Know This

by Mr. John Brockman

  The benefits of gene drive could be huge. Vector-borne scourges like malaria and dengue fever could be eliminated by eliminating (or just adjusting) the mosquitoes that carry them. Food crops could be protected by reversing herbicide-resistance in weeds. Wildlife conservation would be free of one of its worst threats—the alien invasive rats, mice, ants, etc. that destroy native species on ocean islands. With gene drive, the invaders could be extirpated (driven extinct locally), and the natives would be protected permanently.

  Developments are coming quickly. A team at Harvard proved that gene drive works in yeast. A team at UC San Diego inadvertently proved that it works in fruit flies. Most important, Anthony James at UC Irvine and colleagues showed that malaria mosquitoes could be altered with gene drive so that they no longer carry the disease. Kevin Esvelt is developing a project to do the same with white-footed mice, the wildlife reservoir for Lyme disease in humans; if they’re cured, humans will be as well.

  The power to permanently change wild populations genetically is a serious matter. There are ecological questions, ethical issues, and many technical nuances that have to be examined thoroughly. Carefully, gradually, they will be.

  Humanity has decided about this sort of thing before. Guinea worms are a horrible parasite that once afflicted 2.5 million people, mostly in Africa. In 1980, disease-control experts set about eliminating the worms from the world, primarily through improved water sanitation. That goal of deliberate extinction is now on the brink of completion. One of the strongest advocates of the project, President Jimmy Carter, declared publicly, “I would like the last Guinea worm to die before I do.”

  Gene drive is not a new kind of power, but it is a new level of power. And a new level of responsibility.

  Life Diverging

  Juan Enriquez

  Managing director, Excel Venture Management; co-author (with Steve Gullans), Evolving Ourselves

  The two rules governing what lives and what dies in the long term have been pretty clear: natural selection and random mutation. But over the last century or two, and especially over the last decade, humans have fundamentally altered those rules. Life as we know it will undergo rapid and accelerating change; it will will diverge, especially post–May 2014.

  Already we largely determine what lives and dies on half the surface of the planet—anywhere we’ve built cities, suburbs, parks, farms, ranches. That makes cornfields and gardens alike some of the world’s most unnatural places. Nothing lives and dies there except what we want, where and when we want. Orderly rows of plants that please us. All else is culled. (But leave it fallow and untended for a couple of years and you will begin to see what is driven by natural selection.)

  In redesigning our environment, we create and nurture unnatural creatures: miniature pigs the size of Chihuahuas; corn that cannot self-replicate; the big tom turkeys to dine on at Thanksgiving, animals so grossly exaggerated that they can’t copulate and require artificial insemination. Today’s big-breasted beasts are on average 225 percent larger than they were in the 1930s.

  Without human intervention, most of the creatures that live around you would have been selected out. (Let a Lhasa Apso loose on the African plain and watch what happens.) Same is true of humans: In an all-natural environment, most of humanity would not be alive. But unnaturally selecting out microbes and viruses—like smallpox, polio, bubonic plague, and most infections—means billions of us get to live.

  As we practice extreme human intervention and alter the course of natural selection, we create a parallel evolutionary track, one whose rules and outcomes depend on what we want. Life begins to diverge from what nature would design and reward absent our conscious and unconscious choices. A once unusual observation—that during the Industrial Revolution black moths in London survived better than white moths because they were better camouflaged in a polluted environment—has become the norm. Life around us is now primarily black-moth-like adaptations: cute dogs, cats, flowers, foods. We have altered plants, animals, and bacteria so extensively that to survive they have to reward us, or at least be ignored by us.

  These two parallel evolutionary systems—one driven by nature, the other by humans—expand diverging evolutionary trees. The divergence between what nature would choose and what we choose gets ever larger. Many of the life-forms we are so accustomed to and dependent on would disappear or radically modify in our absence. But the true breakpoint began over the past few decades, when we began not just choosing how to breed but rewriting the code of life itself. In the 1970s and 1980s, biotechnology allowed us to insert all kinds of gene instructions. Random mutation is gradually being displaced by intelligent design. By 2000, we were decoding entire genomes and applying this knowledge to alter all kinds of life-forms. Today’s high schoolers can spend $500 and alter life code using methods like CRISPR; these types of technologies can alter all subsequent generations, including humans.

