CRISPR – WORLD SCIENCE FESTIVAL

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NARRATOR: For thousands of years humans have bred horses in much the same gradual way nature does. But soon they could actually be designed. In the lab. Along with other livestock. Plants. And even humans.

Because a new technology has made editing the genome almost as easy as using a word processor.

Genes are made of DNA, long strings of four chemicals best known by their initials A G C and T. Together they form the basis of all life on Earth.

This new genome editing technique is so much faster, easier and more accurate than anything that’s come before that it’s creating a new paradigm for biological research.

It’s called CRISPR which is short for clustered regularly interspace short palindromic repeats. Here’s how it works. Scientists program a guide RNA on a protein called CAS 9. With the address of the targeted gene.

The guide RNA directs the CAS 9 protein to cut both DNA strands precisely at the correct spot like a molecular scalpel.

A new section of DNA is added to the cell and edited into the original DNA sequence which now incorporates the characteristics of both sequences. Biochemist

Jennifer Doud was one of the co-discoverer of the CRISPR technology.

It’s going to enable a lot of science to be done that was impossible to do in the past. The CRISPR technology is so precise that it can actually edit DNA down to a single letter and multiple edits can be made at once. Changes in a genome that may previously have taken centuries can now be made in just a short time. This game changing technology is one of the most powerful in the entire history of science perhaps comparable to the splitting of the atom.

But like that historic event the development of easy cheap and convenient genome editing may also bring a new and sobering responsibility.

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JENNIFER DOUD: One of the roles that we as scientists need to play is to really communicate. The power of this technology and how we can be responsible. Do we know enough about the human genome to understand the impact of making changes to it in a developing embryo.

NARRATOR: In fact the human genome has more than 20000 genes many of which we do not understand at all. Downa has been a cautionary voice but she is also excited about the possibility of solving big problems.

DOWNA: think most people would feel that genome editing in adults is. Or at least might be for some applications a very appropriate technology it might be analogous to taking a pill for treating cancer or some other disease.

NARRATOR: Could we begin to treat previously incurable diseases like sickle cell anemia or cystic fibrosis and do it inexpensively.

DOWNA: I like to call it democratizing technology.

NARRATOR: The CRISPR revolution is already happening in research labs worldwide. For better or worse every life on earth will soon be affected by our ability to reprogram the software of life.

RICHARD BESSER: I want to welcome you to the World Science Festival and I think what will be a very very interesting evening we’re going to be diving into the brave new world of CRISPR. And as you see as you saw in that film CRISPR gives scientists the awesome power to tinker with the software of life. The system was invented only three years ago but already the rush is on for big bucks in prizes. As scientists and industry compete to modify food, develop new drugs and target genetic diseases. CRISPR biotech startups are springing up around the country and a big industry is on board. They’ve been ramping up CRISPR research and development in agriculture and pharmaceuticals. Two American universities are battling it out in court over the basic CRISPR patent. And while the legal dust settles the number of patent applications in the U.S. has jumped from four to 230 in just the last three years. And everywhere it seems people are beginning to imagine a brave new future through CRISPR. Here to help us sort this out our leading researchers and thinkers some who have a stake in the race for CRISPR. Our first participant is molecular biologist and director of technology at Gene editing company CBIS where she is responsible for leading a team of scientists developing non transgenic traits in commercial crops.

[00:05:24] BESSER: Please welcome Noel Sauer.

Our next guest is professor of pathology and pediatrics at Albert Einstein College of Medicine. He develops new technologies and investigates the genetic basis of common and rare disorders. Please welcome Harry Ostrer. Also with us tonight is a post-doctoral research associate at the Rockefeller University. He has adapted genome editing techniques including CRISPR to investigate the genes and neural circuits that control behaviors in the mosquitoes that carry diseases such as dengue, Chikungunya and Zika virus. Please welcome Ben Matthews.

Our next participant is director of research at the Hastings Center and an expert on the ethical legal and policy implications of biomedical technologies. Please welcome Josie Johnston.

Joining us is assistant professor of biochemistry and medicine at the wheel Cornell Medical College. He’s a pioneer in using CRISPR Gene editing in animal studies. He demonstrated a simple genetic tweak that can turn cancer cells into healthy tissues in a matter of days. Please welcome Luke Dow.

And our final guest tonight is a professor of genetics at Harvard Medical School. He directs personal genomes.org at the NIH Center for Excellence in genomic science. His innovations have led to the creation of 12 companies ranging from medical genomics to biosecurity policies. Please welcome George Church.

So there is a lot of ground to cover here when it when it comes to to CRISPR and I have a ton of questions to ask our panelists and I do hope that you tweet your questions as well at #WSF16. So you can join the conversation.

So to start, one of the world’s most accomplished biologists, Nobel laureate David Baltimore has called the discovery of CRISPR a monumental moment in the history of biomedical research. What I’d like to start us off so people have an understanding is help us understand the excitement in the scientific world and what is powerful. What is so powerful about CRISPR. So what makes it a game changer. I’ll start with you George. What is it about CRISPR that’s captured everyone’s attention?

GEORGE CHURCH: Well I’m a little subdued about it having contributed a little bit but I think as a placeholder for a collection of technologies that have not been recognized and suddenly are this includes next generation sequencing, a variety of ways of doing Gene editing and Gene therapy without editing. All of these things are given the name CRISPR for communication purposes as I see it. That said it is very very easy for academics to use. It is extraordinarily inexpensive and you know high school students are doing it.

BESSER: We’ll get into the ease of doing CRISPR. Luke what’s your what’s your take.

LUKE DOW: So. I’m a cancer biologist by training and cancer geneticists and we’ve been for many years trying to manipulate the genetic information in a model system to try to mimic human cancer. And that’s been tedious sometimes and the tools have been relatively blunt and now CRISPR allows us to go in and make these changes and you heard in the introduction we have tens of thousands of genes and we need to be able to go and precisely engineered the changes we see in human cancer to understand the biology and find ways to treat.

BESSER: And CRISPR gives you a way to do that.

DOW: It does I mean as George said there’s been technologies that have led up to CRISPR that have allowed that but there’s sometimes been difficult to implement and not very scalable. So you might spend a long time on one gene. Now we can spend the same amount of time studying 10 or 20 genes. And cancer is extremely complex. So we need to understand all of that complexity to get a handle on it.

BESSER: Harry is the excitement warranted?

HARRY OSTRER: The excitement is totally warranted. You know in addition to these you know thousands of genes that we have we have millions of genetic variations. And for instance if we sequence your genome Rich would find that you have 3.5 million you know genetic variants that’s a major challenge that George faces and you know the personalized Genome Project, we don’t have a clue of what most of those variants are doing and CRISPR provides a handle for discerning that.

[00:10:22] BESSER: And Noel there’s applications for agriculture as well.

