Gene drive technology

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JOSHUA COLBURN: Hello and welcome to SciLine’s first ever media briefing. I’m Joshua Colburn, a program associate here at SciLine, and I’ll be going over a few brief technical points before our moderator, Rick Weis, introduces our panelists. After the panelists have presented, there are going to be two ways for reporters to ask questions.

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If you’ve either called in or are using a mic today and want to ask a question over audio, let us know by clicking the raise hand icon at the top middle left of the screen and select raise hand. As time allows, Rick will announce you, and you’ll hear unmuted on your line, which is when you can begin to ask your question. After your question, you’ll be muted once again so that everyone can hear the panelist’s answer. Should you have a follow-up question, please raise your hand again, which will restart the process.

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If you are listening to the conference today with no microphone but would still like to ask a question, please type it out and submit it in the bottom right Q&A box. Once selected, Rick will read your name, outlet, and question to the panel and they’ll respond. If you’d like to pose the question to a specific panelist, be sure to include that information in your message as well. If you are having any technical difficulties, please use the same Q&A box to ask it there, and some of the SciLine staff will be able to respond directly to help. With that, I’ll turn it over to SciLine’s director and today’s moderator, Rick Weiss.

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RICK WEISS: So before I introduce the presenters, a quick thing on SciLine. We are, as some of you know already, an editorial independent free service hosted at the American Association for the Advancement of Science dedicated to the mission of helping reporters who are covering stories about science, health, and the environment, or covering stories that are not necessarily about science but that can be enhanced or made more substantive with the addition of some science.

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So let’s get started. I’m just going to give a one sentence introduction to each of our four presenters because their full bios are available on the page that you’re looking at and will be available on our website as well. We’ve got four speakers.

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The first person you’re going to hear from is Tony James. And Tony is a professor of microbiology and molecular genetics in the School of Medicine at UC Irvine. He’s also a professor of molecular biology and biochemistry in the School of Biological Sciences there.

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Renee Wegrzyn, you can get the spelling on the page there, it’s R-E-N-E-E W-E-G-R-Z-Y-N, is a program manager at the Defense Advanced Research Projects Agency, better known as DARPA, who runs some genetics and genes programs there, including, I think, most notably for our discussion today, the Safe Genes program, which, as you’ll hear about, has a very interesting take on how to move the science of gene drives forward. DARPA, of course, is also one of the major funders of gene drive research in this country.

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Third will be Zach Adelman, that’s A-D-E-L-M-A-N. He’s an associate professor in the Department of Entomology at Texas A&M who will both be able to tell you about some of the research he’s working on with gene drives in insects but also has great experience in the regulatory side, including sitting right now on the Recombinant DNA Advisory Committee, which oversees gene transfer research under the NIH and can get people up to speed on some of the regulatory oversight of this branch of science.

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And last, fourth, is Dr. Jennifer Kuzma:, that’s Jennifer with two N’s, K-U-Z-M-A. She is a distinguished professor in the School of Public and International Affairs at North Carolina State University, and she’s also codirector of the Genetic Engineering and Society Center there. So we really appreciate you being on board to hear each of these four speakers. They’re just going to talk for five or six minutes each and give an overview of their area, and then we really want to open it up to questions and allow you to find out what you need to know to help you. So with that, I’m going to turn it over to Tony James. Thank you.

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ANTHONY JAMES: Great. Well, welcome to the briefing here. So I’ve been given the charge of defining gene drive and then talking a little bit about the research that we’re doing here. So I think the easiest way to think about gene drive is just a very fast way to move genes into populations, and these populations have to have the attributes of having very short reproductive cycles and lots of progenies. So if you meet those two criteria, these technologies can actually work to move, for example, a gene of interest or a designer gene, so to speak, into that population quickly. And basically it works by manipulating normal cell biology.

When a chromosome in a cell is broken, the cell will stop just about everything it can that it’s doing in order to repair that chromosome, and it has a couple of ways of repairing that. I think I can do my hand waving here if I get it setup right. If you break the chromosome, it could actually put itself back together, and this is called enjoining. So it sticks itself back together. And this process is actually quite faithful and works very well in most circumstances, but in some cases, it doesn’t work as well as we would like it to and the cell has another approach to doing that. And that is that there’s another copy of that DNA molecule in the cell in the other chromosome, and it will often copy that other chromosome as a way of repairing it. So it’s a simple act of breaking chromosomes and inducing the repair system that allows us to exploit this for gene drive.

Now the famous CRISPR-Cas9 system that you’ve heard about is just a technique for specifically breaking a chromosome at a desired location. And so the Nobel laureate earning aspect of this is the guide RNA that allows the cut or the break to be made exactly where one wants to have that. And you can flood the cell with copies of DNA that the broken chromosome, instead of using its other chromosome to copy it will use the DNA that you put in. So that actually can get that in there. And so you can setup a system where you can move DNA in and then have it reproduce fairly quickly. I hope you all understand.

