and then they buy up the IP um to what extent is like not that like bother you but in the sense that like um if everyone’s I think in like the 70s or 80s like there’s like this myth that like uh there was an electric car and like some oil people bought it up so that no one could have electric cars so um how do you make sure that like no one
(16:22) just buys up the IP and like puts it on shelf granted like I guess if you sell it to like Ginkgo bioworks like the E coli stuff would just fit into their program and then they would just love it so much but um how do you make sure that like the IP actually goes to good people like that are actually going to use it yeah that’s that’s an excellent question uh there are two ways uh one is that Harvard usually almost always puts a clause in the agreement that says if you don’t meet the following Milestones okay
(16:50) the uh IP returns to Harvard and they don’t return your money so it’s actually it’s Harvard’s advantage to to monitor it and make sure that they do meet the milestones and the Milestones are usually crafted to be pretty easy to observe the second one way that that one avoids this is by um spinning off companies rather than being reactive to companies on the outside buying it you spin out a company that that is formed by the postdocs that invented it and they’re highly motivated to see it succeed
(17:24) because it basically it’s their entire life up to that point their entire professional life has been developing this technology and if anything they’re biased in favor of it where they they think it’s the greatest thing where it may or may not be but a big company when it buys up stuff is because a lot of big companies have lost their ability to innovate they’ll even admit this I’ve been inside such big companies as a board of directors and and and the way they innovate is by buying companies
(17:55) that have already innovated so so basically uh they don’t know they don’t see it coming when Harvard says hey we have this IP available they don’t see the value of it the way that a postdoc that invented it would and even if they did Harvard’s going to tend to favor the the the young startup because eventually it will get out either on its own or by being acquired by one of these big companies at a later date makes sense and then uh just uh when people are transitioning from Academia to the startup like the postdocs like
(18:28) narrowing in center and so so many different projects are there are there problems are there things that they need to adjust because like the Academia from the from I haven’t worked in Academia but I’m totally it’s kind of like it’s one mode of success like how to do something but then startups likes entirely differently have to be faster like whatever um what what transitions or what what’s new skills that they have to develop uh to make that jump successfully so they can build something and without it like
(18:53) you know crash and burn it yeah I think that’s a great question and it happened it [Music] um I think some environments are better for that transition than others so so and over the years we’ve accumulated a bunch of alumni that have done this successfully and they either Inspire from a distance or up close uh they will inspire the Next Generation and tell them where the land mines are and where the pasta gold are and uh that that all helps uh helps them know whether they want to go into uh join a big company form their own
(19:31) company or stay in Academia or something else um and then so if they have the prepared mind that’s that’s a a big part of it but the main thing is that academics are uh the job is to spend money and companies to make money and that’s a big cultural difference uh and also there’s there tends to be a lot more deadlines and Milestones in companies which isn’t necessarily A Bad Thing more productivity a little more focus on incremental improvements rather than radical um risk-taking um but each of these is you know it’s
(20:07) some people like it one way some people like the other some are willing to go through the academic in order to get to the commercial uh stage uh you know companies don’t typically train graduate students uh and you know and so you have to kind of pass through this academic phase uh at some point or another it’s like Metamorphosis but but I think it works out overall uh now one thing to be particularly careful about is when the entire company is made above academics uh in other words there’s often they’re fine you know a a
(20:46) scientists postdoc will find a business person either mature or you know just finished business school and then they’ll make a symbiosis and they make a company that that’s healthy but sometimes um that they’ll want to be they’ll want to have their their buddies be CEO CSO CTO et cetera and that also works but it’s uh it’s much more challenging as you know it’s like elephant balancing on a ball it definitely can be done in fact most of my companies are of that second type at this point but it took a
(21:23) few years to get to the point where we could do that routinely I have a friend who when he left postdoc and I don’t uh people may know I don’t know but um when he left he tried putting like a doctor people like you know my stocks on sales calls and it was like he was like why did I do this I’ll just hire sales people because like the how a scientist thinks about conveying risk is different than like oh you convey a risk if you’re if you’re like really trying to understand what people want and so that like like he lost a lot
(21:51) of money it was like yeah it’s a it’s a it’s a different skill set though I do think the the the structure of questioning things is transferable to sales I think people just need to like think about it a little bit more I think maybe they’ll figure it out it’s good to have communication uh throughout the organization especially when you’re small uh people will wear multiple hats at the at the startup phase they’ll be they’ll be both uh human resources and CTO for example or something like that
(22:21) but uh It’s Tricky Yeah It’s Tricky the um some sometimes it feels like this is a great time to be alive because there’s so much development going on and we’re talking about longevity and for the most part A lot of the longevity interventions are for Geared for like as early as possible or it’s like cholesterol so it’s like you know you could do that at any point but assuming probably as soon as you have a cholesterol problem I’m thinking like okay oh O’Connor and uh what he’s
(22:48) working on but um do you do you feel like the your age grouping tends to get ignored in terms of longevity and in the sense that like most things aren’t like I think most people are like shooting for like staying in like the 30s ish range like getting everyone to like having like like the Mind Body of a 30 year old so then and then it takes time to like group it out so do you feel like in your age grouping and I think I have a big idea how old you are I think you’re like I don’t want to say I guess I’m wrong
(23:13) but um don’t look as old as 68. yeah yeah like the thing is like you don’t you don’t look the age you know so it’s like you’re still doing great like if someone said you were like 45 I’d be like okay I get it um but my father went went white when he was 19. so uh I was a little bit later so maybe I’m a little younger yeah well it’s also a benefit having the white hair I think you know maybe people like were like hey this guy has a point then they don’t realize how old you are you know like because
(23:40) sometimes people are like oh you’re young you gotta wait your time but uh so uh for developing longevity technology do you see uh like kind of a shift from my point of view it seems like people are more geared towards like the like the 20s to like 40s but I don’t and then there’s like some for like cholesterol Etc from like 40s to 60s on up um but like if I were to like make a bell curve on it I would I would think like the the largest amount is like in the younger grouping so then do you feel like for your age group and they’re kind
(24:05) of like left out and then are you developing technology to like account for your age grouping I I don’t I don’t I didn’t think about it that much from that point of view uh no partly because I mean there’s I see a lot of drugs being developed for uh late onset Alzheimer’s for example which is 70 80 years old which is older than me uh you know I see um you know uh you know a lot of heart disease and cancer is still mainly affects people at end of life by almost uh and the end of life is is moving up
(24:45) there I mean we’ve basically been adding uh one year of life to every four years the human race is around uh and we’ve now doubled the average lifespan uh over the last 170 years so uh uh but we need to do faster than that if we’re going to save people alive today it has to be one year year not one year for four years and I think that’s happening because we suddenly we you know it’s like the exponential is really starting to take off and biotech um and I and I think it’s hitting you know first it hit reading and writing
