News Article | May 5, 2017
There’s no shortage of stories about clashes between science and politics throughout history, and there are plenty still being written today. Scientific evidence has been distorted and manipulated in the name of ideology since Galileo suggested the earth revolved around the sun. But perhaps few battles may be as dramatic as the one that unfolded in the Soviet Union in the early 20th century, under the rise of the Bolshevik regime. In the 1920s, Joseph Stalin tried to turn science into an arm of the Russian state, putting researchers under strict political control to ensure their obedience. He sought the kind of research that validated political doctrine, not the kind that relied on the scientific method. At one point, Stalin supported a scientist who denied the existence of genes but had promised that his germination theory would yield many crops and pull the Russian people out of famine. Recommended: Why Americans Smile So Much Turns out, though, that’s not how science works, and for years, scientists would pay the price. They were praised, promoted, and well-funded if the Bolsheviks saw use for their specialties, and fired, interrogated, or jailed if they didn’t. They became swept up in deadly purges. The stories of some of these scientists, mostly young men, are told in Stalin and the Scientists: A History of Triumph and Tragedy, 1905-1953, by Simon Ings. Ings follows Soviet science from the early days of the revolution until Stalin’s death, an era of political terror that somehow managed to produce formidable technological achievements, like the Russian space program. “You were safe only as long as you could demonstrate your powerlessness,” Ings writes. “And if Stalin raised you, it was inevitable that, sooner or later, he would cut you down.” I spoke with Ings about this period in Soviet history. Our conversation has been edited for length and clarity. Marina Koren: So your book is called a “history of triumph and tragedy,” but there seemed to be a lot more tragedy than triumph for the scientists you describe. If the state didn’t kill you, famine would, and if you were lucky enough to be doing work, your lab was poorly supplied or your home could be overrun with refugees. How did anyone get anything done? Simon Ings: Before the [October Revolution in 1917], what you had were a remarkable generation of scientists and a handful of well-educated capitalists who wanted to produce a new kind of education for a new kind of Russian state. So even before the revolution was happening, there were institutions being set up along the lines of the Pasteur Institute in Paris and the Kaiser Wilhelm Institute in Germany. The reason the Bolsheviks reacted so strongly against that generation, against liberal academics, is that these were not simply people who had a sort of general opposition to the communist project. These were themselves revolutionaries, who had conducted a failed revolution in 1905, who were capable of running a state. They were serious competition for the control of the state, and so one of the reasons people were able to get things done is they were surprisingly well-organized even before the revolution [in 1917]. Recommended: How The Gospel of Prosperity Explains the American Health Care Act Looking a little bit later, you had the Bolshevik desire for education. It’s rather like the saying, ‘he did terrible things, but he made the trains run on time.’ The Bolsheviks did terrible things, but they really believed in public education. There were something like 80 institutions running in the immediate, post-October Revolution period, most of which was set up under the Bolshevik regime. They didn’t have money to give you, but they had buildings and they had a bit of furniture. And for a generation that couldn’t actually get much done under the Tsarist regime, to have the support of the government was an extraordinarily exciting time. The final reason people were able to get things done is they were thrown into prison. And they were thrown into the kinds of prison that enabled the state to rely upon your good works, because you had no political voice. This is the system known as sharashka, or sharashki, plural. The idea actually came from academics themselves. A party of engineers did not want to be sent to Siberia and had written to [senior official in the Soviet secret police] Lavrentiy Beria, saying, look, if you don’t send us to Siberia, give us a problem and we’ll solve it for you. Just let us stay in the warmth and give us some pencils and we’ll work for you. Beria took them up on this. Koren: So some of the Soviet science and innovation came straight from prisons? Ings: They wouldn’t have won [World War II] without it. There were a lot of engineering marvels created through the sharashka system, and perhaps the biggest marvel of all was the world’s most reliable space program. Recommended: Seven Reasons the Left Is Losing Koren: How did Stalin’s system create a foundation for that space program, and allowed the Russians to launch Sputnik into space in 1957, four years after he died? Ings: It was Stalin’s regimentation of the state that made Sputnik possible, which is a very unfair thing to say, because what really made Sputnik possible was the talents of the people who actually did the work. Stalin’s regimentation created the sharashka system, which gave people the space to do work. Nowhere else would’ve given people the space to work like that. Tasked with [building] the atomic bomb, tasked with producing a space program, only the sharashki could deal with such a project. In the American experience, it’s not wildly different. At the same period, you start having Lockheed create and hide groups of researchers [to develop fighter jets during World War II]. The idea of a small team working within an organization—that is a very good way of solving technical problems. It’s a very good academic idea, but it came out of imprisonment. Ings: Well, it speaks to, how do you want to get science done? What you need to do is give people a lot of money and leave them alone. And that’s a very difficult sell if you’re dealing with public money. How do you justify handing money over without very obvious returns? When you look at the hoops that today’s researchers have to jump through, in terms of impact of their research, and what this research is likely to achieve, and what the applications of this research are—it astounds you that anything ever gets discovered at all. You arrive at a solution of, throw a bunch of people in prison and leave them alone, you know? But to have got there after the deaths of how many millions of people, it makes one pause for thought. It really does. Koren: What were sharashki like? Ings: One that plays the biggest part in my book is the one geneticist Ressovsky Timofeev ended up in. He found himself in a gulag, nearly died, was rescued, and put in a sharashka. He ended up on this island in this rather beautiful part of the country, on a very beautiful lake with the Ural Mountains in the background and flowers awaiting him on his doorstep—and far in the distance, men with dogs and some barbed wire. He was working for an economist who knew nothing about science, but Timofeev’s research was supported