Our DNA: What’s Next & How Far Should We Go?

welcome everyone was so thrilled to see you here for this what's promising to be a very exciting talk our DNA what's next and how far should we go my name is Bettina Hamlin I'm the president and CEO of Ontario genomics and/or Terra genomics we are in the business of bringing people and ideas together researchers companies partners whoever is interested to come to the table to solve big challenges with genomics innovation and technology and so we are so thrilled to have the eminent dr. tor church with us it's a real privilege and if you haven't appreciated yet please do appreciate in our conversation just before we started he told us that ninety-five percent of the time when he gets invited to give a talk he says no so we're in the five percent where he said yes and not only thank you and and so we're doing this exciting talk with you today and George's is doing another couple of events with us over the next two days so we're really thrilled and I'm so pleased to also share with you our great partnership with the Royal Canadian Institute for science who has really helped organise the venue here the Gardner foundation and also to run to health to bring this public event to you today so just briefly what's genomics anyways and I'm just curious by a quick show of hands how many of you have you know done 23andme ancestry.com or any other of these services okay a few awesome awesome so you're no novices to the field but just for for for the rest you know the DNA is this elegant complex molecule that really carries all the information that gives signal to ourselves so that we can function properly and you know I think a way to think about the DNA is really a code think about your computer you look at your iPhone and you see a beautiful picture but your computer only sees zeros and ones the DNA is a little bit similar to that in that there is four letters and that is the code that signals to yourselves how to work properly and by the way did you know that the DNA you know is sort of you know spread around across living organisms and whether it's a mouse or a dog or a tree or us as humans or the Pinot Noir that you might drink the genome is really quite similar and it has the same number of genes so and and also when you look around the room we all look very difficult different but 99.9% of our DNA is actually the same so it's really that point one percent that's different between us and so we're at a very exciting time in that we have so much more understanding about our DNA and there is this convergence of technologies around it we get much better and faster and analyzing the DNA and we have some great minds here with us today to share where we came from and where we are going with this and so we will have a keynote address by dr. church and then a discussion with dr. Rhinehart right Meir and Steve Shara from the University of Toronto and then there will be plenty of time for you to ask questions so to kick it off I'll introduce dr. Steven sharer and dr. Shara is likely not unknown to you and he holds the Gia's case EHR chair in Genome Sciences at the Hospital for Sick Children and the University of Toronto and Steve and his team have made many seminal discoveries but particularly regarding how the genes are organized on our genome it's called gene copy number variants and he has looked at how these gene copy number variants are important for specific genes for example how they relate to the etiology of autism and so autism has really become his area of expertise Steve is highly published he has received numerous awards and he runs the center of applied genomics at SickKids right here down the street so please join me in welcoming dr. Shara ok Thank You Bettina it's really a great honor for me today and for all of us to have George church with us in Toronto and I get to introduce him so my introduction of George will only capture a snippet of his enormous productivity and bandwidth over the years George currently leads synthetic biology at the Wyss Institute where he oversees the directed evolution of molecules polymers and whole genomes to create new tools with applications in regenerative medicine and bio production of chemicals George is also a professor of genetics at the Harvard Medical School professor church is widely recognized for his innovative contributions to genome sciences and as many pioneering contributions to chemistry and biomedicine in the early years of molecular biology he helped to develop the first directed genome sequencing technologies with Walter Gilbert he also helped to develop the first massively parallel next-generation sequencing technologies having his fingers or his ideas probably in every technology used in a laboratory today it extends into synthetic biology and also gene editing technology which is now captivating the imagination of scientists around the world in fact he's actually one of the very few people in the world who can deliver a talk on reading writing and editing genomes based solely on his own scientific contributions that's quite a compliment George George has co-authored over 500 peer-reviewed articles cited roughly a hundred thousand times placing in the top 400 most highly cited scientists in history of the world not bad he's a way to go he has 143 patents and has authored one book which surprised me when I was doing my research called Regenesis so let's all rush out and buy that book and I think he'll probably talk about some of the ideas today of course he's received numerous honors including the 2011 Bauer prize for achievement in science from the Franklin Institute and he's elected recently to the National Academy of Sciences and engineering but perhaps his most important contribution to science are the hundreds of postdoctoral fellows and students that have trained with him these alumni have started their own laboratories and with jours their own companies and in fact they represent the many of the people who I would consider the leaders along with George church himself who will define and lead science into the 21st century so we're really quite lucky he's going to share his ideas with us today and I just wanted to reminisce about one story he told me the very first time we met and I went on his website and saw he has roughly a hundred trainees in his laboratory at any given time and he told me that he always tried to have at least one Canadian in the laboratory because they they're really smart and they're really worked hard so I know Fritz Roth is on faculty or I'm not sure if he's here today and there's many others I know who have graduated I read their papers very carefully so George we welcome you to Toronto to take the stage and deliver your presentation on our DNA what's next and how far we should we go thank you very much yeah some of the other Canadians were Raj Shari and Francoise Vignon females this is our DNA what's next and how far we go this is my conflict of interest slide and my first of many thank-you slides so we could say the genetic medicine has been here for many decades but from the show of hands very few of you are participating in this revolution very few of you have your hold you know how many we asked about 23andme that's not your genome sequence how about your genome so you know how many people here have their genome sequence I see one two three okay so that's pretty typical almost every audience I go to no matter how well educated no matter how wealthy they are they have not had their genome sequence that means that it's there's something wrong and I'd say it's his perception of the costs the privacy and the utility and I'm gonna address these all very quickly the cost is now close to zero dollars to you somebody has to pay for it but it's like Google Maps and in searches and so forth so we want to reduce not just the diagnostic but ultimately therapeutic we do the Diagnostics really to get the therapeutics or preventive and the problem is there's fixed costs of doing the research to development on the order of hundreds of millions of dollars that's per successful drug because quite a few of them fail so it's billions of dollars per successful drug but you have a large enough market then that is reduced for many genetic diseases the market is hundreds to thousands of people worldwide that's the problem and I'll address that you