Gene Drives Steer toward Road Tests
PSW 2378 The Mosquito, Synthetic Biology, CRISPR, and Malaria
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Developing Safety Standards for Germline Use
Technologies that would bias the inheritance of a gene or a group of genes in a population have been discussed for decades.
Such technologies, scientists have long proposed, could exploit translocation mechanisms to prevent, contain, and eradicate vector-borne infectious diseases, some of which are global public health emergencies. An especially interesting possibility was introduced back in 2003, when Austin Burt, Ph.D., an evolutionary geneticist at Imperial College London, described how site-specific “selfish genes,” such as homing endonuclease genes, could be engineered to target new host sequences and skew population sex ratios.
At the time, Dr. Burt’s suggestion could not be tested because a convenient means of retargeting selfish elements didn’t exist. Such a means, however, has come to the fore in recent years. It is, of course, the CRISPR/Cas9 genome-editing technology. It is already being used to construct gene drives that could be used to spread desirable mutations through populations in super-Mendelian fashion.
“In CRISPR gene-drive technologies, probably the biggest challenge is making sure that we understand the environmental consequences and the unintended consequences, if any,” George M. Church, Ph.D., professor of genetics at Harvard Medical School and MIT, tells GEN. Several years ago, Dr. Church’s group was the first to create a gene drive in the budding yeast Saccharomyces cerevisiae. In a more recent study on wild and laboratory strains of S. cerevisiae, Dr. Church and colleagues showed that CRISPR/Cas9 gene drive systems can bias inheritance over successive generations at efficiencies over 99%.
Historically, several model organisms have been used to study gene drives, and while each of them provided important lessons, there are key differences between them in terms of the types of information they provide and the challenges they help address. An area of particular concern in gene-drive studies revolves around the accidental escape from the laboratory of even a single organism, and the subsequent consequences over time on wild populations. “Because fruit flies are present outside of every laboratory, escape is easier in this model,” warns Dr. Church.
Dr. Church and colleagues recently developed and validated two molecular confinement methods. One method encodes Cas9 on an unlinked episomal plasmid and ensures that the gene drive element contains only the single guide RNA. (In this arrangement, the single-guide RNA-only gene drive is unable to spread in wild organisms, which lack Cas9.) The other method involves using exclusively synthetic target sequences, which are not encountered in wild-type organisms.
As part of these studies, Dr. Church’s laboratory illustrated the benefits of testing CRISPR/Cas9-based gene drives in the budding yeast before conducting work on multicellular organisms. Additional work with mathematical models led Dr. Church and colleagues to propose the use of alternative designs that could select against resistant alleles and improve the gene drive’s evolutionary stability.
One of the technical challenges in engineering mosquitoes is the need to perform the engineering within or near essential genes. “Engineering genes that are not important to the organism will quickly eliminate the gene drive because the organism does not need the target site,” explains Dr. Church.
Engineering Parasite-Resistant Mosquitoes
“As part of our efforts focusing on malaria, we are trying to create tools and generate mosquitoes that could be used for rigorous tests including large cage trials and subsequently, if the regulatory approvals are given, for field trials,” says Ethan Bier, Ph.D., professor of cell and developmental biology at the University of California, San Diego. Dr. Bier’s group was the first to show that a gene drive can be created in the fruit fly.
Overall, two competing strategies have been envisioned and developed for using gene-drive technologies. One strategy involves the use of mosquitoes to distribute or disseminate an immunizing gene cassette. If this strategy is implemented correctly, notes Dr. Bier, it would not have much or any impact on the health or fitness of the mosquitoes. The other strategy involves using gene drive to sterilize or reduce the population of mosquitoes. According to Dr. Bier, this is a version of genetic insecticide.
Dr. Bier’s laboratory is pursuing the first strategy in collaboration with a team of scientists based at the University of California, Irvine, and led by Anthony James, Ph.D., a professor of microbiology and molecular genetics, and of molecular biology and biochemistry. The collaboration is focusing on population-level mosquito modifications in which genes that confer a parasite-resistant phenotype are engineered into the mosquitoes that transmit the pathogen.
“The immunizing cassette, originally developed by Dr. James’ laboratory, would just stay in the population and not be subject to evolutionary pressures that try to rid those mosquitoes from the environment,” explains Dr. Bier. “They might therefore be present long enough to have a significant impact on the prevalence of the malaria parasite by blocking its transmission.”
In a recent study using Anopheles stephensi, a malaria vector on the Indian subcontinent, Dr. Bier and colleagues in the Dr. James’ group revealed that CRISPR/Cas9-directed homologous recombination drives gene conversion at a more than 99.5% efficiency in mosquito transgene heterozygotes. The technology to perform this work is based on the mutagenic chain reaction, which Dr. Bier and colleagues previously developed in Drosophila melanogaster, and in which a heterozygous mutation is converted to a homologous loss-of-function mutation in germline and somatic cells.