to the point where he was producing data that is still used by the United Nations today to measure the radiobiological load of radioactive releases in the soil. If you’re working at how serious a nuclear accident is, you’re using figures that Ressovsky Timofeev was coming up with in the sharashka. Koren: Stalin sought to, as you write, “make science over in the service of the state.” What was his vision for Soviet science? Ings: The entire Bolshevik project is premised on the idea that you can make government scientific. There is that wonderful moment in the 1870s, when everything seemed as if it was about to be explainable in terms of everything else. Marxism is supposed to be that science, the science that will actually put all the other sciences in the science of the state. But the clever, scientific community is realizing it doesn’t work, that scientism doesn’t work. There’s an immediate crisis. Stalin’s response is to conceal it, to talk over it, to look for practical solutions. Koren: How did the scientists and engineers fit into that? Ings: He tried to get the young educated as fast as possible in batches, in brigades. On the other hand, he tried to wipe out generations that were operating under the old patronage system [that funded scientific research.] Stalin’s attempt was to do away with the patronage system by becoming the only patron. By making the state the only possible patron, you have this absurd situation in which even as engineers are being paid more than they’ve ever been paid before, you’re also getting show trials in which engineers are shown the door or exiled or shot. Koren: It did seem like someone could be running a medical institution one day and sentenced to hard labor the next. What happened to scientists when the state liked them, and when it didn’t? Ings: Each specialism lost people during the Great Purge [ordered by Stalin to scare and eliminate opposition between 1936 and 1938]. When that happens, people want an explanation for what happened. They think, if genetics got it in the neck, it must have been because of the genetics. But most of the purges were to do with bureaucracy, not with learning. We tend to look at the research and think, how did the research rub people up the wrong way? Where we should be looking is, what patrons they had, what clients they had, what institutions did they run, whose ear did they have. The astronomers at Pulkovo were important because of whose ear they had, because of where they were getting their funding. It wasn’t because they were spotting things in the stars that were rubbing the Stalinist regime up the wrong way. Koren: Many scientists seemed to move in and out of exile, and it didn’t always seem like a bad career move. Ings: The classic example of that is Alexander Luria, who led what on the surface looks to be a normal life. He never betrayed anyone, he had foreign visits, he had good correspondence with colleagues all over the world. But he did this by ducking and diving, and he moved from institution to institution. He was never exiled, but he simply jumped before he was pushed. It was possible to land on your feet, to make exile work you. To be pushed out of the center, from Moscow to Odessa, could actually play to your hand. It could be out of your advantage to be out of the limelight. Koren: There was a lot of deception and back-stabbing among scientists themselves. I’m thinking of Trofim Lysenko’s decision in 1939 to send his rival Nikolai Vavilov on a expedition to the Caucasus so he could replace Vavilov’s department’s staff. Can you tell me more about those dynamics? Ings: You have these big organizations that are stuffed full of people who were alive before the Revolution, who hold more to a liberal democracy scheme than to a socialist scheme, and so you have these internecine rivalries between generations. It’s made worse by the fact that at the time in Russia, you didn’t have a retirement age, and that’s a really big problem. People were staying in posts until they dropped dead, and these guys lived quite a long time. So unless you stabbed people in the back, there was no way move forward in your career. Koren: You write that “Soviet science was extraordinary, and ought to have delivered many more miracles than it did.” What were some missed opportunities? Ings: Genetics. Only America was ahead of the Soviet Union. Germany was recruiting Russian geneticists in order to catch up. The ability to square evolution and natural selection was a Soviet development, if you trace it back. The problems the Americans were agonizing over simply weren’t known to the Russians, so the Russians got a bit of paper and worked it out. They weren’t aware that this was supposed to be difficult. All the pieces were in place for the Soviet Union to become streets ahead of everyone in genetics, even the Americans—and that’s saying a lot, because the Americans were amazing. Ings: The people running the vernalization project, [a failed attempt to boost crops by regulating the temperature of seeds], like Lysenko, could simply turn around and say, you’re sitting in the lab with fruit flies and we’re generating this many more crops. What are you doing for the state? Have you not noticed there’s a famine going on? Genetics was doomed because it could not lie to the extent that Lysenko could lie. Lysenko just had to point at these mistaken figures and say, look, vernalization works. Genetics seemed to have no practical consequences. Koren: So Lysenko basically used his powerful position to push genetics out of favor. Ings: And it was because he couldn’t do math. His philosopher sidekick, Isaak Prezent, couldn’t do math either. He made it a point of principle that math should not be part of biology. The moment you mix up political discourse and scientific discourse, you’re at a very, very dangerous point. It makes these conversations incredibly hard. It makes fact impossible. It makes truth impossible. Koren: You write at the end of the book that “we are all little Stalinists now, convinced of the efficacy of science to bail us out of any and every crisis.” What do you mean? Ings: Let’s take an example reasonably local to you, what’s happening with the EPA. The EPA has over the years, on the basis of international work, come up with this set of data which are troubling to oil-based industries. Global warming is another example. We look for scientific solutions that aren’t going to upset the apple cart, and the thing about scientific solutions is that they do always upset the apple cart. Time and again we look for scientific solutions that aren’t scientific at all. We look for quick fixes, and we expect science to come up with quick fixes. Politics deals with the human world, and most people are reasonable. Science doesn’t. Science deals with the world out there, which is profoundly unreasonable. There’s not another earth to go to, and we’re not going to be able to bail ourselves out through a technological fix. And we’ll blame the scientists for this. We’ll blame the scientists for this every time. Read more from The Atlantic: The GOP Health-Care Bill Is an Act of Cruelty How the Trump Administration Could Worsen Corruption in the Border Patrol This article was originally published on The Atlantic.