NOEL SAUER: Yes there is. So I actually think of CRISPR as being the fancy new scissors that are available that are cheap and easy to use but there are other technologies like George’s mentioning that have been around for years that can actually do similar things that CRISPRs can do. They can make cuts in DNA in a very targeted manner. So CRISPR is just the fancy new kid on the block if you will in the genetic toolbox that we can use. But there are other technologies that have enabled this revolution if you will such as DNA sequencing. We can’t do it faster much more inexpensively as well as in plants you can take single cells that have been edited and regenerate them into entirely new plants so all of these other technologies have really pushed and made it more of a gene editing technology instead of a CRISPR revolution.

BESSER: So Gene editing as such isn’t new it’s it’s the ease of being able to do that.

SAUER: It’s the fancy new way of doing it. Gotcha. And Ben your take.

BEN MATTHEWS: Yeah no I think that’s absolutely right. So as somebody who works on a mosquito aedes aegypti which has not traditionally been tractable in terms of studying the genetics in that organism. CRISPR is sort of the latest genome editing tool that allows us to scan through dozens of genes at once rather than one or two with previous technologies. And so rather than turning to something like a fruit fly which is what we would have done in the past to understand the genetics in a non model organism. Now we can do those studies directly in the animal that we care about and that has biomedical relevance

BESSER: And Josie, excited, frightened, a little of both?

JOSEPHINE JOHNSTON: No I think I’m a little bit building what George said is that this tech… this particular technology I think makes real in and can be a sort of point to discuss a range of technologies in genetics including sequencing technologies and really makes vivid some of the of the things that have really been fantasy in this sort of substance of science fiction before sort of seem like they might be closer. And so we have you know we don’t know we have to see how far we get towards some of those sort of futuristic scenarios but this definitely has ignited interest and made some of those things like modifications in humans seem closer and therefore puts an urgency in a kind of, brings a lot of conversation that we probably need to have.

BESSER: What I want to do it at the top of this is go through some of the applications for CRISPR. We have people here from very different backgrounds who are looking to use CRISPR as a tool for many different things and then after that I want to explore some of the ethical challenges that may be there in trying to apply this in an appropriate fashion. So Luke let’s start with let’s start with the work that you’re doing. You’re a cancer research researcher you’ve been doing pioneering work in creating animal models of disease using CRISPR. Tell us a little bit about how you are using CRISPR in particular the work you’ve done in mice with tumors.

DOW: Yes so the mouse has been the backbone of genetic research outside for decades at least the last 30 years when we’ve really been able to manipulate the genome and study genetic effects. So our goal and our mission really is to try and create mass models of cancer that mimics the precise mutations that happen in human cancer with the ultimate goal of producing a model system that we can use for preclinical studies and develop therapeutics and move towards the clinic for treating patients with those same cancers with those same mutations. So maybe I should step back and say that initial introduction may have seemed like we were all playing down the impact of CRISPR and taking a step back and I think that’s important. It’s not the only thing. It was not the only kid on the block. But in practical terms it really has changed the way we do research in the lab.

And so you know take one example that we have chromosomes made up of genes and we often have mutations in these genes but sometimes we have huge segments of these chromosomes that are deleted or that flip around and these create fusions and therapeutically targetable genes. These have been very very difficult to study in a mouse model. Now with CRISPR we can actually engineer them by creating two cuts and at some frequency the chromosome will flip and creates exactly the same lesion that we see in the human cancer. And we just hadn’t thought really pursuing those studies. It was doable but just not practical. And so now we can do it. We’ve spent the last year building these rearrangements and it’s actually told us a lot about the initiation of tumors in the colon.

[00:15:23] BESSER: And have you actually been able to reverse cancer in a mouse.

DOW: We have actually but that might be a different topic. Wasn’t Using CRISPR. No I mean this is an important point and it gets back to you know there was a predecessor technologies that led up to this in multiple ways to manipulate genes and the way we did that one was to take a gene that’s mutated in nine out of 10 colorectal cancer and we think it’s one of the drivers of the disease. We used a tool called short hairpin RNA’s or SH RNA’s where we can suppress that gene specifically. The mice develop tumors, get aggressive disease and then we can turn the gene back on. And what we saw was that within two weeks all the cancers disappeared. And so we were following that up trying to mimic that effect therapeutically. And to do that we’re using CRISPR’s to build the models and using SH RNA’s to mimic the therapies. So in that sense we’re really combining all of the best tools we have to create our ultimate dream model.

BESSER: And how does this relate then to to colon cancer in humans. Can you take what you’re learning there and will it work in people.

DOW: So we can’t go in and turn genes on and off as easily as we can in the mouse because we engineered them specifically for that purpose. But we can understand the pathways that go awry and then we can design drugs or other type of therapies that can come in and intervene in those pathways. So that’s really the ultimate goal. Understand the genetics and then figure out a way to apply it with a drug.

BESSER: So editing DNA is just one of the things that CRISPR is being used for. But other researchers are using it in different ways to study cell development and disease and here I’d like to turn to you and your work. How do you use CRISPR to understand genetic risk for disease.

OSTRER: Right. So you may recall that we had a famous lawsuit that was settled on gene patenting in 2013 and up until that time. The BRCA one of two genes which when mutated you know increase a woman’s risk for developing breast and ovarian cancer you know also have an effect for men as well. And there was one company that was offering testing and they had their own catalog of variants that they had curated over their 20 year history. So it wasn’t really available to the public. And as a result of that case you know BRCA 1 and 2 and other genes are no longer patented but we still have the problem of dealing with this issue of knowing what genetic variant is going to increase risk. You know what genetic variant is going to have no effect whatsoever. Well we can mimic these mutations by or we can mimic these variants in cells and then we can look to see well is there a pattern that is being expressed by these cells that we see in the individuals who are at increased risk for breast cancer.

OSTRER: This leads for instance to the development of what’s called CRISPR libraries where we can create quite large catalogues that these variants put them into cells and then identify those cells through genomic sequencing that have these paths that have these patterns that one would observe in people who have this increased risk for breast and ovarian cancer.

BESSER: And why couldn’t you do this before CRISPR what did CRISPR allow you to do.

OSTRER: It’s an incredibly efficient technology. You know so you know as the other panelists have said there have been other methods along the way and the whole issue with regard to doing targeted engineering, the genome has certainly existed since the late 1970s and early 1980s when genetic engineering really became a possibility as a result of recombinant DNA. But what you’re hearing now is not recombinant DNA. You’re hearing Gene added. It’s conceptually somewhat different thing it’s not really putting in something new. It’s changing what’s already there but it’s changing what’s already there in many different ways in many different cells and then sorting out the patterns that are occurring in these cells to predict what they might be doing.

[00:20:07] BESSER: And at what point does it reach a clinical application that you can say to someone you’ve got this variant that does this to your risk.