can also reduce the failure rate that's the promise of precision medicine is not quite quite there yet we can have preventive medicine is is really great and that's why the zero dollar genome is is important it has to be combined with some kind of genetic counseling a lot of it can be done by computers so I mean we became experts in computers without having computer counselors maybe we could do the same thing with genetics a little more dangerous and there are things like vaccines gene drives and germline which in principle are $0 because if you eliminate a virus fit by a vaccine as its extinct then it then it doesn't cost anybody in the world any money if ever they're after and that's a that's a big deal because the amount of money that we spend on HIV drugs is trillions of dollars and the same thing could have applied to smallpox and polio so part of the reason we're having this discussion and I'm going to be quite brief because I don't really want to get to the discussion part of the discussion but but i but I try to my wife and I both try to encourage all sorts of discussions all sorts of people it's because we have these exponential technologies these are even more exponential than computers which are alarmingly exponential so this is like super alarmingly exponential and for example here I'm just plotting the cost but there's also quality and improvements as well that are also quick so around 1990 to 2004 we got this three billion dollar genome for the three billion bases of your genome so you know that should be easy to remember that all our base but it was a very bad genome I should say and I helped start the project in 84 but I it immediately mutated in a bad direction in the sense it wasn't clinical it was they were averaging your mother's and your father's genome and so you got one genome when you really have six billion base pairs so it was off by a very important factor there so it was not clinically useful the technology had to be completely redone as soon as the genome was over and I would say that that's but as was redone the price came down is called next-generation sequencing so by 2015 for the last four years we've had a thousand-dollar genome which is mostly based on fluorescence sequencing just call it jargon fluorescence sequencing it it also can be used Nana ports this is you can have a sequencer at the end of your cell phone here that's a smidgen for the Nana pore but but the new thing that's just happened this year is now that we can get a zero dollar genome and I say it's analogous to two things you come to expect like Wikipedia on the Internet and there but not only is it less expensive but it's also deals with some of the privacy issues we do this sorry more jorgens zone here homomorphic encryption and blockchain these are ways that you can ask questions about it completely encrypted genome so you don't actually you own your genome nobody else owns that you never give it away that in fact they never no one ever sees it in an unencrypted form but you can ask questions that give you better health care or better research so that's the that's nebula $0 and the reason this is all possible is not because we fill a room up with with technicians or machines because that just spends money faster it's because every now and now with multiplexing multi molecular multiplexing every time you pipette a drop of liquid now instead of having one reaction and it has billions of reactions simultaneously and you don't have the micromanager you don't have to have a billion robots in order to do a billion reaction it just happens a molecular scale that's called molecular multiplexing that's analogous to what Edison did in nineteen eighty 1874 with Telegraph's whereas could send four messages simultaneously on one wire that's molecular multiplexing I think that's the revolution and we use it again and again I'm a claim that the future medicine is prevention I'm not but you can see just like that not everybody here got their genome sequence not ever a funding agency spends a lot on prevention this is the National Cancer Institute where that little sliver that a little 1% that's how much they spend on prevention nevertheless the the the power of prevention is incredible almost everything we do that's been of great value you know eliminating environmental sources of carcinogens and and microbes and so forth that cause cancer now one of the things we can do about the environment again is this little nano nano force so we've been working on this my lab is been working on this since the 1980s and there's two different ways embodied in two different companies one of them is Roche you know there's officer nana pore and they have a lot of differences we don't need to go through but the point is it is it is going to be it is already portable it's the sort of thing where it's just minutes from from your sample to the ants big difference from from the use of years but what we really want something that's real time always on constantly surveying your your your mouth and your air for possible things you're allergic to or toxins and and pathogens and we're not quite there yet but we're getting very close and it should be immediately hooked up to your Twitter feeds it's a other people what's wrong with your environment if any now when we do when we apply human genetics to real human diseases there's very different outcomes for different diseases I picked these two is kind of the extreme cases case acts in sickle cell both have long histories where we've known the molecular cause of these diseases they both have the same kind of inheritance where two carriers here in purple eventually give an on carrier who is normal in blue or a doubly affected one who really has a disease either sickle so tay-sachs can be a very severe disease there's they're slightly different on age of onset and severity but the point is that the real difference is in one community they decided to to have matchmaking where were you avoid getting getting introduced to or marrying people who are going to result in very severe disease and so it tastes acts a part of us because the rabbi Eckstein had I think four out of his first five kids had this very serious disease that kills the kids in four years after a horrible short life in contract and so that's almost eliminated in the populations that practice this typically Ashkenazi population but sickle-cell could have done gone the same way but instead it it is not typically genetic counseling it is monitored from among athletes even young amateur athletes but it is not used in any way for decision making for making and it's the the favorite place for really high tech stuff so developing gene therapy so for all the CRISPR companies that that I know and love in Cambridge Massachusetts are aiming there's a one thing this is the one disease they have in common but I think there's a misunderstanding about the value of human genetics and it's related to the - to our reluctance to use seatbelts so it's not a Matt is all-sufficient to bring the price down snot even sufficient to legislate that you need to get your genome sequenced because here you you had a seat belts in every car it was legislated you had to use them there were advertisements and and jingles that you can't forget on the on the you know buckle up for safety you know you can't forget nevertheless people wouldn't buckle up the thing that that was the tipping point was this little invention right here where the the buckle when it goes in it's it completes a circuit which stops the annoying sound in the car we need something like an annoying sound because what in both cases your chances of getting something really life-altering something that will affect your family like a car accident or a genetic disease it's only about 1% and people can't wrap their head around that they say well I it's not I'm in the 99% obviously I mean nobody my family ever had a genetic disease I'm exempt and that's just not true no one in my family has ever had an accident in a car so why should I buckle up it's the same kind of argument and it's a public health argument it's very difficult one so if you do make it all the way if you don't get the genetic counseling and you do have disease in your family then then there are therefore fairly high tech solutions much more expensive solutions I should stress if you