News Article | November 10, 2016
A previously unknown feature of the malaria parasite development has just been published in the journal Cell Host&Microbe. An international research team, led by a parasitologist at University of São Paulo and Pasteur Institute, Paris, has shown that, contrary to what has been assumed so far, a Plasmodium surface-protein plays an essential role at a stage of its life cycle that occurs not in the body of the host, but in the guts of the Anopheles mosquito. The finding has consequences for the search for vaccines or drugs that could alleviate the suffering caused by malaria. By 2015, 214 million people were affected by the parasite, especially in Africa. Throughout its life cycle, the malaria parasite assumes different forms, at different points in the host and vector bodies. The infected female of the mosquito, when it bites a human, inoculates the parasite present in its saliva in the form called sporozoite. Through the bloodstream, sporozoites reach the liver of the host, where they invade a class of cells called hepatocytes. Inside them, they become merozoites, the form of the parasite that invades the red blood cells. It is when the red blood cells break because they are full of parasites that the typical fever attacks of the disease occur. Typically, the stages of the life cycle that happen inside de host are assexual. Part of the merozoites, however, remains inside the erythrocytes and differs in gametocytes, male and female. The next stages of the life of the parasite now occur in the body of the mosquito which, by sucking the blood of the host, brings into its body the blood cells laden with parasites, now sexually differentiated. It is in this comeback to the mosquito organism that lies the discovery published in Cell Host and Microbe. To continue their development, the gametocytes need to leave the vacuole in which they are harboured inside the red cell. In cells modified to not express the surface protein (called MTRAP), the team has verified, gametocytes cannot leave the vacuole. As a result, the life cycle of the plasmodium is interrupted and the mosquito can no longer transmit it. Until now, parasitologists have attributed to this protein the ability of merozoites to invade red blood cells still within the host's body. The experiments also showed that for this step, the MTRAP protein is innocuous. "The experiments allow a new approach to influence the life cycle of plasmodium," says parasitologist Daniel Bargieri of the Institute of Biomedical Sciences at USP. "We now have yet another target to be studied to block transmission of the parasite, which increases the potential for achieving the ambitious goal of eradicating malaria." Plasmodium Merozoite TRAP Family Protein Is Essential for Vacuole Membrane Disruption and Gamete Egress from Erythrocytes Bargieri et al., 2016, Cell Host & Microbe 20, 618-630 November 9, 2016 ª 2016 The Authors. Corresponding Author: email@example.com
News Article | February 23, 2017
The discovery, published on February 23, 2017 in the journal Cell, reveals new details about the evolution of sex. The protein acts as a nearly universal, biochemical "key" that enables two cell membranes to become one, resulting in the combination of genetic material—a necessary step for sexual reproduction. New details about the protein's function could help fight parasitic diseases, such as malaria, and boost efforts to control insect pests. "Our findings show that nature has a limited number of ways it can cause cells to fuse together into a single cell," said William Snell, a senior author of the study and a research professor in the University of Maryland Department of Cell Biology and Molecular Genetics. Snell joined UMD in June 2016, but performed the majority of the work at his previous institution, the University of Texas Southwestern Medical Center. "A protein that first made sex possible—and is still used for sexual reproduction in many of Earth's organisms—is identical to the protein used by dengue and Zika viruses to enter human cells," Snell said. "This protein must have really put the spice in the primordial soup." Snell and his colleagues studied the protein, called HAP2, in the single-celled green alga Chlamydomonas reinhardtii. HAP2 is common among single-celled protozoans, plants and arthropods—although it is not found in fungi or vertebrates such as humans. Prior results from Snell and his collaborators, as well as other research groups, indicated that HAP2 is necessary for sex cell fusion in the organisms that possess the protein. But the precise mechanism remained unclear. For the current study, Snell and his colleagues at UT Southwestern used sophisticated computer analysis tools to compare the amino acid sequence of Chlamydomonas HAP2 with that of known viral fusion proteins. The results suggested a striking degree of similarity, especially in a region called the "fusion loop" that enables the viral proteins to successfully invade a cell. If HAP2 functioned like a viral fusion protein, Snell reasoned, then disrupting HAP2's fusion loop should block its ability to fuse sex cells. Sure enough, when Snell's team changed just a single amino acid in the fusion loop of Chlamydomonas HAP2, the protein entirely lost its function. The sex cells were able to stick together—a process that depends on other proteins—but they were not able to complete the final fusion of their cell membranes. Similarly, the cells could not fuse when the researchers introduced an antibody that covered up the HAP2 fusion loop. "We were thrilled with these results, because they supported our new model of HAP2 function," Snell said. "But we needed to visualize the three-dimensional structure of the HAP2 protein to be sure it was similar to viral fusion proteins." Snell reached out to Felix Rey, a structural biologist at the Pasteur Institute in Paris who specializes in viruses. Coincidentally, Rey and his colleagues had just determined the structure of Chlamydomonas HAP2 using X-ray crystallography. Rey's results demonstrated that, indeed, HAP2 was functionally identical to dengue and Zika viral fusion proteins. "The HAP2 protein from Chlamydomonas is folded in an identical fashion to the viral proteins," Rey said, referring to the molecular folding that creates the three-dimensional structure of all proteins from a simple chain of amino acids. "The resemblance is unmistakable." HAP2 appears to be necessary for cell fusion in a wide variety of organisms, including disease-causing protozoans, invasive plants and destructive insect pests. So far, every known version of HAP2 shares the one critical amino acid in the fusion loop region. As such, HAP2 could provide a promising target for vaccines, therapies and other control methods. Snell is particularly encouraged by the possibility of controlling malaria, which is caused by the single-celled protozoan Plasmodium falciparum. "Developing a vaccine that blocks the fusion of Plasmodium sex cells would be a huge step forward," Snell said, noting that Plasmodium has a complex life cycle that depends on both mosquito and human hosts. "Our findings strongly suggest new strategies to target Plasmodium HAP2 that could disrupt the mosquito-borne stage of the Plasmodium life cycle." Explore further: Sperm-egg fusion proteins have same structure as those used by Zika and other viruses More information: The research paper, "The ancient gamete fusogen HAP2 is a eukaryotic class II fusion protein," Juliette Fedry, Yanjie Liu, Gerard Péhau-Arnaudet, Jimin Pei, Wenhao Li, M. Alejandra Tortorici, Francois Traincard, Annalisa Meola, Gerard Bricogne, Nick Grishin, William J. Snell, Félix A. Rey and Thomas Krey, was published February 23, 2017 in the journal Cell.