OSTRER: Well you know I think it can be used every day now and I think it’s being you know I think it can be used for prediction of breast cancer or I think in this gene APC that Lucas studies, you know we now have the possibility of introducing those variants as well and really sorting out the variances uncertain significance from the ones that are the pathogenic mutations that increase someone’s risk for developing colon cancer.

[00:20:45] BESSER: Ben I want to pull you in on a topic near and dear to my heart. Mosquitoes. So much of the conversation about CRISPR has revolved around the potential for treating disease or editing genes in human embryos. Something we’re going to we’re going to discuss. But researchers say the real revolution right now is in the lab and you’re a ben scientist. You’ve been working with mosquitoes. Tell us what you do and how CRISPR is involved in that.

[00:21:16] MATTHEWS: Absolutely. So as you said I work directly on mosquitoes which previously have not been really a genetic model meaning that we can’t edit and engineer their genomes directly until the advent of tools like zinc finger nuclease and talens and now CRISPR. And so what CRISPR lets us do is actually mutate genes in the mosquito that we think are responsible for their system of smell and taste. And so what we are interested in specifically is figuring out how a mosquito in its environment will find you for example and take a blood meal. And so what you’re looking at up here is a female aedes aegypti mosquito. And so she is the vector for a number of Arboviruses including Zika Virus which is a big problem these days and some that have been around a little bit longer like dengue fever yellow fever and chikungunya. And so a female mosquito is exquisitely tuned to find and bite human beings and females do this because they need to develop eggs so that blood meal that you see you’re taking right there is going to by about double her bodyweight and so she is going to drink about two milligrams of blood.

And then she’s going to turn that into a batch of 100 mosquitoes. And so this is why evolution has really acted on their sense of smell and taste. And so what we do with CRISPR and this slide is just kind of schematizing how we do it. So we have taken these components that George and others figured out in bacteria are responsible for cutting DNA at specific places and we re engineer them in the lab and then re-inject them back into mosquito embryos and we do this not to make that embryo mutant but we do it so that we can mutate a sperm or an egg in that embryo which is going to give rise to a stable mosquito mutant in essence. So it’s a mosquito that either is missing a certain gene or we’ve engineered a certain mutation in a gene or what we’re doing now which we’re really excited about is actually introducing new sequence into…

So this would be the analogy of the paste of your word processor to hearken back to the video. And so what we can do now is we can get genes that we want to express in cells that we want to have those genes expressed and then we can get control over neural circuits. We can image the brain of the mosquito as it’s hunting for a host in the environment. And so these are things that we could have dreamed of five years ago and our colleagues in the fruit fly have been doing for decades.

But that’s because they had a hundred years of genetic history to work from. And in the last three four or five years since the advent of CRISPR we’ve been able to catch up in a lot of ways and now ask questions about blood feeding that we can’t ask in a fruit fly. And so this is showing you just what happens when we put in a sequence of DNA in a particular look. So we have a blue and a red mutant strain of mosquitoes. Each one of them is missing a gene that we think is involved in their ability to find an appropriate place to lay eggs. And what we’ve done is we’ve actually replaced that gene with a ubiquitous fluorescent reporter.

So either a blue or red protein that we can see under a microscope. And so we do this so that we can follow them in the lab and then we assess their behavior with really sensitive behavioral assays to identify which of these genes are involved in the critical behaviors for the mosquitoes life cycle and disease transmission. And so this has really been the result of the last two or three years we’ve come much much further than we had in the previous five or 10 specifically because of the advent of CRISPR. And so my experience with people who work on other non model organisms is that if you can figure out how to get these reagents into an embryo CRISPR will work. It will make its cut and that didn’t have to be the case. And so that’s one of the most amazing things to me at least is that something that’s so evolutionarily agent that will work in human cells or mouse cells or mosquito cells.

[00:25:05] MATTHEWS: And so what we do and this is my hand. So we’re not going to release these anytime soon into the environment but you can imagine that by generating certain strains of mutant mosquitoes that may be poor at targeting human beings or have other altered behaviors that we can understand the processes that they use to find and bite people and by proxy transmit disease.

BESSER: So you create a mosquito that no longer finds people tasty.

MATTHEWS: That’s one idea. Yeah. And if we do that then we have a handle on what the genes or families of genes that they use to do that. And you can start thinking about developing a repellent for example. So we have things like DEET right now but we still don’t understand how DEET works. And so we would like to be able to know what are the genes that they use to find humans and then we can start thinking about how to interfere with them similar to how in cancer you need to know what the genetic basis of a cancer is before you can think about treating it genetically.

BESSER: George you got a lot of the CRISPR ball rolling and you stunned the science world when you demonstrate that you could modify 60 genes at once in a pig. Who cares about modifying 60 genes in a pig.

CHURCH: Well we didn’t set out to set a record. I mean we were already all of us were pretty excited about being able to change one or two with great ease or make a library where you’re doing one at a time but hundreds of thousands of them in the library each separate. But in the case of the pig there was a promise, a wish for about two decades to be able to transplant organs from pigs into humans to solve you know one of the most severe crises in medicine which is this under a unavailability of a sufficient number of organs for transplant.

There is about a billion dollars invested in it about 15 years ago and it kind of came crashing. It was a pretty good roadmap even for using the old tools that we had that we’ve been alluding to. But it came to a crashing halt because it was discovered that there were viruses built into every cell of the pig that when in an immune compromised patient could escape from the pigs organ, the donor that was going to save the life of the recipient. But these viruses would get out and then infect this immune compromised patients so it became kind of a perfect storm incubator for the next really bad virus so we didn’t want to create the next Ebola or HIV or swine flu. And so there was a moratorium on that research for about 15 years. CRISPR came along and we thought oh we can do one or two pretty easily, Let’s try 62.

And actually we were quite concerned that it wouldn’t work but it certainly wouldn’t work if we didn’t try it. So we tried it and after 14 days and this is not 14 days of hard labor this is 14 days of it sitting in the incubator. We came back in and all 62 of these retroviral genes that were in the pig genome were dead and we show that there were no no infectious virus being spread anymore so this released… it showed great promise for now, doing all the things we need to do to make pig organs acceptable for humans.

BESSER: So a direct practical application where this may provide organs for people.

CHURCH: That’s right. You know, millions of people.

BESSER: Noel. Let’s talk plants. Potential applications of Gene genome editing for global agriculture are huge. Can you talk a little bit about what the problem is there and what it is you’re trying to address and how CRISPR feeds into that.

SAUER: Oh certainly so. It has been predicted that by the year 2050 there’ll be over 9 billion people on earth. That’s a lot of people and that’s a lot of people that are going to be hungry. So what are we going to do to feed them. Well one of the solutions would be to make agricultural acres that we typically grow plants on a lot more productive.