genetic counseling is less than a thousand dollars it may even be free at some point soon but the orphan drugs or genetic therapy is a million dollars or more maybe up to 20 million dollars over a lifetime and you can fix it by adding genes that are missing subtracting genes there causing trouble precise editing is kind of the Holy Grail and regulation and it's gonna give a couple examples of regulation because they're kind of interesting eye candy where we can regulate genes in order to make whole new organs here there are some cell stem cells from my body actually almost all the human experiments we do on me rather than my students so those are the lining of your blood vessels on the left and neurons on the right both coming from the same kind of cell just under a different regulation and this is work from Alex and Paris to crosswalk who have now started the company to provide not just cells but organs made from these universal stem cells and here's here's a kind of a slower-moving verse of this where in red you see the capillaries it form these are like these are the normal capillaries about five microns thick through it's red red and white blood cells will flow and then the blue or the neuronal nuclei and we have a betting pool in the laboratory as to when there will be more of my neurons outside of my body than inside my body and it's getting pretty close and here's an example of the white matter in your brain is that and this down your spinal column you want to go long distances very quickly so you wrap it with myelin that insulates it and makes the the signals jump from node to node and we've recapitulated this this is the interaction of multiple cell types now happening outside of my body where that's that that axon little a is wrapped many many many times by this insulating myelin and that's what happens when you get multiple sclerosis or other demyelinating diseases so we're using this to fight those understand and fight those diseases and I should mention that that all like I said almost all the experiments are done with my cells but I'm just part of a bigger project which is worldwide and and one of the best examples of it is here in Canada that thanks to Steve Shore and his colleagues it's called the Personal Genome Project I argue the world of only fully open access source for human genome environment and trait data and cells including stem cells it's probably not quite the world's only only but it is certainly the first and and the only one that that it stands up it says that's what it's about and it includes all kinds of data like molecular data to the whole brain data that's actually my brain slices in 2009 there's been a update actually done here in the city just a few months ago and those are of course virtual slices not actual slices and and it's been used by the nist in fda with two US government agencies big ones that that looked around the world for suitable cohorts and they decided officially that there was only one in the world that which they had been properly consented for for the sort of thing they needed which was to provide standards of genomics and an al cell data as well this is in US Canada UK Austria and we're now a growing some in China Korea India and Taiwan so here's that kind of the probably when you heard the title of this talk which I didn't choose but I'm happy with about you know how far should we go probably the first thing that jumps in your mind is germline manipulation and I'm gonna make the provocative statement that what if during initiation isn't the biggest thing isn't the scariest thing what is if it isn't the most impactful thing what if its adult genetic enhancement or even adult gene therapy and what if this is safe effective and inexpensive does that change the conversation at all and the reason that amount I'm not advocating anything here I'm just saying what if and and the reason to consider this seriously is if you wanted to do germline that what this means it's changing the the the genetics of say an embryo or sperm or egg such that it will be passed on from generation to generation I mean it sounds like it might be both and cost-effective cost-effective in the sense that once it's working you never have to do it again and like I said these are million dollar cures but scary in the sense that you are you're changing generations without their permission of course when we eliminate smallpox we were changing generations without their permission in fact almost everything we do to our kids is without their permission usually they don't even like what we're doing to them like educating them and disciplining them and so forth and all these things we do to them as surely as faithfully inherited as as with sperm and egg in fact a little bit more so you know you you know the the cell phone is my daughter and my wife and I we all have the same cell phone but we don't really look alike so anyway but the other thing is if you made if you make a journal on alternate alteration it's gonna take 20 years to see that turn see how that turns out or maybe more if you're trying to fight Alzheimers or something but let's say 20 years roughly and then if you need a little tweaking it's another 20 years before you even consider it for for public consumption you know these are really low on clinical trials and then finally if it's ready for public consumption if you're lucky you did it in just one iteration of debugging then you're talking about 60 years out but if you come up with something that works in let's say does cognitive it deals with cognitive decline of our aging population does cognitive enhancement say to do that that could be used off-label it could be used it could it could it's something you could debug in weeks cognitive enhancement and it could spread as fast as the latest software application maybe a little slower so kind of in cognitive decline cognitive enhancement to fight that it's just a subset of what you might consider enhancement which is extension of longevity or what we prefer to think about in terms of FDA approval is aging reversal if you say that I'm an extend your life by 30 years then the FDA or the equivalent agencies around the world will say fine come back with your 30 year clinical trial which is prohibitive but if you aging reversal you can see effects sometimes in weeks in the animal models that we use and that's the difference that's an easier thing and in a certain way is more interesting - you don't particularly want to extend the the worst part of your life you want to reverse to the best part or at least the most useful best part in all you know health-related sense and so there there's a nice review here hallmarks of aging which have nine different pathways so these are whole these are fairly well understood biochemical pathways some of you may have heard of these like telomeres is a buzzword it's often used for the ends of your chromosomes are involved in aging you can you can get rid of senescence cells called sin oolitic therapies caloric restriction is something you've probably heard of and don't particularly want to do and the list goes on there the blood rejuvenation this is like the the the you know the idea of transfusing from from you know young people to old this has actually been done and very successfully in mice and you'll see it as a popular theme in Hollywood as well and the list goes on mitochondrial function anyway we I think that there's a lot of wishful thinking in the field of aging and aging reversal you know that what you eat or don't eat is sufficient I think this is going to be very challenging but not necessarily slow or ultimately difficult but but it may have a require very challenging gene therapy or or other therapies to hit all these pathways at once in a very deep and fundamental level the advantage the in therapy is you you take the therapy once and you're done for four in principle for life while many other therapies you have to take the pill several times depending on several times a day for some of the early ones had would turn over in 15 minutes so for gene therapies one of my ex postdocs Peter to my college started a database when he was in my lab and it's still going many over a decade later on and it includes hundreds of genes for different organisms a lot of this was learned from worms and flies but it is applicable to mouse and human