(25:20) DNA which is very molecular and which is not that far away from like Electronics uh but now it’s hitting in the cell biology developmental biology and that’s they’ve got their own exponential which is similar and I think that will uh impact and then and finally the the biggest thing that makes me not worry about what age group is being favored this is kind of like uh I am worried about uh ethnic ancestry groups and uh gender uh discrimination and research but with aging you’ve got this big thing
(25:51) which is aging reversal um and we’re seeing we’ve seen plenty of examples of it in animal systems in human cell culture um and it’s it’s a real thing and so that that changes the discussion as to what age group you’re looking at in fact my ex post Doc and co-founder of rejuvenate bile Noah Davidson’s group just published a paper where they applied the therapy a gene therapy uh a triple gene therapy almost all our Gene therapies for aging are multiples uh applied that at 124 weeks of mouse
(26:32) age which to put that in perspective about half of the cohort had died from old age by the time they climb the other half got the treatment and it showed a very significant uh increase in in lifespan so so you know it’s within our power to to aim for very late in life uh treatments uh there’s two kind of two schools of thought is that you you need to treat early in order to extend life the other is that maybe pretty late you can reverse things and so um you know I I’m keeping my mind open on those two schools
(27:11) yeah there’s a a great series I think it’s the kamalo series where for the the longest time they just would like every like 20 years they’re getting like this they’re going to like this pod or something they would rejuvenate their body back to like 20 and then they would aged up to 40 and then to go back to you know doing that again and then um sometimes I wonder to what extent is that something we’re gonna be doing like we don’t cure Alzheimer’s but we can run Rejuvenation up to the point where we
(27:33) basically don’t have it functionally kind of like how like some nuns are so active up until the point they die that we don’t realize that they had uh like blacks and stuff going on in their brain I wonder just to some extent like it is that what we’re gonna do and then eventually we can cure it you know but uh I wonder about these things do uh what is your position on that do you think we’ll have like Rejuvenation and then eventually uh cares for uh the illnesses or anything well just like a
(27:55) jump Rejuvenation in the sense that I’m talking about it and have cures for the different illnesses which is yeah yeah well again there’s a few schools of thought here that are not really exclusive one is that that there’s serious uh damage to DNA RNA and proteins and you have to go in there with your pliers and fix them uh the other is that if you just convince the cell epigenetically you know that you know like you change the culture of the cell uh it will think it’s young and then it’ll get its own pliers out and
(28:25) fix itself now they’re obviously some things that are hard to fix uh uh by oneself uh for example if you delete both copies of a tumor suppressor Gene there’s you’ve lost that information from that cell in principle you could get it from another cell but but that doesn’t there’s no that mechanism hasn’t been shown to be common um so those you might have to literally go back and reinsert the the Gene maybe put in a few extra copies um and that could be done preventatively or or reactively I think that my I fall
(29:01) on the camp where I think that most of it is epigenetic and if you if you change the epigenetics either naturally or unnaturally you can you can fix a lot of things um and we’re getting better and better at delivery so we can deliver extra copies of tumor suppressors preemptively so uh I you know I think it’s gonna be a mixture of things that that deal with specific symptoms of aging and things that aim at the core mechanism of aging and hence once you get the core mechanism you can you can reverse it so I think we’re going to see both
(29:37) um in big time in the next few years has there been anything in the last five years just think of it from the book ends of like first interview and now that has surprised you that has come out I think the first time we spoke they’re crisper in terms of therapy was um like they’re still developing it and I think this year they came out with the first two crispr therapies I believe like that people are actually gonna be using them so I think that’s been a change but I think that’s like an expected change is anything like
(30:00) surprising last five years either yeah definitely not surprised in fact yeah about anything about Christopher is not particularly surprising other than people’s reaction to it that was surprising to me um because we had really great editing uh prior to Christopher uh for what’s uh Mario capecci and Oliver Smith he’s got the Nobel Prize for pre you know uh eight 1980s work uh it just wasn’t that efficient so you know uh normally I don’t think making things a little bit more efficient is such a big deal if you
(30:34) make it 20 million times more efficient like sequencing that’s a big deal but Christopher was maybe four times more efficient or something like that um what has been really surprising uh well you know I was really pleasantly surprised by how easy it was to edit repetitive elements uh so you know with all the edit all the best editing methods uh it was very hard to get above say 70 editing so you know 70 of the cells would have one at it right and so if you think well they get two edits uh you know the the you’re gonna
(31:16) have to the square and a three out of the cube and pretty soon you know none of your cells have all the edits that you want right and so the idea of making uh dozens of edits was was seemed unlikely uh but nevertheless um uh we we did we had to do it for the pigs uh organ transplants we had to get rid of the viruses that they produce all Pig organs produced uh retroviruses and retroviruses we were a little the world was a little gun shy about retroviruses because that’s what Screwed Up gene therapy around the year 2000 is that the
(31:59) retroviral therapy caused uh cancer via the lmo2 oncogene and so we the FDA did not want to have a bunch of pig retroviruses infecting humans cells in immune compromised patients anyway we we did that in our first experiment we got 62 at once 62 edits Each of which individually seemed like it was you know 50 to 80 percent probability so it just seemed astronomically unlikely that you know it’s like that you would uh you know pull up the Ace of Spades 62 times in a row uh and uh and then since then we’ve extended it we’ve now done 25 000
(32:42) edits uh and that that I never cease to be amazed at how easy it is actually to to make that number of edits and I think we’re going to see more and more uses of Multiplex editing just like we have more and more uses of Multiplex therapies or polypharmacy is sometimes called um so for in you know for engineering agricultural species industrial species and even human cells for uh cell Therapies the uh I think I was watching uh an interview with you we were talking about how like you’re working or like there’s a
(33:19) theoretically we could get to like a million cell edits at the same time with multiplexing and that’s um I I guess like the timeline from like 20 to 20 000 is pretty which seems pretty fast so then twenty thousand to a million doesn’t seem like it’d be that far off I think we may already have the protocol we just haven’t uh uh you know applied it uh yeah we have definite applications for it and we’re moving in that direction I mean for example the virus resistance that we have any coli only took uh 20 000 edits
(33:55) the virus resistance in um Amelia the equivalent viruses million cells would probably be hundreds of thousands of edits maybe a million um so so that’s that’s that’s that’s that’s one driver um uh um the extinction of genes not necessarily species or maybe even species could involve millions of that it’s I think we’re going to get away with hundreds but but since this is moving so quickly I wouldn’t be totally surprised if we get to Millions by the time we need it is there um is there
(34:36) I don’t I don’t know I’ve been playing Kerbal Space Program it’s a game on like uh space flight so everything’s in like Space Jams for me which is bad but uh and apogee is like the top point before you start going down is there is there an apogee where like uh if you did more like you have like reduced returns for how many more edits you can do so like if you had like you know 10 million the ability to affect 10 million cells at the same time um versus like 1 million is like getting the the extra difference in 10 million