It’s quite a challenge to explain this without using any genetic terminology at all, but the bottom line is that we’re looking at a system that moves genes rapidly through populations and depends on fundamental aspects of cell biology. Okay.

So how are we using this. Well, I work with a mosquito-borne disease called malaria. About three point four billion people are at risk of this disease every year. There’s about 216 million cases a year and about 450,000 deaths. We’ve seen a recent downtrend in the disease over the past ten to 15 years.

But actually, within the last two years, that downtrend has been reversed, and malaria is actually getting worse. And so we were experiencing some advantages of the deployment, for example, of insecticide treated gnats, but we’re seeing marked reversals with that right now. In the current absence of a vaccine, the development of parasite drug resistance and insecticide resistance in mosquitoes, the situation’s becoming worse.

And so new technologies are needed urgently, and the ones that we’re developing in our lab are basically genetically engineered mosquitoes that are resistant to malaria. And we described before how you can use the CRISPR-Cas9 system to put genes into chromosomes, and that’s how we do that. We build genes that would make the mosquito resistant to malaria parasites, and we use the CRISPR-Cas9 system to integrate those in them and to continue to spread them.

So basically what we have are synthetic antimalarial genes coupled to this drive system. And we think the advantages of this are that it’s sustainable, low cost, and resistant to the movement of mosquitoes into an area, and the resistance to the movement of people into the area, who are carrying the parasites because the mosquitoes of the locale will remain resistant to the parasites. And just as a final comment, we don’t expect our technologies alone to be sufficient to eradicate malaria, but we think in combination with the development of vaccines, carefully used drugs, and other measures that we can have a role to play in that. And I’ll stop there and pass it on.

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RICK WEISS: Thanks, Tony. Renee.

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RENEE WEGRZYN: Great. Thanks very much to the folks at SciLine for inviting me to participate and tell you a little bit about my work here at DARPA and the work of those that we fund under the Safe Genes program.

So a little bit about DARPA, very briefly, is that we are in the business of technological surprise in the context of national security. So we want to both be able to understand and create technological surprise but also prevent that technological surprise. And for me, the advent of CRISPR-Cas9 was a moment where I was very excited about the potential for the good uses of those technologies but also acknowledge that there is a potential for nefarious misuse and also accidental misuse of those tools. And so really the Safe Genes program is meant…we can actually put a slide up here that shows the different aspects that the program is aimed to address.

It’s to really move forward and create a capability to use the powerful tools of genome editing that Tony just described, the ability to go anywhere in the chromosome and make a cut and introduce new DNA where we would like it to go but also tools that have the potential to bias inheritance. These are very powerful tools, and there are good uses for them. But we want to make sure that we protect against their accidental or nefarious misuse.

And so we’ve grouped the program into three technical areas where we saw there were capability gaps that existed, and we wanted to fund researchers to address those gaps and create new technical tools to better control genome editors who want to turn on a genome editor in the cells and tissues where we want them, when we want them, and once they turned over their target to be removed from that system. We also wanted to generate first in class countermeasures and inhibitors of genome editors. So at the start of this program, there was no way to shut down an editor if there was an activity that was unintended or unwanted.

And we are developing and have funded groups to look at small molecules that can inhibit genome editing activity as well as nucleic acid so other DNAs and RNAs that can shut down CRISPR-Cas9 activity as well as proteins that can bind to these types of gene editors and shut down their activity.

And then finally, we are exploring the space of genetic remediation, and this is actually correcting an edit that may have been introduced that’s unwanted and restoring that system back to its baseline state. And this is certainly one of the most ambitious aspects of this program. But collectively, if we’re able to make progress to control, counter, and reverse the effects of genome editors, that can give us more confidence in moving forward for applications like therapeutic uses or gene drives, which is the focus of this discussion. And this would really give us an idea of what’s even possible with regard to these tools. Importantly, in addition to the wet lab research, we are looking at modeling both ecological modeling but the modeling of how these constructs and organisms that are modified will behave over time.

Mother Nature, of course, will evolve these systems, and something like a gene drive has never really existed in this manner in the environment before so we’d like to understand in a closed setting, in the laboratory, how we may investigate that. And I should be clear. There’s no open release as part of the safety and progress. In a very basic and fundamental, we want to understand how these tools work. I know Jennifer will be speaking in a moment about ethical, legal, societal issues. But that’s also an important aspect of our program where we funded each one of our teams to make sure that they are addressing those issues and feeing that back into their technical plan and even doing experiments to look at how they may address any concerns that arise along the way.

So thank you.

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RICK WEISS: Zach, you’re up.

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ZACH ADELMAN: Okay. And then I have two slides. I tried to put this together without slides, and it just became a little bit too confusing. So to keep myself straight, I have two slides here.

So just a brief bit about some of the work that I’m doing. So whereas you heard Tony talk about work with malaria, I’m interested in the mosquitoes that transmit viruses like Zika virus, dengue viruses, Chikungunya virus, yellow fever virus that are also causing a lot of problems in the world. And along with some collaborators at Virginia Tech, we’ve discovered a gene that can basically confer maleness.