Gene-drive technologies have applications for other vector-borne diseases, such as leishmaniasis and Chagas disease, as well as for population reduction schemes to control crop pests. “Any scheme that goes after reducing the population of any insect or organism in the wild, even though it may be successful, will at the end, always be an uphill battle,” cautions Dr. Bier. A more desirable alternative involves modifying attributes that are undesirable, such as an organism’s ability to propagate disease or its preference for one type of crop versus another. “One can obtain more of an effect by just changing that characteristic and not trying to kill the organism,” advises Dr. Bier.
In introducing genetic modifications into mosquitoes, Dr. Bier and colleagues extensively rely on the ability to generate effector molecules that bind to parasites and render them unable to transfer to the body of the mosquito. One of the key requirements of these molecules is their ability to bind with high affinity to epitopes on the parasite.
“Technologies that we would value for this work include rapid protein evolution binders, which are molecules that are capable of binding random input peptides,” maintains Dr. Bier. After peptides are provided, genetically encodable binders that interact with them could be used in vivo to tether them to components in the mosquito to either kill the parasites or make them aggregate. “[Using] evolutionary synthetic biology approaches to make novel protein-interacting peptides,” adds Dr. Bier, “would be extremely valuable for our work.”
Sterilizing Populations
“We look at gene drive as something that can bias inheritance and is differentially included in the offspring, and that can be coupled to a trait that might be of use in terms of controlling the mosquito population,” says Tony Nolan, Ph.D., senior research fellow at Imperial College London. In a recent study, Dr. Nolan and colleagues designed a CRISPR/Cas9-based approach to individually target and disrupt three Anopheles gambiae genes that have high ovarian expression and tissue specificity.
“We disrupted key fertility genes,” informs Dr. Nolan. “That allowed us to introduce an element that can cause population reduction, which is viewed as the most successful strategy today to control malaria.” For two of these loci, the constructs were predicted to disappear from the population over time, but for the third one, the gene disruption met the minimum requirements for targeting female reproduction by gene drive in a mosquito population.
One of the challenges related to the implementation of gene drives is intimately related to the emergence of resistance. “Anything that tries to suppress a population would impose a selection pressure on the population,” states Dr. Nolan. An advantage, when using gene drives, is that some of the resistance mechanisms are foreseeable. “Therefore, one can plan in advance and make the emergence of resistance much less likely,” asserts Dr. Nolan.
Another challenge is the need to demonstrate that gene-drive technology, which is still new, can be trusted. Large amounts of data are needed to confirm that gene drive works and is safe. “There is a lot of testing that should happen between building something in the laboratory and making something the field,” advises Dr. Nolan. “This is going to be a very long process.”
Comparing Alternative Strategies
“We think of gene drives as having three categories of challenges or issues,” says Austin Burt, Ph.D., professor of evolutionary genetics at Imperial College London. The challenges, Dr. Burt suggests, are technological (the ability to “generate constructs that do what we want them to do”); regulatory (the ability to “obtain permission to use the technology that we develop”); and in a sense, communal (the ability to “broaden stakeholder acceptance in terms of people wanting to have this technology”).
Almost 15 years ago, Dr. Burt was the first investigator to propose the use of gene drives based on homing endonuclease genes. Homing endonuclease genes encode highly specific endonucleases with recognition sequences that occur only once in a genome and can activate recombination repair systems by inducing double-stranded chromosomal breaks in the homologous chromosome. As a result of the homology-directed repair process, the endonuclease gene is copied to the broken chromosome. This process can be used to spread the gene through a population.
In a recent modeling analysis, Dr. Burt and colleagues evaluated three different strategies—population suppression through dual-germline fertility disruption, population suppression with a driving-Y chromosome, and mosquito population replacement—to predict how each strategy would perform in a real-life setting from sub-Saharan Africa. Each strategy, despite presenting a unique set of challenges, was highly effective at reducing malaria transmission.
“The point of this work is to help define what it is that would constitute technical success,” declares Dr. Burt. A broader understanding of success, he adds, would encompass the gene-drive attributes that “need to be in place to predict the successful transition of the work from the laboratory to the field.”
Gene Drive in Practice
Many different techniques have been developed, and many more could be developed, to incorporate gene drives, says Zach N. Adelman, Ph.D., associate professor of entomology at Texas A&M University. What these techniques have in common, he suggests, is the need to address the issue of specificity.
The blessing of specificity is that off-target effects are minimized with a highly specific nuclease. The curse of specificity is that when sequence variation is pronounced in a natural population, or when new changes arise, a very specific nuclease will lack or come to lose the ability to recognize the genomic region that needs to be targeted. “This is what investigators have come up against recently,” insists Dr. Adelman.
Even though sequence variations may naturally occur at low levels in a population, such variations could quickly become more prevalent if a gene drive were to bring with it any kind of fitness cost. “We are trying to develop nucleases that are so specific that they do not cause undesirable changes, but are not so specific that it takes only a single change, one that might already occur in nature, to make them nonfunctional,” explains Dr. Adelman.