and we harvest these and we look particular kinds of genes we tested 45 it turns out it's actually was much easier for us to do gene therapies than any other kind of therapy we tested 45 of these and eventually came down to a smaller subset which we did in combination aging reversal gene therapy where we took five different diseases in this list it will grow very soon but these are the number we've tested so far and five out of five of these diseases are affected by this combination gene therapy and these include high fat obesity where we specifically put them on a high-fat diet it causes them to double their weight and then we can reduce it back to their normal weight by this gene therapy type 2 diabetes it's exactly what people want they want to overeat and still be trim and type 2 diabetes osteoarthritis cardiac damage model where we do accelerated just sort of aging like cardiac damage and in kidney disease so this is work of noah davidson who has now relocated to San Diego and started a company called rejuvenate bio which is aimed at dogs so not just dogs as a model organism but as people care about their dogs and they will buy these gene therapies but also as an attempt for us to get and inexpensive gene therapy so people stop thinking of gene therapies as million-dollar drugs we hope this will be thousand-dollar therapy because the the FDA approval is faster and and easier this is just a list of enhancements that's on my website we have these universal car t-cells this is forget the jargon Carty is just a way of treating cancers and this is I'll you can actually make them so you can take them from any person and give them any person that's different from almost all transplants since the dawn of Trent organ transplantation never before have you been able to alter the genetics of either the donor or the recipient in this case you can do the donor because it's just cells you're transferring these T cells and and with gene editing and not just CRISPR but all kinds of gene editing zinc fingers talent because with different technologies for five different genes here that make them more compatible both with the recipient and with possible chemotherapy you might be doing so this gene editing were you doing knockouts typically of the genes can have this powerful possibility of making Universal donors you can make anybody who can donate to anybody now we took that you give us a cookie with more yeah so we've said well if we can do it from human to human we can do it from animal to human this is an old idea it's about 20 years old but there are there more things you have to make compatible to go from pigs to humans they have the right size organs right physiology but you have to fix their immune compatibility as it as we did in the last slide but also there's clotting and coagulation clotting in complement and most importantly twenty years ago and two billion dollars ago the FDA didn't like the idea that every organ of every pig in the whole world is spewing out retroviruses all day and all night and in an immune suppressed organ recipient this is probably not a great thing it's kind of a recipe for evolution of zoonotic disease like analogous to the Zilla nanak diseases of a swine flu HIV Ebola those are all famous sonic diseases where humans got too close to animals this is very close if you have an organ in you and so the first thing we did so we were invited by the pioneers that have started this twenty years ago when we invented CRISPR they said hey you guys might be interested in we might need to knock out a lot of genes we thought it was just gonna be one gene but it looks like it might be done many dozens so we counted the number of genes in her first Pig strain that we did it was 62 and so wow that's a lot we have never done more than two at a time with CRISPR and Chris was only about a year old at this point as a technology and we said well we'll try it and and it turned out to be ridiculously easy and we knocked out 62 in about 14 days just sitting in the incubator it wasn't even hands-on time and then we were and then we did it again in a different strain made this cute little pig here and a hole now we have whole herds of pigs both in the United States and China and they're going there now in preclinical primate trials at Massachusetts General Hospital and other places so that's that's moving along very quickly we hope to have human clinical trials theories it very very soon but keeping on that trend of we we had two genes at a time 62 genes at a time I'm not gonna show slide but we now have 15,000 genes at a time in oneself so we can really go make a lot of changes and I'm excited not about transplants not just because we can solve the millions of people who need transplants including many people who aren't even in in line for them right now because they're so rare we can now make it available to anybody but you can now actually enhance the organs and it's it would be hard to enhance organs in a healthy person to donate to somebody else but if you're going to be transferring to Pig any way you want that those organs to be as good as they can be want them to be resistant to pathogens you want to have the immune components very talked about what we know how to make animals resistant to cancer and senescence we can extend the life of mice by twofold and we might even want to make them resistant to DNA damage and and to freezing and so here's three examples of organisms that are resistant to freezing this one is also quite resistant to radiation it's about a hundred thousand times more resistant to radiation and then we are and so we are inspired by these in synthetic biology as converting we're trying to get these into humans and other in Pig cells we can also do gene drives where we engineer ecosystems the first thing we did was not to engineer ecosystems but to draw attention to the problem and almost everything I've talked about has an ethical component that my lab has weighed in on typically before we do it or before anybody does it to talk about what the issues are and clearly we you've got invasive species we've got malaria lyme disease all of these could be addressed by if we can do controlled release where it can contain the gene drive but this needs to be done very cautiously so I'm just gonna end there I want to get to the conversation thank you very much you may have a seat so my name is Ryan air right man I'm the chair of the rotating Institute for science how many are CIS members are your hands oh great thanks for coming out as usual if you understand when are CIS does you can go to our website we have a lot of very exciting panels and presentations coming up our SAS is a hundred and seventy years old this year rollers in Canada our founder was Cerf Sandford Fleming of Standard Time he actually also was the creator of the first Canadian stamp which featured a beaver and one of our panelists today was involved in sequencing the beaver genome Steven sort of a Canadian made in Canada project uh I mean he might want to talk about why he did that as well in terms of developing some technologies so we're gonna have a little chat I'm gonna kind of moderate a discussion here and they were gonna open it up to the floor questions from the audience cuz I'm sure you probably have many so hold the start with that I was a wonderful presentation very thoughtful and thought-provoking I thought so the title may be that B word given was our DNA what's next and how far should we go but before we go there like I want to go back to the future so Fred Sanger Paul Berg and Wally Gilbert received Nobel Prize in Chemistry in 1980 for developing DNA sequencing methods and you did your PhD studies with Wally Gilbert so many he tell us a little bit about that time and what your contribution was that effort to develop methods for sequencing DNA well even though I had been in Wally's lab for three years I can't take any credit for that particular prize but it was an amazing time there's a doubt if it was a lot of team spirit we kind of we we knew we were we were changing the way biology was not just molecular biology biology in general it's been its DNA sequencing has been used for forensics for you know history for are all sorts of things so we knew that I think at some level and and you know and Wally was a very interdisciplinary person that was part of the