  In May 2014, a team of molecular biologists led by Floyd Romesberg created a new genetic code, a self-replicating system that codes life-forms using chemically modified DNA. Insofar as we know, for almost 4 billion years all life on this planet replicated using the four known base pairs of DNA (A, T, C, and G). Now we can swap in other chemicals. This third evolutionary logic-tree of life would initially be completely human-design-driven and could rapidly diverge from all known life. In theory, scientists could begin breeding plants and animals with a very different genetic makeup from that of any other creature on the planet. And these new life-forms may be immune to all known viruses and bacteria.

  Moreover, if we discover life on other planets, something that seems likely, the biochemistry of these other life-forms will doubtless further increase the variety of life on Earth, providing life designers with new instruments and ideas to program/redesign existing life-forms so they can adapt to different environments.

  Thus the biggest story of the next few centuries will be how we begin to redesign life-forms, spread new ones, develop approaches and knowledge to further push the boundaries of what lives where. And as we deploy all this technology, we will see an explosion of new forms that could make the Cambrian explosion look tame.

  Life is expanding and diverging. Humans won’t be immune to this trend. We’ve already coexisted and interbred with other versions of hominins; it was normal and natural for different versions of ourselves to be walking around. Soon we might return to this historically normal state, but with far more, and perhaps radically different, versions of ourselves. All of which may lead to just a few ethical, moral, and governance challenges.

  Fundamentally Newsworthy

  Stuart Firestein

  Chairman, Department of Biological Sciences, Columbia University; author, Failure: Why Science Is So Successful

  The all-consuming news story in biology last year—this decade, really—is the discovery of the CRISPR/Cas9 system and its practical application for gene editing. There have been numerous articles in the popular press. Most of that attention has been directed at the tremendous and potentially dangerous power of this new technology: It allows editing the DNA of genomes, including those of humans, in a way that would be permanent—that is, heritable through generations.

  All this attention on the possible uses and misuses of CRISPR/Cas9 has obscured the real news—which is, in a way, old news. CRISPR/Cas9 is the fruit of years of fundamental research conducted by a few dedicated researchers who were interested in the arcane field of bacterial immunity. Not immunity to bacteria, as you might at first think, but how bacteria protect themselves against attack by viruses. Weird as it may seem, there are viruses that specialize in attacking bacteria. Just as most viruses we know about are specific to one species or another (you can’t catch a cold from your dog), there are viruses that infect only bacteria—in fact, only certain types of bacteria. These have a special name: phage. And they have a long history in the development of molecular biology and genetics. Indeed, molecular biology began with the study of phage and its ability to insert its
genome into the genomes of bacteria—even before Watson and Crick’s famous articulation of DNA as the molecule of heredity.

  For the past forty years, restriction enzymes, another family of bacterial proteins, have been the mainstay of the biotech industry, and they too were discovered first as an early example of bacterial protection mechanisms. And they were also discovered in university research laboratories devoted to basic research. CRISPR/Cas9, however, is a more sophisticated mechanism, approaching that of the immune system of higher animals: It is adaptive, in the sense that a bacterium and the bacteria it generates by dividing can “learn” and destroy the DNA of the genome of a particular type of phage after the bacterium has been attacked by that phage once. The researchers who discovered CRISPR/Cas9 and recognized its potential value as a gene-editing tool in living things other than bacteria were not searching for some new technology; they were after a deeper understanding of a fundamental question in prokaryotic (microbial) biology and evolution—the back-and-forth competition between bacteria and the viruses that invade them. Could that be any more arcane-sounding?

