Koch Foundation

Draper

<p>The same technologies that will rid the electric grid of fossil fuels could also save it from potential disaster.</p>

Saving the Sun





  
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<p>
 In the last few years, biologists have realized something remarkable: We might finally be able to beat evolution at its own game.
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<p>
 Using the gene editing tool CRISPR, which snips DNA and inserts a new gene of the designer’s choosing, biologists can arrange it so that a gene will spread exponentially through a population of organisms. While that occasionally happens in nature, with certain caveats, evolution has generally been against us: If a few mosquitoes are released with a gene that prevents them from carrying malaria, the gene will be swamped in the gene pool. The mosquitoes will only pass it on to half their offspring, who will in turn pass it on to only half of theirs, and before long it will drop out of the population. In the meantime, malaria kills more than 1 million people per year, mostly children five years old or younger. And other mosquitoes spread Zika—linked to severe birth defects—and yellow fever and dengue fever, whose numbers have escalated alarmingly in recent decades.
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 So when, in 2014, researchers began to point out that there was a way to help such genes take over, it caught people’s attention. If a mosquito is given a bit of DNA that not only codes for that gene but for the CRISPR machinery itself, then the CRISPR proteins will go around inserting themselves and their cargo, ensuring that all the insect’s offspring will have them, as will all of their offspring. As the gene (and the CRISPR machinery) are passed down, it will spread exponentially. Soon, it might take over the population or perhaps even the whole species—and, in this example, no mosquitoes would be capable of carrying malaria. The same technology could just as well spread a gene that could cause a mosquito population crash, however, which has yielded many calls for caution and prudence in studying gene drive systems, as these constructs are known.
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 But there is a chink in gene drives’ armor. Specifically, it is possible for organisms to escape though an age-old trick, one that we’re growing more familiar with by the day—by evolving resistance, just as bacteria evolve resistance to antibiotics. In a recent paper
 <a href="http://biorxiv.org/content/early/2016/06/11/058438">
  posted to the biorXiv
 </a>
 , evolutionary geneticist Rob Unckless of the University of Kansas and colleagues lay out mathematical models of what may happen when gene drives are released, and find that even under the best of conditions, resistance is certain to arise. Exactly what that insight means—whether it is a fatal flaw in the technology, merely an obstacle to be overcome, or perhaps even a tool to be used—is still an unanswered question.
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 Botched Repairs
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<p>
 It’s been known from the earliest work on
 <a href="http://www.pbs.org/wgbh/nova/next/evolution/crispr-gene-drives/">
  CRISPR gene drives
 </a>
 that resistance was a strong possibility. That’s because CRISPR will cut DNA only at places with a specific sequence of DNA bases. The recipe for the CRISPR machinery and its cargo gene then have to be pasted into that cut. The cell will usually cooperate because this bit of genetic material is designed to blend in. But with each cut, there is a chance that the cell will instead try to repair the gap by putting in some new DNA base pairs. “It tries to do its best,” Unckless says, “but it makes a lot of errors.”
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<p>
 Once the gap has been repaired, it might well have a different sequence of DNA bases than the CRISPR system can cut. And after that, there’s nothing the gene drive system can do to it. It’s immune. “We think that is going to be the biggest source of resistance,” Unckless says, echoing a general consensus among a number of scientists. “CRISPR breaks the sequence, but instead of having the CRISPR machinery inserted, the repair is done through this [other] process.”
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            <figure class="richtext-image full-width"><img alt="gene-drive-schematic" class="richtext-image full-width" height="449" width="800"
            src="/wgbh/nova/media/images/gene-drive-schematic_QCVdY0Q.width-800.png"/><figcaption>
  Here, a mosquito with a gene drive (blue) mates with a mosquito without one (grey). In the offspring, one chromosome will have the drive. The endonuclease then slices into the drive-free DNA. When the strand gets repaired, the cell's machinery uses the drive chromosome as a template, unwittingly copying the drive into the break.
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 If the repaired area prevents mosquitoes from being modified, depending on the modification, it might suddenly become a very handy thing to have. If all the mosquitoes that receive a gene drive die or become infertile or simply produce less offspring than those that are resistant, the resistant type will eventually take over. By putting our thumb on the scale of evolution on behalf of one gene, we create a situation where an opposing version can take over, if the benefits of having it are great enough.
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 There are a lot of “ifs” in that paragraph, but what Unckless and his collaborators found in their models—which assign numbers to those unknowns—was that even at very low rates of erroneous self-repair, resistance is a clear specter. If 100 copies of the gene drive are released, and the rate of self-repair is as low as one in 100,000, resistant organisms will still make up half the population after 100 generations have passed. A larger population will have more problems with resistance than a small one—more cuts mean more chances for resistance to arise. And in fact, Unckless and his collaborators made a very conservative assumption for the rate for this kind of repair, to see whether resistance would happen even then. Experiments suggest the rate is much higher in real organisms, perhaps one in 100. “I think [resistance] will block the drive much sooner than their model predicts,” says Kevin Esvelt, an evolutionary engineer at MIT.
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 By itself, this isn’t terribly surprising, says Omar Akbari, an entomologist and molecular biologist at UC Riverside. “It just highlights the fact that it’s going to be an issue,” he says.
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<p>
 But the question of what effects this kind of resistance will have is something the community has been thinking hard about, says Valentino Gantz, a post-doc at UC San Diego who has made gene drives in fruit flies and mosquitoes. “This is exactly one of my worries from when we started going in to mosquitoes,” he says. “I was hoping that population geneticists would do a nice analysis such as [this] one.”
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 “One of the realizations we’re coming to is that resistance is almost inevitable.”
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 How big of a problem this will be depends on what exactly a gene drive’s goal is. “If you’re targeting dengue,” says Akbari, “if you’re able to block all disease transmission for a few weeks”—in order to create a situation in which after running its course in infected individuals, the virus cannot spread any further—“that could essentially eliminate the virus. So you don’t need it to last indefinitely.” On the other hand, if the goal is to create a lasting alteration—to permanently keep mosquitoes from transmitting Zika, for instance—it would be a non-starter if in a hundred mosquito generations, around four to eight years, half of all mosquitoes would again be able to spread disease.
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<p>
 Which is why researchers have begun to design ways to thwart resistance. In one strategy, the CRISPR machinery cuts at a gene that is required for life, so that if the self-repair mechanism screws up, it’s lethal to the organism. In another, the CRISPR machinery can cut at five different sites, so that if one gets repaired so as to be immune, the others are still available. Another option would be to release a drive knowing resistance will arise, and, for however long is appropriate, releasing others that target the resistant genes, engaging in a kind of arms race with evolution.
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<p>
 It’s possible, too, that resistance, in certain situations, could be useful. “One of the realizations we’re coming to…is that we think resistance, probably at least in a simple system, is almost inevitable, so maybe we should embrace that,” Unckless suggests. If a drive is gradually out-competed by a resistant version, well, maybe there are situations where that would be preferable. Perhaps resistance could be part of a containment plan, for example in situations where a population is already isolated from others, and the inevitable resistance could catch up with the drive before any pioneering individuals could leave and spread their genetic payload. This is still conjectural, however. And there are likely to be much more predictable tools to accomplish the same task.
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<h2>
 Out of the Lab
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<p>
 Still, all these models and ideas and proposals being tossed around eventually have to acknowledge the fact that there have not been very many tests in real organisms or in realistic populations. No one thinks we have enough information yet about how gene drives work in practice to be able to reliably predict their effects.
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 There are reasons aplenty why they might not function as planned. Anna Lindholm, an ecologist at University of Zurich, studies a naturally occurring gene drive system in mice, which is carried by males and spreads itself to more than 90% of the sire’s offspring. While researchers have never seen genetic resistance to the system evolve, she says, it hasn’t spread as quickly as you might think. That seems to be because of a simple fact of mouse mating behavior: These females mate with many males in quick succession, and the males with the drive often see their sperm out-competed by those of rivals. The drive is out of the game before it ever gets a chance to do its thing.
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 A gene drive released in a mosquito population could nose-dive because of some unforeseen feature of the natural world—or even of the particular area where it is released. “When you’re doing it with one species of one mosquito in one location, it might work perfectly, exactly as on paper,” Gantz says. “And when you do the same exact experiment in a different location, it might just not work for some other reason.
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 “I think we’ve gotten to the point where I believe the technology should move toward generating mosquitoes that are field-ready and extensively testing them in the lab and making sure there are no unexpected behaviors of the system in populations in the lab before you go into the field,” he says.
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 Gantz isn’t worried that a drive will spread too well, taking over populations so fast as to be uncontrollable. Rather, he is worried that a much-anticipated test will fall flat. Others in the community are more preoccupied with the first scenario. Esvelt and his colleagues have proposed a control mechanism that would split up the machinery required for the gene drive system and disperse it throughout the genome, arranging it so that without intervention, it will eventually go defunct. “We like that because it’s less of a blunt instrument,” says Charleston Noble, a graduate student at Harvard University who is working on the idea alongside Esvelt. But until more experiments happen, there is not enough information to tell which scenario is most likely.
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 As such tests unfold and the data are released, scientists will be looking for signs of problematic resistance, and whether, with these new tools, we really can reliably steer evolution toward our own ends. Gene drives are potentially powerful, but also potentially very delicate—a technology full of contradictions.
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 Image credits: Steve Dixon/Feng Zhang/MIT, Esvelt et al 2014 (CC BY)
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<p>With the power to modify entire populations, gene drives promise to upend evolution—or not.</p>