News Article | February 23, 2017
Researchers determine that a protein required for sperm-egg fusion is identical to a protein viruses use to invade host cells; discovery could help fight parasitic diseases like malaria Sexual reproduction and viral infections actually have a lot in common. According to new research, both processes rely on a single protein that enables the seamless fusion of two cells, such as a sperm cell and egg cell, or the fusion of a virus with a cell membrane. The protein is widespread among viruses, single-celled protozoans, and many plants and arthropods, suggesting that the protein evolved very early in the history of life on Earth. The discovery, published on February 23, 2017 in the journal Cell, reveals new details about the evolution of sex. The protein acts as a nearly universal, biochemical "key" that enables two cell membranes to become one, resulting in the combination of genetic material--a necessary step for sexual reproduction. New details about the protein's function could help fight parasitic diseases, such as malaria, and boost efforts to control insect pests. "Our findings show that nature has a limited number of ways it can cause cells to fuse together into a single cell," said William Snell, a senior author of the study and a research professor in the University of Maryland Department of Cell Biology and Molecular Genetics. Snell joined UMD in June 2016, but performed the majority of the work at his previous institution, the University of Texas Southwestern Medical Center. "A protein that first made sex possible -- and is still used for sexual reproduction in many of Earth's organisms -- is identical to the protein used by dengue and Zika viruses to enter human cells," Snell said. "This protein must have really put the spice in the primordial soup." Snell and his colleagues studied the protein, called HAP2, in the single-celled green alga Chlamydomonas reinhardtii. HAP2 is common among single-celled protozoans, plants and arthropods -- although it is not found in fungi or vertebrates such as humans. Prior results from Snell and his collaborators, as well as other research groups, indicated that HAP2 is necessary for sex cell fusion in the organisms that possess the protein. But the precise mechanism remained unclear. For the current study, Snell and his colleagues at UT Southwestern used sophisticated computer analysis tools to compare the amino acid sequence of Chlamydomonas HAP2 with that of known viral fusion proteins. The results suggested a striking degree of similarity, especially in a region called the "fusion loop" that enables the viral proteins to successfully invade a cell. If HAP2 functioned like a viral fusion protein, Snell reasoned, then disrupting HAP2's fusion loop should block its ability to fuse sex cells. Sure enough, when Snell's team changed just a single amino acid in the fusion loop of Chlamydomonas HAP2, the protein entirely lost its function. The sex cells were able to stick together -- a process that depends on other proteins--but they were not able to complete the final fusion of their cell membranes. Similarly, the cells could not fuse when the researchers introduced an antibody that covered up the HAP2 fusion loop. "We were thrilled with these results, because they supported our new model of HAP2 function," Snell said. "But we needed to visualize the three-dimensional structure of the HAP2 protein to be sure it was similar to viral fusion proteins." Snell reached out to Felix Rey, a structural biologist at the Pasteur Institute in Paris who specializes in viruses. Coincidentally, Rey and his colleagues had just determined the structure of Chlamydomonas HAP2 using X-ray crystallography. Rey's results demonstrated that, indeed, HAP2 was functionally identical to dengue and Zika viral fusion proteins. "The HAP2 protein from Chlamydomonas is folded in an identical fashion to the viral proteins," Rey said, referring to the molecular folding that creates the three-dimensional structure of all proteins from a simple chain of amino acids. "The resemblance is unmistakable." HAP2 appears to be necessary for cell fusion in a wide variety of organisms, including disease-causing protozoans, invasive plants and destructive insect pests. So far, every known version of HAP2 shares the one critical amino acid in the fusion loop region. As such, HAP2 could provide a promising target for vaccines, therapies and other control methods. Snell is particularly encouraged by the possibility of controlling malaria, which is caused by the single-celled protozoan Plasmodium falciparum. "Developing a vaccine that blocks the fusion of Plasmodium sex cells would be a huge step forward," Snell said, noting that Plasmodium has a complex life cycle that depends on both mosquito and human hosts. "Our findings strongly suggest new strategies to target Plasmodium HAP2 that could disrupt the mosquito-borne stage of the Plasmodium life cycle." In addition to Snell and Rey, co-authors of the study include: Juliette Fedry, Gerard Péhau-Arnaudet, M. Alejandra Tortorici, Francois Traincard and Annalisa Meola (Pasteur Institute); Yanjie Liu, Jimin Pei, Wenhao Li and Nick Grishin (UT Southwestern); Gerard Bricogne (Global Phasing, Ltd.); and Thomas Krey (Pasteur Institute, Hannover Medical School and German Center for Infection Research). The research paper, "The ancient gamete fusogen HAP2 is a eukaryotic class II fusion protein," Juliette Fedry, Yanjie Liu, Gerard Péhau-Arnaudet, Jimin Pei, Wenhao Li, M. Alejandra Tortorici, Francois Traincard, Annalisa Meola, Gerard Bricogne, Nick Grishin, William J. Snell, Félix A. Rey and Thomas Krey, was published February 23, 2017 in the journal Cell. This work was supported by the United States National Institutes of Health (Award Nos. GM56778 and GM094575), the Welch Foundation (Award No. I-1505), the European Research Council, the Pasteur Institute and the French National Center for Scientific Research. The content of this article does not necessarily reflect the views of these organizations. University of Maryland College of Computer, Mathematical, and Natural Sciences 2300 Symons Hall College Park, MD 20742 http://www. @UMDscience About the College of Computer, Mathematical, and Natural Sciences The College of Computer, Mathematical, and Natural Sciences at the University of Maryland educates more than 7,000 future scientific leaders in its undergraduate and graduate programs each year. The college's 10 departments and more than a dozen interdisciplinary research centers foster scientific discovery with annual sponsored research funding exceeding $150 million.