But another solution to this problem was to be able to grow plants in environments that are unfavorable that we typically don’t grow plants on for example in environments where there’s very little water or there’s very little nutrients in the soil. Now we can develop plans that actually are drought resistant so they can grow in areas where there’s very little water. We can develop plants actually that has sustainability traits in which they are actually more efficient or very much more effectively utilize nutrients in the soil such as fertilizers. So we can actually do that and so one of the real world problems that we face right now is in developing countries. So what I’d like to draw your attention to is cereal yields over time. And what you can see clearly is that in Africa cereal yields have been stagnant whereas in other areas of the world they have increased.

[00:30:26] SAUER: So why is that? So besides the reason for lack of infrastructure. Some of the reasons why it’s been stagnant is because they use very little or no fertilizers and there’s no arrogation so we can actually develop plants that these farmers are growers in developing countries can use to feed themselves that can feed their families and also their surrounding communities. So it’s a very exciting time.

BESSER: Now one of one of the topics that’s been in the news a lot and concerns and debates has to do with genetically modified organisms and things that people are going to be eating. What you’re doing here in these plants is that genetically modified organisms as that is typically defined.

SAUER: So let me tell you how we do things a little bit differently than others in the plant field at cibus. So up here you can see is a slide that we like to use as an analogy. So what we do at cibus is actually if you were to change one letter or two letters in one word in the entire Sunday edition of The New York Times you would actually change the sentence so for example if you had the word cats and you change the C to a T. Now you have. I’m going to bring home a new cat to Now I’m going to have a new tat. And so you have actually actually have changed the meaning of that particular sentence. So what we do implanting editing at cibus is we actually will change one or a few nucleotides or letters of genetic code in a gene in a very targeted manner. And this will actually give us a trait or a phenotype that we actually desire to have. So some of these traits are for example drought resistance which I’ve already talked about. So plants are able to grow with using very little water. The next slide we show corn so you can make drought resistant corn.

And so what our technology actually does is we actually provide instructions that are delivered to single cells of plants along with a gene another gene editing tool for example CRISPR but it can be on other tools as well. And we, actually these instructions do that tells the cell the plant cell to make changes in a very targeted way to genes within the cell so it actually changes its own DNA. Then once it actually does this our instructions are degraded through natural cellular processes. So it’s a little bit different than what others have done in this field. And so some of the products that we have coming out which one of which is already in the market is canola. We also have a product coming out in flax and future products consist of potato as well as rice.

BESSER: Josie what’s your take. Are we splitting hairs to not think of this as a genetic modification or is it different in that there’s no foreign microbes DNA being being inserted. Does this get around some of those issues?

JOHNSTON: So. That was the plan.. in plant’s? Yeah. So I mean it is genetic modification. I don’t think that it’s genetic modification. I don’t think that’s necessarily in dispute. And you would have an organism that was modified as in its genes were different than they would have been if you hadn’t done this. But. There is you know I guess there is a difference between introducing foreign DNA into something versus making a change in the DNA that already exists. And so that you know people have to think about how significant is that difference. And certain regulators have to think about that difference. You know some, whether that makes something where that something falls on a regulatory line in that way. But you know it’s really I mean this is important to think about the genetically modified foods debate and how that has had transpired and then this is not a steep in that it’s not exactly the same but it’s also you know part of the same kind of activity really.

BESSER: We will definitely get into some of the regulatory issues as well as some of the public discussion of how you how you bring the public along as these new technologies come come into play. George a leading CRISPR food researcher has said that if you’ve eaten yogurt or cheese chances are you’ve eaten CRISPRized cells.

[00:35:11] CHURCH: That’s true. Dairy products have a problem with the viruses that get in and kill the bacteria that are making the, changing it from a regular raw milk into something tasty with distinctive taste. So if the viruses kill the bacteria then you get bad yogurt and cheese. And so the companies that make yogurt cheese have harnessed natural bacterial defenses against these and these-and this was one of the first applications of CRISPR back in the mid 2000s. So it’s very exciting. Everybody should be very excited that they participate CRISPR revolution in 2007. And yogurt.

BESSER: So a question a question about that then is is CRISPR something that was invented or something that was discovered.

CHURCH: Well you know it’s a little of each. Almost every major invention involves some basic scientific discovery. It is not at all obvious that just because you’ve made a discovery it’s going to turn into an invention. There are many many discoveries that that that take forever or a long time to, or never become invention.

And some of these things that we most many of these molecular technology come originally from microorganisms but some of them are still a microorganism. So for example we have a competing, another technology that we’re using that only works in ecoli K-12 called mage or beta. And I think eventually it will escape but it’s been we’ve been working on it much longer than CRISPR and then we happened to try CRISPR and it worked almost first time.

DOW: So maybe one thing just to follow up what George was alluding to is that it actually the plots that are involved in CRISPR are part of a bacterial immunity or defense system in those bacteria so they existed but it took a suite of very smart people to figure out how to adapt that and make it useful for us. So it’s been around and it’s in this room right now.

CHURCH: It’s something they may have always used, maybe another way of saying it is the bacteria use it to kill viruses we use it to edit genes. Obviously that’s a very different thing. It’s not just the discovery that. That’s right. That’s the difference.

BESSER: Ben. I’m hoping you can help explain another concept to further the discussion. But one of the fascinating aspects of the new science relates to something called the gene drive. Sure. So what is that and how that gene drives and CRISPRs all all relate.

MATTHEWS: Yeah. So a gene drive is sort of CRISPR that’s been harnessed to another level in that you actually take the components that make up the CRISPR system and you insert those into the genome of for example a yeast or a mosquito. And there have been people who have done this in the mosquito. And the idea there is that you have now kind of vectorized which is a word that means you’ve turned that animal into a vector for the CRISPR system. And if you were to release that into the environment it would conceivably edit its own genome and then it would drive that genetic package into its offspring in a way that kind of breaks the normal rules of inheritance. So you’re basically adding a genetic weapon if you will to a mosquito or to a yeast or to another animal so that when it’s released in the environment it will target the endogenous genome in a way that will copy that weapon and so on and so forth. So it will actually drive itself into the population of wild animals that will mate with the animal that you release.

BESSER: In some of the papers I’ve been looking at talk about that as a way to possibly wiping out mosquitoes that that spread malaria.

MATTHEWS: Yup. So there are a lot of a track, attractive kind of aspects of this in that you know if you think about trying to eradicate the malaria mosquito for example you could drop a ton of insecticide everywhere where that mosquito is but that’s going to be extremely nonspecific. And that’s going to get the malaria mosquito it’s going to get all the other species of mosquitoes and all of the other insects in addition to whatever else those those drugs may target. So the one of the really attractive parts of this is that it should be species specific. Assuming that you don’t have something called horizontal gene transfer where it will jump from one species to another and that’s one of the big issues that people talk about when they urge caution and rushing these out into the field. So it’s specific and you should be able to use it to engineer those animals to have a specific trait.