For Gene Drives, Resistance May Be Inevitable





  
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<p>
 Fifteen years ago or so, when
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  Helen Sang
 </a>
 , a geneticist at the Roslin Institute in Edinburgh, and her colleagues wanted to get a gene into a chicken, the process was anything but fast.
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 They would begin by making a virus that would insert genetic material into a chicken embryo. As the embryo developed, they would cross their fingers and hope that some of the cells that received the infusion of DNA became the chicken’s reproductive cells. Even if they did, it took waiting six months until the chicken reached maturity and could be bred to get a generation of chickens that had the gene in all their cells.
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 Depending how on the process went, by that point, more than a year might have passed. And the researchers still would not have gotten to do the actual science they were interested in—studying how the new gene worked in chickens, for instance. Even in mice, the well-studied, well-understood workhorses of the biology lab, it could be a lengthy and delicate process to get an animal that carried a gene of your choice. And if you were thinking of trying out a gene in a less-studied animal, say, parakeets or honey badgers, it could take a significant chunk of your career just to figure out how to do it.
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 This was the reality of doing science that involved gene engineering for many years, and researchers still managed to make enormous progress. One of Sang’s projects, to develop chickens that lay eggs containing melanoma and multiple sclerosis drugs,
 <a href="https://www.technologyreview.com/s/407193/drugs-sunny-side-up/">
  made headlines in 2007
 </a>
 , for instance. The idea was to harvest the drugs from eggs, part of a trend to grow pharmaceuticals in engineered organisms. (It’s not as far out as it might seem at first blush, as
 <a href="https://www.nytimes.com/2009/02/07/business/07goatdrug.html">
  the FDA has already approved
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 goats that make antithrombin, an anti-blood-clotting protein, in their milk, and insulin is now commonly grown by vats of engineered bacteria.)
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<p>
 But in the last few years, a new technology has arrived on the scene. CRISPR-Cas9 gene editing has made its way into labs around the world. It’s a comparatively cheap, fast, and adaptable way of precisely snipping out pieces of the genome and swapping in new pieces, which can be used directly on the DNA in reproductive cells and
 <a href="http://www.genetics.org/content/199/1/1#sec-4">
  produces a finished mouse in three weeks
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 . In chickens, it nearly halves the amount of time needed, Sang says. The tools are so quick, she says with a laugh, that “I sometimes think I should have sat with my feet up for a long time and waited for them to come.”
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 With something like this in hand, ideas that might have seemed overwhelmingly difficult are now potentially doable. In particular, scientists have swiftly adapted CRISPR tools for use in animals beyond mice, fruit flies, and other model organisms. That opens up a whole menagerie of creatures where quick, accurate gene editing is possible, with implications for agriculture and medicine.
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 “I sometimes think I should have sat with my feet up for a long time and waited for them to come.”
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 In Sang’s lab, using CRISPR, the researchers are able to get their genes into chicken eggs with much higher efficiency. Using viruses, they succeed only a portion of the time, but now, with CRISPR and some additional screening, the success rate approaches 100%.
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 Other parts of the process have gotten more efficient as well. “CRISPR has come along when we’ve got a lot of genome sequence information,” Sang says. She and her colleagues can make informed choices about which genes might be most interesting or useful to put into a modified animal, without having to do as much testing ahead of time in dish-grown cells as they used to. She is now interested in using CRISPR to give chickens greater resistance to disease, especially to the avian flu. If there are some strains of hardy chickens that can stand up to an infection, perhaps researchers can figure out what quirks of the genome contribute and then use CRISPR to make alterations in meat and laying breeds.
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 The hold-up now, Sang says, is not the time it takes to make chickens anymore, but having proper facilities to house them.
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 CRISPR at Sea
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 CRISPR has also opened new doors for Anna Wargelius, a salmon geneticist at the Institute of Marine Research in Bergen, Norway. For many years, she and her colleagues had been working toward the goal of making a salmon for farming that was sterile, so that if any escaped into the open sea—a real risk in Norway, where salmon are farmed in the ocean—they would not be able to breed with wild ones.
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 The group wanted to use genetic engineering to study which genes were involved in the development of salmon reproductive, or germ, cells. But they had little luck with zinc fingers, an earlier form of gene editor. “We had tried for several years to functionally study genes, but it did not work well in salmon,” she said. When they read a study demonstrating that CRISPR could work in zebrafish, the most common fish model organism, they were delighted. “We were just so happy to see this technology,” she recalls. “We were ready!” In 2014, the group published
 <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177897/">
  a paper
 </a>
 demonstrating that CRISPR could be used to knock out genes in salmon. Since then, they have successfully made salmon without germ cells, and are moving on to using CRISPR to see whether the fish can be encouraged to generate more of their own omega-3 fatty acids.
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  Sterile farmed salmon wouldn't be able breed with wild populations if they escaped.
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 Wargelius says the efficiency—the fact that every organism they generate has the gene they want very quickly—has rapidly accelerated work not just in her lab, but in other groups whose study species take a long time to reach reproductive maturity. Having to wait out multiple salmon generations, which are about three years long, to begin the real work is a serious and expensive gamble. “For everybody working with long-generation animals or plants, they are really happy with this,” Wargelius says, “because you can functionally start with something already in the first generation. It saves a lot of time and money.”
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<h2>
 Pigs and Beyond
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<p>
 The subtlety of the changes that CRISPR allows is also advancing projects in some creatures in remarkable ways, says Simon Lillico, a geneticist at the Roslin Institute who works with pigs. Funded in part by a breeding company, Lillico and colleagues have been studying how to keep pigs from catching a viral disease called porcine respiratory and reproductive syndrome, or PRRS. While it may not be a household name for most people, the PRRS virus, which causes pneumonia and stillbirths and abortions in pregnant pigs, is behind massive losses in farming—
 <a href="https://www.prrs.com/en/prrs/cost/">
  $664 million a year in the U.S. alone, by one estimate
 </a>
 . The virus gets into pig blood cells by clinging to a surface protein called CD163, specifically to a particular stretch of the protein called domain 5.
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            <figure class="richtext-image full-width"><img alt="pig" class="richtext-image full-width" height="450" width="800"
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  CRISPR pigs have successfully evaded a typically deadly virus.
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 Taking advantage not only of CRISPR’s efficiency and speed but its delicacy, Lillico and colleagues were able to
 <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5322883/">
  generate pigs that were missing just that snippet of CD163
 </a>
 . “When you put the virus on the pigs, it cannot infect them,” he says. “It’s kind of like a lock and key mechanism—the virus has the key, but we’ve removed the lock.” The domain-5-less pigs are otherwise healthy.
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 It’s not just pigs that are benefiting, Lillico says. It’s now more plausible to use pigs and other large mammals as models for human disease. There are some diseases and situations where mice might not be as good as a model as other mammals, he suggests, and CRISPR makes it more feasible for these options to be explored. There may be a more direct benefit, too: A group at MIT has also been
 <a href="http://www.sciencemag.org/news/2017/08/crispr-slices-virus-genes-out-pigs-will-it-make-organ-transplants-humans-safer">
  using CRISPR to remove portions of the pig genome
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 that contain remnants of old viruses, which might be a liability if ever it becomes possible to transplant pig tissues or organs into humans, an idea that’s been given some new life lately. And in Australia, a group at the CSIRO has been
 <a href="http://www.abc.net.au/catalyst/stories/4529197.htm">
  investigating how egg proteins can be modified with CRISPR
 </a>
 so that they don’t trigger allergies in those who eat them. (No honey badger or parakeet CRISPR studies yet, though, according to a search in PubMed.)
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 “It’s only just starting,” says Helen Sang, who notes that the technique has caused a shift in many scientists’ thinking about whether it is worth trying to engineer animals. “Somehow, the fact that we have a new technology that is so easy to use, and so precise, it’s beginning to get people to think, oh maybe we will be able to use it,” she adds. “Because there are so many advantages, and there really are a lot of opportunities.”
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<p>Gene editing with CRISPR is so fast, cheap, and adaptable that scientists in a variety of fields are putting it to use.</p>