Dr. Adelman and colleagues recently proposed a two-step approach for gene editing in organisms that are difficult to manipulate genetically, such as mosquitoes. In this approach, the first step is to evaluate candidate site-specific nucleases. (Many synthetic guide RNA molecules are initially examined in vivo.) The second step is to carry out germline-based editing while constraining the choice of DNA repair response. (RNA interference is used to suppress components of the nonhomologous end-joining response.) Suppression of the Ku70 component substantially improved the rates of homology-directed repair and resulted in gene insertion frequencies of around 2–3%.
“The regulatory agencies are still coming to grips with what it means to have a technology that will be used in an environment that is beyond a containment barrier,” says Dr. Adelman. In the case of previous initiatives to generate genetically engineered products, such as salmon and crops, these were confined to a contained environment, did not move beyond where they were breeded (salmon) or planted (crops), and did not admix intentionally with wild population.
“But the goal in gene drive is to admix, and we are still working out the pathways,” declares Dr. Adelman. The pathways from the laboratory to the field will have to be constructed de novo at the same time that the regulatory frameworks are constructed, he suggests.
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This story appears in the April 2017 issue of National Geographic magazine
When I met the cyborg Neil Harbisson, in Barcelona, he looked like any local hipster, except for the black antenna arching impressively from the back of his skull over his mop of blonde hair.
It was December, and Harbisson, 34, was wearing a zippered grey shirt under a black peacoat, with narrow grey pants. Born in Belfast and raised in Spain, he has a rare condition called achromatopsia; he cannot perceive colour. His antenna, which ends in a fiber-optic sensor that hovers right above his eyes, has changed that.
Harbisson never felt that living in a black-and-white world was a disability. “I see longer distances. Also I memorise shapes more easily because colour doesn’t distract me,” he told me, in his careful, neutral English.
But he was deeply curious about what things looked like in colour too. Having trained as a musician, he had the idea in his late teens of trying to discover colour through sound. After some low-tech false starts, in his early 20s he found a surgeon (who remains anonymous) who was willing to implant a device, a cybernetic enhancement to his biological self.
The fibre-optic sensor picks up the colours in front of him, and a microchip implanted in his skull converts their frequencies into vibrations on the back of his head. Those become sound frequencies, turning his skull into a sort of third ear. He correctly identified my blazer as blue and, pointing his antenna at his friend Moon Ribas, a cyborg artist and dancer, said her jacket was yellow—it was actually mustard yellow, but as he explained, in Catalonia “we didn’t grow up with mustard.”
When I asked Harbisson how the doctor had attached the device, he cheerfully parted the hair at the back of his head to show me the antenna’s point of entry. The pinkish flesh was pressed down by a rectangular plate with two anchors. A connected implant held the vibrating microchip, and another implant was a Bluetooth communication hub, so friends could send him colours through his smartphone.
The antenna has been a revelation for Harbisson. The world is more exhilarating for him now. Over time, he said, the input has begun to feel neither like sight nor hearing but a sixth sense.
12,500 YEARS AGO: EVOLVED TO LIVE AT HIGH ALTITUDES Until recently it was thought that our species had stopped evolving far in the past. Our ability to peer inside the human genome has shown that in fact our biology continues to change to suit particular environments. Most of us feel breathless in high mountain air because our lungs must work harder to capture the reduced level of oxygen there. But Andeans have a genetically determined trait that allows their haemoglobin to bind more oxygen. Tibetan and Ethiopian populations independently adapted to their high elevations, showing that natural selection can take us on different paths to reach the same outcome: survival.
The most intriguing part of the antenna, though, is that it gives him an ability the rest of us don’t have. He looked at the lamps on the roof deck and sensed that the infrared lights that activate them were off. He glanced at the planters and could “see” the ultraviolet markings that show where nectar is located at the centres of the flowers. He has not just matched ordinary human skills; he has exceeded them.
He is, then, a first step toward the goal that visionary futurists have always had, an early example of what Ray Kurzweil in his well-known book The Singularity Is Near calls “the vast expansion of human potential.” Harbisson hadn’t particularly meant to jump-start Kurzweil’s dream—his vision of the future is more sylvan than silicon. But since he became the world’s first official cyborg (he persuaded the British government to let him wear the antenna in his passport photo, arguing that it was not an electronic device, but an extension of his brain), he has also become a proselytizer. Ribas soon followed him into what is sometimes called transhumanism by having a seismic monitor in her phone connect to a vibrating magnet buried in her upper arm. She gets real-time reports of earthquakes, allowing her to feel connected to the motions of the Earth and interpret them through dance. “I guess I got jealous,” she says.
“We will transcend all of the limitations of our biology,” Kurzweil promised. “That is what it means to be human—to extend who we are.”
Clearly Harbisson’s antenna is merely a beginning. But are we on the way to redefining how we evolve? Does evolution now mean not just the slow grind of natural selection spreading desirable genes, but also everything that we can do to amplify our powers and the powers of the things we make—a union of genes, culture, and technology? And if so, where is it taking us?