reason I was attractive because ever since I was young I did not want to specialize I felt that if I could do everything at once that would be really great and Wally has always done that himself I'm not it raised it easy even including think not just entrepreneurship and all the sciences but but archaeology and he's now exhibiting photographers so I could see that from as a beacon from the distance but it but it literally was ground zero for molecular biology innovation in the Harvard bio labs in general not just in Wally's lab it's great yeah I think well the governor now as an undergrad in physics actually in Alaska and then when telling a story took one biology course cuz he kind of had doing that kind of school this is kind of cool to go from there so that's good so it doesn't really until associate professor when Jim Austin recruited him from the theoretical physics department you become a biophysicist which just meant that he was willing to work with hundred militaries of two without worrying about of the way most biology was worried that's good that's right it's great so those kind of early days in sequencing and that sort of transforms just say a lot of things but how did that kind of work and inspire the human genome project in new again kind of on the leading edge of that kind of initiative - and I know you talked about the limitations about number of base pairs etc but so of that kind of what was the what was the kind of conversation for having that done this is something we could do when we talked about so the value proposition if you like the cost of every beginning yeah so I think there were so I came to always lab I had ambitions to do what I called multiplexing and and sequencing everybody on the planet which was not something we typically talked about any of us did but it it was definitely something there was not just sequencing one genome and I knew that do that we had to bring the price down quite a bit and that was the idea behind multiplexing and I kind of messed up a few experiments to create my rotation because I were trying to multiplex way before I even learned how to do sequencing the ordinary way but when we get when we proposed the in in 1984 the Department of Energy had a meeting to get a mutation rate and we decided in the first five minutes we couldn't do what they wanted us to do who was it was like you know a dozen of us in the room we said well but maybe we could sequence a human gene that's and they just kept kept going from there but unfortunately there were kind of three camps on which people who felt that sequencing human genome was a complete waste of money because 99% it was junk in etcetera it was in cost a dollar base and there were some that the ones if one were the ones in the middle who said well we're just going to do with whatever avail whatever is available very pragmatic we're going to turn the crank and then the third set was the rare set that I was in which said no we have to reduce the cost radically and so most of the cost reducing was done in the shadows you know like the mammals surrounded by dinosaurs but anyway eventually the last one also one it's great yeah so we already asked I couldn't the audience about what had their DNA sequence than which people think about 23andme and maybe ancestry.com any Steve you can talk about your project and when people say I've had well I've had my genome sequence maybe can clarify for people the audience what kind of the differences between something like 23andme and Sausalito and the kind of PGP project that you're working on yeah right so we designed our project in Canada based on what George's started first in the United States he didn't take Canadian citizens there actually had to be a US citizen to be enrolled in their project so we saw the power really to learn the lessons of how you apply genomics into populations into the hospitals into the general health care scheme we needed to learn how to do consenting how to do DNA preps do the chemistry the technology and most importantly to translate that information back to the citizens in their jurisdiction so here are genetic counselors do that in the hospitals so that it was an experiment was a decade-long experiment we mimicked all the consents and things and work with George's team so we went very very deep we we thought we would want to do you know we'd like to do millions we'd like to decode evolution by doing this to everybody and we will get there someday but we went deep on sequencing and and there's a few people in the audience who were involved but just very quickly and I think it's important as George pointed out in his talk when you generate a genome sequence now the technology for your thousand dollar genome is a bunch of short read segments of DNA that you then map against the reference genome which is a collection of over 700 different pieces of DNA from different individuals spliced together so ideally the ideal experiment and that's something that's coming is to do a de novo assembly of that genome and get the six billion nucleotides so that compliment of variation from your mom and your dad and I think that will have a lot more impact but in saying that I think as George Luda to already there's a ton of data there he mentioned the 1% number where I think for that 1% it will change your life at all it could save your life but in our study and we published it just over a year ago and was covered the global male many of you remember it um every person who participated when we did a full annotation got data back that could influence their healthcare decisions because we did a very thorough annotation we included recessive disease carriers we included pharmacogenetics we did save a few lives it wasn't reported in your articles but but for most people you know we're ascertaining their they're healthy so we didn't expect to find anything devastating what what's really coming now though is as we increase the numbers through worldwide projects we're getting much better at interpreting what that data means and so I think many of us believe that the genome is going to be like a Global Positioning type system where once we get more and more data and maps to compare against it'll start to make more and more sense and I'll just throw one slang term to keep your eye on it's everywhere in genetics in the last 12 months but you'll start reading about this thing called polygenic risk scores or genetic risk scores there are some massive projects in the United Kingdom and now in the US where they're using bio banks of millions of people to develop that fundamental underlying GPS system for genetics and then we can take actually smaller sample sets from specific disease cohorts and then compare the coordinates you have in your cohort versus populations and make correlations and come up with statistics of likelihood you'll develop certain diseases or traits or things you might want to try to modify at some pointer and the data is getting surprisingly good and fast and I think it's because there's been an inflection point where we've reached millions of samples now where is the past it was dozens or hundreds or thousands and it would just wasn't enough data so this might come up in terms of you know privacy issues you know corporate versus public interest maybe I'll just pose a question should human genes be patented that was a discussion a few years ago I got an email yesterday that our latest patent application was approved so I was happy to get on genes it occurs less and less you really have to have a unique scenario but I mean there are obvious reasons to to promote patenting of genes to protect intellectual property so you can do you know specific research on that on the utility of the application and things but you know patent e also is a way to get to date out to the community to that's you know we use the patent databases in the same way we use the public literature so but I mean he's an expert let me just throw one thing that I think the the point is that for the young younger scientists in the community is the technology is in a large part what George and his group have developed really you know the you're only limited by the creativity of the experiments you want to do now it's the ideas you can pretty much do anything so you can sequence you can you can edit you can you know you can do any and it's