(35:04) doesn’t actually do much more like you reached like a cap or like you’re not doing that much more if that makes sense so like um is there a cap where like editing more cells at once would actually not be useful or is it more generally as useful I just want to point out there’s there’s two kinds of multiplexing here that you nicely pointed out uh that I had glossed over there’s one is the number of edits per cell and that’s the thing that I was talking about we’re at 25 000 we’re
(35:32) heading towards a million um and then there’s a number of cells edited at once and then you could have both which is a large number of cells added a large number of positions each um so um um so as early as 2009 we made billions of cells that each had a small collection of edits so it was it wasn’t one edit Purcell it might be five or ten per cell but billions of cells so we had a very large diversity of of genomes that were designed not not random not entirely random um you know I think that uh points of no of
(36:12) diminishing returns certainly for for the let’s say codon remapping there’s a certain number of edits you have to make before you can delete the the transfer RNA or or swap that’s the Syrian and Lucy in them instant get you virus resistance and if you stop before that you’re going to have a you know a key Protein that’s got a mixture of syrians of leucines just like the virus and so the cell is going to die so um so that’s a threshold thing um for the extinction let’s say there may be as few as a hundred that that
(36:45) allow the elephant to be cold resistant and to do its thing on restoring the the uh Arctic you know the Vibrance Arctic ecosystem as a keystone species maybe as few as a hundred um but it might take Millions to make it genetically identical to its ant to its uh common ancestor or uh something like that um and that would be a point of diminishing returns where the ecosystem impact you got most of it in the first hundred uh and the only reason you keep going is because you can right makes sense yeah and then um I
(37:22) definitely see the an application for the I’m gonna call it the you know the like make it so like the viruses can’t impact uh animals like uh testing out on agriculture so that you know you don’t have those problems wherever because like for the most part oh viruses come from animals like when they hop over to humans and then that’s what kills humans because it’s not built for our body yeah which uh uh anyone familiar with the shell will know that I comment on like how when when uh when the Europeans came to America we brought
(37:48) horrible stuff here but there was not really a transition from America’s back to Europe because uh the Americans didn’t really have that many domesticate animals I think they only had alpacas that they really domesticated so there wasn’t that many like Europe had like pigs chickens you can only had so many different things so there’s just many more opportunities for it so making agriculture uh something where uh that jump doesn’t happen then when we don’t potentially won’t have like you know
(38:10) Covenant stuff that happens to us um there was you talked in one of your uh recent interviews uh about software as biology and um you you made a comment and like I was like oh what do you mean by this because like you weren’t able to expand on it so I thought I’d just ask you now you stated that uh using that as an analogy you say that there is a lot of biology and analog circuits that people are overlooking and whenever you say hey someone’s overlooking someone’s like oh wow I definitely want to learn more what
(38:33) do you what do you mean by that foreign well I mean there’s two opportunities one is making a put making cells more digital and the other is um using what is the strength of uh cellular Computing which is more analog okay and and examples of analog is uh you know uh measuring uh the temperature uh and you can turn that into you analog to digital and digital analog are very common in electronics and the same thing happens in biology is you can you can say build up a certain amount and then you decide where it is in the day and you set your
(39:16) security and clock or you get a certain temperature and you decide that it’s spring and it’s time to do the whole Vernal uh cycle thing uh Etc so um but then there are other things where there isn’t a switch that’s flipped you stay analog where um you know the temperature increases a little bit then you uh then you uh stop shivering and you and you get rid of your uh thermogenesis Brown fat stuff um and vice versa so um there’s no I don’t know hard and fast rule where something has to be digital
(39:55) has to be uh analog but there definitely are cases where it’s a little more efficient from um engineering standpoint or an evolutionary standpoint uh one one thing that uh keen on getting the digital going back in is recording information into the DNA of of cells we’ve we’ve uh set a record of recording two terabytes of information into the DNA of um mice about you can record physiological and developmental data and we think we can scale that up to 20 petabytes by hiding the information in in the parts of
(40:35) repetitive elements that that we will find in empirically are not uh disruptive so the reason I describe it in petabytes rather than analog terms is because DNA is is essentially digital and you know it’s got It’s got two bits per per base pair um but a huge fraction of biology the thing about biology it does this is very natural gradation between analog and digital so for example uh group in UC Irvine has used our method to encode hypoxia data in in from analog State into this digital DNA state so um and we need to be able to go the
(41:16) other direction too so we need to be able to take the digital DNA data and turn it into analog physiological um um responses yeah I think uh what uses well when I think of uh is you know sometimes we want to put like uh biobanks or something on the moon or you know in different spots but if we could just like record all the data and like hide it in cells or like a really like power like you know like the people make comments like there’s nuclear war like cockroaches to the real world so we could like hide that stuff in like
(41:47) cockroaches for us to pull out in the future but uh that’s like more like you know apocalypse type stuff what what uses are is there to trans you know have like 20 petabytes of data stored in cells right okay so um I mean there’s a a fork here in the road where you’re storing uh data that is definitely digital let’s say uh you know tape you know tables of where all the cities are and things like that uh that’s digital information and Syria cultural um the other is where you’re storing data that is biological that was
(42:25) essentially biological analog and Digital Data you’re storing it in a new form it’s more compact um and so you’re essentially creating a time record kind of a a tape recording or a flight recorder is I think the best analogy where uh um in case something goes wrong you can go and inspect the record in whatever cell you want so if something went wrong in the liver you can go into the liver and itself and see what his flight recorder is says so uh so I think this could be used medically or potentially environmentally
(43:01) to if something bad happens you go in and you can go to a particular coordinate where the bad thing happened and uh and lift out some some DNA and figure out what happened you don’t have to sequence the entire ecosystem or the entire organism to figure it out um so it’s just like a flight recorder I think is is the is the main use case that I have so far but you know it’s one of these things a little baby you don’t know where it’s going to go next so yeah that would be interesting if it was like
(43:33) if you had it in every organism on the planet so whenever you were exposed to it you kind of like you could see like what was happening to it for the course of its life it’s kind of like a tagging sharks you could just you know take a little biopsy and then he’d you’d have all the information then yeah be really cool the one thing that you do and one of one of your other talks today I wanted to touch on before I think we jumped in more longevity related things um is uh you talked about using synthetic biology
(43:56) as manufacturing well we talked about this in our first one um I don’t know if anything’s developed it any faster on this but you talked about it as a way to alleviate uh poverty you know if we came in and we could build uh manufacture through synthetic biology medicines and that’s one last thing that the the uh the society that is in poverty has to worry about something invest in other things but I was I was reading that uh in like Poland for instance they use clams to determine if uh if a water treatment