8,000 YEARS AGO: ADAPTED TO A DESERT CLIMATE The desert presented an evolutionary challenge for the inhabitants of Sahul, the continent that once united Australia, New Guinea, and Tasmania. After the ancestors of modern Aboriginals made the crossing to Sahul, around 50,000 years ago, they developed adaptations that allowed them to survive below-freezing temperatures at night and days often exceeding 100 degrees Fahrenheit. A genetic mutation in a metabolism-regulating hormone provides this survival advantage, especially for infants, by modulating the excess energy that’s produced when body temperature rises.
Conventional evolution is alive and well in our species. Not long ago we knew the makeup of only a handful of the roughly 20,000 protein-encoding genes in our cells; today we know the function of about 12,000. But genes are only a tiny percentage of the DNA in our genome. More discoveries are certain to come—and quickly. From this trove of genetic information, researchers have already identified dozens of examples of relatively recent evolution. Anatomically modern humans migrated from Africa sometime between 80,000 and 50,000 years ago. Our original genetic inheritance was appropriate for the warm climates where we first evolved from early hominins to humans, from knuckle-walkers to hunters and gatherers. But a lot has happened since that time, as humans have expanded around the world and the demands posed by new challenges have altered our genetic makeup.
Recent, real-life examples of this process abound. Australian Aboriginals living in desert climates have a genetic variant, developed in the past 10,000 years, that allows them to adjust more easily to extreme high temperatures. Prehistorically, most humans, like other mammals, could digest milk only in infancy—we had genes that turned off the production of the milk-digesting enzyme when we were weaned. But around 9,000 years ago, some humans began to herd animals rather than just hunt them. These herders developed genetic alterations that allowed them to continue making the relevant enzyme for their whole lives, a handy adaptation when their livestock were producing a vitamin-rich protein.
In a recent article in the Scientist, John Hawks, a paleoanthropologist at the University of Wisconsin–Madison, wrote how impressed he was at the speed with which the gene was disseminated: “up to 10 percent per generation. Its advantage was enormous, perhaps the strongest known for any recent human trait.”
Similarly, the ancestors of all non-Africans came out of Africa with dark skin. Indeed even 10,000 years ago, according to researchers, European and African skin looked much the same. But over time humans in darker northern climates evolved less heavily pigmented skin, which helped absorb the sun’s ultraviolet rays and synthesize vitamin D more efficiently. The Inuit of Greenland have an adaptation that helps them digest the omega-3 fatty acids in fish far better than the rest of us. An indigenous population near the Argentine town of San Antonio de los Cobres has evolved to be able to drink the high levels of arsenic that have occurred naturally in their groundwater.
Evolution is relentless; when the chance of survival can be increased, it finds a way to make a change—sometimes several different ways. Some Middle Eastern populations have a genetic variation that’s different from the one northern Europeans have to protect them from lactose intolerance. And there are a half dozen distinct genetic adaptations that protect Africans against malaria (one has the significant drawback of also causing sickle-cell anemia, if the altered form of the gene is inherited from both parents). In the past 50 years researchers have uncovered a variety of adaptations in Andeans, Ethiopians, and Tibetans that allow them to breathe more efficiently at high altitudes. Andean populations retain higher levels of oxygen in their blood. Among Tibetans there is evidence that a gene was introduced through interbreeding with Denisovans, a mysterious branch of the human lineage that died out tens of thousands of years ago. All these adaptations give indigenous people living at high altitudes an advantage over the woozy visitor gasping for oxygen in the mountain air.
Early in origin of species, Charles Darwin comes out fighting: “Natural Selection, as we shall hereafter see, is a power incessantly ready for action, and is immeasurably superior to man’s feeble efforts, as the works of Nature are to those of Art.” The book was published in 1859. Is what was true then still true today? Was it true even in Darwin’s lifetime? Biological evolution may be implacable, and indeed more skilful than the genetic evolution humans can effect with crossbreeding in plants and animals, but how important is it, measured against the adaptations we can devise with our brains? To paraphrase the paleoanthropologist Milford Wolpoff, if you can ride a horse, does it matter if you can run fast?
In our world now, the primary mover for reproductive success—and thus evolutionary change—is culture, and its weaponized cousin, technology. That’s because evolution is no match for the speed and variety of modern life. Despite what evolution has accomplished in the recent past, think of how poorly adapted we are to our computer screens and 24-hour schedules, our salty bags of corn chips and pathogen-depleted environments. Why are our internal clocks so rigid? Why can’t our seemingly useless appendix, which may have once helped us digest grass, shift to break down sugars instead? If human genetics were a tech company, it would have gone bankrupt when steam power came along. Its business plan calls for a trait to appear by chance and then spread by sexual reproduction.
