The Science and Ethics of Genome Editing - Professor Jennifer Doudna

[Music] [Applause] good evening good evening Melbourne it's my first trip to Australia certainly won't be my last and I'd like to thank the organizers and certainly all of you for for coming tonight I'm here you know Anna I was attending a scientific conference and we're you know we have this opportunity right now to talk about a moment kind of a proverbial moment we're sort of at this extraordinary time in human development when human beings now have a convergence of technologies that allow us to read write and as we'll talk about tonight rewrite the code of life the DNA that makes us who we are and and is the the code that controls all of the life on our planet it's a sort of an astounding thing to think about and what both of us want to do tonight is to tell you about the genesis of that technology for for gene editing and talk about what that enables what that means for the future both the near-term and long-term future and the awesome opportunities and challenges that we have to we now have in front of us that I think are both very exciting but also require careful thought to think about responsible progress and the story really begins with thinking about the structure of DNA because if we go back to the 1950s when the double helical structure was first discovered it opened the door to a lot of modern biology because scientists for the first time understood the chemistry underlying life they could read the code and start to ask questions about how this code operates in all cells and all organisms and since then it's been possible to understand now have the DNA sequence for the entire human genome think about that it's amazing and also the genomes for many other organisms plants animals bacteria fungi increasingly we understand how that code is used in cells to control the way they develop and become certain types of organisms how they have how these organisms have the properties that they do and even much more detailed things like what genes are responsible for human diseases or what genes are responsible for human traits and so the the potential to be able to not only look at the code and then try to understand what it means but also to go in and tinker with it change it is is is really it's truly enticing and it's really this question that's been I think grappled with really for at least several decades thinking about scientists asking what if you could actually edit the DNA in a Cell much like we would edit the text of a document and the idea would be what if you could erase some of the sequence what if you could replace it what if you saw a typo somewhere in the code and you could you had a tool that Ola would allow you to accurately correct that sequence this is not a new idea it really goes back to like I said I think really to the discovery of the DNA structure I can remember as a graduate student in the 1980s learning about research that was going on in chemistry labs that were using methods that would allow cutting DNA at a precise place in the human genome and while I was working doing my graduate work at the Massachusetts General Hospital in Boston a scientist there Jim goose ella was able to actually use a technique like that to map the gene that causes Huntington's disease a very severe neurological disorder it was one of the first genes to be you know mutations to be mapped that way that gave scientists an insight into the genetic basis for disease but in those days it was very hard there wasn't really good robust technology for how you would actually be able to correct a mutation like that so now fast forwarding to to the present day there have been a series of technologies that have come along especially in the last few years for editing DNA being able to make precise changes to the DNA in cells but the one that we're gonna talk about tonight comes from a very interesting line of research that was not intended to create a technology originally it was curiosity driven science that was asking a question about how bacteria fight viral infection and that line of research led to uncovering the actions of molecules that are part of this CRISPR bacterial immune system that allowed scientists to harness that capability for a very different purpose namely for altering the DNA in cells in a precise fashion and that's what I want to want to tell you about in the next couple of minutes it's how does that actually work and so when a when a virus infects a cell and here you're seeing a cartoon of a virus it almost looks like a lunar lander landing on the surface of a bacterial cell the infection begins by that virus injecting its genetic material into the cell to take over and begin making more viruses and in this example you can see a piece of DNA that's coming out of the virus and it's going into this cell if the cell is a bacterial cell that cell has only 20 minutes before it will be broken apart and more virus particles will burst forth and infect other cells so there's a very short window of time for the bacterium to defend itself from the infection now in cells that have a CRISPR bacterial immune system these cells have a way of acquiring DNA sequences from the virus storing them in the genetic material of the bacterium and then using them for to us in a seek and destroy mechanism that allows the cell to find and viral DNA should it appear in the cell again and the way that that works is through a protein that's known as cast 9 now this picture here is is a 3d printed model of this protein the protein is obviously very very tiny we can't actually see it with our eyes but we can visualize it using a technique called x-ray crystallography and this this 3d printed model is using coordinates for the atoms in the protein and the RNA and DNA that it's holding on to that we get from x-ray crystallography and then we can feed those to a 3d printer and print out this model so this model sits in my office at Berkeley it's about yay big or so and and in what you can see here is the white protein holding on to an orange molecule which is the program for