So why is a mosquito a female or a male? Female mosquitoes drink blood, and they transmit viruses and other pathogens. And male mosquitoes don’t drink blood. They don’t transmit any pathogens. And so we are trying to engineer this switch, this gene, so that we can develop populations that are biased towards being male, and then that will, of course, be self-limiting at a certain point when you run out of females. And then it would hopefully have some effect on the problem.

But mostly what I want to talk to you guys about today is both laboratory containment and open field containment in terms of for a regulatory structure that currently exists, that these experiments do not occur in a vacuum, and they do not occur on the whim of an individual investigator, that there is a lot of oversight over these things. And I want to walk you through what that was and what the gaps are in those oversight processes.

So on the first slide, it deals with laboratory based containment. And basically all work that is funded by NIH or done by entities that receive funding from NIH is subject to following the recombinant DNA guidelines that NIH has put out. And gene drive research is not specifically called out in those guidelines, but it is a form of recombinant DNA or synthetic DNA that is inserted into organisms. And so I’ve illustrated where those experiments would fall. And some of those experiments, for example, recombinant DNA added to model organism yeast is exempt from the NIH guidelines. And so if you’re doing gene drive experiments in yeast, largely those will not come under the purview of the NIH guidelines. They may or may not be regulated at your institution.

Doing gene drive experiments in rodents, which are largely exempted from a lot of guidelines, or in some plant species that are noninvasive will require eventual approval by an institutional biosafety committee, but do not require approval prior to the beginning of work. Most experiments that we’ve heard of, or that are being done so far, would be in insects, arthropods, other kinds of animals, and these require approval by a committee of experts institutional biosafety committee before these experiments can begin. And so those committees will evaluate the laboratory containment, the physical structure, the work practices, the expertise of the personnel conducting the work, and the overall environment and appropriateness of how those experiments will be contained before they give the go ahead for those investigators to begin whatever manipulation, whatever gene drive strategy, they seek to begin.

But those are not the highest risk classifications in terms of how recombinant DNA is reviewed. As you can see in this tower, things like human gene therapy or the cloning of potent toxins or generating microorganisms that are resistant to antibiotics or other treatment strategies require much higher stringency review right now from NIH either at the RAC, Recombinant DNA Advisory Committee, level or at the level of the Office of Biotechnology or the NIH director itself.

So in terms of how these things weight, like I said, they’re not specifically called out, but they do fall under the current guidelines for the most part. An individual institution like a university or an institute may be more strict than the NIH guidelines. They can dictate that all recombinant DNA work, no matter the organism, is subject to review before it beings, and any institution can certainly do that. Institutions or entities, private companies, or even individuals that don’t receive money from NIH do not legally have to follow the NIH guidelines. They are not a law document. They are just a condition of receiving funding.

And so is there gene drive research being done outside the purview of these guidelines? We have no way of knowing, but it’s possible. Most individuals, I would think, would intentionally try to follow the guidelines even if they weren’t subject to them because they may face legal repercussions if they were able to accidentally introduce something into the environment.

So I’ll go on to the second slide. And this deals with the current, as we think of it, regulatory landscape for how gene drive research might be regulated in the field. So in the US, we have what’s known as the Coordinated Framework for Biotechnology, which is coordination between the EPA, the USDA, and the FDA. And one of those organizations would take the lead, but they would confer with the others in terms of how that product would be regulated.

In recent guidance issued by the FDA on the scope of genetically modified mosquitoes, they’ve provided some clarification into their current thinking, which is, of course, nonbinding. But suggesting that there are examples of applications where if the goal is to reduce the detricompetence, or the ability of a mosquito to transmit a pathogen that the FDA will maintain being the lead regulatory agency there, whereas if the goal of that modified mosquito was to reduce or eliminate the population, then the EPA would take the lead, still conferring with the other agencies as needed.

They did not specifically mention gene drive technology at any point in that guidance document, but presumably it will fall into either or both or neither of those categories depending on the particular application as it comes forward. And certainly, gene drive strategies towards agricultural pests or things that may affect livestock or crops, USDA may be the agency that takes the lead role on those.

Outside the US, the WHO has issued a guidance framework for testing genetically modified mosquitoes. Again, this document does not call out gene drive mosquitoes or separate them from just a standard genetic modification that is not self-propagating or does not bias inheritance. And so it’s kind of uncertain what path that will take. My guess is these things will all come on a case by case basis as they are developed, and this landscape will shift as one product or another moves its way towards the potential for an open trial.

And I will stop there.

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RICK WEISS: Thanks, Zach. And I think one of the take home points there, of course, is that as far as we know, no one has applied for environmental release of this technology.

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ZACH ADELMAN: Correct.

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RICK WEISS: So we’ll see how it goes. Jennifer.

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JENNIFER KUZMA: Great. Well, it’s a pleasure to be here.