This works nimbly in mice, which can produce a new litter in three weeks, but humans go about things more slowly, producing a new generation only every 25 to 35 years or so. At this rate, it can take thousands of years for an advantageous trait to be spread throughout a population. Given genetic evolution’s cumbersome protocols, it’s no surprise technology has superseded it. Technology now does much of the same work and does it far faster, bolstering our physical skills, deepening our intellectual range, and allowing us to expand into new and more challenging environments.
“People get hung up on Darwin and DNA,” says George Church, a molecular engineer with a joint appointment at Harvard and MIT. “But most of the selection today is occurring in culture and language, computers and clothing. In the old days, in the DNA days, if you had a pretty cool mutation, it might spread in the human race in a hundred thousand years. Today if you have a new cell phone or transformative manufacturing process, it could spread in a week.”
PRESENT DAY: TECHNOLOGY VERSUS NATURAL SELECTION We big-brained humans have done much to neutralize the power of natural selection. With our tools, medicine, and other cultural innovations, we have started a potentially deadly race—one we could lose to a highly evolved superbug. Given the speed with which we can spread disease around the globe, “we are in a new pandemic era and must take action now to stop it,” says Kevin Olival, a disease ecologist at EcoHealth Alliance. Shifts brought about by habitat destruction and climate change are also bringing more people into contact with pathogens previously isolated from human hosts.
To be sure, the picture is more complicated. As the cyberpunk writer William Gibson has pointed out: “The future is already here. It’s just not evenly distributed yet.” Some of us live in Church’s world of jet travel and intersociety marriage, of molecular medicine and gene therapy, and seem to be heading toward a time when our original genetic makeup is simply a draft to be corrected. But outside the most developed parts of the world, DNA is still often destiny.
Not all trends are irreversible, however. There are scenarios under which natural selection would return to centre stage for the rest of us too. If there were a global disease outbreak, for instance, along the lines of the great influenza pandemic of 1918, those with a resistance to the pathogen (because of a robust immune system or protective bacteria that could render such a pathogen innocuous) would have a huge evolutionary advantage, and their genes would carry forward into subsequent generations while the rest of us died out.
We have medicines today to combat many infectious diseases, but virulent bacteria have recently evolved that do not respond to antibiotics. Jet travel can send an infectious agent around the world in a day or two. Climate change might prevent cold temperatures from killing off whatever animal carried it, as winter may have once killed the fleas that harboured the plague.
Elodie Ghedin, a microbiologist at New York University, says, “I don’t know why people aren’t more scared.” She and I discussed the example of AIDS, which has killed 35 million people worldwide, a death toll roughly equal to that of the 1918 pandemic. It turns out that a small percentage of people—no more than one percent—have a mutation of the gene that alters the behaviour of a cellular protein that HIV, the virus that causes AIDS, must latch on to, making it nearly impossible for them to become infected. If you live in New York City’s Greenwich Village, with access to the best antiviral drugs, this may not decide if you live or die. But if you are HIV-positive in rural Africa, it very well might.
There are many more scenarios by which genes could return to centre stage in the human drama. Chris Impey, a professor of astronomy at the University of Arizona and an expert on space travel, foresees a permanent Martian settlement within our grandchildren’s lifetimes, stocked by the 100 or 150 people necessary to make a genetically viable community. A first, smaller wave of settlement he regards as even closer at hand: “When Elon Musk is glue-sniffing, he might say 10 to 15 years,” Impey says, “but 30 to 40 doesn’t seem that radical.” Once the settlement is established, he adds, “you’re going to accelerate natural evolutionary processes. You’re going to have a very artificial and physically difficult environment that’s going to shape the framework of the travellers or colonists in a fairly aggressive way.” The optimal Earthling turned Martian, he says, would be long and slender, because gravity on the red planet has about one-third the force of Earth’s. Over generations, eyelashes and body hair might fade away in an environment where people never come directly into contact with dust. Impey predicts—assuming that the Martian humans did not interbreed with terrestrial ones—significant biochemical changes in “tens of generations, physical changes in hundreds of generations.”
One human trait with a strong genetic component continues to increase in value, even more so as technology grows more dominant. The universal ambition of humanity remains greater intelligence. No other attribute is so desirable; no other so useful, so varied in its applications, here and on any world we can imagine. It was indispensable to our forebears in Africa and will come in handy for our descendants on the planet orbiting the star Proxima Centauri, should we ever get there. Over hundreds of thousands of years, our genes have evolved to devote more and more resources to our brains, but the truth is, we can never be smart enough.
PRESENT DAY AND NEAR FUTURE: DO-IT-YOURSELF EVOLUTION Pairing in vitro fertilization with another process allows us to test embryos for mutations that could lead to serious medical conditions. Now we’re developing powerful new gene-editing tools that could bring about human-directed evolution. Most research has been on other organisms—for instance, attempting to change a mosquito genome so that the insect cannot transmit Zika or malaria. We could harness the same techniques to “design” our babies—simply to choose a preferred hair or eye colour. But should we? “There’s definitely a dark side,” says bioethicist Linda MacDonald Glenn, “but I do think humanity-plus is inevitable. We are, by our nature, tinkerers.