News Article | October 26, 2016
MONTREAL, Oct. 20, 2016 - A Canada-US study led by Luis Barreiro, a professor at the University of Montreal's Department of Pediatrics and researcher at the Sainte-Justine University Hospital Center, has demonstrated that Americans of African descent have a stronger immune response to infection compared to Americans of European descent. The study establishes for the first time this difference in immune responses and shows that it is mostly genetic -- inherited from our ancestors and influenced by a relatively recent natural selection. The study is published today in the scientific journal Cell. The study was conducted among 175 Americans, half of which were of African descent, the other half being of European descent, in collaboration with the University of California, Wayne State University, Cornell University, the University of Minnesota, and Duke University. While the immune system of African Americans responds more strongly, Professor Barreiro is careful to qualify it as better: "The immune system of African Americans responds differently, but we cannot conclude that it is better, since a stronger immune response also has negative effects, including greater susceptibility to autoimmune inflammatory diseases such as Crohn's disease. Too much inflammation can damage organs and leave sequelae. In short, a strong immune response can be beneficial in some areas but a disadvantage in others. The immune system reacts to infection by causing inflammation (redness, heat, swelling, etc.) to neutralize and eliminate the infection. It was already known to scientists that African Americans are more susceptible to autoimmune inflammatory diseases and thus more likely to suffer from tuberculosis or scleroderma, for example. The 175 participants in Professor Barreiro's study provided blood samples, from which were extracted macrophages ¬-- cells of the immune system whose role is to kill pathogens responsible for infection. The research team then infected the macrophages with two kinds of bacteria (Listeria and Salmonella) to observe various immune responses: after 24 hours of infection, the macrophages from African Americans killed the bacteria three times faster. The research team also uncovered the molecular mechanisms acting on the genes responsible for these differences in immune responses. "This is one of the firsts of our study," said Barreiro. People of African and European descent have intermingled over the past centuries, and we are even able to determine which part of an individual's immune system is associated with African ancestry and which part with European ancestry." "Although we found these differences in immune responses between African and European Americans, we are still unable to demonstrate what evolutionary pressures led to the observed differences. One of our hypotheses is that in the prehistoric period, after human populations had migrated out of Africa, they were exposed to fewer pathogens (bacteria, viruses, parasites), which reduced the immune response and thus tissue inflammation. This reduction in the immune response (and inflammation) was most likely an advantage because of the adverse consequences of acute or chronic inflammation, which are major contributors to the development of autoimmune inflammatory diseases." Another hypothesis is that the weaker immune response detected in Europeans is the result of a less vigorous natural selection in an environment in which there were fewer, or at least different, pathogens compared to Africa. Neanderthals also played a role in the immune response to infection. Neanderthals, before disappearing, colonized Europe, but not Africa. In the process, they mixed their genes with African Cro-Magnons, who were spread throughout Europe. The analysis of Barreiro's team shows that about 3% of the genes involved in the differences in immune responses between African and European Americans come from Neanderthals! "There is still much to do. For example, we have not yet studied the immune response to viruses and parasites. In addition, genetics explains only about 30% of the observed differences in immune responses. Our future studies should focus on other factors, emphasizing the influence of the environment and our behaviour. The idea is to find immune mechanisms to help understand why some individuals react differently from others in the presence of certain viruses and bacteria," said Barreiro. Luis Barreiro specializes in the evolution of immune responses and was named one of the "40 under 40" (most promising researchers) published in 2014 by the prestigious journal Cell. The first time he set foot in a laboratory after completing his graduate studies in biotechnology at the University of Lisbon in his native Portugal, he found his vocation. After graduating, he obtained a six-month internship in mycobacterial genetics at the Pasteur Institute in Paris. Within five years he had completed a doctorate in human population genetics. After receiving his Ph.D., Barreiro moved to the United States, where he did a postdoctoral fellowship in functional genomics at the University of Chicago's Department of Human Genetics. Today, the same theme runs through Luis Barreiro's work at the University of Montreal and the Sainte-Justine University Hospital Research Center, which he joined in 2011. He is the holder of the Canadian Research Chair in Functional and Evolutionary Genomics of the Immune System. The main project of his laboratory is to discover and define the genetic bases of the variations underlying the differences in immune responses between individuals and human populations. While Barreiro's team is among the two or three groups in the world interested in immune responses and their genetic basis, it is the only one to explore this issue among different species of primates. http://www. Y. Nedelec, J. Sanz, G. Baharian, Z. A. Szpiech, A. Pacis, A. Dumaine, J.-C. Grenier, A. Freiman, A. J. Sams, S. Hebert, A. Pagé Sabourin, F. Luca, R. Blekhman, R. D. Hernandez, R. Pique-Regi, J. Tung, V. Yotova et L. B. Barreiro published the article "Genetic ancestry and natural selection drive population differences in immune responses to pathogens in human" in the journal Cell on October 2016. This study was funded by the Canadian Institutes of Health Research (Grants 301538 and 232519), the Human Frontiers Science Program (CDA-00025/2012), and the Canada Research Chairs Program (950-228993). Y.N. received a grant from the Network of Applied Genetic Medicine Network (RMGA); A.P.S. received a grant from the Fonds de recherche du Québec-Nature et technologies (FRQNT); and G.B. received a grant from the Fonds de recherche du Québec-Santé (FRQS).
News Article | April 27, 2016