My task is to talk about the societal aspects of gene drives that are broader than potential regulatory systems and frameworks. So I’ve decided to organize the comments, because these are such a broad area of different issues, according to the elements of responsible innovation. And those are anticipation, inclusion, reflexivity, and responsiveness. So we’ll see how that works.

So gene drives really challenge some of these activity and governance frameworks in pretty key ways. So the first one, when you talk about anticipate is how can we anticipate for the consequences of gene drives prior to a release. As we’ve discussed, the intention is that very few organisms would then be able to spread throughout a population in a geographic area and to drive that gene through the population.

So really, any field test is basically almost like an open release and is an open release in some respects. And so therefore, it challenges the regulatory framework in the anticipation of consequences in that most of our regulations are written for confinement. If you think about genetically engineered plants in the first generation of GM foods, there were very specific isolation distances. These plants were meant to be grown on certain fields. And gene drives really challenge that particular notion of confinement during regulatory field trials but also during marketization, too, where different product streams or different areas. So it also challenges risk analysis in several ways.

Again, there is the design of spread, if you will, of the gene is very different than the first generation of GMOs, and we’re not exactly sure how ecosystems are going to respond. So really, they’re plagued by a high degree of uncertainty. So that really gets to the point of how much uncertainty are we willing to accept in the release, the first open release, of gene drive organisms.

And ecological systems are complex and unpredictable and sometimes very sensitive. Some systems are resilient, but other times small changes can lead to large consequences. So some of the unintended effects might be, for example, if you suppress a particular pest in an area, a more dangerous pest might come and fill that niche, something that’s more able to spread disease or to wreak havoc on ecosystems. There’s also a lot of uncertainty about horizontal gene flow and its consequences.

Now again, these are probably low probability events in and of themselves, but they’re kind of like the black swans where if it does occur and you might have some consequence you would need to worry about and those things are very difficult to test for prior to the first open release or really prior to full release. So although researchers are working on ways to recall gene drives and limit them using various molecular or geographic confinement strategies, these have a lot of uncertainty associated with them as well.

So that really gets to the second question that I wanted to address and the second component of responsible innovation, which is inclusion. So who gets to decide how much uncertainty we’re willing to accept upon the first release of a gene drive organism? Who has the right to have a voice in the debate? Who has the right to define what we consider as a risk or as a harm? And also broader values of what kind of species are desirable to different populations or different cultures? What ones do we want to see now or in the future? What about the next generation? And then how do these gene drives compare to more conventional methods? There’s not a really good system in the US, or really anywhere, to have a central place where the broader socioeconomic and ecological harms are addressed.

Regulations are very narrow, and agencies have very specific mandates. And it’s done in quite a piecemeal way. But where is the body that’s going to include the public in these conversations, especially populations living in areas where gene drives are released, and to engage the public in this and also to compare gene drives to other technological or more conventional options.

And then a very practical kind of question is who should be engaged? Is it just people in the local area? Is it in a wider area? If we don’t know exactly how far they’re going to spread, we have a lot of questions about how broad our engagement should go. And sometimes this could cross international boundaries or cultural boundaries, and so where do you draw the line?

And then finally, what type of engagement should it be? A lot of times, when we as expert or technology experts tend to think we need to educate the public, and that’s a very unidirectional view of engagement. And social science scholars and others are talking about a more bidirectional model where people actually have a voice and a say in what’s done and that the experts learn from people on the ground as well as the people on the ground learning from experts.

So that brings me to my third element of responsible innovation, which is responsivity. So even if we do engage people and we do anticipate consequences, how responsive are researchers and developers and deployers in gene drives going to be to public and stakeholder concerns? Will they stop what they’re doing if people have significant concerns?

Now this doesn’t necessarily mean that everybody has to agree on the release. I think that would be unrealistic, but people living in the area if a vast majority or greater or a consensus is that these are not good for their particular society or culture or ecosystem, will we be able to slow down or even stop research and take the advice of the public and stakeholders?

And then there are bigger questions about economic effects, and so I’ll just mention one example, organic farmers, for example, or lost trade to other countries. Spotted wing drosophila is a pest of fruit, and if you were to develop a gene drive, and many people are, and successfully in some cases, to drive down a population of this fruit fly, would a genetically engineered insect, either the eggs or the larvae, in the fruit consider the product tainted or adulterated and not organic anymore?

And given the spread of insects, this could be more of a problem for organic farmers and for lost trade to other countries as well. So how responsive is the system going to be to those types of concerns? Again, most of our regulations are very much based on direct harms, direct environmental or human health harms and not so much on these broader economic and social concerns.

The other thing is there’s few incentives in regulatory systems right now for post-market monitoring and for really making sure that post-release data is collected. We sort of have a gate, and once that gate is open for GMOs, it’s pretty well open with some exception. And so will that be the case for gene drives? How much information is going to be required to be collected on the ground? And how responsive is the next generation of the technology, the release, going to be to that information?