  It is also important to recognize that this was not a serendipitous discovery, a happy accident along the way. This is often the case made for supporting fundamental research: You never know where it might lead; serendipity intervenes so often. But this is a false conception, and CRISPR/Cas9 is a perfect example of why. This was no simple accident resulting from good luck or happenstance. It was the fruit of hard and sustained labor, of whole careers devoted to understanding the fundamental principles of life. The particular groups that discovered CRISPR/Cas9 were looking for precisely such an adaptive, immune-like response in bacteria. Understanding the value of restriction enzymes, as these researchers would have, was a sensible step to appreciating the value of an even more sophisticated DNA-based protective system. This is how research works—neither by accident nor purposefully: It is the result of hard work at every level of inquiry. Advances are indeed often unpredictable, but that doesn’t make them merely lucky. Certainly not like winning some type of lottery.

  We continue to have this misguided debate about fundamental versus applied research as if they were two spigots that could be operated independently. They are one pipeline, and our job is to keep it flowing. This is old news, but we should never tire of stating it.

  Paleo-DNA and De-Extinction

  W. Tecumseh Fitch

  Professor of cognitive biology, University of Vienna; author, The Evolution of Language

  When prehistoric humans arrived in America, they found a continent populated by mammoths, woolly rhinos, giant sloths, saber-toothed cats, horses, and camels. By the time Columbus arrived, all those species were extinct, due mainly to human hunting. But today paleobiologists are sequencing their genomes. Furthermore, genetic engineering is approaching the point where genetically engineered versions of those extinct species may walk the Earth again. Last year’s big news—cloning of a dead pet dog—is a small beginning.

  In the near future, the news will concern what paleo-DNA specialist Beth Shapiro dubs “de-extinction”: generating living organisms bearing genes recovered from extinct species. Paleo-DNA (the somewhat degraded DNA recovered from bones or hair of extinct species) can be extracted from extinct species like mammoths and those exterminated by humans during historical times, including passenger pigeons, dodos, and thylacines (Tasmanian wolves). Trace amounts of DNA can be recovered, amplified, and sequenced. Key genes could then be engineered into cells of the closest living relatives (Asian elephants, for mammoths) to produce shaggy, cold-tolerant elephants. This is nearly within our technological reach. (Jurassic Park fans, take note: The truly ancient DNA from dinosaurs is too degraded to currently allow sequencing.) Although birds pose unique challenges—being unclonable with current technologies—the de-extinction of passenger pigeons and moas (3.5-meter-tall flightless birds exterminated by hunting when the Maori arrived in New Zealand) appears within our grasp, and major de-extinction projects for these species are already under way.

  So should we do this? Shapiro’s recent book, How to Clone a Mammoth, provides an excellent introduction to the arguments. Given the polarized opinions generated by reintroducing wolves to Yellowstone, one can easily imagine the diversity of public reactions to reintroducing saber-toothed tigers or giant cave bears. The best pro arguments are ecological: By reviving lost species, we can restore habitats damaged or destroyed as our own species spread around the planet. Mammoth-like elephants stomping through the tundra of Siberia’s Paleozoic Park would benefit the environment by slowing the process of permafrost melting and the attendant carbon release. From a purely scientific, curiosity-driven viewpoint, de-extinction will offer biological and ecological insights available in no other way. Tourists would pay top dollar to watch moas wandering the beech forests of New Zealand, or mammoths roaming Siberia. The con arguments are mostly practical (Why spend money reviving extinct species rather than saving living endangered species?) or techno-fearful (humans shouldn’t play God), but no less passionately advocated.

  By far the most significant issues will concern extinct hominids, like Neanderthals, and society needs to prepare for the challenging ethical questions raised by such research. In 1997, researchers at Svante Pääbo’s paleo-DNA lab in Leipzig made the news by sequencing mitochondrial DNA from Neanderthals. Today, after breathtaking technological progress, a full Neanderthal genome is available online. Even more exciting, in 2010 Pääbo’s group discovered Denisovans, a previously unknown Asian hominid species, based on DNA extracted from a finger bone. The discovery of Denisovans from paleo-DNA makes it crystal clear that when modern humans emerged from Africa, they encountered a world inhabited by multiple near-human species—all of them now extinct.

