 The moderator for that panel will be Dr. Laney Ross. Dr. Ross is the Carolyn Matthew Bucksbaum Professor of Clinical Ethics at the University of Chicago where Laney also holds appointments in pediatrics, medicine, surgery, and in the college. Dr. Ross has written four very influential books, including Children, Families, and Healthcare Decision Making, another book called Children in Medical Research, Access Versus Protection. More recently, she worked with Bob Beach to write the second edition of the great textbook called Transplantation Ethics and then wrote Defining Death, the Case for Choice. Laney has also written many peer-reviewed articles in a wide range of topics, including organ transplant, genetics, pediatrics, human subject research. Laney is an associate director of the McLean Center and serves on the Secretary's Advisory Committee on Human Research Protection. Today, Dr. Ross will moderate a panel of talks in clinical ethics, and that will include her own talk, which is titled an Ethics Framework for Living Donor Transplantation. Please join me in giving a warm welcome to Dr. Laney Ross. So it's great to see all of you back. It's great to be celebrating the 30th. I think I missed the first five because I was still in school. Not trying to say I'm young. I color my hair for the purpose. Anyway, my real privilege to start, we're actually, Laura Roberts is not able to be here today, so we're not going to have her give a talk. David Cheetamire is actually going to give some of her remarks later because she sent them to him, but we're going to do that last. So just for those of you who are trying to keep track of the order of the program. So I'm going to begin with Laurie Zola, who I am thrilled, has become a colleague here. We had to steal her from Northwestern. So Laurie is the Margaret Burton Professor of Religion and Ethics. She's also the senior advisor to the provost for programs on social ethics here at the University of Chicago. She's a scholarly interest in bioethics and Jewish studies. She's been the president of the American Academy of Religion, the American Society for Bioethics and Humanities. She's worked with NASA. She's actually worked on the DNA Recombinant Advisory Committee. We got to overlap for about six months. She's also been on the Executive Committee of the International Society for Stem Cell Research. Professor Zoloth also served as chair of the first bioethics advisory board at the Howard Hughes Medical Research Institute. And it's testified in front of Congress, the President's Commission on Bioethics and State Legislatures. Today, Professor Zoloth will give a talk titled, May We Remake the World? Gene Drives, Malaria and the Limits of Nature. Please join me in giving a warm welcome to Laurie. So gene drives on a talk in the session on clinical ethics. One of the things I want to convince you is why you need, as clinicians, to know about this, okay? Fair enough. Thank you, Lainey, and thank you, Mark, for the invitation. And here's my plan of talk. So first, I'm going to talk about one very curious idea, a new idea called gene drives. They're a natural occurrence and they're synthetic forms and then I'm going to move from gene drives into why we need such a thing, a crazy new genetic intervention using genome editing and to the problem of malaria, the central problem of malaria and the history of malaria as a failed policy, a failed health care policy and what we should do about it. I'm going to talk about the ethical issues in applying the theory to the practice and give a brief description of target malaria, which is a not-for-profit academic consortium I'm involved in. And I'm going to talk a little bit how hard it is to make policy in the face of sincere and serious competing ethical and theological appeals and then I'm going to say thank you, okay? Fair enough, we're ready to go? Plan of talk, okay. So this is Chrissie Hall. This is a rural academy retreat center in England, right in your Bletchley Hall, which you know from the war. Chrissie Hall is where they get people together like scientists and me to talk about things like cutting edge issues and genetics, okay? So you've all been invited to things like this. I know you, your ethicist. You're invited to come and talk about the ethics of something new and revolutionary at beautiful places like this. And I was there to talk about gene drives. Gene drives, and that's the question, are gene drives ethical? Now what's a new gene drive? Since 19, since 2003, Austin Burt, native on Ontario, a very malaria-ridden place in Canada, who teaches at Imperial College London had been thinking and putting forward this idea of using nature itself to manipulate epidemics that naturally occur. Gene drive is when the laws of Mendelian genetics are broken and there's a preferential inheritance of a particular gene that goes on from generation to generation. It occurs in nature in many sexually reproducing species. It's a gene that sometimes is not even beneficial to the organism, can be driven without affecting the fitness of the organism. So even a harmful gene can be passed on in multiple generations. And on all