How CRISPR is Spreading Through the Animal Kingdom





  
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 The genome is full of secrets. And some of them can kill you: Tiny alterations in key genes can send a newborn’s body into a downward spiral as poisons build up, seizures wrack the brain, and organs go into failure.
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 When doctors see a patient whom they suspect of having such a disease, they call in clinical geneticists, who have a keen eye for symptoms that point to specific conditions. Even so, for newborns with a genetic disease, death may come before an answer.
</p>
<p>
 For older children whose symptoms were not evident immediately, their families must often go through what is called a “diagnostic odyssey” as clinicians conduct test after test trying to determine the cause. It’s a phrase that encompasses all the pain, fear, and uncertainty of not knowing what you can do to help your child, whether they will live to adulthood or die next year, and even whether you should have another child, knowing there’s a chance they will suffer in the same way.
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 In the last few years, however, something remarkable has happened—so quickly that clinical geneticists’ voices are filled with awe when they talk about it. Nearly science-fictional advances in the speed and cost-effectiveness of genome sequencing now allow physicians to sequence large swaths of their patients’ genomes, or even, in a few select places, the entire genome. If traditional genetic tests, which usually check for a particular disease, are like pointing a telescope at a distant star, then this is like standing in a planetarium surrounded by the Milky Way, lost in a sea of brightness and information. Last fall, two papers in
 <i>
  JAMA Pediatrics
 </i>
 showed the effects of deploying these methods on a large scale, with exciting results. The rise of these techniques signals a shift in how genetic diseases are diagnosed and treated.
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<h2>
 Race Against Time
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<p>
 To give a sense of the stakes here, perhaps one of the most immediate changes is for babies who, in the normal way of things, might never have lived long enough for their parents to get a diagnosis, not to mention a hope of saving them. One such newborn recently arrived at the Rady Children’s Hospital in San Diego. The baby shook with constant, uncontrollable seizures, even when treated with the strongest anti-epileptic drug available. Though the doctors upped the dose to the point where the infant had to go on a ventilator, the seizing went on. “The EEG readings are telling us that this baby, as we watch it, is frying its brain,” recalls Dr. Stephen Kingsmore, who is the president and CEO of the Rady Children’s Institute of Genomic Medicine, which works with the hospital. “And so we are counting the days until this baby will die. We are aware that progressive neurologic damage is happening as we watch.”
</p>
<p>
 Traditional genetic tests may take months or weeks to come back, by which time this child would have been long gone. At the Rady Institute, however, a whole genome sequence can be turned around in an average of four days. The Rady family gave $120 million to help establish the Institute of Genomic Medicine that Kingsmore leads, and it’s widely acknowledged as a leader in these techniques. Within 72 hours of the child’s arrival, geneticists were looking at a whole genome sequence, checking their suspicions against the data. And there the problem was: The infant had a mutation in a gene for an enzyme that controls the breakdown of the amino acid lysine.
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  Genome sequencing has come down in price considerably, enough so that it can be cost effective in clinical settings.
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 “It turned out that the seizures were treatable with injections of vitamin B6, arginine, and a modified diet” with low lysine, Kingsmore says. These treatments will be lifelong, but they protect the brain from further damage. Ten days after being admitted, the baby went home.
</p>
<p>
 It’s enough to make your head spin, especially since it wasn’t that long ago that single mutation tests were a pretty exciting technology, says Dr. Seema Lalani, a clinical geneticist at Texas Children’s Hospital and Baylor College of Medicine who led one of the new
 <i>
  JAMA Pediatrics
 </i>
 studies. When she started her training in 1999, such assays were already a big part of a geneticist’s toolkit. Then in the early 2000s, the chromosomal microarray (CMA), which allowed geneticists to look at multiple regions of the genome, came on the scene. If the genome is a book, she explains, then “CMA was able to help us with finding if there was a page or a paragraph missing.”
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 “The entire field of inherited genetic disorders was going to be cracked open. Progress was going to massively accelerated.”
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 Still, as progress on sequencing accelerated, a new world came into view for Lalani and other geneticists. 2009 was a key year. In August, a team led by Jay Shendure
 <a href="https://www.nature.com/articles/nature08250.epdf">
  published a proof-of-concept paper in
  <i>
   Nature
  </i>
 </a>
 demonstrating that even if you just sequenced the portion of the genome that makes proteins—the exome—you could identify the gene behind a genetic disorder. In November, they published another study where they put it into practice: They discovered the gene behind Miller syndrome, a disorder whose precise cause was unknown, using exome sequencing.
</p>
<p>
 That changed everything. “That’s when we knew it had really hit,” remembers geneticist Dr. Leslie Biesecker of the NIH, who was present at the American Society of Human Genetics meeting in Honolulu that year, when the researchers first released their work to the community. “The entire field of inherited genetic disorders was going to be cracked open. Progress was going to massively accelerated.” This was like getting all the letters in all the words of a very significant part of the book.
</p>
<p>
 Indeed, research boomed. Between 2010 and 2015, about 250 new genes a year were connected to human disease. The number of genetic disorders with a known cause skyrocketed, and plans to take the technology from the lab to the clinic got into gear. “It happened faster than any of us thought and paid off more richly than any of us thought,” Biesecker says. Within a couple of years, there were labs set up where doctors could send patient samples for clinical sequencing.
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 Limitations
</h2>
<p>
 Still, these kinds of sequencing can’t help with everything. Children with autism, for instance, don’t have nearly the luck with whole-exome sequencing as some others, Lalani says, noting that only about 4–5% of them get useful information. The sequences also don’t just come off the presses with an answer written in red ink. Instead, it’s just a jumble of letters that geneticists have to pore over carefully, going through a list of genes that their experience has taught them may go along with certain symptoms. Even then, mistakes can be made. “There are certain genes in the genome that are very hard to interpret,” Kingsmore says. In those cases, assuming a simple cause-and-effect relationship may be a mistake.
</p>
<p>
 All the same, in a surprising number of cases, clinicians can go to their patients and their families with a useful answer. In their
 <i>
  JAMA Pediatrics
 </i>
 study, Lalani and colleagues used whole-exome sequencing with nearly 300 infants suspected of genetic diseases that came through their hospital doors over the course of five years, starting in December 2011. These were children who, like the baby in San Diego, were critically ill. In 36% of cases, a genetic diagnosis came back.
</p>
<p>
 For some, the diagnosis meant a different course of action than might have been taken without the information. Sometimes doctors could tell families definitively that there was nothing that could be done for the baby, beginning the process of helping them think through what would come next. For others, the genetic information meant a better chance at life, pointing toward treatments like heart transplants or stem cell transplants and away from medications and other therapies that had no bearing on the disorder. As well, in a surprisingly high number of cases, Lalani says, the doctors could give the parents of children who had died information about whether future children would be likely to have similar problems.
</p>
<p>
 The number of cases in which sequencing gave useful information is similar to what Kingsmore and colleagues reported in a study two years ago, suggesting that this may be the yield doctors can expect when sequencing infants suspected of a genetic disease in an intensive care unit.
</p>
<p>
 In the other recent
 <i>
  JAMA Pediatrics
 </i>
 study, an Australian team focused on older children seen by geneticists at a clinic at the Royal Children’s Hospital in Melbourne, the kind of children for whom the diagnostic odyssey had gone on and on—in this case an average of six years. They were suspected of having a genetic disease, but had not had any sequencing. With sequencing of the whole exome, 52% of them received a diagnosis. For about a quarter of those, it changed their treatment plan. It also changed plans for future tests. For instance, says Dr. Tiong Tan, a clinical geneticist at Victorian Clinical Genetics Services who coauthored the study, one child had been lined up to have a spinal tap and a brain MRI. But they were canceled after the sequencing came back with a clear answer. “You can avoid a whole bunch of tests by making a specific diagnosis,” Tan says.
</p></div>
  