pretty darn easy yeah it's not perfect pretty darn easy we're gonna weigh on that just so yes I think patenting and privacy are two different topic I mean in principle I can patent things from my own body without invading anybody's privacy I think what's misunderstanding about patenting is the alternative patenting is not everything's free it's the opposite everything is trade secret and when you have trade secrets and biology is particularly harmful because that means that it's unlike uh you know something of Traci going I could practice in my in my factory the biology is out in the world instead of in order to keep it a trace if you have to offer you skate it meaning you have to put you have to put all kinds of stuff that makes it hard to understand what's going on there that's not what you want for for human genetics or agriculture or anything else I think that's we want to have their way of breaking out of trade secret in terms of privacy that that I think it's one of the main reasons people don't get their genome sequence now that it's so close to zero dollars it's both understanding and misunderstanding but mostly understanding that that you could even even in countries like the United States where there is a law protecting you from genetic discrimination by employers and insurance companies there's still all kinds of ways you could get Germany used against you in some way or another and that's why I think it was it's it it's a potential breakthrough to have homomorphic encryption with blockchain forget the mouthful that way that you can ask questions that are a value to health to your own health without anyone ever seeing your genome without ever anyone possessing it other than you that said we're so that's if you voluntarily go out and get your genome sequence nobody can pry it loose from you but they can just go and collect your DNA off this chair so be wary of that particular loophole Steve not about a chair so much so it's worth just emphasizing that in Canada we do have a genetic non-discrimination Act bill s21 was passed about two years ago now that protects pretty much against everything but but there were a lot of people for that time who were dropping out either dropping out of research or not enrolling in research also not taking genetic tests that could be life-saving for their children we saw because of fear of genetic discrimination so that legislation was hugely important and I just comes back to what I said earlier every society deals with the information and it deals general information in a way and genetic information is I think the ultimate form of information because it gives you a vantage point into your present but also your past and your future and that of your relatives too so you have to protect it you have to be very careful how you use it and you have to think about others when you're making decisions then that's what perhaps makes it a little bit more unique so you eluded the Stila solo DNA sequencing obviously involves massive amounts of data those are some of the challenges are really human genome project so maybe George how important was the kind of things that you were involved with software development nowadays the buzzword is AI what kind of impact does you know those kind of technologies have on what the kind of work some things you can do what's really computing is very big for things as Steven I do you know AI machine learning these are buzzwords that are just a piece of the computing infrastructure that needs to be built up there are certain things that we're using machine learning for that it in biotechnology they're quite valued I think already more valuable than they are in Human Genetics so for example we use machine learning for designing new generations of viral vectors for gene therapies we've now built over a million different computer design viruses these are these are viral capsids not viruses that deliver our genes they know there's no living virus there so I think there will be a growing number but so far most of the human genetics can be practiced a lot of it can be practiced without so one of my professors Michael Smith it was at UBC we got a Nobel Prize in 1993 for development of directed mutagenesis and I think that's a technique it's still widely used to understand the effects of mutations linked to disease and designing proteins and engineering etc so there was a literature talked as a new method developing something called CRISPR so maybe briefly what is crisper and maybe could you relate it to yogurt or cheese Mickey there's a link there as well so so yogurt has and many dairy products have a problem with sages killing the bacteria that are good for the production of the the dairy product and and it in one of the way one of the ways that the bacteria killed the viruses called restriction enzymes which was a an important breakthrough at the big dog recombinant DNA and then the other way they do this which is kind of pre-programmed or resistance and then CRISPR is a adaptive immunity where you learn the viruses you don't like and you store a memory of their sequences in you colum and that was hard it was hardest in 2007 as specifically in the Odin industry without full understanding of how it worked and it was a long step from that 2007 harnessing in his first practical application to what we what we all really wanted was something that was applicable to human health care and agriculture in general which happened in 2012 2013 when it's turned into a technology and I would and I think CRISPR as much as I love it and as much as it loves me the CRISPR is credited with too much I think it's it's it's it's I think a lot of people missed the revolution in recombinant DNA and in other editing methods and even hedging even in next-gen sequencing these are all kind of rolled into one and they're given the name CRISPR and I just feel that it's my duty to say as much you know it's a great name there's a lot more to the revolution than just that it's good to have a historian and so I think new you looking better to the Future now a little glimpse of it in your presentation area some that crisper there's certainly a nobel-prize discussion in the window general solid is here from the Gare near they usually recognize there's sort of one step ahead of the Nobel Committee and recognizing importance of Christopher so other than George church I'll put you on the list who else would you think well I'm not the expert I'm too smart to go in this I think it's I think it's actually wise this could be as damaging as they are helpful it's helpful to to raise consciousness and the public gets excited about them but you just saw that JK ho yep who who did crisper babies what you're getting to yeah just to get a little head he was clearly excited about Nobel Prize and I think that that's that's that should be a warning to us that if you if you make a prize to is too important also there's always somebody and it's left out this rule of three yeah means there's always a fourth one and a fifth one and I think that that's that's counterproductive it creates it hot us politics that we don't we don't really know so you know I think it's a team the most important thing is this team effort and the teams are getting bigger and bigger and I'm proud to be parts of big teams and I don't particularly want to be singled out I'm happy to to you know flip my body around to get talks like discussions like this I'm willing to take that hit for the team but I particularly want to I don't think we need to see the grants are good yeah give us some grants yeah they're not not prizes look yeah maybe I just I was gonna ask you earlier [Music] but as you showed you know these technologies were increment or incremental and some were massive leaps in technology but you were you were there for the you know the maximum Gilbert sequencing I know there's a few people in the room who would have done that versus the Sanger die deoxy sequencing eventually one one over one out over the other but at a time they actually you'd use them for different applications really in sequencing based on your strengths and weaknesses that's how first elector biology I I learned and I said this before when I introduced him I was the guy on the floor who had to make all the church Gilbert hybridization solutions so that's how I knew George church when I first started that