And finally, I think the fourth element of responsible innovation and that’s called reflexivity. And really what that means is the need for all of us, all stakeholders, even consumers and people on the ground, to hold up a mirror to our own motivations and biases and world views. And if we don’t do this, it really is a barrier to all the other elements of responsible innovation.

For example, if we think that decisions should only be based strictly on science when there are all these other harms and concerns, that is a motivation or a bias that we have. If we think we know what’s best for society as technology developers or people that understand the technology, that’s another lack of reflexivity. And then on the flip side, people on the ground really don’t trust GMOs or industries that develop them. Now the good news is that gene drives aren’t really going to be a big money maker, probably, if they work well, and so you have more of the public sector and foundations doing this type of work. But people will have to check their biases about the lack of trust on the motivations of the scientific community as well.

So I think I’ll stop there because I’ve probably taken up my time. I have more to say, but there’s really a need, I think, if there ever was a need in the GMO area, to really proceed with these four elements in mind. And that’s anticipating consequences, including broader voices, reflecting on our own motivations and biases, and being responsive to concerns of not just the researcher community or the funding community but also the wider public community.

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RICK WEISS: Thanks, Jennifer. That was really interesting. And I’m glad to be back on camera now. Apologies for that opener.

I think it’s really interesting, actually, for starters, just that this depth of conversation is going on right now with regard to this new emerging and still not released technology. It’s very different than what we saw back in the 90’s when the first instances of genetic engineering for agriculture and other applications started to come out. So in some senses, it does seem like we’re ahead of the curve and maybe have learned a few lessons from then.

So I want to open it up to Q&A. I know that some reporters joined late. So let me just quickly reiterate how you can ask questions. If you are enabled with a microphone or on a telephone, if you go up to that little icon at the top of your screen just a little bit to the left of center, there’s a little man with his hand up. Maybe it’s…I think it’s a man. But anyway, you can click on that icon and that will electronically raise your hand and notify us that you have a question you’d like to ask, and we call tell who you are and we’ll call on you and you can state your question.

If you are not enabled with a microphone in your computer or with a telephone, you can still send a question in by writing it into the chat box on the lower right part of your screen there, and I can read that question aloud to the panelists. And if you want to direct it to someone in particular, type that in. Otherwise, we’ll just open it up.

So we’ll let some questions start coming in.

In the meanwhile, why don’t I just get things started? I’d like to get back to Renee with one question just to get things off the ground because you mentioned a little bit briefly in passing the modeling effort. And it seems to me we’re talking about a technology here that has the potential to sort of grow and self-propagate. That’s its benefit and it’s also part of its risk.

It’s obvious these insects, if we’re talking mosquitoes, for example, are going to propagate into a very complex ecosystem. There’s a ton of variables involved. And I’d love to hear you say a little bit more about how the modeling is happening and whether you think there’s some hope for getting our arms around being able to predict what would happen if a release of a gene drive insect, for example, were to be approved. How assured would we be that it would go the way we think it will go and maybe not need some of the reparative mechanisms that you’re also researching as a just in case scenario?

[0:33:49]

RENEE WEGRZYN: Absolutely.

So each of our teams is investigating different types of models to look at all the different ways that you can build a gene drive. So in some cases, you can build a drive with what we would call self-sustaining, that once it’s released it just sort of goes in perpetuity, in theory.

Of course, that assumes that all the genetic population of that organism in the wild is identical, which we know is not the case. There’s a lot of biodiversity out there. So we can sort of bend these models with real world information that we have.

Okay, we know that this is the level of diversity that we have in mosquitoes. How penetrant will this really be if we release those organisms? So that’s important. But we could also model different types of gene drives.

There’s things called split drives where you would actually break the gene drive component that Tony described into more than one organism so that those two would have to come together in order to get drive to occur. And so looking at those models, how many copies would you have to release to achieve that is really important.

I think there’s two sides to focus on here. It’s not only being able to predict how far they may spread, but also understanding will they spread at all. So there’s that risk. There’s a lot of promise and hope behind these tools, but how good are they if we are going to implement this to discriminate populations of something like mosquitoes for vector control?

We really want them to be able to work. And we’re trying to validate those models in the laboratory, too, with high-throughput organisms. Somebody mentioned yeast earlier. I think it was Zach. So these are sexually reproducing organisms that reproduce every two hours or so. That’s much faster than the two weeks or more that it may take a mosquito. So we can very quickly test a gene drive construct in that scenario to see how robust is it and does it break down over time. And those are the types of things that we’re exploring.

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RICK WEISS: Yeah, I want to actually mention, you reminded me by mentioning the fast turnover time for generations in yeast and how convenient that is, that a lot of the strength of a gene drive has to do with generation time. And people have asked us here as we were creating our fact sheet, which I encourage people to look at on our website, about gene drives whether gene drives could be a way to drive some new trait into the human population. And we reproduce kind of slowly compared to yeast and mosquitoes, so not the best way, I think, to accomplish that.