  
      

<div class='pullquote'>
  <div class="rich-text"><p>
 It cost $6,838 less to just sequence the children right away than to go through a lengthier set of tests and visits with other specialists.
</p></div>
</div>

  

  
      <div class="rich-text"><p>
 That’s an important observation, because another focus of the study was cost. While sequencing prices have plummeted, these tests still cost thousands of dollars. Insurance companies may question whether such an expensive option is worth it. Part of the goal with this study, Tan says, was to see whether doing sequencing when patients first come into the clinic results in not only a less painful, frightening, and dangerous process—about 60% of the children had had to go under general anesthesia at some point for a diagnostic procedure—but also a cheaper one.
</p>
<p>
 As it turns out, it does. According to the study, it cost $6,838 less to just sequence the children right away than to go through a lengthier set of tests and visits with other specialists. The researchers hope that this study will encourage the Australian government to include whole-exome sequencing in the list of treatments that the national health service will pay for and help colleagues in other countries make similar cases to insurance companies.
</p>
<p>
 While sequencing is changing how patients and families get answers, it’s also provoked some interesting observations about these diseases. More often than expected, when the results come back, the geneticists realize the child has a disorder that they didn’t know could look like this. Years of training and clinical observation have trained their eyes to certain symptoms, textbook cases. But about 30% of the diagnoses the Melbourne team saw were surprising. Often, Tan says, “the exome sequencing shows us an unknown form of a known syndrome.”
</p>
<p>
 Lalani and her colleagues experienced this too. “We saw this recurrently, again and again,” she says. “About 38% had atypical presentation of their disorders” or a form that hadn’t been recognized before. As doctors continue to explore the use and usefulness of these tests, they may learn not only what to tell their patients and their families, but more about how these diseases work, potentially benefiting patients who have yet to be born.
</p></div>
  

  
      <div class="newsletter"></div>
  

  
      <div class="rich-text"><p>
 Photo credits: garymilner/iStockphoto, Roy Kaltschmidt/Lawrence Berkeley National Lab
</p></div>
  



<p>Newborn genetic diseases are often swiftly fatal, but gene sequencing can help doctors make life-saving diagnoses.</p>

Gene Sequencing Speeds Diagnosis of Deadly Newborn Diseases





  
      <div class="rich-text"><section class="entry-content instapaper_body clearfix" itemprop="articleBody">
 <div class="add-container clearfix" id="add-block-placer">
 </div>
 <p>
  “That’s a cosmic ray.” A few seconds later: “And that’s another cosmic ray.”
 </p>
 <p>
  Samuel Ting, a Nobel Laureate and professor of physics at MIT, is standing before a monitor in his office above a high-ceilinged control room outside Geneva, Switzerland, calling out cosmic rays striking a detector orbiting hundreds of miles above the Earth. The monitor shows a schematic of the detector picking up the events. Lines draws themselves across the screen, turning green where they hit the instrument.
 </p>
 
            <figure class="richtext-image full-width"><img alt="AMS_on_ISS_700k" class="richtext-image full-width" height="450" width="800"
            src="/wgbh/nova/media/images/ams_on_iss_700k.width-800.jpg"/><figcaption>
  The AMS detector aboard the International Space Station
 <div class="credit"></div></figcaption>
            </figure>
            
 <p>
  The control room below is dominated by a map of the world that covers an entire wall. Unfurling across it in lazy S-curves are a series of trajectories—the future paths of the International Space Station, the orbital home of the Alpha Magnetic Spectrometer (AMS-02), a 7.5-ton, $2 billion device that’s tasked with looking for dark matter. Computers manned 24 hours a day by researchers monitoring AMS sit in a horseshoe shape before the massive map. Ting, lead researcher on AMS, has shepherded the project from the its conception nearly 20 years ago, and he looks at the detector schematic with a certain pride.
 </p>
 
            <figure class="richtext-image full-width"><img alt="AMS control room" class="richtext-image full-width" height="449" width="800"
            src="/wgbh/nova/media/images/ams-control-room.width-800.jpg"/><figcaption>
  Inside the AMS control room at CERN
 <div class="credit"></div></figcaption>
            </figure>
            