Unlike our forebears, we may soon not need to wait for evolution to fix the problem. In 2013 Nick Bostrom and Carl Shulman, two researchers at the Future of Humanity Institute, at Oxford University, set out to investigate the social impact of enhancing intelligence, in a paper for Global Policy. They focused on embryo selection via in vitro fertilization. With IVF, parents can choose which embryo to implant. By their calculations, choosing the “most intelligent embryo” out of any given 10 would increase a baby’s IQ roughly 11.5 points above chance. If a woman were willing to undergo more intensive hormone treatments to produce eggs faster—“expensive and burdensome,” as the study notes with understatement—the value could grow.
The real benefit, though, would be in the compound gain to the recipient’s descendants: After 10 generations, according to Shulman, a descendant might enjoy an IQ as much as 115 points higher than his or her great-great-great-great-great-great-great-great-grandmother’s. As he pointed out to me, such a benefit is built on extremely optimistic assumptions, but at the least the average recipient of this genetic massaging would have the intelligence equal to a genius today. Using embryonic stem cells, which could be converted into sperm or ova in just six months, the paper notes, might yield far faster results. Who wants to wait two centuries to be the scion of a race of geniuses? Shulman also mentioned that the paper omitted one obvious fact: “In 10 generations there will likely be computer programs that outperform even the most enhanced human across the board.”
There’s a more immediate objection to this scenario, though: We don’t yet know enough about the genetic basis for intelligence to select for it. One embryo doesn’t do advanced calculus while another is stuck on whole numbers. Acknowledging the problem, the authors claim that the ability to select for “modest cognitive enhancement” may be only five to 10 years off.
At first glance this would seem improbable. The genetic basis of intelligence is very complex. Intelligence has multiple components, and even individual aspects—computational ability, spatial awareness, analytic reasoning, not to mention empathy—are clearly multigenetic, and all are influenced by environmental factors as well. Stephen Hsu, vice president for research at Michigan State University, who co-founded the Cognitive Genomics Lab at BGI (formerly Beijing Genomics Institute), estimated in a 2014 article that there are roughly 10,000 genetic variants likely to have an influence on intelligence. That may seem intimidating, but he sees the ability to handle that many variants as nearly here—“in the next 10 years,” he writes—and others don’t think you’d need to know all the genes involved to start selecting smarter embryos. “The question isn’t how much we know or don’t know,” Church says. “It’s how much we need to know to make an impact. How much did we need to know about smallpox to make a vaccine?”
If Church and Hsu are right, soon the only thing holding us back will be ourselves. Perhaps we don’t want to practice eugenics on our own natural genomes. Yet will we pause? If so, for how long? A new technology called CRISPR-Cas9 has emerged, developed in part in Church’s lab that will test the limitations on human curiosity. First tried out in 2013, CRISPR is a procedure to snip out a section of DNA sequence from a gene and put a different one in, quickly and accurately. What used to take researchers years now takes a fraction of the time. (See “DNA Revolution,” in the August 2016 issue of National Geographic.)
No technology remotely as powerful has existed before for the manipulation of the human genome. Compare CRISPR and IVF. With IVF you select the embryo you want from the ones nature has provided, but what if none of the embryos in a given set is, for instance, unusually intelligent? Reproduction is a crapshoot. A story, likely apocryphal, illustrates the point: When the dancer Isadora Duncan suggested to the playwright George Bernard Shaw that they have a baby together so it would have her looks and his brains, he is said to have retorted: “But what if it had your brains and my looks?” CRISPR would eliminate that risk. If IVF is ordering off a menu, CRISPR is cooking. In fact, with CRISPR, researchers can insert a new genetic trait directly into the egg or sperm, thus producing, say, not just a single child with Shaw’s intelligence and Duncan’s looks but an endless race of them.
So far many experiments using CRISPR have been done on animals. Church’s lab was able to use the procedure to reengineer pig embryos to make their organs safer for transplant into humans. A colleague of Church’s, Kevin Esvelt at the MIT Media Lab, is working to alter the mouse genome so the animal can no longer host the bacterium that causes Lyme disease. A third researcher, Anthony James of the University of California, Irvine, has inserted genes in the Anopheles mosquito that prevent it from carrying the malaria parasite.
NEAR FUTURE: SCIENCE FICTION BECOMES REALITY More than 50 years ago two scientists coined the word “cyborg” for an imaginary organism—part human, part machine. It seemed science fiction, but today around 20,000 people have implants that can unlock doors. Neil Harbisson, who can perceive colours only by transforming them into sounds he can hear through an antenna implanted in his head, sees a future vastly improved by widening our senses with such technology. “Night vision,” he says, “would give us the ability to adapt to the environment: design ourselves instead of the planet. Designing the planet is harming it.”
Around the same time, however, researchers in China surprised everyone by announcing that they had used CRISPR in nonviable human embryos to try to fix the genetic defect that causes beta-thalassemia, a potentially fatal blood disorder. Their attempt failed, but moved them closer to finding a way to fix the defect. Meanwhile there is an international moratorium on all therapies for making heritable changes in human genes until they are proved safe and effective. CRISPR is no exception.