RICK WEISS: Zach, let me turn to you for a minute. I’m wondering what you can say about the current status of the regulatory mechanisms you’ve talked about. You laid out sort of what the agencies have said. Are those agencies, do they seem active right now? Some of what you were talking about I think was in the last administration. I’m not sure if anything in the new administration has come out. Do you have a sense that people who are currently in the relevant agencies are actively looking at this? Or what’s the status?

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ZACH ADELMAN: That’s kind of a little bit speculative. I think the most recent guidance from the FDA was October 2017 so that’s pretty current. They began revising their opinion in January of 2017, and so I think that we’re seeing how they’re leaning towards that. But again, they stayed away from calling out gene drive in particular, and I think that a lot of these agencies, they may be preparing behind the scenes. But they are not going to talk publicly about something in the general context.

They’re going to wait to see who files what and then evaluate that specifically, which I think they’re kind of going to wait it out and see. And I don’t think anything is anywhere close to being at that stage here in the US. So they’re probably going to let somebody else go first.

[0:37:47]

RICK WEISS: Well, that’s an interesting question about who may go first. We’ve talked a little bit about programs in this country. Can either you or Tony, would you like to weigh in on what’s going on elsewhere in the world? I take it this is not a field of research unique to the United States.

[0:38:03]

ANTHONY JAMES: Yeah. Zach’s correct though. I mean, the stance by the US regulatory agencies is that when a specific product is available, so something has been developed in the lab, at that point, they’ll be ready to talk about it because it would be easy to be very specific about it. They’ve been very careful about avoiding generalities, and probably to the benefit of both the research and themselves, because it’s difficult to put together a whole regulatory framework based on hypotheticals.

So they really want to see a product. And what’s interesting is essentially one of the major countries that I’m working with now is in the same position. They would like to see what the specific product is first, and they may be ahead of the United States in terms of having a product available that they can evaluate, but it’s all going to be product driven at this point. And everybody’s not only looking over their shoulders but looking over the fence to see what’s going on everywhere else.

And so it’s not likely that any one of the things that Zach and I have talked about or Renee’s talked about is going to be done in secret and all of a sudden just appear. There’s a lot of visibility.

[0:39:15]

JENNIFER KUZMA: This is Jennifer. There’s some…although I agree that it’s important to have specific products, I do think there’s some balance that you can achieve here with being anticipatory in trying to prepare a governance system and collect the data in a more transparent and inclusive way. You can look at things that people are developing in the labs and have some sort of idea of what the kinds of products are going to be like and then develop case studies in order to really test out the regulatory system and see if there’s a lot of coverage.

And in some cases, there will not be much knowledge really discriminated to the wider public or even stakeholders or even wider experts. For example, if it goes through FDA, which is transgenic animals, and now they’ve got a guidance that seems to include also gene edited animals, that is under the new drug authorities. And the new drug authorities, you can be a little bit more secretive with the confidential business information, and we might not know of a regulatory package until it’s been approved in that case. So I think there are some downsides to waiting until you have a product knocking at the regulatory agencies’ doors, and I would maybe caution regulatory agencies against that.

There were case studies that they developed last year, or was it two years ago now, on the Coordinated Framework to kind of test it and see its robustness with some emerging products. They didn’t include gene drives as one of the types of products, but they really could. And it could go through these exercises, these thought exercises.

We know the basic science that’s being done for the most part right now. It’s in the peer reviewed literature, a lot of it. Some of it isn’t but much of it is. And so take some of those examples. So the regulatory system is very complex, and some of it’s going to depend on product, yes, but others, it’s going to depend on process as well.

And sometimes it’s going to depend on whether there’s a claim made by the particular developers. For example, the Oxitec mosquito, which is population suppression, not by gene drive, but by transgenic, it was initially to go under the FDA because it’s an animal, insect. But the developers now have been taking away the drug claims, and so now with this new policy, it goes under the EPA.

So there’s going to be a little bit of that fudging with the claims of your product in order to get it in the right place as well.

[0:41:46]

RICK WEISS: Interesting.

It seems to me that the approval or consideration for approval process ultimately will, obviously, have to deal with the specifics of the requests and balancing the risks versus the perceived or anticipated benefits. A benefit of actually eliminating transmission of malaria seems pretty huge.

So I wonder if any of you could speak to the question of just how realistic is it to imagine pushing a genetic trait from some modest number of mosquitoes that are transformed in a way that makes it impossible for them to transmit malaria, to have the gene drive built in so that this trait quickly spreads from generation to generation of mosquito until most mosquitoes have it? And suddenly there’s a million people a year who are not getting malaria who would have in some of the most poor and health affected countries and societies in the world. Some people might say that’s a pretty big health benefit and worth a pretty big risk.

But I wonder how practical that is and whether I’m leaving out some important elements here. Does anyone want to address that?