 <p>
  Elsewhere in the sprawl of buildings that makes up CERN, physicists tend experiments that happen beneath their feet in the Large Hadron Collider. Here, the AMS team looks up instead, waiting for signs of dark matter via cosmic rays, the high-energy particles that whip through the solar system from regions beyond. Dark matter is one of the items on CERN researchers’ to-find list.
 </p>
 <p>
  When the LHC comes back online in 2015 after maintenance is completed, physicists will continue searching for signs of dark matter in its more powerful collisions. But for the AMS team, the hunt for dark matter is happening now. As you read this, data from the detector is streaming down from the ISS to computers on Earth, each a tiny pixel in the very large picture that is the universe.
 </p>
 <h2>
  Eighty Years
 </h2>
 <p>
  The first suggestion of dark matter’s existence was in 1933, when Swiss astronomer Fritz Zwicky was studying the Coma galaxy cluster. He calculated the mass of those galaxies in two ways: first, by judging their speed, which is related to the pull of gravity they exert on each other, and then by judging from the light they released. Far from lining up, the two numbers were terrifically different. The gravitational mass was ten times more than the mass implied by the galaxies’ light. The best explanation, the one that drives the search for dark matter today, was that there was a whole lot of matter in those galaxies that telescopes couldn’t detect—matter that didn’t produce radiation or light of any kind.
 </p>
 <aside class="pulledquote">
  What, exactly, it consists of is a puzzle.
 </aside>
 <p>
  Cosmologists and astrophysicists have since built simulations of how dark matter might be distributed around the universe, producing beautiful three-dimensional mazes of clumps and strands. And research has established that there is much, much more dark matter—more than five times as much—than the kind of matter that makes up both us and the stars. But what, exactly, it consists of is a puzzle that experimental particle physicists and theorists alike have been spinning stories about for decades.
 </p>
 <p>
  One leading idea is that dark matter is a particle that almost never interacts with anything else, called a weakly interacting massive particle, or WIMP. That would fit nicely into existing theories about the complement of particles that populate the universe. But first, researchers have to find them.
 </p>
 <h2>
  Three Possibilities
 </h2>
 <p>
  Sitting at a table in the CERN cafeteria, Heidi Sandaker, a professor at University of Bergen in Norway and a physicist on the ATLAS experiment in the Large Hadron Collider, sketches diagrams on a sheet of graph paper. She lays out the three types of experiments you can do that would show signs of dark matter.
 </p>
 <p>
  For one of them, physicists place detectors at the bottom of a mine, where the earth filters out a lot of noise, to look for signs of an extremely rare interaction between a dark matter particle and a standard matter particle. The results of these types of interactions would be very subtle, perhaps just a few electrons out of place. The second option involves ramming particles together in an accelerator and checking afterward to see whether there’s less energy released than you’d expect, which could be a sign that a dark matter particle was created and went off on its merry way. And the third requires sending a detector up into space, far from the interference of the atmosphere, to see whether certain particles bouncing around out there are more or less numerous than you would expect, which could be the result of dark matter particles colliding with each other. The last, of course, is why AMS is up on the International Space Station.
 </p>
 
            <figure class="richtext-image full-width"><img alt="bulletcluster_comp_f2048" class="richtext-image full-width" height="450" width="800"
            src="/wgbh/nova/media/images/bulletcluster_comp_f2048.width-800.jpg"/><figcaption>
  The blue hues in this composite image of the "bullet cluster" show where dark matter is distributed. The image was created by gravitational lensing of galaxies in the background.
 <div class="credit"></div></figcaption>
            </figure>
            
 <p>
  These different approaches complement each other because the search for dark matter has a lot in common with looking for your missing keys. It’s all about ruling out places they might be—or in this case, what traits dark matter might have. But unlike looking for your keys, coming up empty-handed at the end of one trawl for information can actually be cause for celebration.
 </p>
 <p>
  Last year, the LUX experiment turned up no sign of dark matter at all, and scientists reported it with a certain sense of glee, according to Dennis Overbye, who
  <a href="http://www.nytimes.com/2013/10/31/science/space/dark-matter-experiment-has-found-nothing-scientists-say-proudly.html?_r=0" target="_blank">
   wrote about the “failure” wryly in the
   <i>
    New York Times
   </i>
  </a>
  . That’s because the LUX experiment, one of the underground variety, would only detect signs of dark matter if the WIMPs were especially light and numerous. That it found nothing means that they must be on the heavier and rarer side, if they exist. (It’s not in the couch, everyone—onward, to the shelf in the bathroom!) Given the wide variety of error margins and detector types, lining up the results from all the different experiments isn’t a simple task. But that’s the idea.
 </p>
 <p>
  In the years before the maintenance shutdown, experiments at the LHC already ruled out a swath of lighter solutions. But when the collider starts up again in 2015, it will be accelerating particles at higher energy levels than ever before. That means the collisions will be more intense, and in the traces that remain, researchers will be able to look for signs of dark matter candidates in the heavier, yet-to-be-ruled-out range. Physicists also intend to ramp up the number of collisions to many times more than when the LHC was working at lower energy levels, so that means there will be plenty of chances to see something, Sandaker says.
 </p>
 <h2>
  Shower of Particles
 </h2>
 <p>
  AMS, for its part, has been gathering data continuously since its launch in 2011. And the team has already seen some suggestive tentative results. As cosmic rays pass through the detector up on the space station, researchers on the ground can tell certain things about the particles. The detector has a cylindrical magnet at its heart, explains physicist Mike Capell, a senior research scientist on AMS, and when cosmic rays pass through the magnet, their paths curve ever so slightly. This curve, along with myriad other measurements taken by a suite of devices, tells researchers the particles’ momentum, charge, and classification—for instance, if it’s an electron versus a proton. Anywhere from a few hundred to a couple thousand particles whiz through every second, depending on where the space station is in its commute. (The display in Ting’s office, with one ray every few seconds, is a kind of “greatest hits” from that shower.)
 </p>
 <p>
  AMS is taking a census of those particles, making a note of whether they’re, say, a stray nucleus from helium atom, one from a carbon atom, an electron, a positron (a particle with the same mass as an electron but opposite charge), or any number of other things. The idea is to see whether that census corresponds to what current theories about cosmic rays imply should be there. If there’s a discrepancy, that could be a signature of dark matter. For instance, when two dark matter particles collide, they are thought to produce an electron and a positron. If there are more positrons at high energies than expected, then that could be a clue that dark matter is out there, colliding with itself.
 </p>
 
            <figure class="richtext-image full-width"><img alt="CERN AMS control building" class="richtext-image full-width" height="450" width="800"
            src="/wgbh/nova/media/images/cern-ams-control-building.width-800.jpg"/><figcaption>
  The AMS control center at CERN
 <div class="credit"></div></figcaption>
            </figure>
            
 <p>
  In 2013, the AMS team announced that they had, in fact, seen just such an excess. “You expect a fraction of positrons from garden-variety physics, but it’s not nearly as many positrons as we found,” Capell says. “So why would you have an excess of positrons? You would have them if you didn’t have garden-variety physics happening, if you had dark matter colliding.” Earlier experiments with the Fermi Large Area Telescope and the satellite-borne PAMELA had reported similar results, but not with AMS’s precision.
 </p>
 <p>
  Still, it’s not proof that dark matter is producing these positrons. Unlike in LHC experiments, where researchers can control every input and predict outcomes in detail, AMS is just recording what nature produces. There could be other sources that explain the positron bump. One possibility among many is that the positrons are being emitted by a pulsar, a dense left-over from the death of a gigantic star that sprays out a plume of radiation. But if a pulsar were the source, the positrons would all be coming from one particular direction, and the AMS team has reported that was not the case.
 </p>
 <p>
  Work to clarify those results goes on because there are still plenty of other things that could be yielding these results. “If this was dark matter, depending on the properties of the dark matter, we would expect to see deviations in other spectra and ratios,” Capell says. “For example, anti-proton to proton ratios would have something goofy. And we’re also working on that.”
 </p>
 <h2>
  Twelve Million to Go
 </h2>
 <p>
  Clearer answers will emerge as AMS continues to collect data. Yes, these extra positrons are predicted by theory, but so is a dearth of positrons at even higher energies, where the picture provided by AMS is still fuzzy. It’s a measurement that’s only possible with more time and more events recorded. “It agrees with the dark matter model, but it doesn’t prove it,” Ting says of the current data. “It’s necessary but not sufficient.”
 </p>
 <p>
  Ting estimates it will take a few years to gather enough data to fill in the picture of the positrons, about 12 million more collisions between cosmic rays and the detector. For now, Ting says, “Something unusual is happening. We still do not know what it is.”
 </p>
 <p>
  One the way out, I stop in the lobby outside the AMS control room, where the view from a camera looking out from AMS is projected on a screen. An array of solar cells looms and then drifts into shadow, leaving just the bright line of the edge of the Earth. Invisible to my eye, thousands of particles strike the detector and send their messages, via a string of satellites, down to this building. Here, they’ll be added to the great puzzle of experimental and observational results that is our sense dark matter and, in a way, of the universe.
 </p>
</section>
</div>
  

  
      <div class="rich-text"><p>
 Photo credits: NASA,
 <a href="http://www.flickr.com/photos/simsullen/sets/72157630882599456/with/7678048358/">
  Simon Bierwald/Flickr (CC BY-NC-SA)
 </a>
</p></div>
  



We're about 12 million cosmic ray collisions from better understanding dark matter, say physicists at CERN.