the enzyme it's an art it's a molecule called RNA it's a little transient copy of a viral sequence from the bacterium that will tell this protein where to go what DNA sequence it should find and cut and in this model it's holding on to a piece of DNA the blue double helix that has a sequence of letters matching the sequence of the orange RNA when that match occurs the protein holds the NA opens the two strands of the double helix and then has chemical scissors that come in and make a cut they make a double-stranded break in the DNA and for bacteria that's a terrific way to seek and destroy viruses that would otherwise cause infections that would kill the cell but once Emmanuelle Charpentier my collaborator and I figured out the mechanism of this enzyme we realized that it could be harnessed for a very different purpose and that is because in animal and plant cells when cells experience a double-stranded break to DNA something that happens naturally during cell division and sometimes due to DNA damage that happens the cell has a very sophisticated way of detecting that break and fixing it and in the process of fixing it a change to the DNA sequence can be introduced and scientists have ways of controlling we can actually find ways to induce the cell to repair DNA either by making a small disruption to the DNA sequence or by inserting or integrating a new piece of genetic material at the site of the break and that was not something that that was something that has been known for it for a while about the way that cells repair DNA and so what has been appreciated for the past few years is that if there were a way to introduce a break in DNA in the genome at a particular place where a change was desired that would trigger this kind of repair process that could lead to efficient gene editing and the challenge was how do you how do you program a break in DNA at a place where you want to trigger a change and that's where CRISPR casts nine comes in it's an enzyme that does exactly that it can be programmed to cut DNA at a desired sequence so let me show you a little video that illustrates how we imagine that this enzyme this bacterial enzyme cast line with its guide RNA operates when it gets into an animal or a plant cell and so here we're zooming into to a plant cell or an animal cell where the DNA is inside the nucleus and not only that the DNA is highly packaged so it's wrapped around green proteins called histones to form structures that allow the DNA to be highly compacted and somehow this caste 9 enzyme with its guide RNA is able to seek a search through the whole genome and find a sequence of DNA matching the sequence of the guiding RNA when that match occurs the DNA unwinds inside the protein the chemical cleavers make a cut and then the broken ends of the DNA are handed off to repair enzymes that can fix the break sometimes by integrating a new piece of DNA and new genetic and nation at the site of the break so it's truly a phenomenal process that gives scientists now this precision tool for altering the DNA sequence itself and remarkably this enzyme which comes from bacteria works in virtually every type of cell or organism where it's been tested and that means that human beings now have this awesome technology for altering the DNA sequence in ways that could allow us to correct the causes of genetic diseases and of course to do all sorts of research that has been enabled by the convergence of this technology with also the abilities to synthesize DNA very inexpensively and also to sequence DNA inexpensively and those are technologies that are all coming together right now that allow us to manipulate the genetic material the code of life in ways that even a few years ago none of us could have imagined being sort of a reality so this is a picture that illustrates some of the different kinds of organisms that have been modified using CRISPR cast nine and you can see on this slide that we have animals we have insects we have various kinds of plants we have organisms that are important commercially agriculturally that are important for research and of course we have human cells as well so it's a wide range of opportunities for scientists now to use this technology to alter the DNA sequence in cells and organisms that in ways that have accelerated the pace of research if nothing else that's a you know just an awesome thing that you've seen the increase in the the scale and the and the and the number of scientific publications that have been generated just using this kind of technology and we can already see opportunities on the horizon for using this in various ways that will be important commercially but certainly also very important for biomedicine I thought I would just give you a few a few examples if you sort of concrete ID for how this is going to be a technology that will change all of our our lives in various ways and the first one really comes as an example of something that research that's going on in my own laboratory so one of the things that happened after the work that I did with Emmanuelle on the original curiosity driven science about CRISPR caste 9 and how it works was the idea that we could collaborate with clinical colleagues and for me in the Bay Area that's the University of California San Francisco our local medical school to figure out how we could deliver these gene editing molecules into cells of the brain because one very exciting opportunity with this technology is that one day we may be able to correct genetic mutations that lead to disease so I mentioned Huntington's disease earlier now this is one of the neurological disorders for which there's a well-defined genetic cause and so the opportunity to use gene editing to correct that mutation is really a very very exciting one and what I'm showing you on the slide is an experiment that was done by a postdoc in the lab Brett Stahl who was able to inject modified versions of the CRISPR cast 9 protein that had been chemically altered so they can enter neurons they're able to actually get inside of neuro neuronal cells he injects these into the brain of