MATTHEWS: So you could either kill them or you could render them immune to the types of viruses that mosquitoes spread. So if there are aedes aegypti out there but they’re incapable of spreading Zika now they’re a nuisance rather than a killer. And so you could potentially use these gene drives to change the phenotype of animals in the environment with this type of tool.

[00:40:20] BESSER: George you argue that if you’re going to do something like this there should be an off switch.

BESSER: How do you do an off switch. Sounds like it once once you let this out into the into the world it’s going to take off.

CHURCH: Yes. So for many the technology as we develop that there is there are concerns we raise concerns and we did that in this case before we did any experiments, We wanted to have a way of reversing it in case somebody did it without permission or did it with permission but it didn’t work as well as we thought we need to be, Every technology needs to be reversible and the way you do it in this case is use the gene drive another gene drive against the first one. So basically you drive through a population first time through where you recode the target so that the CRISPR will only cut the normal version and won’t cut its the the gene that you’re targeting in its new form. Then the reversal just goes and says Oh I’m only looking at the form I’m looking at not looking at the old form.

And so then you can get it back to where it was and this and we’ve tested this in one species so far that I know of. And it’s very important to test it in multiple species just like it’s important to test that we don’t see horizontal transfer and you need to scale these things up to pretty large scale to make sure that it works at scale.

BESSER: So given how how new a lot of these technologies are and the concept sounds wonderful. How do you how do you assure that there won’t be untoward effects. Things that hadn’t been thought of, some of it downstream or are…. How big do you have to scale it up to be comfortable saying OK we’re going to release this in 10 countries.

CHURCH: Yeah. So the the… There are entire villages of artificial villages that are contained within domes where where the entire villages of physical containment. There are also ways that you can put a biological containment on top of that. But I think you do have to do it. You start out with something small as you know you know a small laboratory sized experiment and then you go to these artificial villages where you simulate the crops and the animals and the multiple species of a mosquito and the rain and all that.

BESSER: So… Malaria kills more than 500000 people every year, mainly mainly children. And it looks like it may soon in the not too distant future be possible to wipe out off the face of the earth the mosquito that transmits the infection. How is it ethical to not take this step to eliminate that mosquito.

JOHNSTON: It seems to me that if it were all the things that George was just saying, if it were safe, if it could be reversed if necessary if it was not going to do these unpredictable horizontal things if we knew that in a complex environment which is what our environments are, that it would function the way that we hope. Then we would have you know it could be a slam dunk in favor. And so the that these these are really significant questions, safety questions really that have to be right that must be resolved. And when you have such a significant benefit then there’s a lot of incentive to really try to work on those and make sure that they are resolved. But we know you don’t have to look very far into human history to see examples of changing environments introducing species that then take over or that do unpredictable things or so we don’t want to make those same kinds of mistakes again.

And so a lot of that effort and a lot of the of the coordination and oversight and international bodies looking at these things and trying to figure out exactly how to achieve the dream without having any you know disastrous effects on environments or these kinds of unpredictable sort of sideways leaps that we wouldn’t want to happen.

DOW: This is the Jurassic Park effect. I mean maybe I was conditioned because I was 12 or 13 when Jurassic Park came out. You know there’s a lot of parallels there. That’s not what’s happening with mosquitoes but you know it’s it sort of worries me a little bit because it’s very unpredictable. We can do a lot of test and you do have to go to scale to try and do these things but then at some point there is a tipping point where it’s the potential benefit outweighs that and there’s no right answer and there’s no line where you can say OK we’ve finally crossed it. Just as a wealth of knowledge comes in. So we have to pull the trigger.

BESSER: Ben, you want to get in on it.

[00:45:13] MATTHEWS: Yeah I was just going to say that for every case there are going to be unique considerations as well. And so for malaria in particular it’s more than one species of mosquito. And so now you’re looking at potentially editing Anopheles Gambiae, Anopheles Stephensi and maybe a dozen other species as well depending on where in the world you are. And there are different strains of these mosquitoes in different geographic locations so you may have to think about building different gene drives for Africa than you would for India or other parts of the world.

And so it’s every case of this is going to be kind of laden with complexity which does not mean that we shouldn’t be pursuing this research but it does mean that we’re probably a ways off from actually implementing it at scale.

JOHNSTON: It’s kind of that the the beauty of engineering minds it, the way of thinking that comes with engineering meets the complexity of biology and being very careful about that intersection.

BESSER: I’m going to…Up… up the level of concern and just a second but I want to latch on to what you said Luke about the Jurassic Park effect. Is the gentleman sitting next to you has talked about creating a woolly mammoth. So the first question is can you do it? And the second question is did you see the movie?

CHURCH: We we we picked a herbivore.

BESSER: Thank you.

DOW: We should have that Jeff Goldblum on this panel.

CHURCH: Life finds a way.

JOHNSTON: With the third question maybe would it be a woolly mammoth actually. Would it be a modified version of something with some traits of woolly mammoth.

CHURCH: I think if we get sufficiently compulsive which scientists tend to do, it would, we would eventually asymptotically approach it but probably many people would be quite satisfied once we had a cold resistant elephant that’s comfortable at minus 40 and looks like the woolly mammoth.

BESSER: I don’t know if a lot of people would use the word satisfied. Yeah.

CHURCH: I mean… And it’s saving the tundra and then you know saving the Asian elephant germline and various other positive things. I think that would probably be a milestone that we should celebrate. But yeah and then the compulsive folks will get in there and change every single base pair and figure out every epigenetic change and what it eats and all the rest of that stuff. But I think they’ll be a great deal to celebrate if we get even to a cold resistant asian elephant.

BESSER: So I want to move away from from mosquitoes in plants and woolly mammoths to one area where where there’s probably been the most debate and concern and that’s whether if ever we would want to use this technique to edit the human germline and change human inheritance affecting generation after generation of unborn children by changing everything from eye color to IQ to inherited diseases. You know all these changes would be carried in all cells and passed on to subsequent generations. But let’s talk a little bit about the science of how that could happen and Harry can you explain a little bit about what it means to added a germ line versus added a cancer cell in an adult.

OSTRER: Well you know we heard some of that already with regard to mosquitoes and you know getting it into the germline the same sort of principles apply. The editing is done early in an embryo before there is so-called you know segregation of the germ cells and cells will divide, cells will differentiate into lineages including you know the germ line and of course the issue or one of the issues that tends to concern people is you know what are the long term consequences. The issue with Gene editing focus is always on the degree of specificity and

BESSER: What do you mean by degree of specificity?