Will such a halt last? No one I spoke to seemed to think so. Some pointed to the history of IVF as a precedent. It was first touted as a medical procedure for otherwise infertile couples. Soon its potential to eradicate devastating genetic diseases was clear. Families with mutations that caused Huntington’s or Tay-Sachs diseases used the technique to choose disease-free embryos for the mother to carry to term. Not only was the child-to-be spared much misery, but so were his or her potential offspring. Even if this was playing God in the nursery, it still seemed reasonable to many people. “For this sort of technology to be banned or not used,” notes Linda MacDonald Glenn, a bioethicist at California State University, Monterey Bay, “is to suggest that evolution has been benign. That it somehow has been a positive. Oh Lord, it has not been! When you think of the pain and suffering that has come from so many mistakes, it boggles the mind.”
As IVF became more familiar, its accepted purpose spread from preventing disease to include sex selection—most notably in Asia, where the desire for sons has been overwhelming, but also in Europe and America, where parents talk about the virtues of “family balancing.” Officially, that’s as far as the trend toward nonmedical uses has gone. But we are the species that never knows when to stop. “I have had more than one IVF specialist tell me that they can screen for other desirable traits, such as desired eye and hair colour,” Glenn told me. “It is not advertised, just via word of mouth.” In other words, a green-eyed, blond child, if that’s your taste, could already be yours for the asking.
CRISPR is a vastly more powerful technology than IVF, with a far greater risk of abuse, including the temptation to try to engineer some sort of genetically perfect race. One of its discoverers, Jennifer Doudna, a professor of chemistry and molecular biology at the University of California, Berkeley, recounted to an interviewer a dream she’d had in which Adolf Hitler came to learn the technique from her, wearing a pig’s face. She emailed me recently to say she still hoped the moratorium would last. It would, she wrote, “give our society time to research, understand, and discuss the consequences, both intended and unintended, of changing our own genome.”
On the flip side, the potential benefits of applying CRISPR to humans are undeniable. Glenn hopes at least for “thoughtful discussions” first on how the technique will be used. “What becomes the new norm as we try to improve ourselves?” she asks. “Who sets the bar, and what does enhancement mean? You might enhance people to make them smarter, but does smarter equal better or happier? Should we be enhancing morality? And what does that mean?”
Many other scientists don’t think everyone will wait to find out; as soon as CRISPR is shown to be safe, ethical questions will recede, just as they did with IVF. Church thinks this still misses the point: The floodgates are already open to genetic reengineering—CRISPR’s but one more drop in the river. He notes that there are already 2,300 gene therapy trials under way. Last year the CEO of a company called BioViva claimed to have successfully reversed some of the effects of aging in her own body with injections from a gene therapy her company devised. “Certainly,” Church notes, “aging reversal is just as augmentative as anything else we were talking about.” Several gene therapy trials for Alzheimer’s are also in progress. These won’t likely produce any objections, because they are to treat a devastating medical condition, but as Church points out, “whatever drugs work to prevent Alzheimer’s will probably also work for cognitive enhancement, and they will work in adults almost by definition.” In February 2016 the boundary crumbled a bit more when the United Kingdom’s independent fertility regulator gave a research team permission to use CRISPR to explore the mechanisms of miscarriage with human embryos (all embryos used in the experiments will ultimately be destroyed—no pregnancies will result).
Church can’t wait for the next chapter. “DNA was left in the dust by cultural evolution,” he says, “but now it’s catching up.”
DISTANT FUTURE: CAN HUMANS ADAPT TO THE RED PLANET? Large-scale evolutionary divergence from the human norm requires a population to be isolated for thousands of years—unlikely on Earth. But it’s possible we could have a small settlement on Mars before a half century passes. Then would come a larger community—100 to 150 people, with members of reproductive age to sustain and increase its numbers. Could we evolve into ideal Martians? Space travel expert Chris Impey, a professor of astronomy at the University of Arizona, foresees a colony of Martians among whom scientists could accelerate natural evolutionary processes. Bodies would become tall and thin in response to an atmosphere with less than 40 percent of Earth’s gravity, and hairless in a controlled environment where there is no dust.
Our bodies, our brains, and the machines around us may all one day merge, as Kurzweil predicts, into a single massive communal intelligence. But if there’s one thing natural evolution has shown, it’s that there are many paths to the same goal. We are the animal that tinkers ceaselessly with our own limitations. The evolution of evolution travels multiple parallel roads. Whatever marvellous skills CRISPR might provide us 10 years from now many people want or need now. They follow Neil Harbisson’s example. Instead of going out and conquering technology, they bring it within themselves.