was him anyways so you know and I was gonna ask you what do you think's coming coming with the latest sequencing so back then one one out over the other I think because of simplicity I don't I don't think it's simplicity I think in the end it's it's reproducibility you can have a very complex protocol as long as it works and the maximum Gilbert one originally because you had to have single strand DNA for the ID oxy later they figured out how you didn't need single strand then the maxilla covert was slightly lower quality I would say in general and just a slight difference in quality makes the will will sweep through and I think that's true for a next-gen sequencing it not only is 10 million times cheaper which is really amazing but it's much higher quality as well I mean you can really get so do you think we've got now with Oxford nanopore I think Oxford nanopore has advantages of length well I would say Nana pulled both an important methods have have longer reads Oxford has a record now with half a million base pairs but it's not not quite not every read is that long it's just every now and then you'll get a read that that long so that'll be a consideration the fact that it's portable and it could conceivably be something you wear and 24/7 that that's a nice right and there another type of sequencing that we're gonna see is being able to read things in their three-dimensional context so normally we just shred the the cells and the three dimensions out that you lose that information but we're going to seeing increasingly a trend of knowing where that DNA RNA protein is in this in the cell at super-resolution so that you can think of that it's like the ultimate in microscopy so it's it's sequencing as far from stop being its revolution and even though we've brought it down ten million fold in price I wouldn't be surprised we brought down at least another thousandfold it's just a couple other things very limit to the audience so he mentioned JK hey and the used CRISPR too in human embryos did and at the gene which is a receptor for HIV virus so that you know generated a lot of excitement I guess medical community and elsewhere so maybe controversial a bit you talked about this a bit in your talk about which you know genes can be repaired or replaced so where do you see those kind of you know technologies going in the future right so I mentioned a little bit my talk that then figuring out what to do with germline is first of all there's not that many things you can do with it you can't do some other way so if you this was done by in an in vitro fertilization clinic in fact the couple was in there because the husband had HIV and so typically you wash the sperm before you do that so the child doesn't get HIV but the things that you can do with it can either be avoided by genetic counseling as I mentioned much less expensive much less invasive much less risky to future generations some of it can be done with gene therapy after it's born there there's there's some alternatives interestingly he's criticized for picking something that for which there were alternatives which is HIV it is true there are alternatives or safe sex there multiple drugs and there's the promise of vaccines that have been promised for decades now it doesn't alter the fact that a million people die every year from HIV is 2 percent of all deaths worldwide as HIV so to say that it's the solve problem and you don't need any you don't need to look at new solutions is I think an overstatement so I you know it needs to go through safety and efficacy testing just like any other therapy but it's not like just any other therapy it needs more scrutiny and it's certainly getting more scrutiny see if you have a comment on it well you know I Janet's here she may want to come but they're doing the experiment Wendell went against it's not to say it's right or wrong in that person's eyes but went against the international community's at least the stem cell community's development awhile just who recommended a moratorium on germline editing and so so I think that's important and in a way it's - these things are put into place to study the technology to understand things like specificity because genome editing by definition is you're trying to edit a very specific site in the genome which you can do but you don't yet know what's happening elsewhere it's pretty darn good by all indications but probably need some more time to know these again these off target effects we talked about with drugs and everything else well even well how we define off target right now may not be how we define off target so anyway it's it's like any new technology is moving so fast but in in in the case when you start to do experiments on germline which is considered sacred by many different societies I think you you want to just really think about things so but you know in many other conditions editing is being used in rare disease somatic so in a somatic way sense and it's happening at Hospital for Sick Children and other places and in the clinical research setting clinical trials going on so the technology will bring some solutions to two diseases that don't exist right now yeah it's pretty that's why it's so so important to continue the research but really to think about the ethics of the questions and the cells that you're modifying so Jordan made comments on that one one is the moratorium there is already a moratorium on on all therapies not just gene therapies not just germline in that you can't practice medicine on with a new drug until it's been through a process and approval and so the moratorium was on top of that and then a certain since redundant and off target there is already an improved fda-approved clinical trial on ccr5 editing different editor dozen finger around the CRISPR booth same the same how did you create alleles that never been seen before in the human population and you generate billions of them in the case of t-cell therapy which was was approved while in JK Ho's case he could test the clonal derivative to make sure that they were not all targeted and he could test them again after the pregnancy was established which he did and he did that hundreds of tests yeah but I watched that presentation I went and watched the videos and I stopped the videos and look at all the slides and yeah that really needed to go through scientific peer review and I'd love to see the data I have seen I've seen two articles from his lab that are going through peer review but they're getting rejected because of the concerns and so the the you know no editor wants to be responsible for publishing something that's gonna get fired and fired and so we have a chicken and egg thing I totally agree we need pure we need this to be in the public needed peer review instead of all these rumors and you and people like you having to look at the slides for because the date there's tons of data on these two papers I think it's kind of it's a tragedy that this couldn't have been done some other way yeah so go back to back to the future so George Church goes ahead 30 years what will you see my side project that we have most of what we do is going medical but there's there are environmental issues and the Asian elephant is an endangered species and they're 17 19 million square kilometers of endangered tundra where the endangerment is carbon and methane and carbon dioxide it could be a release 1408 gigatons which is put in perspective nine Giga tons is what the entire human consumption so 1,400 is a much larger amount that could be lost by the mere melting or could be some of it could be gained by sequestration story but elephants are and other herbivores are missing from the environment and they would they would change the ratio of grass to trees in a very favorable way for us so I would hope not zoos but spread through the 19 million square kilometers of the Arctic in Canada and Alaska and Russia and and there's a park already in Russia that's dedicated to testing these ideas in in Siberia that's one thing but I think there'll be many other things that will be mind-boggling in the next 30 years many of them will be medical and agricultural well hope your interventions for aging as well in my case yeah so we're going to open it up for questions and Kristin has a microphone just put your hand up and she'll go around and pose either this to