OSTRER: Right, right, right. So you know it’s made out to be you know a magic set of scissors that you know always works. It’s like going to a master tailor you know who is able to make a specific correction. But in order to insert you know exactly the sequence that you want requires that a set of enzymes that are present in the cell you know are doing their jobs and doing it efficiently so that you know a cut is being made on you know as you heard but then it’s being repaired. It may be repaired in the way that you want it to be repaired or it may be repaired in some you know in some other way. There’s also the possibility that a cut is being made someplace else in the genome. And unless you look for it you might be missing it. And this refers to the so-called off target effects that might be occurring with gene editing.

[00:50:46] OSTRER: For those reasons I think you know this panel probably would see it principally as a research tool right now rather than a specific therapeutic tool for humans. But as you know so often happens with medical research. We have been down this path before with regard to gene therapy, you know, take the term gene therapies and use Ben’s paste and put editing in the middle then you know wala. You know here we are right now.

BESSER: If we had the ability to edit out heritable diseases or to make people more resistant to infectious diseases would it be, would there be a problem with with going that route.

OSTRER: So it really depends upon when this is being done in the lifecycle and whether it is meant to edit the germline versus you know editing the so-called somatic cells. For instance. Now with the use of gene therapy it’s not specifically Gene editing therapies it’s possible to engineer retinal cells and cause them to produce photo pigments or other proteins that may be deficient within these photoreceptor or other retinal cells. And for people who are blind they’re now able to see. So it’s been you know quite miraculous frankly.

BESSER: Josie is human germline editing something that we should ever permit. Do you see a way that that that would be permissible ethically.

JOHNSTON: So the question is a good one and so far as there are people who have a principled objection to making changes in the human genome that are permanent, that would be passed on. And they would only be in favor of some of these, what are we, talking about somatic treatments where you know a child or an adult has a particular problem and there might be something you can do. But that that wouldn’t be inherited. And there are people who draw a line in the sand and say that’s a lie and we should never cross. And certainly that’s why there was a large international meeting and recently to talk about this issue, this very question and I’m not one of those people so I don’t think that there isn’t any principled line in the sand that we shouldn’t cross but I think for some of the same reasons that were cautious you will be very cautious about introducing changes into ecosystems.

We know we are an ecosystem and so I would want to be very very very sure about the safety of any change that we were going to put put in place that would be inherent, would be heritable and that we understand how that change was going to work. Now when we think about like the kinds of reasons like what what would be a good reason to try to make inheritable change you know. It’s not hard to come up with devastating conditions that we would think would if we could not have Huntington’s disease being passed on in families some people might think Well that would be an obvious thing that would be a good. It just gets very complicated when you start thinking about complex traits. So we don’t know enough.

We don’t know anything like enough about what what most of her genes do. And we certainly don’t know like what will fix a lot of our traits. So the idea of being able to increase intelligence or being able to control anything related to personality or even things like complex diseases like obesity or cancers. It’s very we don’t have the know… we wouldn’t know how to do it, what to do even if we had that option todo it right now. So I do think there’s a complex difficult discussion that we’re going to have to have about about germline modification because when I don’t think we’re going to be able to justify and in principle a ban on that. Once it’s proven to be safe a particular way we’re going to have to have a conversation about what the limits for how we would use that technology.

There are also people who would you know who are like I see Hep-C there is a line in the sand that we we should never cross. But my belief is that we will and should Creusa in some cases in the hard work is going to be justifying those cases. And understanding when and agreeing really because it’s going to be hard to agree with that there are any limits to it.

[00:55:11] BESSER: George who would you see getting to decide what’s an improvement of the human genome and what should be allowed to go forward.

CHURCH: Well I mean I think the interesting case is how we get from here to there. I agree with what you just said that we’re probably going to go there and what’s the transition state. And I think that one will be that when you have two parents that are carriers for a serious disease the only options they have today are to adopt children or to do abortion or to do in vitro fertilization which many people consider a form of abortion because you have frozen embryos without resuscitating them. So an alternative would be to alter the sperm so that at least one of the parents is no longer a carrier in the germline sense. And that would put no embryos at risk and would appeal to people who do consider embryos in a form of human life. That is a possible transition zone that we could have or the process of curing infertility would be another one.

But then I think your question is you know where where where do we stop. I think the way the experience of most medicine has been that if it’s safe and effective it doesn’t necessarily have to be life and death. So if you look through all the drugs that have been approved by the FDA only a tiny fraction of them deal with life and death. You know a lot of them have to do with headaches and you know athlete’s foot. And you know all a whole variety of of things that are not that serious. Facial reconstruction is serious after an accident but most cosmetic surgery is not that serious. In fact sometimes it’s contra indicated because people are already pretty good looking.

OSTRER: There does become an issue of personal choice as well you know we did a survey about 10 years ago and our patients who came to see us NYU for genetic counseling and we asked people what did you want genetic testing for and what do you want to do embryo selection for. And basically the answer was you know everything. And this was before the era of easy Gene editing that we have now. But about 10 to 12 percent of these reproductive age people said that if there were a test that would be predictive of superior intelligence or superior athletic ability in their children they would want to have it. And as we’ve seen for instance with consumer genetics that people won’t be denied in terms of the types of information that they’d like to be able to achieve but it was certainly a topic that has emerged from this panel is that scientific progress occurs sequentially. And there are all there is always the anticipation that a series of milestones are going to be met in order to get from here to there. I hope you’re going to get into the issue of terrorism because

BESSER: I do want to hit that but I want to reflect back on a comment that Jennifer Dowden made at the beginning that she feels a responsibility as a researcher to educate people and to listen to their concerns and she says that one of her biggest fears would be waking up one morning and reading about the first CRISPR baby. And having that create a major public backlash where people ban the use of CRISPR or regulators shut down CRISPR research and that she thinks that that could be very detrimental to the field. What are your thoughts what are your thoughts on that.

OSTRER: You know what does that mean you were talking about genetically modified organisms earlier and the European Union is you know notoriously opposed to a genetic modification. You know I don’t think that the issue is one of safety or ethicacy for human health with regard to genetically modified organisms I think it’s one of economic hegemony from American seed producers that Europeans don’t want to be you know under the heel of Monsanto. So to what extent there is going to be economic domination by virtue of having access to these technologies with patent protections becomes a very important issue.

[01:00:01] CHURCH: George I you know I think that as far as I know the Europeans are not opposed to genetically modified insulin. It’s produced in bacteria. It’s it’s used for serious diabetes. So there is a line between major health issues and you know quite frankly genetically modified foods do not have obvious taste, even economic benefits to the average groceries store shopper. So so I think that that’s what’s happening there. And when you get back to your question about Jennifer’s fear that the first CRISPR baby I think back to the first in vitro fertilization baby. I don’t think that the the people that invented that were upset when Elizabeth Brown was born. They were delighted that finally there was a solution for infertile couples. And Elizabeth Brown was a very healthy baby so the different… The important thing about that break there was a lot of worry upfront.