Pursuing Dark Matter, Hundreds of Miles Above Earth





  
      <div class="related"></div>
  

  
      <div class="rich-text"><p>
 In 1987, a group of researchers in France discovered something peculiar. When they protected single-celled organisms from background radiation—the sort that comes from cosmic rays and radioactive rocks—the creatures’ growth was stunted. Colonies that receive a background dose of radiation actually grew more quickly than their shielded brethren. That’s radiation—not vitamins, not nutrition, not anything people generally suggest you should get more of.
</p>
<p>
 Was background radiation somehow required for life?
</p>
<p>
 The dangers of radiation
 <a href="http://www.methodquarterly.com/2014/11/the-cat-went-over-radioactive-mountain/">
  loom large in our cultural memory
 </a>
 . With good reason: From the melting, cancerous jaws of factory workers exposed to radium-infused paint in the 1920s, to the gruesome after-effects of the atomic bombs dropped on Japan, the results of exposure speak vividly against taking radiation lightly.
</p>

            <figure class="richtext-image full-width"><img alt="licorne" class="richtext-image full-width" height="449" width="800"
            src="/wgbh/nova/media/images/licorne_w5SB1up.width-800.jpg"/><figcaption>
  Aboveground nuclear bomb tests, like this French test over Fangataufa Atoll, have seared the image of dangerous radiation into our collective memories.
 <div class="credit"></div></figcaption>
            </figure>
            
<p>
 On the cellular level, radiation’s particles wreak havoc on DNA, ripping through the double helix like bullets and causing the creation of corrosive free radicals. Irradiated cells form strange structures in their nuclei as they attempt to replicate themselves, the genetic material twisting and clumping sickeningly. The general rule is the less radiation exposure, the better: In this view, “there is no safe amount of radiation,” says New Mexico State University researcher Hugo Castillo.
</p>
<p>
 Separately, however, since life’s beginnings—long, long before humans began toying with things like uranium—all organisms have been exposed to what is known as background radiation. This is naturally occurring, with some of it coming from the sky, in the form of cosmic rays, and some of it coming from the Earth, from isotopes like potassium-40 in the soil and rock. The amounts are not huge—something like having a
 <a href="https://www.radiologyinfo.org/en/info.cfm?pg=safety-xray">
  mammogram every couple of months
 </a>
 —but they exist.
</p>
<p>
 You’d think that when you protect cells from the natural background radiation, they’d do better—no radiation means no stress, no damage, faster growth. But as the French experiment suggested, some level of radiation may be beneficial.
</p>
<p>
 Since the 1987 paper, a small community of researchers have worked to understand what happens to cells in low-radiation environments. In the Gran Sasso Cosmic Silence experiments, under a mountain in Italy, scientists have found that cells grown under such conditions respond more poorly than controls to damaging radiation. And at France’s Laboratoire Souterrain de Modane, a team has been studying the evolutionary effects of very low radiation. “We wanted to quantify as precisely as we could what effect radiation is having on cells,” says Nathanael Lampe, a graduate student there. But there are limited places on the planet where it’s even possible to contemplate such experiments.
</p>
<p>
 Castillo, his supervisor Geoffrey Smith, and their colleagues at NMSU have such a set-up: In a salt mine deep beneath the New Mexico desert, they are investigating background radiation’s importance to life in a very unusual series of experiments. In
 <a href="http://journal.frontiersin.org/article/10.3389/fmicb.2017.00177/full">
  a paper published this February
 </a>
 in
 <i>
  Frontiers of Microbiology
 </i>
 , they report that, indeed, bacteria grown in an extremely sheltered environment there—at levels of background radiation nearly 80 times lower than at the surface—appear to be stressed. It’s the same kind of reaction you get if you starve cells or heat them, but in this case, it’s because of the lack of radiation. That implies that there is something cells have evolved to expect, over the eons, from the background.
</p></div>
  

  
      <div class="ad"></div>
  

  
      <div class="rich-text"><h2>
 Down Deep
</h2>
<p>
 Castillo and Smith’s New Mexico group works out of a small lab in a shipping container more than 2,000 feet underground, in a man-made system of caverns created for storing nuclear waste. The facility, called the Waste Isolation Pilot Plant, has socked away thousands and thousands of containers bearing strongly worded labels since 1999, in chambers chiseled from a salt formation. Entering the WIPP facility is not for tourists, and even the scientists are few. The team only has access for a few months out of the year, and on the way down, they crowd in a small elevator. “After 20 seconds, all the light is gone,” Castillo says, recalling his first trip down. “I’ve never seen such darkness before in my life.”
</p>

            <figure class="richtext-image full-width"><img alt="WIPP Panel 7" class="richtext-image full-width" height="449" width="800"
            src="/wgbh/nova/media/images/wipp-panel-7_x3NdAAb.width-800.jpg"/><figcaption>
  A corridor in Panel 7 in the Waste Isolation Pilot Plant.
 <div class="credit"></div></figcaption>
            </figure>
            
<p>
 When the researchers disembark at the bottom of the shaft, they are cocooned in a bubble of salt, exceptionally poor in natural radioisotopes, and so far down that cosmic rays can’t penetrate. They make their way to the lab space, where their neighbors are physicists doing similarly sensitive experiments. Finally they come to their most important piece of equipment: A steel vault, built by the military before World War II, that does not have the trace radiation that steel made afterwards acquired as a result of the fallout when the atomic bombs went off. That means that it does not have the trace radiation that everything aboveground acquired as a result of the fallout.
</p>
<p>
 Within this vault, hidden in the salt bubble, more than 2,000 feet underground, the background radiation level is already ten times less than at the surface. The group has erected even more shielding around an incubator, bringing down the level to 79 times less than normal. And there they have grown two kinds of microbes:
 <i>
  Shewanella oneidensis
 </i>
 and
 <i>
  Deinococcus radiodurans
 </i>
 , both stalwarts of radiation biology experiments. In a control incubator with identical bacterial cultures nearby, they have added back in an amount of radiation comparable to the surface.
</p>
<p>
 It’s delicate work, designing an experiment where you know the effects are from the lack of background radiation, and not from, say, myriad other small differences that can creep in. You must account for differences in air pressure, if the cells are grown in different places; too, the cells aboveground and below may grow more genetically distinct over time, making it harder to tell what alterations are radiation-related. The best course of action, if possible, is making the level of radiation the sole difference between control and treatment, as the New Mexico team has done.
</p></div>
  