Emmanuelle Charpentier's office is bare, save for her computer. Her pictures, still encased in bubble wrap, are stacked in one corner, and unpacked cardboard boxes stuffed with books and papers are lined up in the adjacent room. But across the corridor, her laboratory is buzzing with activity. When Charpentier moved to Berlin six months ago, she had her science up and running within weeks, but decided that the rest could wait. “We were all determined to get the research going as fast as possible,” she says, leaning forward from her still-pristine office chair. Charpentier's workspace is a fitting reflection of her scientific life — one in which she always seems to be moving while keeping science on the go. Now 48, she has climbed her way up the academic ladder by way of 9 different institutes in 5 different countries over the past 20 years. “I always had to build up new labs from scratch, on my own,” she says. Her eureka moments have occurred amid packing boxes and, after years on short-term grants, she was 45 before she was able to employ her own technician. “She's so resourceful, she could start a lab on a desert island,” says Patrice Courvalin, her PhD supervisor at the Pasteur Institute in Paris. The itinerant lifestyle doesn't seem to have hampered the microbiologist as she has carefully dissected the systems by which bacteria control their genomes. Charpentier is now acknowledged as one of the key inventors of the gene-editing technology known as CRISPR–Cas9, which is revolutionizing biomedical researchers' ability to manipulate and understand genes. This year, she has already won ten prestigious science prizes, and has officially taken up a cherished appointment as a director of the Max Planck Institute for Infection Biology in Berlin. The gene-therapy company that she co-founded in 2013, CRISPR Therapeutics, has become one of the world's most richly financed preclinical biotech companies, and she is in the middle of a high-profile patent dispute over the technology. Last September, Charpentier's phone kept on ringing. Journalists from around the world were trying to reach her, thinking — prematurely, as it turned out — that the imminent announcement of the 2015 Nobel prizes might well include her. The academic limelight is not a comfortable place for Charpentier, which is why she remains the least well known member of the small international group tipped for the 'CRISPR Nobel', if it arrives. “Jean-Paul Sartre, the French philosopher, warned that winning prizes turned you into an institution — I am just trying to keep working and keep my feet on the ground,” she says. She seems to be succeeding, this week publishing a paper1 in Nature that reveals the mechanism of a CRISPR system that might prove even more efficient than CRISPR–Cas9. Colleagues who know Charpentier well describe her as intense, modest and driven. “She's a tiny person, with a very strong will — and she can be pretty stubborn,” says Rodger Novak, who was a postdoctoral researcher with her in the 1990s and is now chief executive of CRISPR Therapeutics. As Courvalin sees it, “She is like a dog with a bone — tenacious.” Small and slight, with eyes so dark that they seem black, Charpentier looks as restless as she evidently is. Growing up in a small town near Paris, she had a clear idea from the start of what she wanted in life: to do something to advance medicine. A visit to an aunt, a missionary who was living in an old convent, set her dreaming of being able to do this “in a lovely setting, where you can be a bit alone with yourself”. Her socially engaged parents, she says, supported her ideas without guiding her in any direction. She pursued piano and ballet — but her leaning towards medicine eventually flowered into studies in life sciences. As an undergraduate at Pierre and Marie Curie University in Paris, she decided to do her PhD at the nearby Pasteur Institute, which was gaining a strong reputation in basic research and had a programme on antibiotic resistance that she wanted to join. Her PhD project involved analysing pieces of bacterial DNA that move around the genome and between cells, allowing drug resistance to be transferred. Her years at the Pasteur Institute were formative. Her department in the historic institution was “young and fun”, she says. She loved to study at the old St Geneviève library close to Notre-Dame Cathedral, happily isolated in the triangle of light from the green-topped desk lamps. “I realized I had found my environment,” she says. Her ambition was to lead a lab at the Pasteur, and she decided that this would require a postdoc period abroad to gain expertise. “I was a typical French student of the 1990s — I imagined that after a short excursion I would work the rest of my life at home.” Charpentier sent out 50 or so exploratory letters to labs in the United States, and got a postbag full of offers in reply. She chose a position with microbiologist Elaine Tuomanen at the Rockefeller University in New York City to work on the pathogen Streptococcus pneumoniae. This microbe, which is a major cause of pneumonia, meningitis and septicaemia, has a particularly free-wheeling relationship with mobile genetic elements, shifting them about its genome while maintaining its vicious pathogenicity. Tuomanen's lab had priority access to its recently sequenced genome, offering the tantalizing prospect of discovering where these elements were landing and what happened when they did. Charpentier carried out a stream of painstaking experiments to work out how the pathogen monitors and controls such elements, and contributed to a study identifying how the pathogen acquires resistance to vancomycin, an antibiotic of last resort2. She had set out for New York with some trepidation but, absorbed in her work, was surprised to find that she wasn't homesick. When Tuomanen moved her lab to Memphis, Tennessee, Charpentier wanted to stay, so she found a home in the lab of skin-cell biologist Pamela Cowin at New York University School of Medicine, where she also had the opportunity to learn about mammalian genes through working on mice. Cowin remembers Charpentier as her first postdoc who did not need looking after. “She just ran with the programme,” she says. “She was driven, meticulous, precise and detail-oriented” — as well as a rather quiet, private person. Charpentier soon discovered that genetically modifying mice was a lot harder than manipulating bacteria. She spent two years on the project and emerged with a paper on the regulation of hair growth, a solid grounding in mammalian genetics and a strong desire to develop better tools for genetic engineering. After another postdoc in New York, Charpentier knew that her next step needed to be complete independence — and a move back to Europe. Her time in the United States had taught her that she was European rather than solely French, and she chose Vienna. She arrived at the university there in 2002, and spent the next seven years running a small lab that was precariously dependent on short-term grants. “I had to survive on my own,” she says. Nevertheless, “I had in mind to understand how every biochemical pathway in a bacterium was regulated.” It was an exciting time scientifically, with the importance of small RNA molecules in regulating genes being revealed, and she embarked on many different projects on various bacteria — possibly too many, she admits, but she kept winning the grants. She discovered an RNA that controls the synthesis of a class of molecules that are important for virulence in the bacterium Streptococcus pyogenes3. It was in Vienna that Charpentier first found herself thinking about CRISPR. In the early 2000s, this was a niche area: only a handful of microbiologists were paying attention to the newly discovered, curiously patterned stretch of DNA called CRISPR in the genome of some bacteria, where it serves as part of a defence system against viruses. By copying part of an invading virus' DNA and inserting it into that stretch, bacteria are able to recognize the virus if it invades again, and attack it by cutting its DNA. Different CRISPR systems have different ways of organizing that attack; all of the systems known at the time involved an RNA molecule called CRISPR RNA. Charpentier was interested in identifying sites in the genome of S. pyogenes that made regulatory RNAs — and found that bioinformatics took her only so far. So she forged a collaboration with molecular microbiologist Jörg Vogel, then a junior group leader at the Max Planck Institute for Infection Biology, who was developing methods for large-scale mapping of RNAs in a genome. He agreed to map S. pyogenes — and by 2008 he had sequences of all of the small RNAs generated by the bacterium. The first thing that the researchers noticed was a super-abundance of a novel small RNA that they called trans-activating