(44:21) plants have filtered enough of the water for it to be drinkable they use like you know a biology process so I was really taken by this idea of using biomanufacturing to alleviate poverty if you could go in and then build uh you know water treatment like uh self replicating and uh rejuvenating system for Like Water Sanitation and all these other things because when poverty one of the biggest things is like they don’t really have clean water you know medicine’s a huge one of course so if you could alleviate all those things
(44:47) then I make it something that they just have to like you know beat I guess let me be really cool I was just like really taken by that idea of can we use synthetic biology to alleviate poverty and lift people up and build systems because like even in America we have like Flint Michigan that has like I think it still has lead in the uh the waters and we have um like chemical spills and all these other things so like having like a biological process I could break it down um and then um or a manufacturer to create something uh because biology does
(45:14) seem extremely efficient compared to like what humans can do like I don’t think we’re as efficient as what biology can do yet yeah so oh you you you’re touching a nerve here uh in a good way uh in that I think that not only can we uh create a virtuous circle for um poverty where you alleviate a little bit and that gives them a little bit more health and education to to to make the next increment in in lifting up out of poverty lifting themselves out of poverty in particular I think that one can that
(45:49) one can imagine and we’re working on a a a a a a box essentially where uh where it produces food and then and you do complete recycling so you can think of the house you could have a house that’s like a space station or a submarine completely sealed in nothing exchanged with the outside world other than you know energy from geothermal or solar or wind whatever um that that then uh helps Recycling and because you’re in complete control each household it has its own system once you have a clean system that doesn’t have lead and it
(46:28) doesn’t have other industrial pollutants in it um it will stay clean and also you will have known the mechanisms for cleaning it up in the first place so you know they’re no mechanism by which you can biologically decompose dioxin and other toxins where you can take heavy metals and sequester them into a lump in the in the side you just leave it there but then from then on the this internal you eliminate supply chain uh costs and and insecurity so a lot of the problem with poverty is is not so much they’re
(47:03) impoverished today it’s that the next time there’s a supply chain issue you know they have they have to pick up and and go when they become refugees and all kinds of things like that so you need to have a more stable supply chain and what could be better than having it you know all within your house um also a huge amount of the the uh environmental damage is done due to you know making pipelines and Roads and and uh manufacturing of of uh trucks and so forth and that could be eliminated if if you know 90 of the manufacturing occurs in
(47:41) your kitchen can I even the like some of the basic stuff that people do for like biohacking uh or just like when they’re first learning genetic engineering is like hey can we add something and then have like it like be um bioluminescent at the same time so um if there was like something going wrong in the system like it could be as simple as like you know you know color coding it so the you’re reducing the level of technical expertise that a person using the system would even need to have to it’s kind of like the Chinese
(48:08) box like they would just need to know like these cut these colors correspond with these things that inputs they have to put into it they just go over their day it’s even better than that uh and you can make it so they just ask what they want so they say I want you know a vegan burger right and you press vegan burger and out comes one and so that there’s no colors that match or anything like you just you just see what you like and or it even remembers what you like you know to have on Fridays um and it’s kind of like uh it’s kind of
(48:38) like GPS you know on your phone uh you have most people have no idea idea of how many satellites there are and what angle they have to be at and and uh how they’re synced up with 37 atomic clocks uh and all this stuff that is required for it to tell you to turn left um and that’s uh that’s that’s the beauty of it is you don’t you don’t even need to have simple programming skills you just need you talk to it the way you would talk to a a extremely knowledgeable person so I I think that same thing will be true for
(49:14) manufacturing it’s it’s not that hard to recycle um you know complete do complete recycling uh we have plant and animal systems have been going for you know eight decades uh in a completely sealed container it doesn’t have to be completely sealed with humans but if if you can do that then you have a whole new set of capabilities even submarines and the International Space Station um you know rarely go the more than a few months uh they’re always getting resupplied so it’s not really a sealed
(49:48) system um except for those short periods times been between Supply runs but we can definitely do it we know how to do it for animals so and it would also reduce certain existential risks so uh you know uh certain kinds depending on your sources of energy certain kinds of you know asteroids uh pandemics uh [Music] um uh you know the super volcanoes and so forth that uh you could you could and and you could also prepare for for leaving the planet if you you test out the whole um survival and small Clans uh or small
(50:34) um uh isolated systems you test it out on Earth where the risk is lower but if something goes wrong on Mars you’ve got a couple of years to get back to the nearest emergency room on Earth you test out these modules um right right in the shadow of a city there was a I was watching this uh this it was a smarter every day he’s a great YouTuber he like goes and discovers things he went on a submarine and he looked at like how they produce food and they had like this like like a like a cord or stocked with food and but to get
(51:08) to something they have to take it all out to get in there to find like you know ketchup or you know maple syrup and they’ve organized as best as they can but there’s not that much space in a submarine so instead of needing like uh so many different food stocks you could just have like several food stocks and then use this biomanufacturing process to then create the food from there so I think that like even like it’d be space efficient and you know to like play a Tetris with it too much uh which would
(51:32) be pretty pretty cool yeah yeah and in fact it’s doing the tetris because it’s probably all that all the different producing micro industrial microbes are inside the box and you just say make this and then somebody else’s program that it adds a whole new level to the idea of recipes right yes where the input is something much closer to uh to uh to to you know raw synthetic biology yeah um I think the closest to this type of system that I could think of is like you know cellular agriculture in terms
(52:06) of you know taking cells and just producing it based on what you’re giving it is there anything that you can think of that’s working towards this type of system um well that’s the disappointing thing is there aren’t I mean there there are some uh algae that are fairly uh nutritious and tasty like spirulina uh that also uh but but the no one has there’s almost no recipes for making things entirely out of uh such organisms um usually they use them as garnish or or uh you know a little bit of seasoning
(52:40) just to feel good about it but uh having recipes entirely basically but it’s not that far away either I mean making recipes are something that everybody can do it’s like it’s one of the few citizen sciences that literally everybody participates in in one way or another um so I think this would just be incredibly enabling uh to to be able to it can keep track of the nutrition for you you just you just tell it what you like the taste and you experiment with with new um you know sources of metabolism
(53:17) could um so the the interesting thing with like energy generation for instance is it’s all basically just built on a turbine you know like even like nuclear power plants I thought that’d be cooler you know like people were like oh they’re gonna like you know kill people or whatever and I actually looked into how they’re how they work it’s no different than just like you know spinning a turbine like just like steam is generated whether it’s like coal or whatever and um a turbine Insurance uh