  
      <div class="newsletter"></div>
  

  
      <div class="rich-text"><p>
 In the shielded incubator,
 <i>
  D. radiodurans
 </i>
 grows more slowly, its numbers lagging behind controls throughout the duration of the experiment, they report, in line with what’s been found by prior groups.
 <i>
  S. oneidensis
 </i>
 , however, after a short delay, matches the growth numbers of the controls.
</p>
<p>
 Delving into this, the group checked the organisms’ expressions of 10 genes involved in coping with stress. They found that
 <i>
  D. radiodurans
 </i>
 was laboring along with few of these genes expressed any differently from the norm, and apparently suffering for it.
 <i>
  S. oneidensis
 </i>
 , on the other hand, had at least doubled the expression levels of some of them. “This is a subtle effect,” Castillo says. “But it appears the cells can turn some genes on and off to compensate for this lack of radiation.” Moving the microbes to the control incubator with more radiation erased both the growth problems and the change in gene regulation, confirming the connection with radiation.
</p>
<p>
 The genes that
 <i>
  S. oneidensis
 </i>
 upregulated are associated with particular kinds of genetic repair. Specifically, they help mend damage caused by free radicals, which can be produced by radiation exposure, but also can be made by cells themselves as waste products. Since they certainly aren’t getting free radicals from radiation, this suggests that
 <i>
  S. oneidensis
 </i>
 may be responding to an over-abundance of free radicals produced internally, Castillo hypothesizes. Perhaps the usual steady dose produced by background radiation on the surface serves as a signal to the cell to keep free radicals low—like a finger pushing on a button. Maybe without those regular prompts from the environment, cells accumulate the molecules to an unhealthy level and then struggle as a result.
</p>
<h2>
 “A Billion Detectors”
</h2>
<p>
 Still, this opens up an even greater mystery. Background radiation is sparse stuff, just a few particles bouncing through a very large volume of space. And cells are tiny—the vast, vast majority of the cells in a dish grown on the surface are never struck by a particle at all, says Lampe, from the French group, who has been modeling the number of mutations arising from the background. “This is why observations of different biological effects in underground labs are so fascinating,” he says. If in the normal course of life cells are never struck by a radiation particle, how in the world does the presence or absence of such particles register? Perhaps the answer lies in incredibly swift and complete communication between cells. “If you have a cell population, you effectively have an array of a billion detectors,” Lampe proposes. “They can aid each other in figuring out what’s going on with the radiation background.” And perhaps it takes only a very small, conditioning dose of free radicals—or something else, something still unknown—to keep closely communicating cells at the surface in working order.
</p></div>
  

  
      

<div class='pullquote'>
  <div class="rich-text"><p>
 “If you have a cell population, you effectively have an array of a billion detectors.”
</p></div>
</div>

  

  
      <div class="rich-text"><p>
 Then, though, there are the effects observed by the Italian group, led for many years by Luigi Satta of the Italian National Institute for Nuclear Physics, which has been working on the problem since the late 90s. In those experiments, yeast, hamster, and human cells were grown in low-radiation environments underground and also in a lab on the surface. Then, the underground cells were brought up and both sets were given challenging doses of radiation. The team found that cells grown below had more DNA damage afterwards, measured by the appearance of twisted wads of DNA in the nucleus. “If the cells had been living for a few months in an environment in which the background radiation was normal,” says Massimo Pinto, a radiation scientist who worked on the experiments, “these cells were more ready to respond to an insult in the form of a challenge dose. The sister cells that had an artificially reduced background radiation level were not as capable.”
</p>
<p>
 It’s a peculiar finding—why would being without radiation make cells more vulnerable? One theory is that very low doses of radiation can cause cells to keep their repair machinery switched on, and those without it are unprepared, like a runner who skipped one too many workouts before a marathon. But the answers are not clear yet. Satta says that the next step would be to try similar experiments with fruit flies, to get a sense of whether the effect occurs in more complicated creatures. “All this suggests that these experiments should go on,” he says, “but due to budget limitations, this plan is unfortunately not sure.”
</p>
<p>
 Still, despite the difficulty of finding dependable funding for such esoteric experiments, “we’ve got a very fascinating phenomenon on our hands,” Lampe says. Life has evolved to take advantage of the light shining down on Earth, by developing photosynthesis. It’s evolved to take advantage of an oxygen-rich atmosphere, using it to help generate energy at the cellular level. It’s evolved to be comfortable at a specific range of temperatures commonly available on our planet. Is it any wonder that there may be another, less noticeable aspect of our environment that we’ve missed the significance of until now?
</p></div>
  

  
      <div class="rich-text"><p>
 Image credit:
 <a href="http://www.flickr.com/photos/7969902@N07/511287693">
  Pierre J./Flickr (CC BY-NC-SA 2.0)
 </a>
 , NASA, U.S. Department of Energy
</p></div>
  



<p>Deep in the Earth, experiments are revealing how life suffers when it’s deprived of background levels of radiation.</p>

Life Needs (Some) Radiation





  
      <div class="rich-text"><p>In a greenhouse in tropical southern Taiwan grows a small tree. From its hardy trunk sprout stems with wide, fuzzy leaves and sprays of white star-like flowers. Some of these flowers have already transformed into inedible green fruits about the size of marbles. Mohamed Rakha, a plant breeder here at the World Vegetable Center, splits open one of the fruits with his fingernail. “You can see a lot of seeds inside,” he says. Each one is packed with the plant’s DNA—and lots of potential.</p><p>Odd as it may seem, this fruit—a wild eggplant—is an ancient relative of the big purple eggplant sold in grocery stores worldwide.</p><p>At the World Vegetable Center, experts are studying a wide variety of eggplant relatives for their hardiness and ability to produce appealing, edible fruits—but it isn’t typical, business-as-usual breeding. Rather, plant breeders are on a mission to save the human diet from climate change.</p></div>
  

  
      <div class="newsletter"></div>
  

  
      <div class="rich-text"><p>All of the fruits and vegetables available in markets and grocery stores today are products of domestication. Their ancestors were not-so-edible organisms like the little tree Rakha tends. But centuries ago, humans began to take the biggest and tastiest wild plants and breed them together. They repeated this over and over, weaving together the genes that made a juicier fruit or a fatter wheat kernel so that many generations down the line, modern plants are now quite different.</p><p></p>
            <figure class="richtext-image full-width"><img alt="eggplant-1.jpeg" class="richtext-image full-width" height="600" width="800"
            src="/wgbh/nova/media/images/eggplant-1.width-800.jpg"/><figcaption><p>Eggplant seedlings at a street market near the World Vegetable Center | Photo credit: Veronique Greenwood</p><div class="credit"><p></p></div></figcaption>
            </figure>
            <p></p><p>These domesticated plants, despite their advantages, have some significant weaknesses. They’re not as sturdy as many of their wild relatives when it comes to resisting diseases, droughts, and other challenges. When a problem arises, they do not have the genetic diversity that allows wild populations to ride it out—all the individuals are so similar that what kills one, kills them all. And crops are already facing a serious challenge that’s bound to get worse: climate change.</p><p>As temperatures warm and pests shift their territories around the planet, large swaths of the human diet are at risk of crumbling under the onslaught of disease, insects, saltier water, and unbearable heat. Scientists estimate that U.S. corn, the country’s dominant crop, will see a decrease in yield of about 50 percent with a 4-degree Celsius temperature rise, which is predicted by the end of this century. In the later years of the 21st century, increased ozone in the atmosphere and lack of water due to climate change may reduce yields of vegetables by more than 30 percent, another study found.</p></div>
  

  
      <div class="rich-text"><p>These crops’ wild relatives—spunky, straggly plants—might be able to help. Breeders think that if they can collect seeds from these relatives, they may be able to breed resistance to drought, heat, and other threats back into the crops we depend on. But time is short. And so, in a daring move, scientists under the direction of the Global Crop Diversity Trust—based in Germany—have hatched a plan called the Crop Wild Relatives project. Starting in 2011, with 10 years of funding from the government of Norway, they set out on a mission.</p></div>
  

  
      