[0:43:01]

ANTHONY JAMES: It sounds like a setup for me but that’s…once again, I’d like to reiterate, we don’t think the gene drive alone is going to be the single factor that’s going to eradicate malaria globally. It’s a very specific application for circumstances where the complexity of malaria transmission is such that you have one or a very small number of species that are responsible for transmitting, and you have the capability to actually deliver a system like this.

Other circumstances, we’ll just have to wait for the availability of a vaccine, and that could take a long time. It’s already taken a long time. So I think it’s really important to remember that this is only part of a larger set of tools that are being applied to this goal of malaria eradication.

So today is World Malaria Day. I’m wearing a pin but you can’t see it. But I think that on the WHO, World Health Organization’s, website, they’ve listed a number of challenges, and drugs and the lack of vaccine are high up on the list as well as the continued resistance of the insects to insecticides.

So we need new tools and that’s what we’re doing. But once again, we don’t think this alone is going to be sufficient, but there would be places where this will, I think, have a very important role in sustaining the absence of malaria because you don’t have to keep coming back with drugs. You don’t have to keep coming…and by models, you don’t have to keep coming back with drugs or vaccines. The mosquitoes will maintain the resistance there.

That’s the idea. Yeah.

[0:44:47]

JENNIFER KUZMA: And this is Jennifer. I mean, I definitely think there are benefits to the technology. I think my critique is that there’s not a place in a governance system where we can inclusively weigh these risks and benefits and these different types of harms. And so the kind of thing we’re talking about, is it better than pharmaceuticals or not? Is it a complement? What’s the strategy? There’s not really good comprehensive life cycle risk assessment, benefit assessment in any place for making choices among different options.

[0:45:19]

ANTHONY JAMES: Right. And Zach may want to speak to this, but for example, our tool set for controlling dengue transmission or Zika virus transmission is woefully inadequate. And so to say well, we want to compare gene drive or genetically engineered mosquitoes with what’s already existing, well, what’s already existing doesn’t work that well. So it’s not wise to make those types of comparisons. Yeah.

[0:45:49]

ZACH ADELMAN: Yeah, I’ll just add to that and echo what Jennifer had said at the beginning, is that even if you can imagine benefits, who’s deciding what’s a benefit and who’s deciding what’s a harm? And then who’s making the decisions? Are the people that are subject to potential harms, do they have a real voice in whether technology is used or not? And so even if there are benefits, if they’re not distributed equally or if the people making the decisions don’t distribute that responsibility equally, then there are issues there. So a lot of things have to be solved and worked out in addition to the technology.

[0:46:22]

RICK WEISS: Yeah, it seems like a very different question than if you’re just distributing bed nets where people choose to use them or not. This is one of those approaches that’s going to affect people whether they’ve opted in or not if it’s deployed.

[0:46:35]

RENEE WEGRZYN: Right.

[0:46:36]

RICK WEISS: Renee, let me throw one question your way because I think you have sort of a high ground view of the field as a funder of this kind of research. We’ve been talking a lot about insects and how they can be engineered to help prevent the spread of disease, but that’s not the only application, or at least potential application, for gene drives. Can you talk a little bit about some other areas in agriculture or elsewhere where we could imagine wanting a new trait to spread quickly in a short number of generations?

[0:47:06]

RENEE WEGRZYN: Sure. So under the Safe Genes program, we’re also exploring gene drives in mammalian species. So looking at rodents, some of these rodents could be carriers of disease themselves as a reservoir for a variety of viral and bacterial diseases that may also be an invasive species that can really have devastating affects on crops, that consume crops very quickly.

They can also decimate local biodiversity, especially in island type settings where they can quickly wipe out some of the local flora and fauna as they take over as an invasive species. So those are more ambitious applications of gene drive technologies, but we really have very limited understanding of how they would work in those types of systems. Obviously, mammals have much smaller litters of offspring compared to a mosquito, which may have hundreds.

So these are the types of things that were important for us to really explore as we develop models and systems, that we wanted to really look at the whole gamut of what might be possible.

[0:48:16]

RICK WEISS: We do have a question from Reporter Ingfei Chen out west who writes for Undark Magazine and other publications. She’s asking how much will the technology cost and how quickly might it work in eliminating a disease like malaria, maybe we won’t use the word eliminating but contributing to the elimination of malaria, once a gene drive were introduced into a population? What’s the rate of spread of efficacy there?

[0:48:43]

ANTHONY JAMES: I guess I’ll take this one as the malaria representative right now. In terms of cost, once again, this is going to be comparative to what’s already being used. And so for example, if we go back to some of the costs for controlling species of Aedes mosquitoes, which Zach works on, and those measures are largely ineffectual. One can see that you’re just pouring money down the drain.

We have notable examples of very wealthy societies attempting to control dengue, for example, transmission, very sophisticated systems based on insecticides, and they’re just not working. And so one could argue that any cost of something that works is better than the cost of something that doesn’t work. Now having said that, for the types of technologies that we’re considering for our strategy, which is to make mosquitoes resistant to malaria and put them out in the field, the modeling suggests that it’s going to be far cheaper than annual applications of insecticides and annual renewal of other measures where you have to continually do that. At least for the modeling, with the types of works that we’re doing, you would have to do this once or a small number of times.