  Recovering the genome sequence of an extinct hominid species is exciting because it provides answers to a host of biological questions that stones and bones—the previous mainstay of paleoanthropology—will never answer. For example, it seems likely, based on pigmentation genes, that Neanderthals had light skin and some had red hair. Paleo-DNA has clarified that occasional interbreeding probably occurred when the first modern humans migrated out of Africa and encountered Neanderthals. As a result, all non-African human populations bear traces of Neanderthal DNA in their genomes (and many Asians bear additional Denisovan DNA). Similarly, the issue of whether Neanderthals had spoken language has divided scholars for decades. Although the case remains far from closed, we now know that Neanderthals shared the derived human version of the FOXP2 gene, which enhances our speech motor control. This suggests that Neanderthals could at least produce complex vocalizations, even if they lacked modern, syntactic language. Such findings have fueled an ongoing sea change in contemporary reinterpretations of Neanderthals—from oafish thugs to smart, resourceful near-humans.

  Paleo-DNA sequencing has changed our understanding not just of Neanderthals but of ourselves. Neanderthals were not modern humans: They lacked the rapid cultural progress characterizing our species, and thus presumably some of our cognitive capacities. But what precisely were these differences? Do these differences make us, the survivors, “human?” Or were Neanderthals human but “differently abled?” Certainly, with the bodies of Olympic wrestlers and brains slightly larger than those of modern humans, they’d be first picks for your rugby scrum; perhaps they had unique cognitive abilities as well. Progress will be rapid in addressing these issues, because each new insight into the genetic basis of the human brain yields parallel insights into our understanding of Neanderthal brains—and of the cognitive differences between the two.

  But the deep ethical issues concern the possible de-extinction of Neanderthals or other extinct hominids. From a scientific viewpoint, this would promise insights into hominid evolution and human nature unimaginable a decade ago. But from a legal viewpoint it would involve creating humans expressing Neanderthal genes, and thus require human cloning, already forbidden in many countries. But few doubt that within this century genetic en
gineering of our own species will be both technologically possible and ethically acceptable in at least some subcultures. Clearly, a human expressing Neanderthal genes (as many of us already do!) would retain all basic human rights, but the moral and ethical implications raised by Neanderthals in the workplace (or on college football teams) might easily eclipse those raised by racism or slavery.

  Clearly, paleo-DNA will remain in the news for the foreseeable future, offering scientific insights and posing unprecedented ethical quandaries. It thus behooves all thinking people (especially politicians drafting legislation) to get acquainted with the technology and the biological facts before forming an opinion.

  The Wisdom Race Is Heating Up

  Max Tegmark

  Theoretical physicist and cosmologist, MIT; scientific director, Foundational Questions Institute; cofounder, Future of Life Institute; author, Our Mathematical Universe

  There’s a race going on that will determine the fate of humanity. Just as it’s easy to miss the forest for all the trees, however, it’s easy to miss this race for all the scientific news stories about breakthroughs and concerns. What do these headlines from 2015 have in common?

  AI Masters 49 Atari Games Without Instructions

  Self-driving Car Saves Life in Seattle

  Pentagon Seeks $12-$15 Billion for AI Weapons Research

  Chinese Team Reports Gene-Editing Human Embryos

  Russia Building Dr. Strangelove’s Cobalt Bomb

  They are all manifestations of the race heating up—the race between the growing power of technology and the wisdom with which we manage it. The power is growing because our human minds have an amazing ability to understand the world and to convert this understanding into game-changing technology. Technological progress is accelerating for the simple reason that breakthroughs enable other breakthroughs: As technology gets twice as powerful, it can often be used to design and build technology that is twice as powerful in turn, repeated capability doubling in the spirit of Moore’s Law.