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  <div class="rich-text"><p>Large swaths of the human diet are at risk of crumbling under the onslaught of disease, insects, saltier water, and unbearable heat.</p></div>
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      <div class="rich-text"><p>In seed “safaris,” hundreds of scientists have fanned out in tall grasses, deserts, and remote mountains looking for wild relatives of staple food crops around the world. Since 2015, these missions have yielded 3,800 samples from 24 countries, including wild carrots from Bangladesh, wild eggplants from Tanzania, and wild sweet potatoes from Nigeria. The Kew Gardens Millennium Seed Bank in the United Kingdom has helped distribute the newfound seeds to breeders and researchers, who will grow them to find out exactly what their strengths are. In this global scheme, the World Vegetable Center in Taiwan is where the wild relatives of domesticated eggplant will get put through their paces.</p><h2><b>Standing Up to Pests</b></h2><p>The World Vegetable Center, founded in 1971 to develop crops for Asian countries, is headquartered in a cluster of low buildings ringed with fields just north of the city of Tainan. Palm trees dot the grounds between glass greenhouses where staff members conduct experiments and maintain the center’s enormous collection of seeds.</p><p></p>
            <figure class="richtext-image full-width"><img alt="eggplant-4.jpeg" class="richtext-image full-width" height="600" width="800"
            src="/wgbh/nova/media/images/eggplant-4.width-800.jpg"/><figcaption><p>Seeds in storage | Photo credit: Veronique Greenwood</p><div class="credit"><p></p></div></figcaption>
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            <p></p><p>On a cloudy day in October, Maarten van Zonneveld, the manager of the center’s seed collection, walks through the greenhouse where the wild eggplants will be grown, pointing out the beds built for new seedlings. The idea is that when the researchers find a plant that can stand up to a pest or keep producing despite a big jump in temperature, they will breed that wild variety with a standard, domesticated crop variety. If they manage to get a hybrid, they’ll keep refining it over the course of many generations.</p><p>This isn’t always a simple procedure because, just as with humans, offspring may not resemble their parents. If the offspring, which gets half its DNA from the wild relative parent, only inherits some of the genes necessary for a desired trait, it won’t benefit from it. And of course, the plant has to continue to produce lots of tasty vegetables as well. This process, called pre-breeding, can often take eight to 10 years or longer, just to get to the point where a seed company could take over.</p><p></p>
            <figure class="richtext-image full-width"><img alt="eggplant-5.jpeg" class="richtext-image full-width" height="600" width="800"
            src="/wgbh/nova/media/images/eggplant-5.width-800.jpg"/><figcaption><p>Four different kinds of eggplant seeds (some wild) | Photo credit: Veronique Greenwood</p><div class="credit"><p></p></div></figcaption>
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            <p></p><p>“For a seed company, a long-term project is two to three years,” says Philipp Simon, a USDA carrot breeder who leads the Global Crop Diversity Trust’s wild carrot project. “A seed company doesn’t want to work with a wild carrot relative—that would take forever from their frame of reference.” So pre-breeding, which creates the materials for mainstream breeders to use in their work, usually happens at universities and public institutes like the World Vegetable Center.</p><p>Eighty-nine new wild relatives of eggplant have been collected and will be grown at the center over the coming years. But in parallel, while those efforts get off the ground, the center’s collaborators at the University of Valencia in Spain have started to forge ahead using wild eggplant relatives that were already in gene banks. Geneticist Jaime Prohens and his group there have drawn on samples from Asia and Africa, as well as two distantly related American relatives, over the past several years. “This means crossing eggplant with a species that separated about 20 million years ago,” says Prohens—an exciting, if difficult, task because they have very different genes.</p></div>
  

  
      

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  <div class="rich-text"><p>Eighty-nine new wild relatives of eggplant have been collected and will be grown at the center over the coming years.</p></div>
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      <div class="rich-text"><p>To its surprise, Prohens’ team has already managed to get fertile hybrid plants from many crosses and, with some lab work, coaxed seeds from a few others. These will mix eggplant genes in new ways, and the most interesting specimens have arrived at the World Vegetable Center, where they will be evaluated for resistance to pests.</p><p>In the greenhouse, Rakha lifts the leaf of a potted cabbage plant to reveal hundreds of tiny whiteflies, which suck the sap out of eggplant leaves. The center keeps thriving populations of common crop pests like whiteflies in a special greenhouse for such experiments. Rakha and his colleagues hope that the new, hybrid plants will stand up to their scourge.</p><p>As researchers record what all these fresh infusions into the domesticated eggplant’s gene pool do in the field, the information will be entered into a database that anyone around the world can access, says Benjamin Kilian, the manager for the project at the World Crop Diversity Trust. “All pre-breeding data will be freely available,” he says.</p><h2><b>An Open Vault</b></h2><p>How swiftly might insights from the wild relatives project hit grocery store shelves? That depends on what researchers find and how seed companies decide to make use of the breeding material. Five seed companies are collaborating with the World Vegetable Center on the eggplant work, testing the new plants in their own fields. “These companies might select [the] most promising materials for their own breeding,” says Kilian, which would accelerate the eggplants’ arrival in stores. So far, no eggplant from the project has reached the consumer phase.</p><p>In just two years, the current funding for the Crop Wild Relatives project will end; partners and other stakeholders will have selected the most promising pre-bred materials and integrated them into their breeding pipelines by then. But the project’s legacy will remain in the seed banks of the world.</p><p>Van Zonneveld visits World Vegetable Center seed bank curators Yung-kuang Huang and Tien-hor Wu—“There are not many people who have seen more eggplant diversity than Mr. Wu,” Van Zonneveld says by way of introduction—and together the three scientists go down white corridors and up a flight of stairs to the door of a vault. Inside, it’s a frigid 41 degrees Fahrenheit. Heavy rolling shelving units can be pushed apart to reveal thousands of little silver envelopes, each one containing the legacy of a plant. “This represents a part of the history of man and plant,” says Van Zonneveld. “It’s one of the—if not <i>the</i> largest—public international gene bank of vegetable germplasm.” A thermostat senses the heat of our bodies and industrial fans slam on, sending a wave of cold air over the room and its precious contents, which anyone willing to do the import paperwork—seed company employee, scientist, interested gardener—can request.</p><p></p>
            <figure class="richtext-image full-width"><img alt="eggplant-3.jpeg" class="richtext-image full-width" height="600" width="800"
            src="/wgbh/nova/media/images/eggplant-3.width-800.jpg"/><figcaption><p>Inside the World Vegetable Center seed bank with Yung-kuang Huang (left) and Maarten van Zonneveld (right) | Photo credit: Veronique Greenwood</p><div class="credit"><p></p></div></figcaption>
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            <p></p><p>Wild relatives are not immune to troubles, as construction projects and other disturbances frequently threaten to encroach on their habitats. Still, they can be found in the most unlikely of places––it just takes a little practice to recognize them. Phillip Simon, the carrot breeder, has collected wild carrots by the roadside in Turkey, Tunisia, Uzbekistan, and Turkmenistan.</p></div>
  

  
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      <div class="rich-text"><p>“My first collecting trip was to what was at the time the USSR in 1989,” he says. In the United States Department of Agriculture’s gene bank are purple carrot seeds he collected near Homs, Syria, many years ago, which may not exist there anymore. The USDA has funding available for collecting missions focused on wild relatives, although not many scientists realize it, Simons says. And within the U.S., there are amateur groups that go out collecting as well, on the hunt for wild garlic and onion and carrots—the global seed safari, on a much smaller scale.</p><p>On the other side of the world in Taiwan, Van Zonneveld spotted a mung bean relative in the wild recently, and he brought it back to his office to press it. Now he carefully lifts a sheet of newspaper to reveal the delicate curl of the dried plant. Its unassuming yellow flowers not yet gone to seed, they resemble those of their much more famous cousin, a crop eaten by millions. For him, it represents the promise of a better future.</p></div>
  



<p>At the World Vegetable Center, experts are looking to the wild relatives of domesticated crops—like eggplant—to save the human diet from climate change.</p>

Veronique Greenwood