CRISPR RNA (tracrRNA). From its sequence and position on the genome — it was at a location that Charpentier's bioinformatics had predicted as being close to the CRISPR site — they realized that it was highly likely to be involved in a CRISPR system that had not previously been described. Charpentier and her colleagues began a long series of experiments to explore this system, identifying that it had just three components — tracrRNA, CRISPR RNA and the Cas9 protein. This was a surprise: “Other CRISPR systems involved just one RNA and many proteins, and no one had really thought that two RNAs might be involved,” says Charpentier. The system was so exceptionally simple that she realized that it might one day be harnessed as a powerful genetic engineering tool. If the components could be controlled, it might provide the long-sought ability to find, cut and potentially alter DNA at a chosen, precise site in a genome. But how exactly was this CRISPR system working? Charpentier suspected that the two RNAs might actually interact with each other to guide Cas9 to a particular DNA sequence in the virus. The concept was radical; that type of teamwork is routine for proteins, but not for RNAs. But Charpentier “always looked for the unexpected rather than the expected in a genome”, says Tuomanen. “She is a very counter-culture person.” Charpentier remembers that it was hard to persuade any of her young students to follow up her intuition and perform the key experiment to test whether the two RNAs might interact, but eventually a masters student at the University of Vienna, Elitza Deltcheva, volunteered. By then, it was June 2009, and Charpentier was again on the move. She had never felt completely at home in Vienna, where she says the grandiose architecture oppressed her. And she knew that she had to find more security and support. “At this time in my career, I needed the luxury of being able to focus on finalizing a big, cool story,” she says. She took a position at the newly created, well provisioned Umeå Centre for Microbial Research in northern Sweden. The pretty, human-scale architecture of the old town made her feel comfortable, and she even learned to like the long, dark winters, which made her lose the feeling of time, allowing an even greater focus on work. In summer 2009, she was still commuting between Austria and Sweden when Deltcheva called her in Umeå at 8 p.m. to tell her that the experiments had worked. “I was very, very happy,” Charpentier says. But she told no one. Vogel says that it was “a very intense time”. He recalls getting a call from Charpentier one night that August when he was driving on a country road outside Berlin. “I stood on the kerbside for ages while we discussed when would be the right time to publish, because by then we had actually got the story.” They both knew that this discovery was going to be a game-changer, but both were afraid of being scooped if word of the system they had stumbled on got out. To make sure that publication would not be drawn out by referees' queries, they worked doggedly and silently for more than a year to cover as many bases as they could think of before submitting to Nature4. Charpentier was unknown in the then-small CRISPR world. She presented the work for the first time in October 2010 at a CRISPR meeting in Wageningen, the Netherlands, a few weeks after submitting it for publication. “It was a highlight of the meeting — a beautiful story that was extremely unexpected and came right out of the blue,” says microbiologist John van der Oost of Wageningen University, who organized the meeting. Charpentier didn't mind being an outsider. “I have never really wanted to be part of a cosy scientific community,” she says. And she was already thinking ahead to the next step — how this neat dual-guide RNA system actually led to cleavage of DNA. At a 2011 American Society for Microbiology conference in San Juan, Puerto Rico, she met structural biologist Jennifer Doudna of the University of California, Berkeley. Doudna was immediately charmed. “I loved her intensity, which was apparent from the moment I met her,” she says. They began a collaboration that swiftly led to the second key discovery showing how Cas9 cleaved DNA5. With the mechanism elucidated, researchers went on to show that the system could indeed be adapted to make targeted cuts in a genome and to modify a sequence. The technique has since been embraced by labs around the world. Charpentier, meanwhile, made two decisions. The first was in deference to her original ambition to do something to advance medicine. She contacted Novak, who was by then working at the pharmaceutical firm Sanofi in Paris, with the intention of co-founding a company to exploit the methodology for human gene therapy. CRISPR Therapeutics, based in Cambridge, Massachusetts, and Basel, Switzerland, was born in November 2013 with a third co-founder, Shaun Foy, and Charpentier remains chair of its scientific advisory board. The second decision was in deference to her ambition to fully dedicate her time to basic research in gene regulation. For this she wanted a permanent post, with more institutional support. In 2013, she moved to Germany to become a professor at the Hanover Medical School and a department chief at the Helmholtz Centre for Infection Research in nearby Braunschweig, where she finally got her own technicians and built up a lab of 16 PhD students and postdocs. Just over two years later, she was recruited by the Max Planck Institute in Berlin. Now she has generous technical and institutional support, and her labs are in the elegant, nineteenth-century campus of the Charité teaching hospital, an environment she can relax in. Maybe in a few years, she says, she'll even find a few moments for reading philosophy. But right now, fame and prizewinning leave little time for that. She values the recognition, engaging fully with the publicity activities that each prize requires — but notes anxiously that on average, each takes two full days from work. She declines to discuss the high-profile and rather complicated patent dispute between herself — alongside Doudna and Berkeley — and the Broad Institute of MIT and Harvard in Cambridge, Massachusetts. She leaves that to the patent lawyers, who are currently arguing it out. Her focus is still on research, and her latest paper1 — an elaboration of a CRISPR system that is even simpler than CRISPR–Cas9 — was once again finalized in the middle of a lab move. The work shows that a protein called Cpf1 can do the jobs of both tracrRNA and the Cas9 protein — “a very important contribution”, says van der Oost, and part of a flurry of recent studies on this system6, 7. But Charpentier is keen not to be defined by CRISPR, which is just one of five themes in her lab; others include the mechanisms by which pathogens interact with host immune cells and the molecular complexes that regulate the behaviour of bacterial chromosomes. Reflecting back, she feels that her life has been tougher than it need have been. She notes that now there are more sources of major grants to help young investigators to start their own independent labs. And although her goals to further medicine and improve genetic-engineering tools have been met, her ambitions have not waned. “I haven't changed, and I won't change,” she says. “The scientist that I am got me here, and that is the scientist that I want to remain.” But some things have changed. Charpentier is not an outsider any more: she is an established member of the rapidly expanding CRISPR community and is inundated with invitations to give talks. Her mischievous ambition, however, is to show up at a CRISPR meeting and report the discovery of something entirely different, but equally important. She has a few things up her sleeve, she says.