Stephen yeah thank you thank you all so much for your time today it was very stimulating to hear your conversation and professor church your presentation I'm curious if you could give us any kind of an update on the Human Genome Project right both on the science as well as you alluded to in your presentation what sorts of other factors are in consideration on a project like that the ethics the communication the the social factors or human factors right so Human Genome Project right we tried we tried to make the communication of a top priority we had 37% of the presentations in our first meeting we're on were ethical ated Genome Project right is like you know the genome project that everybody talks about is reading it was sort of a 1984 and sort of hasn't quite finished yet continues in Personal Genome Project and other sequencing the population we want to be able to synthesize the human genome or at least do modify it and not just make a copy of it because we already have a copy of it I would make something new after a couple years of discussion we decided we should pick a an example project that would illustrate the technical challenges the ethical issues and a practical social outcome and we chose making human and pig cells that were resistant all viruses not just not just the ones we know about but all of them by changing the genetic codes so we've proven this works in industrial microorganisms where you can change the genetic code such that the host is fine but the virus is completely flummoxed it's like what new genetic code I can't handle this and and you can make it's the genetic code with a very small number of changes you can make it so that the virus would have to make so many changes to its genome all in the right direction and not in the wrong direction that it would be is just can't handle it or even of all around so that's that's the that's the kind of the flagship effort in the GP right is to make human cells because human cells are used for production of protein pharmaceuticals antibodies etc and they get when they get contaminated with viruses disaster this happened in Genzyme most companies won't fess up to it but this this wiped out Jen's on both sides of Atlantic for two years and also human cells are used for cell therapies and you would like them to be virus resistant and then pigs I already Illustrated it out you might be using those for transplants you'd like those dolls to be virus resistant so that's that's what we're aiming for it could be as as few as 6700 changes could be as many as a million changes spread out through your six billion base pairs another question um thank you for this Oh fascinating glimpse into the work that you do recently there have been a number of reports about the fact that interaction among genes has proved to be much more complicated than initially thought and another complication that's now surfacing is the influence of epigenetics on the expression of genes you haven't said much about epigenetics are you working on that as well as on the genes themselves yeah I did mention it without using the right without using that particular jargon so the example of epigenesis when when I said there's addition/subtraction precise editing and regulation regulation is epigenetics and the illustration I gave us we can use combinations of genes to turn stem cells from my from my body into any cell so for example brain cells and blood vessels so that's epigenetics and it's also illustration and we're getting in control I wouldn't claim that we're in complete control of any any technology but we're but epigenetics is no longer quite as mysterious as it used to be in terms of gene interaction which is related to epigenetics I gave as an illustration the aging reversal where we went through 45 genes that can interact in various ways through nine different pathways aging and we picked a subset that would now handle five different diseases of aging so many of these things they may seem daunting until you start doing experiments on them and some of these experiments you can do on simple cells and culture you can do like I said you do the same multiplexing with it's advanced reading and writing DNA can also advance the study of epigenetics developmental biology and gene interactions we as many of these things he can do in a very short period of time in the laboratory with millions or billions of cells in parallel so what used to be is something where you would dedicate your life to an experiment you can now dedicate your afternoon to a billion experiments think you have time for one or two questions that one very quickly yeah so so that's great questions and there's all kinds of other molecular information and but just for the audience to emphasize how important it is now that we can finally have the genome sequence because to make sense of all this other data you need to lay it on to the genome sequence so George alluded to you know why humans are different what we know is is is the the number of different types or isoforms are called or forms of a gene they're much more complex than dreaming and you could only actually see that when you lay down the RNA sequences of genes on to the human genome so it's the same with methylation or epigenetic data and all these new things are finding about long non-coding RNAs so having the reference genome now in large numbers allows us to use math and try to figure out what this genetic variation plays into it but it's the genome sequence which is I think the major advance to lay all the other biological data against okay and we're there now now we just need to get huge numbers yes I want the question I have is what I'll get right to what research what well how is stem-cell research being used to fight against the and stem cell transplants being used to fight against the AIDS virus and the HIV virus because I remember I heard this morning that a man in Great Britain who had stem just had a stem cell transplant is now virtually aids-free well one of the first things that happened was in one of the inspirations for the ccr5 is that someone who had had both AIDS and a disease that required human blood transplant was simultaneously cured of both diseases and it was the first indication that you could with a a ccr5 double null t-cell population you could be resistant to HIV so that's one of the first actual cures of HIV is by making somebody who is resistant to the virus there and infected with while drugs are are something that where you have to take the drug for the rest of your life you're not really not really cured you just keeping it in check I'm not sure exactly what we're referring to but it could be something like that there it there are clinical trials that are approved for editing stem cell blood stem cells okay so I think we had a great conversation going to turn it back to Bettina do that kind of wrap up and thank you wonderful well I think I'm stunned like I think a lot of you I would just like to invite you if you have more questions dr. church is is going to be around for a little bit and so is dr. Reinhardt and dr. share I just like to say you know it reminded me that you know the when the Human Genome Project got on its way in the u.s. the Canadian response to that was the creation of genome Canada and the genome Canada Enterprise and the genome centers of which Ontario genomics is a part and has leveraged about 3.6 billion dollars for research to contribute to some of the things that you heard about today so we're very proud of that we're inspired of course listening to dr. church and everything he has started and so we're left with lots of things to think about I'm particularly interested in the fact that now sequencing the genome is zero dollars and your book is still twenty five dollars on Amazon so choices getting harder and harder but with that I would just like to recognize again our partners in the event today the Royal Canadian Institute for Science to run to health Gairdner and us Ontario genomics and please join me in thanking a wonderful panel [Applause]

Channel: RCIScience

Views: 7,600

Rating: 4.8628573 out of 5

Keywords: RCITalks, Genomics, Human Genome, DNA, Sequencing, DNA Sequencing, Genome Sequencing, Biology, Science, 23andme, Human Genome Project, Gene, Genes, Genetics

Id: yAY1clQ1deE

Length: 76min 58sec (4618 seconds)

Published: Wed May 22 2019