things being equal, these naturally occurring gene drives can increase in frequency of transmission in about 20 generations. That's true for both natural and for synthetic. So evolution usually works, just a brief rundown of Biology 101. Remember Gregor Mendel, who sort of cheated on those peas, right? You all know that, but he looked to us as if the Mendelian inheritance would hold up. On average, you know that you've got about a 50-50 chance of inheriting a gene from one of your parents, right? With Mendelian inheritance, not all offspring are gonna inherit the gene, about half will, and the frequency of the gene in future generations is stable. It's similar to the frequency of the gene of the parent generation. But gene drives are a fifth force in evolution. In addition to mutation, migration, selection, and drift, there's also transposable elements, gamete killers, maternal effect killers, homing and dilucidized genes in microbes, for instance. There's many types. And Austin Burt told us that this was a whole zoo of possibilities that operates genetically just under the normal world of Mendelian genetics. Under, like this again, the key thing is when you normally change or create a mutation in an animal species, you reduce its fitness, and it can't compete, but gene drives don't reduce fitness. And so he thought, here's an idea to use this synthetic gene drive to suppress a population, to knock in or knock out genes, to change a phenotype, more binding, less binding, to change a host feeding patterns from human to animal, for instance, to create a different phenotype that doesn't get malaria, doesn't get the plasmodium, or to change the vector component. So these are the kind of things that this entomologist geneticist was thinking about. Now, the basic criteria for the development of gene-modified organisms is all about sexual reproduction. They have to sexually reproduce. They have to do it quick in a relatively short generation time, so not people. The driving element has to remain stable across multiple generations and not drift, and the population structure at the end has to be appropriate to the desired outcome. So you want to eliminate an entire population, you better know what you're doing. So these are designed to change populations. Two ideas are being thought about now when first before Christmas, there was talons and zinc fingers. Now with CRISPR-Cas, you can create easier breaks and repairs with your endonuclease and make both of the sides of the double-stranded DNA heterogeneous into homogenous matings. With a construct, you can replace with a match sequences, plus the capacity to always cut and replace. Because what you do is you not only replace the strip of gene that you want to change, you also take the cutting apparatus along with you. That continues to stay in the genome by 20 generations, as it said. So it works like this. You can see normal sexual reproduction, and the effect of a gene drive is if an individual is equipped with one, it will push its unique trait to nearly 100% of its offspring. And then the process keeps repeating and repeating until every single organism has the engineered gene. So Birch has this idea to use what's called a driving Y chromosome. And you can see a little picture of the driving Y chromosome. And how that works is that it will take a gene, a sequence that's only on the female gene and shred it, and then no females will be born. All offspring will get the inherited gene, no females born. Now why is this important? This is tricky. This is messing with nature. But why? Well, because of malaria. Malaria is a very serious and sometimes fatal parasitic infection that occurs and still occurs in nearly 100 countries worldwide. They have high fever. People get high fevers. They get crushing bone aches. They get anemia. If the infection is severe, then it crosses the blood-brain barrier. The falcipian malaria plasmodium can relieve the coma and death. It disproportionately affects the poor and it disproportionately affects children in low and middle income countries in Sub-Saharan Africa, South Asia, and South America. And still to this day, between 500 and 400,000 deaths a year, two million infections a year, a child dying of malaria every two minutes. Now all human malaria is caused by one of only five protozoan parasites of the plasmodium genus and it's carried in the guts of the mosquito. And then of course when the mosquito bites you, it gets transmitted. Very complicated thing to figure out. Female mosquitoes only need blood meals to mature the eggs after they're being fertilized and only older females with the capacity to produce bites. So we're after older females. What can I say? Okay. There's 3,500 species who are responsible for the majority of African deaths. Only three of them are responsible for the majority of African deaths. There's lots and lots of different species of mosquitoes. They are everywhere. They're in Chicago. They are highly adaptable. And many of them are the anopheles. Most of them in America are ages of gypti that carry Zika and Dengue. But anopheles are also widespread, particularly in the Midwest. They only