They were they were dismissed and demonized as test tube babies that were going to be horrible monstrous babies. But they but it wasn’t. And so the difference was Elizabeth Brown was born was born healthy. So if Jennifer reads about the first healthy CRISPR baby that’s cute and cuddly and undiseased, she probably will be proud of it.

BESSER: The International Group that I think Josie you’re referring to called for a moratorium on making unhearable changes to the human genome it said it would be irresponsible to proceed until the risks could be better assessed until there was a broad societal consensus about the appropriateness of any proposed change and in that opening conference I quoted David Baltimore earlier but he also said the overriding question is when if ever we will want to use gene editing to change human inheritance.

And the question I have is is who gets to make the decision. And in terms of where that line is and how do you go f where is that line between getting rid of Huntington’s disease and in a sense eugenics where you are or are selecting for a baby that you see in the catalogue who’s got the genes that you want to see.

JOHNSTON: So we mean in a way we kind of have some of these questions already playing out now. And so far as different countries have different approaches to the regulation of preimplantation genetic diagnosis and prenatal testing which are two ways not to edit genes but to influence which genetic what the genetic makeup of children is because those without which particular genetic markers won’t be selected so they won’t be born essentially. And so what you see is that there’s no one person deciding, there are different countries with different approaches and in England they have lore on this and they have a regulator of authority and they have a very comprehensive system of oversight and governance and in the United States there a professional guidelines. But there aren’t really there aren’t there’s no national law on this here. So you have very different and then other countries also again different approaches.

There’s not one oversight system. And so now that you know into the research is so international and there there’s absolutely no direct way of controlling what a researcher in a particular country that isn’t strictly regulating these issues might do. And so there’s no way that we can guarantee Jennifer that she won’t wake up and see those… see that story and it might be done really well and done really and have a really good outcome or it might not. And it’s not as if there’s anyone who is ultimately in control it’s really going to be up to individual scientists and at the end of the day probably up to individual prospective parents to decide. You know when things are available and so you see now you know really wonderful uses of in-vitro fertilization technology to help people overcome fertility or to help them to make choices about the kinds of you know inheritable diseases that will continue in their families.

But you also see use people using the technology to not have a baby girl or not have a baby boy. And there is no and in some countries that’s regulated and in America it isn’t. And so there’s no guarantee that you won’t have those kinds of other uses of gene editing technology as well.

OSTRER: But preimplantation genetic diagnosis isn’t an intervention. And once there is an intervention then the Food and Drug Administration is going to argue that this is a new procedure that would require meeting their standards I would think.

JOHNSTON: But they have standards for safety and efficacy, the standards are not about ethical acceptability or moral issues. So I do think that you know it’s not it’s not crazy for us to at all to be having a conversation about the scene in Gattaca when a couple goes in and the geneticist has made that there are various modifications to the to the embryos and they say to him Well we kind of thought we might leave some things to chance because they were kind of trying to have something resembling an old fashioned parenting experience that’s the kind of decision making you know that we might have to engage in in the future. Like what kind of how much control do we as parents or prospective parents want to have over who will be born and some people say I would like to control everything.

[01:05:38] JOHNSTON: I’d like to know about everything and some people will say no I don’t want to be that kind of person, be that kind of parent that gets to decide all these things and one of my concerns is just that that kind of consumer mindset and this sort of competitive nature of society will push people to use technologies PGD, prenatal testing and gene editing in ways that are inconsistent with their values because they feel like that’s the only way to succeed in this world.

BESSER: Alright I’m I’m having what’s known as moderator anxiety. I’m looking at the countdown clock and I promised that I would hit some questions from Twitter. And I also have a number of topics I want to get to so many hit a couple questions from Twitter.

CHURCH: And then there are a couple other topics I really want to get to.

OSTRER: Can we maybe do a little editing for you to help you overcome this.

BESSER: Yeah I don’t know if it will happen fast enough but here we go. OK so I’ll combine a couple here and a topic that you’d asked for. This comes from from Twitter from J lab guy who wants to know how do we regulate CRISPR used in militarized applications for example super soldiers and bio weapons. And then another question from MacSween Dr. Matthews brought up CRISPR as a weapon. That worries me. Would it be possible for someone to delete the the off switch and in the introduction one of the things that that you heard was I spend a lot of years at CDC working on bioterrorism and Emergency Preparedness. And when I hear CRISPR it it’s one of those things that that worries me in terms of of the the things that people who might not want to do good could potentially do. How do you. Anyone can jump in on this. How do you take this technology they can sounds like do incredible things and prevent it from being used to… for harm deliberate harm.

DOW: I mean you can’t. But but I mean people will do what they will do. But what we’re talking about here in very general terms is can we make a super soldier. Not one person on this panel or anywhere in the world knows how to go in and manipulate which genes to create a super soldier. Even if we did the traits that you would give a super soldier maybe like increased healing or something like that would actually probably predisposed them to get more cancer. And so this comes back to how we get into this field of germline editing might be there’s a horrible disease that we want to fix and that’s fine and it works. But what works for gene A is not necessarily going to work for gene B C 20000. So just because it works once doesn’t mean it’s going to work a second time. And even if it did work there’s no off target effects and everything was very clean throughout 80 year life span of a human. We have no idea what that modification might do if it doesn’t already exist in the population and we can understand it.

BESSER: So let’s throw away the Super Soldier. What about a super micro-organism?

DOW: What was it. There’s a shorter time line for testing those things. But how do you how do you regulate that. I think there’s an answer.

JOHNSTON: You can regulate against it but you might not be out to prevent it.

SAUER: Yeah. One thing I’d like to comment on is that in human gene editing they’re still working out how to deliver this effectively to targeted tissue. So we’re, there still in this mode of trying to figure that out. There are a long ways away from actually being able to make human armies if you will that can conquer the world. So I mean it’s what…  scientists are still working out how to deliver them in a targeted way in the field.

OSTRER: But the more immediate of the issue is the one that you faced at CDC which is creating superbugs you know which is you know more tractable issues than creating the super soldier. And you know it’s vigilance. You know it’s you know monitoring you know whose hands the reagents fall into. You know it’s a lot of things.

BESSER: Alright we’re going to need to go through some more little rapid rapid topics. George. I didn’t want to let the evening go without hitting the headlines that you made yesterday when you with your article in Science talking about the human genome project. Right. You called for a public a huge publicly and privately funded project to construct a large plant and animal genomes including humans from scratch.

[01:10:22] BESSER: And what is it that that intrigues you about this what do you see as the promise of this this big project and how does it relate if at all to CRISPR.