So in the long run, it should be cheaper. Now in terms of how quickly can we see an effect, the people working in these technologies have defined two types of endpoints.

One is an entomological endpoint, which is how quickly can they put their trait or whatever it is they’re working with into the insect species. But of course, the more significant one is the epidemiological impact, how quickly we’ll see an impact on morbidity and mortality as a consequence of that.

And there’s been some pretty good modeling which suggests that anywhere within two to eight years we would expect to see, in the right places, very profound impacts on, for example, malaria transmission, so with an epidemiological impact. So it should be fairly quick. I mean, two years would be quite remarkable.

But the modeling, once again, suggests that, and of course, we need lots of modeling as we go forward with this.

[0:50:48]

RICK WEISS: Interesting. Another question from a reporter, Megan Molteni, from Wired Magazine. This one is directed to Renee. Can you give us an idea of the urgency for the US to become a leader in understanding and producing gene drive countermeasures? What are other countries up to that might be driving DARPA’s funding priorities?

[0:51:08]

RENEE WEGRZYN: So from our perspective, again going back to the point about technological surprise, we’re not always in a position that we know what everybody else is doing. And so the premise behind the Safe Genes program was pretty agnostic. We didn’t require proposers to work on a specific threat. We wanted them rather to in a general way develop a toolkit so that regardless of what the threat might look like, we would be ready for it, that we could control a genome editor if there was an accidental threat or counter it through remediation or other types of countermeasures.

I don’t think that the US is insisting on being a leader in its funding of this area, but it is important for us to really understand how those tools work so that if and when we do decide to implement them that we can go forward and in both a predictable and responsible way.

[0:52:06]

RICK WEISS: Great. We don’t have other questions on the line. I want to give the speakers one last chance in the couple of minutes that we have left to make any final point or emphasis, something you think hasn’t come up or deserves restating. Why don’t we just work through in the order that we started. Tony, anything you want to add at this point?

[0:52:28]

ANTHONY JAMES: Just to let the people know that as scientists, we’re also members of the community, and we take very seriously our responsibilities for this work. We’re excited about the technologies, but we’re also concerned that the technologies be applied in a safe and ethical way and that they’re efficacious. And so we share concerns with the general public, and because of our expertise, we’re able to provide something.

But once again, we’re part of the community. We want to be known for doing well and good as opposed to making some mistakes.

[0:53:08]

RICK WEISS: Renee.

[0:53:10]

RENEE WEGRZYN: I think I can echo Tony’s comments here, that at DARPA we develop many technologies, and we want to do so in a responsible way and make sure we’re very transparent about what we’re doing. We definitely want to push our researchers to put the information that they’re generating out to the public so that others may consume it and use it as well.

And so that would be just one point I would like to add. And I hope as a model that sort of went out, the gene drive funding in a very big way here at DARPA, but I we also want there to be some normative value to what we’ve done that we’ve required there to be a bio emphasis onboard and that we really want to understand these tools and check multiple things in the laboratory before you move forward. And if we can get others on board to do those types of things, I’d be very excited and pleased that we’ve been successful to set that up.

[0:54:02]

RICK WEISS: Great. Zach.

[0:54:05]

ZACH ADELMAN: Yeah, I don’t have a whole lot to add, just a general reminder in terms of current regulatory framework and containment is something that as developers we take very seriously and our institutions take extremely seriously.

So this is something that’s still, not necessarily in flux, but it’s still evolving in terms of the best practices for how to do this. And we’re getting better every year with how much guidance and information we can provide based on how well these tools work now and how well they’re predicted to work in the future. So this is an area that I see more growth coming in in the future.

[0:54:41]

RICK WEISS: Great. And Jennifer.

[0:54:43]

JENNIFER KUZMA: Well, I guess I’ll just make one comment. I agree with Tony that this community seems very different than the last community of agricultural biotechnology, which they’re operating in that historical context. So I think there’s a lot of positive things about how this community is proceeding.

But I think we also need just to even do a better job, even try to go further with that, especially the lack of funding for risk assessment research. I know Renee’s program is doing it, but that’s really one of the only places right now. So I think the need for us to fund the risk assessment and the research along with the basic science is really important, too.

[0:55:24]

RICK WEISS: Well, it’s great that this discussion, as I said earlier, is going on so early in the process. This is still, obviously, a nascent technology. It’s still all being done in laboratories and with modeling, and I think it’s a great opportunity for the science community and the community at large to coordinate with one another and communicate with one another, which is what this is about.

So I want to thank you all for being part of this conversation and remind the reporters on the line that you will be able to see a transcript and the video of this entire one hour briefing within the next couple days on the www.sciline.org website. Thank you all very much for participating. We’ll see you at our next briefing.