need one teaspoon or one bottle cap to breed. And the whole thing can dry out and be discarded in a pile. And then with the first rain, it can once again, it can then, the eggs can hatch. They meals vary by species, but human blood is preferred by anopheles almost entirely. And only one of these many mosquitoes is the most significant in Sub-Saharan Africa. And that's the mosquito anopheles gambi. It's the primary vector of plasmonium in Sub-Saharan Africa. And it carries the worst form of the illness, particularly it's infected with talsypian malaria, not vivax. And it is a very efficient carrier. It bites frequently, you know, it's just where to go, and it has the capacity to adapt with the organism very quickly, so that the cycles are fast. Now, it was hard to figure this out. Malaria co-evolved with primates. And there's, you can tell that the long traces, the long mark of trace of death in human populations, because of the duffy negative cells. If you are someone with African-American ancestry, then you're more likely than not to have duffy negative blood, red blood cells, which means you can't get vivax malaria, which will become important in testing later. But you can get falsipium. The other, the falsipium is a much worse kind of malaria. G6PD, thalassemia, and of course, sickle cell disease, likely more responses to that malaria infection. There was a long inquiry to figure out the etiology. And it's a really unlikely story that it's a mosquito and it's inside. Just when people were thinking microbes, diseases, organisms, germs, they had to rethink it and think parasites, mosquitoes, intermediate vectors, right? And took a long time to figure it out. But at the end of the 19th century, they still knew what to do. Quinine, drain swamps, screens, bed nets, avoidance of night exposure, larvae and insecticide, and finally moving away. One of the reasons that there was a great migration to Chicago, right, was because there wasn't malaria here by the 1940s. There was malaria in Louisiana. University of Chicago, by the way, small detour, was at the very center of research on malaria. Two University of Chicago scientists, Lowell Cogshow and Alf Alving, anyone know these people, right? Were enlisted and they ran the trial at the Stateville Prison for malaria, infecting prisoners with malaria to get them sick, to test drugs that they had found in, when they captured Germans they found on chloroquine and they tested it to make sure that it was safe to use. This trial, which by the way, everyone says was done with love and dignity and respect, was actually used by the defense in the Nuremberg case to say, you Americans do the same thing to your prisoners as we did to ours, right? And one of the most famous participants in the trial was Loeb of Leopold and Loeb, who was, of course, a prisoner and also a participant in this trial at Stateville Prison. And there we have our scientists. Okay, DDT was developed to deal with the catastrophe that happened in World War II. In World War II, the only drug with quinine was taken over by the Japanese in Java. There was no way to fight against these mosquitoes and by the second year of the war, 1942, MacArthur was said, I have one division in the hospital, one division recovering and only one division left to fight. And so they developed powerful new pesticides. DDT was the most important of one. They sprayed it and they were able to eliminate malaria throughout the Pacific Theater. Meanwhile, they were taking adabran, which turns you yellow, until they finally, after the Statesville had said that chloroquine could work. They began to wipe out mosquitoes and malaria rates began to drop dramatically after World War I. Malaria was not eradicated in the United States until 1951, but the campaign did not work. Why? The main reason is mosquitoes are complicated, plasmas complicated, they both develop resistance. Mosquitoes develop resistance to DDT and plasmodium develop resistance to the chloroquine. And by the way, it's very, very hard to go to every single hamlet in every single part of Africa, of Southeast Asia, of Thailand, of Borneo, all over Africa, and spray three times a year. Everyone has to take all their stuff out. The walls have to be sprayed and you can imagine how difficult this was. And so was abandon. Around the same time this happened, Rachel Carson wrote the first bestseller on ecology and alerted us to the fact that the very thing that made DDT so persuasive, it stayed on the walls for four months, but that it also stayed in the food chain a disturbing amount of time. And this was one of the reasons why people first began to think ecology, environmental, and they resisted the use of DDT. As I said, there was already resistance, but this was the other kind of resistance, political resistance. Carson polluted the DDT and had their pesticides in irrevocably harmed animals, especially birds with poor shells and contaminated the entire world's food supply. And so DDT was banned, no longer able to be used, more pelicans and many, many more mosquitoes. So we're at a stalemate. The current methods for malaria control, as I said, are late 19th