(53:39) uh turn and then like that’s power that comes out could we ever like obviously you shouldn’t do this because it doesn’t make sense but like if we like took mitochondria and like blew it up and uh I I guess that’s a horrible analogy but can we use a biomanufactured uh energy plant to produce energy as efficiently I think uh I think um nuclear is more sufficient form of energy so can we do the same thing with like with power using uh biomanufactured like like a cell thing about Bob probably yeah well take photovoltaic is
(54:11) an easy example I’ll get back the nuclear um photons come in they get electronically converted to uh you know a voltage and and then that can uh can uh go straight into biological systems so you can have either Electro uh metabolism or it can turn back into photons that are at the right wavelength so photons coming in are include infrared green and UltraViolet none of which are well tuned to a lot of photosynthetic systems anyway so you can essentially remap without turbines um and then and then the then the
(54:48) biology has all kinds of chemistry basically almost all chemistry probably could be done that we’re interested in to be done biologically um nuclear would be uh I think more challenging uh but there are um they’re a thermonuclear devices in a certain space probes that this is past tense is not in the future um that do not involve turbines as far as I know and so they’re not they’re not at the very high level of of a modern fission reactor and we don’t even know what the fusion reactor is going to be
(55:27) like but probably they’re so hot that it’s going to be very tempting to to run turbines um but yeah I mean uh I I’m not uh I don’t think it really matters if you have a centralized facility it does turbines are fine it’s just when you want to be off the grid then you might want geothermal or solar probably probably something geothermal might be the safest one maybe wind because if you get like uh nuclear winter or something like that due to a super volcano or a meteor hitting um then you want to have something
(56:08) that’s that’s a little bit safer than photovoltaics from that kind of standpoint now recently is effective almost anywhere on the planet uh it’s it’s easiest to do when it’s near the surface like in Iceland but uh but everywhere on the planet has you know 600 degrees Centigrade if you drills deep enough uh so uh you know it takes some investment to get down there and uh but then from that point off you’re off the grid yeah I was recently reading how a fit uh efficient uh geothermal is in terms like
(56:46) um how easy it is to hook up because you can actually get them in like for houses and stuff and they’ll last for like 50 to 100 years like the piping that you put under underground it’s like it’s not even that deep I was saying like you have to like really be in a special spot maybe it’s from sci-fi because it’s always like in a volcano we’re doing like geothermal or something but um i i a lot of the a lot of the systems we’re talking about it reminds me of like this science fiction where there’s
(57:07) like sub genres like uh like frostpunk or uh like but but basically there’s like bio punk where like everything’s built out of biological uh systems and it feels like there there could be a future and not too distant future where um you know um like a lot of the things in society are built using biology versus uh you know like people’s hands you know like in terms of like us having to build it uh which would be pretty interesting and if you do want to do stuff like that you should build it in the midwest because it’s much cheaper I
(57:33) tell everyone this all the time if you look at the how how expensive things are unlike the coast to the Midwest it’s so much more affordable out here um though it’s really cool that this can be built where it is and they make use of all the other networks around it in terms of innovation and stuff like that um there was a a fan question about uh the wooly mammoth and I just want to pull it up real quick because uh it’s a really cool thing I think when we first were talking about it it was just like
(57:56) not like a twinkle in your eye like you were working on it I think you had like a there was a book where the guy I think it’s called uh Woolly or Mammoth or like there was like he talked about how like there was a mouse and it like roared like a lion like not a lion like the woolly mammoth because like you put some cells into it uh which I think is just like a really great imagery even if it wasn’t true um in regards to the one we met the mammoth restoration project uh can you talk about the modifications that you’re
(58:20) going to be making to the Asian elephant other than giving it fur I looked online I tried to see if I could like you know reverse engineer what was actually being done um but is it possible to talk about what type of uh work you’re doing on Asian elephants to move it to the woolly mammoth and tournament like in specificity absolutely it’s uh uh we’re we’re gonna have a paper or two coming out uh pretty soon uh where we lay this out um they wouldn’t let within the next uh eight months or so uh
(58:52) but and we’ve we’ve discussed some of this uh but the list is mainly focused on uh cold adaptation or you could say handling both winter and summer where the winter is minus 40 and summer is normal um and Asian elephants actually can tolerate pretty low temperatures and then enjoy playing in the snow and even playing in frozen lakes they’ll break through the ice and they’ll swim around for a while but they can’t do it for very long or for very cold or very low a high wind chill um and so so one needs uh fat deposits
(59:33) so there was like 10 centimeters of fat pretty much all over the body of the mammoths that was not in uh modern elephants um instead of the the short uh spiky uh sparse hairs that are essentially radiative they radiate heat um instead they had the mammoths had the thick woolly hair um so those two probably aren’t that hard um there are more physiological more biochemical things like their hemoglobin was adapted to uh to release oxygen at lower temperatures than is normal so so the skin temperature um uh is getting close to freezing point
(1:00:17) um even though the core body temperature is the same as our Core Body the skin is different so that that uh that that’s one of the genes that has been uh uh restored the extinct and and so to be half plausible functionality uh the ears have to be smaller so they don’t get frostbite uh you know a few things like that there are some things that may not be present in Mammoth that we’re all it’s also on our list uh they’re the president neither the modern elephants nor the ancient ones and those are things like
(1:00:54) resistance to killer pathogens uh in fact back to the whole virus thing that we talked about earlier uh elephants have a very serious virus problem uh they’re partly they’re endangered species because of herpes viruses and um and so we have various strategies we’re exploring to make them resistant to either all viruses or to the specific eehv virus which is uh part of what’s making them go extinct um and then we may have um adaptations to um you know [Music] poached poaching you know where they either have you know very short or no
(1:01:40) tusks under certain circumstances and in other circumstances where they’re well cared for and guarded they’ll have the big you know maybe even bigger tusks than than uh than usual so so those two things uh you know the virus resistance and the test manipulation may not depend on the mammoths but but most of them are inspired we the other place where we could deviate a little bit from the mammoth inspiration we could look at Polar Bears and Penguins and other um cold tolerant animals for for ideas and maybe make these elephants even more
(1:02:15) cold tolerant than the mammoth sore but you know this is the point is we’re not limited um and that’s that’s that’s the short list that you were looking for I think yeah is it uh for controlling the Tusk link would it just be like uh if you gave them like a certain food I think of a like uh uh bees like the difference between a queen bee and a regular B it’s like they’re just fed something differently would that be like how you’d regulate it uh in terms of like being in a safe spot versus not safe spot exactly
(1:02:45) we already have uh projects where we’ve made organisms that are biocontained meaning that if they don’t get this chemical which is not available in the wild it’s only made by organic chemists then then they can’t replicate and uh in the case of the elephants it might be the same chemical which they can’t make tusks without that chemical and so you put that in the feed in a very well protected animal reserve you know it might be um you know hundreds of square kilometers but it’s very well guarded
(1:03:19) but then when you let them out into the millions of square kilometers of the uh Canadian and and Alaskan and Russian Arctic they’re there they’re tussle will be small and that’s already been it’s already been shown their their tribes of elephants that that don’t have tusks and they do fine uh the tribes of elephants have ridiculously long to us uh in the in the in the genetics of this has been studied and we’ll we’ll exploit it is there uh any plans to expedite the gestation period because I think