a mouse and we're doing this in a system in a mouse we're editing of the DNA in these cells turns the cells red and so we have a very nice visual way to look at editing that occurs and I want you to notice in the panel on the right that when this when these injections are done on both sides of the brain we get a very nice volume of tissue in the brain that gets edited and so we we know that we have a technology now that allows precise changes to be made just in the cells that receive these editing tools and this is something that I think holds a lot of opportunity in the future for potentially curing diseases that in the past were completely intractable for which we didn't have any any hope to offer to patients another I think very interesting direction for crisper cast 9 technology is in agriculture I like to say that you know when I think about what the impact will be on on our planet I guess you know for sort of thinking about opportunities for humankind I think the biggest impact in the short term certainly will be in agriculture and this is an example of research that was done at a laboratory in academic laboratory that was investigating how gene editing could be used in tomato plants to create plants that can bear more fruit and in in the matter of a few weeks this lab was able to use CRISPR cast 9 to change genes and tomatoes that create plants capable of bearing three times more fruit than the the starting plants I'm a tomato farmer so I think that's very very interesting sort of example of use of gene editing but I think there will be ways to use this that will also have very exciting impacts in terms of creating plants that are tolerant to drought resistant to disease and that potentially are have hired nutrition levels and to do that in ways that don't require plant breeders to introduce many random mutations as they currently do to create desired plants with desired traits but instead to do the these these genetic alterations in a very precise fashion that allows just the change that's desired to be introduced another interesting development with with CRISPR cast 9 and gene editing has been thinking about how to use this in animals in ways that will be beneficial so there are opportunities and animals that are important agricultural e of course but I'm showing you this picture of piglets because one of the one of the developments that's happened in the last year is work that's being done to create pigs that will be in principle better organ donors for for humans by using the CRISPR gene editing technology to remove viruses for pigs that would otherwise have the potential to infect people and also to create pigs that have organs that are more human-like so they won't be rejected by humans when they get transplanted so that's something that you know even a short while ago no one would have imagined that the ability to really do that in a way that would be that would be you know medically and commercially viable and then there's there's a you know this this sort of brings us to a something I want to point out about different kinds of gene editing that can be done so for a lot of the research that's going on right now that gene editing happens in what we call somatic cells these are cells that are fully differentiated in an aura in an animal or a plant and and they don't they don't end up leading to changes that would be transmitted to future generations but what if we do editing in germ cells this is an example that shows a pipette tip holding a fertilized Mouse egg so this is a mouse embryo that is being injected from the other side by a needle that carries the cast nine protein with its guide RNA and we know that when this kind of editing is done and changes are introduced to DNA at this very early stage of development in germ cells or in these early embryos that those changes become part of the entire organism and they can be transmitted to future generations and so I wanted to show you an example of the precision of this kind of editing by showing you an experiment that was done by a student at MD Anderson University in in the in the United States MD Anderson Cancer Center and this is an experiment in which the student was working with frog embryos these are two cell embryos in which there are literally two cells inside this very early developing frog and she injected into one of the two cells the CRISPR casts nine protein with its guide RNA and a gene that encodes a green protein a green fluorescent protein and the way she did this editing allowed her to remove a gene that is important for brown color in the Frog and replace it with this green fluorescent protein and you can see that every embryo that received that injection in one of its two cells now has a green fluorescent cell and an unedited Cell on the other side and when these when these embryos develop they developed into into frogs and here we're looking at tadpoles you can see in the top panel that right down the center of the animal there is a there's a split and the tops half of the animal has cells that are brown and the bottom half is missing that that pigment and then if we look on the bottom image under a fluorescent light all of the edited cells are green so this shows you that when you do editing in the germline like that then all of the resulting cells that get edited pass along that edit to their progeny so it's a very powerful tool so I was sitting in my office at Berkley in early 2014 and I got a phone call from a reporter who said what do you think about the latest work with CRISPR cast 9 using it to change the DNA in monkeys and I was astounded I got a hold of the the research article that this reporter was referring to and it was talking about work that was being published in an academic journal that reported using CRISPR Castine in embryos of monkeys that were then transferred then were then implanted into female monkeys they females gave birth to these edited animals and they turned out to be normal monkeys that had a single genetic change in the DNA that was sort of a proof of principle that you could do this kind of editing not