century. They have two themes, drug therapy and vector control. The focus is always on vector control. And the mosquitoes have developed resistance to every single thing that human beings have tried, even to the newest drugs, developed by the way in the Cultural Revolution by the Chinese, Artemisian, and to cohort combination therapies. And then bed nets, you think. When you think about a 19th century solution, that is bed nets are very problematic. One is they have other uses that are more valuable to people in Sub-Saharan Africa. Like they're really good to fish. And if you have the choice between putting a bed net over your child and fishing to feed the other five, you might make that choice too. They also need replacement. Babies poop on the bed nets. They get dirty. People scrub out the insecticide. They're very hot. They look like shrouds in so many cultures. You don't wanna sleep under a shroud. They had to dye the green to fix that. There's only space for one child sometimes. And the World Bank decided it would be best if we sold them. And therefore they're expensive. Sometimes people don't use them to our children. So that's why people have turned to gene drives. That's exactly why. Because the 19th century solutions are not working. In the last malaria report by WHO, malaria rates which had dropped precipitously from 2000 to 2015 are now stable for the last two years. And people fear this year will be a rise. Now, how this works is to reduce the transmission by reducing, as I said, the number of females that are born. So you're not altering the females. You're just not having the females. It's the event of non-entity, right? So this is Target Malaria Project. These are three countries, Bali, Burkina Faso and Uganda, where they're working. This is the members of Target Malaria. And it's a not-for-profit, academic and community leadership. It's a university-based research program and they refuse to take profits. They're not doing patents and all the research is all transparent. And they have an independent Ethics Advisory Board, which I am on, right? And that's our role. The obvious role of an Ethics Advisory Committee is to oversee this project, making sure that the standards of community engagement and safety are thought about and there's space to think about the ethical issues involving such a powerful technology. But the opposition is now very powerful. As I said, starting with Rachel Carson, but now there's the Cartania Protocol, the Biodiversity Protocol meetings of the UN. They've become a site of opposition to gene drives. There's a general anti-science zeitgeist and everyone's seen Jurassic Park. So. Now many of the objections to gene drives are familiar. There's a weird 18th and 19th century fear that if you reduced the burden of malaria, you'd have so many African children and the colonialist ideology really didn't like that. You hear that repeated now in current debates. What do we do with all these babies that don't die, right? Monthly issue is fact is secondary to colonialism. That's why the big war on malaria happened. Will those change? Will those relationship change or not? And people are worried that people will go in and make a profit. Many different publics need to be part of the project. There's a real stress on community involvement. If the problem is it looks just like every other European idea or American idea to go in and interfere in the lives of others. And it's opposed for that reason. There's theological issues as well. Of course, I'm a scholar of religion. I see them everywhere. Nature is seen as unfinished and unproblematic versus nature as sacred and untouchable. Notice those two problems have long existed with science. It's the assault on vaccines is the same drama. Is natural law valid? People ask if we can rewrite the book of nature. On the other hand, can you turn from the blood of your neighbor? How does it feel to be an auditorium watching children die, being aware of the death of children? And finally, there's complicated religious systems in African tribal communities have to be understood and respected. Now, how did bioethicists respond? Well, they're old traditional method. We all went to a Silemar. You contain infectious agents. You do a controlled release. You do a stepwise breeding, first in the lab, then in the lab in the country, and then a small-scale field release, then a large release. This has been done before. The cassava mealy bug. Cassava plants were found by the Jesuits in Latin America, brought over to Africa, seen as a crop for women. But then someone brought over the cassava mealy bug, and the cassava mealy bug needed to have its wasp that killed it, brought in to keep the ecology right. And that's been done. That cassava mealy bug project is a very interesting project because you had to take everything from the environment, the cassava, the bug that ate it, and the bug that ate it, the bug that ate it, right? And it's worked pretty well. That was done in a similar place in Africa. The wasps from Paraguay in Brazil was used to target it, and to reduce the bugs by 95% in three to four years. And for the last 15 years, there's been