(1:03:53) elephants have like 22 months which is a pretty long time yeah uh we are definitely interested in short stations here is it’ll probably uh results in smaller animals uh although there are animals that keep growing you know for for in other words they’re born small but they keep growing until they’re quite large um I mean for example the record for short gestation there is in marsupials and in rodents um non-marsupial uh eutherian mammals it’s it’s around 20 days for a mouse and maybe 13 for the fastest marsupial but
(1:04:33) the marsupials are essentially born they’re still they look like fetuses I mean they they can crawl up and get to the milk but they uh and the same thing’s true for the rodents when the rodents were born they’re blind they’re hairless they’re very very fragile uh they’re not like um you know like uh cattle they come out and running you know uh yeah so so there’s a trade-off but but it would be helpful to get feedback quickly by having a short test station and I I don’t think we’re gonna make a 20-day
(1:05:09) gestation period rather than 22. uh months but we might I mean there might be some reason to do that uh um yeah and the other but more important maybe than gestation length is how many we can do in parallel um yeah uh and I think if we can do this x Vivo which which we’ve got a fair amount of uh effort on that uh then we can have them you know essentially in this giant Warehouse or conveyor belt or something where they’re um where we could have 10 000 of them growing without uh interfering with the reproduction of the endanger the current
(1:05:52) uh endangered species we’re close to being able to replicate gestation outside of the womb I thought we were like we only had we only had like artificial you could like test drugs on like a like a little chip I don’t know we could we were close to having something where you could like really take it out of the system out of the it’s hard to say how closely are but but there are parts that make it seem like we might be close if you’re you know embedded in the field so for example you can take mice up to almost
(1:06:26) uh nine ten days which is halfway through gestation from from fertilization and human preemies we can get half we can take them so they’re only halfway through a normal uh uh humans gestation and take them all the way to birth and they’re and they’re fine so that so in a way you can get halfway from both sides so it seems like all you have to do is Bridge it the problem is that most of the protocols for getting uh halfway from fertilization um you you haven’t really hooked it up to uh umbilical cords and placenta
(1:07:07) properly so it’s so you can’t distributes swap into preemie mode um and there’s just a little Gap there so that’s one way of looking at it uh another we are getting um just much better at um producing organs for transplant I mentioned the pig organs is one of them um and this and and keeping transplantable organs alive outside the body so if you can keep the endometrium the uterine wall alive like you would in Oregon outside of the body then implantation is almost automatic um and then then the two halves the
(1:07:50) embryo half and the maternal half have well-evolved mechanisms for all the feedback physiology and so forth so the key thing is getting endometrium to be able to um be healthy outside the body um the the developments um is fairly much on autopilot but no one it’s amazing how little effort has gone into maintaining organs outside the body mainly because most transplants don’t need to be outside the body more than a few hours so there’s not a heavy up until now there hasn’t been a heavy motivation for for setting records on
(1:08:29) that but that’s that’s what we’re doing yeah uh with organ transplant I’ve always felt like like the the time Horizon like they have to move really fast but there’s our there’s also a lot that just like there’s no one around to use them so no one gets to use them so having like a like a bio Bank of organs they can just be maintained until they’re used but then again um you know then just like manufacture on organs is also pretty cool um so I’m I’m generally curious if
(1:08:55) when you’re developing a product sometimes you just like find people and you see what their pain points are and then people can like kind of help and Building Things around that I’m curious for you and your Innovation are there problems that you have that if someone’s like hey I come in with I mean I guess that’s like uh the uh next people process to generate uh elephants would probably be a process you would love help with but are there tools or techniques that you wish were being that that you wish you had to do
(1:09:20) the work that you’re doing to like expedite them well absolutely uh most of the tools I wish they had I’m working on uh but still they some of them seem to take a while uh I would uh plus I mean I I you know wish we had uh better microscopy uh that we’re I mean right now we finally have microscopy that can work at pretty high resolutions like 20 nanometers maybe better uh where we can label the Nar protein so that’s that’s a way of when we’re engineering you want to be able to check to see what
(1:09:58) you’re doing right and so a lot of what we’re doing is invisible um with the naked eye and so we need better better and better microscopes um and the problem is that once you get this super resolution if you want to do both uh large scale and small scale at the same time uh you end up with a lot of data so so you know petabytes uh just to do ordinary things um and then another thing that doesn’t scale well and so a lot of the scaling is uh is is uh say 3D printing there’s a lot of things we would like to be able
(1:10:33) to 3D print anything actually teach a course called how to grow almost anything which is on the Internet it’s International and it’s a sibling course of how to make almost anything and we would like to be able to merge those so that we can make any device that is currently inorganic with Biology um and then and then use two together to you know we should be able to make that and biology is fairly good at inorganic materials as well but it’s not really there yet so I’d like to have um and and to use developmental biology
(1:11:06) rather than uh Cartesian 3D coordinate printing which is very slow and doesn’t scale well biology has trillions of print head equivalents per cubic millimeter in the form of ribosomes and cell division and so forth all these um molecular machines so it has this incredibly high density of simultaneously performing printheads While most 3D printers are you know kind of this simple uh you know Cartesian robot so that’s that’s that’s a partial list uh um but the list goes on and on things that are missing
(1:11:45) um but they’re getting filled exponentially so I’m not panicked but they don’t it doesn’t fill itself by itself yet uh so it requires a great deal of Ingenuity and hard work to fill those caps in technology which is kind of the main thing my group does yeah yeah uh it’s always great to read what you’re up to I wonder if you had like a like uh things we’re not covering and we don’t know anyone who’s covering like if you had like a list and then people go okay you know they could like use that
(1:12:17) to generate some ideas but uh I’ll uh I’ll link the courses in the show notes um so uh uh fan question um Gene therapies that have been approved for rare diseases are very expensive what should we expect in terms of cost of I don’t think you’ll be able to answer this but cost for gene therapy stands targeting okay well it’s for a rejuvenant bio which I think is what should we expect in terms of cost for Gene therapies targeting the biology of Aging like those developed by rejuvenate bio because I think like you you can
(1:12:44) guess even at this point this is pretty early this is a great question is this is this a fan question did you say yes yes okay it’s a great question um and I’m ready for it okay so I have uh pointed out that uh there may be a different strategy for rare diseases and common diseases and I would put Aging in a common disease category another common disease is pandemics or or you know very large uh um vaccination programs even if they’re currently rare diseases we still have to vaccinate the entire population and what
(1:13:19) happens is for these common diseases infectious and and age-related is since everybody is is a consumer uh the denominator for you know if kind of fixed cost for r d and clinical trials and the denominator is a number of people that benefit so for rare diseases that denominator is Tiny it could be 100 people a year and so the cost is you know the highest cost I’ve seen so far for a therapy is 3.