CHURCH: Right so at least for my this is a committee effort. My particular part of it is is to take a big project and turn it into a little project that is to say to bring down the costs and improve the effectiveness as has happened with DNA sequencing which used to be$3 billion is now a thousand dollars. And it’s happened with CRISPR and other synthesis things. So the idea would be to bring all that radically down so you can test hypotheses. You can you could figure out what’s cause and effect in inhuman diseases. You can make… We’ve already made a multi virus resistant organism by changing the genetic code of every gene in the in the in the in the whole genome. You could do that. You can do that for bacteria doing it in mammalian cells would be about somewhere between five and a thousand times harder. But it has significant advantages both for basic science but also there have been cases where a virus infection has wiped out a pharmaceutical factory for two years. So if you could make the cells they used for manufacturing the human proteins because this is the viruses that would be a big deal. And there are many other examples like that where just just improving the technology would would open up whole new possibilities like that.

BESSER: So this is a project on even a grander scale than the sequencing of the human genome.

CHURCH: I don’t think it’s important to us to say whether it’s grand or not. I mean my and what… like I said what I would like to do is make it less grand to make it something that’s ordinary.

BESSER: Bite sized pieces that it can it can be done. The ethics of doing this in your paper you you brought up those issues.

CHURCH: Yes. I mean I think all these technologies are so enabling and so exponentially growing that we need to bring up ethics constantly in this particular case of projects would be limited to cell lines, to testing hypotheses as we’ve heard earlier in cell lines where organoids where you, it would not be for producing whole organisms necessarily but there would be related projects which would have even more ethical issues where you make whole animals which would have an ethics of of abuse of animals or making humans which we talked about that germ line issue.

BESSER: Harry legal experts have warned that there’s not even a modicum of regulatory clarity when it comes to government agencies and CRISPR and its applications. You have some experience in terms of regulatory work. What kind of path do you see towards regulation here in the U.S. and then more in the international context.

OSTRER: You know I think that if there is a resulting concern that the reagents are going to be misused then there may need to be consideration about you know how to regulate the production of reagents. I don’t know that we’re necessarily at that point yet but it is going to have to be part of the debate that we’re having. The flip side of democratising science is that it makes it accessible so that high school students can do it. But Jihad high school students potentially can do it as well.

And so what constitutes an adequate safeguard there you know with regard to the issue of you know editing the human germline we don’t have a comparable you know regulatory body like the human fetal and embryo authority that they have in the UK. That said you know once people actually started to do it for a therapeutic purpose in humans the FDA would kick in. But then on the flip side of all this which is that in terms of these applications, doing research on human embryos and fetuses you know becomes an issue.

[01:15:05] OSTRER: And that of course is one of the very hot button issues of our time. With the stealth you know photographers you know demonizing organizations and you know individuals who are engaging in procuring human materials that research can be done. And against that whole backdrop we don’t have a common regulatory framework so that in states like New York and New Jersey and California we want to encourage you know human embryonic stem cell research. You know in states like South Dakota and Louisiana it’s illegal. So we’re all over the board in terms of what’s happening in this country.

BESSER: Alright to to end because we are down to our last 10 minutes. I want to go to each of you and and just in a minute or two. If CRISPR can achieve its promise. What do you see as a future CRISPRized world, what would it look like? And and what is your biggest fear or nightmare that could happen if this isn’t done properly?

SAUER: So my nightmare scenario would be that this genome editing technology isn’t deployed to fast enough for us to actually feed our growing population. And my dream scenario would be that no woman, no man woman or child would die of starvation. That farmers or growers in developing countries are able to sustain themselves, their families and their surrounding communities and for CIBUS is that we will develop trades in every major crop that will help feed the growing population.

OSTRER: Better food, better medicine is my you know for people is my dream. I don’t see you know human genome editing as therapeutic, you know coming onboard immediately. My fear you know as I alluded to is bioterrorism.

MATTHEWS: So I work in particular insects that cause pretty terrible disease and so I think whether or not it’s through Gene drive or just simply a better basic biological understanding of these animals in the lab that CRISPR allows us to get towards. The dream is to reduce the impact of these throughout the world. And I think one of my nightmares is somebody who’s still at the bench on a daily basis using these tools is that we see either backlash from the public if something is deployed incorrectly or if we see Conversely a kind of overregulation of these tools so that we can’t deploy them for for good. And that’s something that I worry about on a daily basis.

BESSER: And do you see a way to mitigate against against that?

MATTHEWS: I think having conversations like this and thinking before we act and just doing the best science that we can and engaging with the public I think are good first steps.

JOHNSTON: I mean in humans I see the potential to treat disease and alleviate suffering as the sort of as the drain use. And I guess my nightmare would be that the kind of idea that we are supposed to somehow always be thinking about how we can perfect our children or make them better or improve them that that takes over and really does ultimately changes how it is that we think about what it really means to be a parent, what it really to be in a parent child relationship. So I feel like that relationship is really important and very significant in our culture in just that that is able to be preserved and that we are able to be surprised and to cherish and to love in ways that aren’t only seeing things through the eyes of like how could this have been made better, how could this person be changed. But I think that’s a long way off but that’s the direction that I hope we don’t go in.

BESSER: Luke.

DOW: So I think in many ways from a research perspective and we’ve realized the dream, it’s just a matter of scale now. So my dream in terms of therapeutic application is really somatic Gene editing not germline but treating is monogenic heritable disorders that are debilitating and then the nightmares exactly what Ben said if if something goes wrong and we don’t regulate that process we’re going to get the backlash that we got from gene therapy. And then another moratorium on being able to implement the technology where it might be used effectively.

BESSER: George.

CHURCH: I think everybody’s pretty well covered most of my nightmares.

[01:20:03] CHURCH: Which I have in abundance. You know just a quick summary. Yeah I would hope that we could feed the population, I think we can cure a lot of diseases that affect developing nations because the poverty of the world drags us all down. And I think we don’t need to worry quite so much about overpopulation because as people move into the cities and become wealthier their fecundity drops from 7.5 for family to 1.2 which is below the replacement level. I mean we should still worry about it but it’s a it’s a different discussion.

OSTRER: So is access to technology a dream or a nightmare or both for you.

CHURCH: I think it depends on the technology. So I think cell phones for example was once only for rich people that could have melted their brains. Didn’t as far as we know. But now it’s successful and there’s six billion cell phones and rising and getting internet access to the rest of the world is happening. I think the important thing is that we do this very thoughtfully and cautiously so we don’t get the backlashes that we inevitably get when we bring out the technology that was poorly thought out. And there’s a there’s there’s this tendency for individuals to rush ahead so they get the big prize. And we need to remove those motivations because we are after all human and stop giving out prizes for rushing ahead and making a mess.

BESSER: Well on that note I want to first off thank our tremendous panel for I think a really thoughtful discussion about a topic I knew very little about before diving into this. But thank you so much for your time and your expertise and all of your perspectives. And lastly just want to thank all of you for coming tonight. The World Science Festival is going on all weekend there are events all over the city. Check them out. Explore science. Bring your kids so that they grow up to think that science is cool. Thank you very much.