only in in sort of animals that we use for for investigating human disease in the lab like mice and rats but also in these animals that are much closer to human beings like monkeys and I have to admit that I was pretty I was pretty affected by that that that phone call in that paper and it really made me start to think about the possibility that people might already be thinking about or even starting to do gene editing in human embryos because it seemed likely that if it works in in animals like monkeys and and other animals that this would be something was a reason to think that it wouldn't also work in human embryos so this really was for me the the moment when I decided that I really needed to start discussing publicly the research that I and my colleagues were doing not that we were doing this kind of work ourselves but just understanding that the technology that I had been involved in developing was something that had this awesome power and potential and could be used for wonderful things that I think we would all agree can improve human life but also had the potential to be used for things like eugenics you know altering the the human sort of the human population in ways that might have undesired or unintended consequences and so that led to a series of meetings that happened initially in in the US and now increasingly internationally to discuss this opportunity and also has of course led to a lot of media attention around this I think it's an idea that is very captivating to people you know to think about gee how could I you know how would I like to tweak the gene of my genome or my kid's genome and I recently asked my my teenage son you know about I said you know what do you think about gene editing do you think he would ever want to use that when you when you have kids and he said mom of course and so you know it's just it's an interesting thing I think it's just it's a moment when we are all sort of faced with they were sort of on the verge of a technology that's going to offer that potential and we have to figure out is that a place that we want to go and if we if we go there how do we do it in a responsible fashion this is a report that was published just about a year ago by the National Academy of Sciences in the in the u.s. that was spearheaded by a meeting that had happened the year before an international meeting that was co-sponsored by the Royal Society in the United Kingdom and the Chinese Academy of Sciences so these three groups got together and put on an international meeting to discuss in particular human germline editing leading to this report and if you read it it's a publicly available document if you have a look at it it basically outlines the potential for this technology to alter the human germline and ways that that could be utilized in the future and it makes a recommendation which is that scientists refrain from using this in a clinical way so in other words to do work that would lead to the birth of a CRISPR attitude baby until there's an opportunity for real public discussion and disclosure and transparent conversations with many stakeholders not just among scientists and clinicians but really among a much broader swath of humanity to think through the implications of a tool and a technology like this and I would say that those conversations are very much ongoing but at the same time the technology and the desire to use it in different ways of course is racing ahead and we've seen just in the last few months publication in very prominent scientific journals work that is doing research in viable human embryos using the CRISPR cast line technology that could enable removal of genes that would cause genetic disease and it spurred a lot of discussion and ongoing questions about not only the technical aspects of the technology how it's working but also the bigger sort of more societally based questions about should we go there and how do we ensure that this technology is used responsibly how do we ensure that people understand what's coming and what's going to be affecting our world going forward and I'll really look forward to our our discussion after the talks about that I just want to close by mentioning that with a graduate student in my lab Sam Sternberg we wrote a book called a crack in creation which talks about our experience it's very just personal a story of going through the the process of doing the research that led to the CRISPR cast 9 technology and then thinking through where it's going in the future what does this mean and how does it change the world that we live in and what do we imagine happening in the future how do we engage in the kinds of public discussions that are so critical right now and finally I'll just mention that I've also been involved in the Bay Area in in establishing the innovative genomics Institute an academic organization that's under the umbrella of the University of California Berkeley and the University of California San Francisco we are an organization that does research using gene editing but really importantly also has a big effort in ethics and outreach we have a team of people that are working on ways to educate non scientists about what gene editing is what is it enable and where is it going in the future and trying to we're working with groups like high school teachers to help them develop tools and and and kits they can use with their students to educate them about this and where it's going so it's a it's a very exciting opportunity right now and I would encourage any of you that are interested to check us out on the web I'd like to conclude at this point and thank you for your attention and I definitely look forward to our conversation after the talks Thanks [Applause]

Channel: ConvergenceScienceNetwork

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Keywords: CRISPR, genetics, gene editing, gene drive, Jennifer Doudna, biology, ethics, science, research, health, CRISPR-cas9, Genome editing with CRISPR-cas9, Genetic engineering, Genome editing, amazing science

Id: gC_x2XKJjQo

Length: 28min 59sec (1739 seconds)

Published: Thu Feb 15 2018