(1:13:45) 5 million dollars per dose one of the reasons rare disease on Gene Therapies and in fact that that that caused me some concern when I entered the field of gene therapy you know many years ago is I you know I I’ve been the proponent of making technology equitably distributed so that uh even poor Nations and communities would have access uh and and I realized you know and we did that we brought down the cost of reading and writing DNA by uh you know 20 million fold and improved quality at the same time but for pharmaceuticals they seem to be creeping up rather than
(1:14:22) going down exponentially um but then if you if you re-analyze sort of to a uh uh think about it a different way the recent covid vaccines the top five of them were all formulated as Gene therapies and um one of one category of those five is adenoviral capsid around double-stranded DNA encoding the vaccine protein um and that got down to as little as uh two dollars and 18 cents per dose so down from 3.
(1:15:01) 5 million for a rare disease to two point and they’re both you know viral capsids around double strand DNA and their Gene therapies um so I think that’s where it could go I think that’s going to apply to aging reversal and age and aging reversal or age if if you don’t like hit your reversal then aging disease you know core treatments for hitting multiple aging related diseases which is what we’re doing um that could be in that range now I’m not making a promise from on the behalf of my companies they’re going to sell
(1:15:32) things for two dollars a dose at least initially but it’s certainly we’ve got the proof of principle that works it’s been tested you know these gene therapy like things have been tested in billions of people worldwide and I think that the experience has been fairly positive so I think we’re off and running now um on on on common gene therapy so that so now what about the rare ones uh I think one uh solution that is that is getting better and better every day and was already pretty good uh is uh genetic
(1:16:07) counseling and this can be done either preconception or premaritaly which is the best time because there’s no risk of false pauses causing damage on their own um and it can be done as late as in vitro fertilization or even on um um prenatal um the in vitro fertilization is getting much better one of my company’s Orchid is sequencing every single embryo that goes through the the IVF clinic and that helps not only avoid these very serious uh but rare diseases get them you get them all at once because you get the
(1:16:45) whole genome but it also helps uh with the fertility itself because a lot of failures in the IVF clinic so on average you have to do five rounds of hormone treatment and IVF to get one child um and a lot of those are due to aneuploids or or other genetic diseases that are so fatal they kill the child before it can even be born and so if you’re anti-abortion you should be anti-spontaneous abortion as well and this is a a way by sequencing the IVF embryos you can see which ones are are going to survive and we might get that
(1:17:25) down to five that’s down from five ivfs per baby to one IVF per baby um so I think I I think all of that is going is going to handle the the rare ones uh now IVF isn’t quite as equally distributed as the genome sequencing which will be basically free and once you get the return on investment worked out um and um and aging reversal drugs which might be once in a lifetime and two dollars a dose so and that also could be free because it’d be to the government’s advantage to have people you know working past retirement age being
(1:18:06) healthy not not consuming so I think those are the different answers for rare and and common but they both hopefully will end up with you know Equitable uh distribution to even in even the poorer communities uh something that I thought of um when you’re saying that remind me of the like making it so the viruses can affect things um because you were talking about like uh you mentioned covet and the MRNA vaccines vaccines I actually mentioned adenoviro capsule the double strand DNA but but mRNA vaccines are also formulated as a
(1:18:40) gene therapy it’s just a less common one a new one um I was I was wondering um just as a quick aside is it possible to uh modify a virus to have a gene drive so then when it goes out in the wild it just infects all the other ones and then you know they die really quick could you do that I don’t know if you could I was just wondering so just you know for the listeners Gene Drive is typically something that spreads through sexual uh species that and and ideally ones that read quickly so these would typically be
(1:19:11) insects or rodents um it doesn’t work as such in viruses nor in uh asexual bacteria nor in asexual plants and animals um um viruses already spread pretty quickly uh I guess the question is can you make a virus that will out compete the other viruses or um you know when the when on the rare case the virus is exchange genetic material will it win in some sense uh I think that’s challenging but possible uh that you can but the problem is that getting viruses that outcompete natural viruses sounds a little risky and I think rightly so it’s
(1:20:04) not going to be easy to fund and it should certainly if it is funded it should be done in glaring sunlight with a lot of people watching um and uh yeah a lot of different kinds of voices being heard about whether it should be done I think I get much more powerful than a gene drive and a virus or the equivalent in a non-special species is the virus is vaccines is preparing our immune system for these viruses and um I know we’re coming to the end there’s a um oh also that we could do recoding uh which is which is the ultimate because
(1:20:42) that makes us resistant to all viruses rather than one at a time via vaccines some of which our immune system just doesn’t remember it very well our immune system doesn’t remember a coronavirus or norovirus very well um so so the multivirus resistance we get from recoding would be much more awesome also much harder to get implemented uh is that something uh if we were to do like 10 years out is that something you like if like so woolly mammo is five years ago was something that you were developing with mice and now you’re
(1:21:15) developing it in the actual animal itself 10 years from now do you see um stuff like that being something that would actually be in development um in terms of life for humans um I’m curious like what do you see for the next 10 years I guess it depends on your definition of develop in development it is in development already so it’s like with confidence Say it’ll development but uh uh you know I think that we could if if if the rate at which we can do Multiplex editing you know 25 000 today maybe 250 000 tomorrow
(1:21:52) you know a couple years from now uh we could construct cell lines that are multivirus they’re resistant to all viruses just like we did for the industrial microorganism and then we could use those cell lines to make cell therapies like metaphoric stem cells um you know you know uh neurons in the brain and so forth um which are already happening uh in a non-multivate way so you could say um any any cell therapy or organ therapy or transplant would be better if we’re multivirus resistant so you just pop that in as an option it’s like you
(1:22:32) know do you want bucket seats okay check okay and uh 10 years from now I don’t know where where it’ll probably still be in development uh you know it is true that some clinical trials are now happening in one year rather than 10 years but um until that’s very common I I hesitate to say anything takes less than 10 years in medicine so then uh one of the the listeners wrote in and uh it’s very personal uh question so I I appreciate their courage and asking it um they were they said I have a disability called CRPS and my as
(1:23:08) a result of an amputation reattachment resulted in multiple pain issues due to nerve damage inflammation other issues going on for the last 12 years um is crispr something that could potentially uh fix issues like that or is uh some that something more like that would Chris would be good for like regrowing an arm basically we’re wondering like uh what could crispr and genetic engineering technology do to alleviate the type of suffering he’s going through or um is it more like of the two branches would it be easier to just regrow a limp