no more reoccurrence. But the trouble is they may not be able to be reversed. The first theory in gene drives, a talk I would gave last year, was you could have a recall or a reverse drive if things went badly wrong. But science is pretty tricky, and it turns out you can't do that. So when you hear that people say, well, it's true, it's not true. And meanwhile, the guide RNA and the Cas9 will always remain out there in every mosquito. The first time, a relatively easy technology, which by the way, you can buy this, that parts yourself from 10K on eBay, I've been told, that is deliberately constructed to have a large effect and not be contained. It's the opposite of all of our regulations. It's supposed to spread everywhere. It's the first time that it can be done cheaply and by anyone, okay? A lot of people have come to this point and said, oh, we need ethics reviews. So look at all these people that, all of their reviews, I've read, all of them. The most important one I think is the African Union, hence it's gonna be in Africa. But the National Academy of Science had a very extensive review that I recommend you take a look at. They draw attention to the fact that historians of science and engineering saw how discoveries related to theory, observation and technology change our understanding of the natural world, notice this theological focus on the sanctity of the natural world that ought not be changed, right? The breathtaking pace is noted and not surprisingly, the depth, breadth and practical implications of scientific advances in gene drive research by simultaneously reading many challenges at the interface of science and society, to put it mildly. You can just imagine the implications if this is used not just for malaria, but for other insects, right? Now, the regulatory structure is the one we're all familiar with. It's taken for the structures of the Silomore. When ethicists see a problem, we too have our hammers and that is autonomy and that is consent and that is to find a historic, universally applicable rule, a category of imperative and in privacy. We like what we know and we can comment about what we know and therefore we've tried to use the same language we've developed as we consider the ethics of any other genetic intervention. But no one has mentioned a very important problem. One is there's no money to do anything. It's historically, WHO has had 50% of what they've asked for, 50% of what they've needed and probably this would be the case too. And why? Because no one in the field of bioethics has carefully thought about malaria and its complicated history. So it's been thought about by public health people who use the ontology of agilitarianism but it's a complicated long history. For instance, is consent possible in Burkini Faso? In the ecology devastated by poverty? What use is our ideas about consent? Okay, further research is gonna look at these five problems. Do we have the right or even the obligation to intervene into the lives of other people, especially if it might harm them? If we start, intervene, stop malaria, then people with acquired immunity will lose that immunity and we'll get sick again. That's happened before, it can happen again. If the point of gene drives is to spread, why should we or the communities make the final decision? Who makes the final decision since it may not be located in Burkini Faso but of course every mosquito will meet the next mosquito, right, they'll go across porters. The world is unknowable. What about uncertainty? What about the fact that we don't really know what we're doing with this genetic technology? Malaria is now concentrating places racked by chaos. What's our duty in light of the fact that much of this chaos is a direct result of either colonialism in the struggle for Africa or our subsequent lack of funding and what virtues have to guide our acts. I'm gonna suggest fidelity might be a core virtue. Is that possible? Maybe make the world, apparently we have, we will and yes, we should make the world. And why is this important as a, why am I in the clinical section? There's one reason, because of global warming. Here's the map of climate change. Here's the estimate of world malaria burden and the estimate of world poverty, right? These boundaries are unstable because of climate change. Mosquitoes like it wet, they like it hot and the range will expand. So mosquitoes range is growing including the Gambi, regulatory authorities and oversight at the borders have been cut back. They only check the holes of ships twice a year now. Global warming drives migration and refugees which carry the plasmodium, warmer weather speeds, transmission and replication and malaria is a disease of poverty and of chaos and our world has plenty. So I wanna say thank you to all the people who've helped me learn this much about homing endonuclease. And then I wanna say during this talk of 20 minutes, 10 people, usually children have died and here's the faces of some of them. Thank you. Okay, one question. Take one question, one comment. One horrified scream. I guess you spoke fast enough to leave us speechless. All right, thank you very much, Lori.