Medicine is always the leading edge in these applications, because using technology to make someone well simplifies complicated moral questions. A hundred thousand Parkinson’s disease sufferers worldwide have implants—so-called brain pacemakers—to control symptoms of their malady. Artificial retinas for some types of blindness and cochlear implants for hearing loss are common. Defence Department money, through the military’s research arm, the Defence Advanced Research Projects Agency (DARPA), funds much of this development. Using such funding, a lab at the University of Southern California’s Centre for Neural Engineering is testing chip implants in the brain to recover lost memories. The protocol might one day be applied to Alzheimer’s patients and those who have suffered a stroke or traumatic brain injury. Last year, at the University of Pittsburgh, a subject was able to transmit electrical impulses from his brain, via a computer, to control a robotic arm and even sense what its fingers were touching. That connecting the human brain to a machine would produce a matchless fighter has not been lost on DARPA. “Everything there is dual purpose,” says Annie Jacobsen, whose book The Pentagon’s Brain chronicles such efforts. “You have to remember DARPA’s job isn’t to help people. It’s to create ‘vast weapon systems of the future.’ ”
Human enhancements needn’t confer superhuman powers. Hundreds of people have radio-frequency identification (RFID) devices embedded in their bodies that allow them to unlock their doors or log on to their computers without touching anything. One company, Dangerous Things, claims to have sold 10,500 RFID chips, as well as do-it-yourself kits to install them under the skin. The people who buy them call themselves body hackers or grinders.
Kevin Warwick, an emeritus professor of engineering at Reading and Coventry Universities, in England, was the first to have an RFID device implanted in his body, back in 1998. He told me the decision had been a natural emanation of working in a building with computerized locks and automatic sensors for temperature and light: He wanted to be as smart as the structure that housed him. “Being a human was OK,” Warwick told a British newspaper in 2002. “I even enjoyed some of it. But being a cyborg has a lot more to offer.” Another grinder had an earbud implanted in his ear. He wants to implant a vibrator beneath his pubic bone and connect it via the web to others with similar implants.
It’s easy to caricature such things. The practitioners reminded me of the first men who tried to fly, with long arm paddles fringed with feathers. But it was when I asked Harbisson to show me where his antenna entered his skull that I realized something else. I wasn’t sure whether the question was appropriate. In Philip K. Dick’s novel Do Androids Dream of Electric Sheep? (the book that became the movie Blade Runner) it’s considered rude to ask about the mechanisms powering an android. “Nothing could be more impolite,” the narrator opines. But Harbisson was eager to show me how his antenna worked. He reminded me of how happily people show off their new smartphones or fitness trackers. I began to wonder what the difference really was between Harbisson and me—or any of us.
Nielsen reported in 2015 that the average adult over 18 spent roughly 10 hours a day looking at a screen. (By comparison, we spend 17 minutes a day exercising.) I still remember the home phone number of my best friend from childhood, but not the numbers of any of my good friends now. (This is true of seven of 10 people, according to a study published in Britain.) Seven out of 10 Americans take a prescription drug; of these, one in four women in their 40s or 50s takes an antidepressant, though studies show that for some of them anything from therapy to a short walk in the woods can do as much good. Virtual reality headsets are one of the hottest selling gamer toys. Our cars are our feet, our calculators are our minds, and Google is our memory. Our lives now are only partly biological, with no clear split between the organic and the technological, the carbon and the silicon. We may not know yet where we’re going, but we’ve already left where we’ve been.
Like any other species, we are the product of millions of years of evolution. Now we’re taking matters into our own hands.
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Se busca aplicación práctica para revolucionarias tijeras genéticas
En 2015, Science designaba a la la tecnología CRISPR/Cas como el progreso científico del año. En junio de 2016, la revista TIME la llevaba a su portada. Descrita como “uno de los avances más fascinantes de la ciencia”, esta herramienta molecular, cuya andadura comenzó en Alicante de la mano de Francisco Mojica ( el científico español que caracterizó y dio nombre a CRISPR), permite editar el ADN con “una precisión notable”. Según las citadas publicaciones estadounidenses, tiene el potencial de cambiar las vidas humanas para siempre.
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Children's Hospital Los Angeles asks blood donors to step up
"Another challenge? Newly emerging diseases like Zika and West Nile virus pose a risk to the local blood supply. There are also restrictions for donors who have traveled to a country where they may have been exposed to malaria."
http://www.scpr.org/news/2017/07/05/73530/children-s-hospital-los-angeles-asks-blood-donors/
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TATA Institute Web Site - http://tigs.ucsd.edu/
NBC News - Sunday Night with Megyn Kelly - June 11, 2017
A breakthrough in gene editing, CRISPR, gives humans unprecedented access to the source code of life. ... Up the coast at the University of California, Irvine, they are trying to rid the world of a disease that kills a child every two minutes. Dr. Anthony James is using CRISPR to bred malaria free mosquitoes. [starts at 3:52]
Bier Lab website UCSD - http://bierlab.weebly.com/
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Panel Endorses ‘Gene Drive’ Technology That Can Alter Entire Species
Credit Anthony James
Editing the Genome of Mosquitoes
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