News Article | March 4, 2016
For some adults, Zika virus is a rashy, flulike nuisance. But in a handful of people, the virus may trigger a severe neurological disease. About one in 4,000 people infected by Zika in French Polynesia in 2013 and 2014 got a rare autoimmune disease called Guillain-Barré syndrome, researchers estimate in a study published online February 29 in the Lancet. Of 42 people diagnosed with Guillain-Barré in that outbreak, all had antibodies that signaled a Zika infection. Most also had recent symptoms of the infection. In a control group of hospital patients who did not have Guillain-Barré, researchers saw signs of Zika less frequently: Just 54 out of 98 patients tested showed signs of the virus. Here's what we know about Zika How Zika became the prime suspect in microcephaly mystery Efforts to control mosquitoes take on new urgency The message from this earlier Zika outbreak is that countries in the throes of Zika today “need to be prepared to have adequate intensive care beds capacity to manage patients with Guillain-Barré syndrome,” writes study coauthor Arnaud Fontanet of the Pasteur Institute in Paris and colleagues, some of whom are from French Polynesia. The study, says public health researcher Ernesto Marques of the University of Pittsburgh, “tells us what I think a lot of people already thought: that Zika can cause Guillain-Barré syndrome.” As with Zika and the birth defect microcephaly (SN: 2/20/16, p. 16), though, more work needs to be done to definitively prove the link. Several countries currently hard-hit by Zika have reported upticks in Guillain-Barré syndrome. Colombia, for instance, usually sees about 220 cases of the syndrome a year. But in just five weeks between mid-December 2015 to late January 2016, doctors diagnosed 86 cases, the World Health Organization reports. Other Zika-affected countries, including Brazil, El Salvador and Venezuela, have also reported unusually high numbers of cases. Despite the seemingly strong link between Zika and Guillain-Barré, Marques stresses that the risk of getting the syndrome after a Zika infection is quite low. “It’s important that people don’t think that if you get Zika, you are going to get Guillain-Barré.” The chance is much less than 1 percent, he says. And it’s too early to say whether the rate of Guillain-Barré estimated in the paper will be the same in ongoing Zika outbreaks, says Anna Durbin, a vaccine researcher at Johns Hopkins University. “We have a number now, but it’s not perfect,” she says. Ongoing studies in Brazil and other countries affected by Zika will help refine the rate. As suspected and confirmed Zika infections climbed in Colombia (black lines), cases of Guillain-Barré syndrome rose, too (blue bars). New cases of Guillain-Barré may be added retrospectively as they are confirmed. The syndrome begins as the body’s immune system attacks peripheral nerves, causing weakness or tingling sensations in the lower extremities. In severe cases, total paralysis can result, leaving people dependent on ventilators in intensive care units while they recover. Three to 5 percent of people with Guillain-Barré die from complications, scientists estimate. Other viruses, including HIV, influenza and dengue (like Zika, a flavivirus), are known to spark Guillain-Barré, possibly through their interactions with the body’s immune system, though the details remain mysterious. The timing of Guillain-Barré’s onset may make it easier for scientists to pin the disorder on Zika. Because the syndrome shows up days or weeks after an infection subsides, Guillain-Barré may offer a quicker readout of Zika’s effects than waiting months to see if microcephaly in babies are born to infected mothers, the WHO’s Bruce Aylward said in a news briefing February 19. Scientists conducting a multinational Guillain-Barré study may soon expand their study, called the International Guillain-Barre Syndrome Outcome Study, into Brazil and Colombia to look for signs of Zika infection in people with the syndrome. “We are developing a new version of the IGOS protocol that is more focused on Zika and other flaviviruses, to support the research in those countries,” says Bart Jacobs, an immunologist at Erasmus University Medical Center in Rotterdam, the Netherlands, who’s helping supervise the study. Further studies could also help explain why some people are susceptible to Guillain-Barré. Genetics, previous viral infections or toxins may all play a role.
News Article | January 13, 2016
Genes inherited from ancient hominins have improved the human immune system. Homo sapiens interbred with Neanderthals and other ancient humans called Denisovans less than 100,000 years ago. Janet Kelso and her team at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, looked for Neanderthal and Denisovan genetic ancestry that has benefited humans by analysing the genomes of hundreds of people from around the world. They found a cluster of three Toll-like receptor (TLR) genes, which are involved in rapidly sensing and responding to infections as part of the innate immune response. Two Neanderthal versions of this cluster and one from Denisovans are common in different human populations. The archaic TLR genes are linked to reduced susceptibility to a bacterial infection of the stomach, but also to higher rates of allergies. In a separate study, a team led by Lluis Quintana-Murci at the Pasteur Institute in Paris identified innate immunity genes that Europeans and Asians seem to have inherited from Neanderthals, including the same cluster of TLR genes.
News Article | February 3, 2016
A group of six genes causes some strains of a foodborne bacterium to become highly dangerous, or virulent. Listeria monocytogenes (pictured) can be found in many foods, including unpasteurized milk, and can cause miscarriage in pregnant women or kill infected people if the pathogen moves to the brain. All strains are currently considered to be equally virulent, but Sylvain Brisse and Marc Lecuit of the Pasteur Institute in Paris and their colleagues found differences in virulence when they analysed genomic and epidemiological data from more than 6,600 L. monocytogenes isolates taken from food and human samples. Food-associated strains mainly infected people who had weakened immune systems, but more-virulent clinical isolates were found in healthy people. The 'CC4' group of strains carried a six-gene cluster that, when deleted, made the bacteria less capable of invading brain and placental tissues in mice. Public-health surveillance efforts for foodborne illnesses should look out for these hypervirulent strains, the authors say.
News Article | February 14, 2017
"Will you still need me, will you still feed me, when I'm 64?" The Beatles once asked. In the case of Christian Bréchot, the 64-year-old president of the Pasteur Institute in Paris, the answer is in: nope. Capping an 8-month crisis at the institute, Pasteur's board of directors has decided not to change the strict age limit for its top job, denying Bréchot the extension he was hoping for. The decision was taken on 24 January and explained to Pasteur staff yesterday in an internal memo obtained by Insider. In it, the board announces that Bréchot will step down after his 4-year stint ends on 30 September 2017, and says that the search for a successor is on. "Obviously, I'm disappointed," Bréchot says, "but I respect the board's decision." Nevertheless, he says, the age limit is "ridiculous." The governing statutes of the foundation that runs Pasteur stipulate that a president must not be older than 64 when he or she is appointed or reappointed to the job. Bréchot, who will turn 65 in July, had hoped that the board would change the rules to make an extension possible. "Four years is very short," he says. The board made clear it didn't plan to do so last May, citing potential legal and financial complications. But Bréchot enjoys support among Pasteur scientists for making the institute a more attractive place to work, broadening its research scope, and strengthening its international network. A letter signed by the heads of the institute's 11 research departments praised his "leadership, vision, dynamism and full commitment." To protest the board's decision, Pasteur's General Meeting—a parliament-style body with about 100 members that usually meets once a year—rejected the institute’s annual report last June, a move that triggered the board’s dissolution. The new board had shown itself more sympathetic to Bréchot's wish. During a meeting on 24 January, two-thirds of its members voted for a compromise that would not raise the age limit but would allow the board to extend a president's term by 2 years, a Pasteur spokesperson says. That still fell short of the 75% majority needed to change the statutes, however. The compromise was "an intelligent solution," says Bréchot, if only because it would have allowed more time to search for a successor. While heartened by the support at last year’s General Meeting, Bréchot says he does not expect another uprising at the next such gathering, slated for June. "Nobody wants that to happen again," he says.