(1:23:40) I guess would be my way of summarizing it yeah um so uh complex regional pain syndrome uh it is a subset of pain in general and I think there’s been a breakthrough in pain um in that we have Pathways now that are non-opioid pathways non-cocane Pathways um that are based on sodium channels um that actually reflect a person uh or a set of people in the world that have chronic insensitivity to pain or CPA and so those could be harnessed and those people are not doped up uh the way you would expect of a opioid or a
(1:24:30) cocaine derivative they are they’re fine so and you can make it local or you can make it temporary um and I think that’s that’s happening it could be small molecule drugs or it could be gene therapy I don’t put crispr on a pedestal even though I did have something to do with you know making it out there in the world uh I think it’s just one of a set of tools and if you’re going to be making um transplantable limbs or organs um then crispr is not really the centerpiece of that I mean most of it is
(1:25:07) you know biological and tissue engineering uh and you’re going to use a variety of editing tools uh to to get you there if it comes from an animal then most of the challenges making it um uh you know compatible immunologically and physiologically and and I think we’ve handled that right now we’ll know soon we’ve got uh two-year survival in uh in pre-clinical non-human primate trials uh so that that that bodes well for getting into human clinical trials very soon um I think it the incentivity of pain was
(1:25:48) probably something that’s better done with drugs and with transplants but there are plenty of cases where we will need to transplant limbs as well as uh I mean there’s unfortunately there’s still a lot of War fair in the world there’s uh you know occupational and uh and car accidents and so forth but uh but yeah I I my guess is the pain will come from progress in um in the sodium Channel um pain pathways and then it’s completely separately will be uh organ and limb transplants and then um are there books that you’ve read over
(1:26:30) the last couple years they’d suggest people check out I know yearbook uh basically all the longevity books but um the one thing I’m doing is I’m compiling all the books that everyone’s recommended in 170 plus episodes and I put in a PDF for everyone to read uh so this will be like kind of a nice bookend but um are there any books you recommend people check out I think the first time we spoke you uh were a big fan of what’s his name hitchhiker Sky of the Galaxy I think uh we we quoted that yeah right
(1:26:55) yes yes but uh yeah is there anything else uh anything you recommend people read either on aging on biotechnology just anything that you’ve enjoyed um yeah I have a tendency to read books that are written by friends and they asked me to write a blurb for the cover of the book uh so I have a kind of a bias and oh and then and then things are a complete fiction um totally off topic um uh which is my wife and I read a uh in an audible uh stream uh when we’re doing chores together um uh hopefully that will be on your on
(1:27:38) your bookshelf for your uh 200th uh episode um but uh yeah I don’t I don’t have anything and particular that uh it’s I think there’s a need for more books on um on the revolution that’s occurring in synthetic biology manufacturing aging reversal and so forth uh probably that will be the more than adequately filled in the next couple of years but right now I think there’s they’re most most of the books on synthetic biology are you know like biofuels not terribly useful or and the ones on Aging are you know like you know
(1:28:21) how to eat slightly better things which again is not exactly news uh you know you might mention a few new brand names but they’re really not revolutionary um I hope I’m not insulting any authors or anything but I think it’s it’s we’re just at this interesting transition zone where if you want to write a book that’s not totally science fiction you have to stick to things that are a little bit boring uh in a couple of years science fiction will become fact and then suddenly all the books will become
(1:28:51) exciting uh and it’s not the fault of current or future authors it’s just just the nature of scientific revolution I think that if you were to do like a crowdsourced Kickstarter type thing to to write a book and you could just write it you know as advanced as you want I think you’d get more than enough money to write whatever you’d want like a team researchers too financial problem it’s it’s okay or it’s more time management problem I do as you pointed it out early and I do have a few things that I’m
(1:29:23) doing um that that limit my writing time but but it’s getting done it’s it’s uh it’s getting done more and more quickly so just like what are what is like one fiction book that you’re reading or uh audible reading oh I’ll see um um there’s uh there was one on a sort of darwinian it was the something of all things uh uh and it was it was about a woman a a fictional woman uh contemporary of Darwin who who had her own a very similar Theory uh the signature of all things and it was based
(1:30:11) on uh this principle that that there was a signature that that plants and animals would kind of tell us what their function is could be for medicine or something like out by their shape um that was that was part of it it was much more complicated than that it was a little lovely story it wasn’t I wouldn’t call it a science uh exclusively but it had that little thread going through it that all was nice um oh uh there was one by Andy Weir um the Martian or the new one uh the the Martian but there was another one the
(1:30:51) Hail Mary yeah it has sorry there’s a short story I think it’s called egg which is also pretty good yeah anyway I mean just very those two are very creative and and I think they’re very kind of pro science you sort of feel at the end of it like that’s that’s great you know they think out of the box they do stuff that needs to be done and so forth so I thought those were those were good you know yeah there’s also a story of the dog barking at night and something like that which was written from the standpoint of a of
(1:31:27) a uh autistic uh child older older child and it was I just thought it was very well done uh it was a very interesting mystery kind of lost kind of a small relatable scale see too many Mysteries you know involved 12 murders and you just this was you know nobody no no people died and it just seemed like it was more relatable um but even if you’ve never met or never known you’ve met an autistic person um not all these books are are brand new but you know I don’t I don’t I I some books are so permanent you know that
(1:32:08) they’re they don’t need to be brand new some sometimes you miss it the first time through yeah I’m reading uh like uh some doskasky books and it’s like oh this is nice I prefer like the more like War and Peace type Russian authors yeah because they don’t really yeah yes yes yes yeah thank you I didn’t think of the I couldn’t think of the name uh yeah it’s also like it’s a little uh like those guys like he didn’t know what like an indentation was it’s a little hard to know like where his
(1:32:35) thoughts uh begin and end but it is fun I I so I agree with your point that uh you can go back and pick things up on the second time um so someone someone did suggest that you know you might be qualified to apply for Calico Labs new like CTO position and I was like you know what you might you might have the skills but but I think you have enough things going on uh so um I’ll uh I know we’re going over so then I’ll um just I’ll think of some books that would be good for you and I’ll send them to
(1:33:01) you but then uh so this was the learnable show I suck at outros so I do this together I just want to thank you so much for coming back on the show uh this is great um and thanks so much for taking so much for your time giving like everything you got going on in your day well this is very important to have a conversation with a broad set of voices that can um feedback to to through you uh so I think happy to do it