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Cocaine-Eating Enzyme Could Combat Addiction

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<p>
  They’re found huddling in the soil near the roots of coca plants and swimming in the industrial waste from pharmaceutical factories. They’re a bacteria called
  <em>
   Stenotrophomonas maltophilia
  </em>
  . And they eat cocaine.
 </p>
<p>
  Cocaine overdoses send half a million people to emergency rooms in the United States every year—but once they get there, there’s not much doctors can do beyond alleviating the symptoms. Opiate overdoses can be treated with naloxone, which dulls opiate action by competing with the drug for binding sites; addicts can be given safer alternatives like methadone. But there aren’t any approved medications for cocaine toxicity, and addiction treatment is mostly limited to behavioral and psychological approaches.
 </p>
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<img alt="" class="richtext-image full-width" src="https://staging.pbs.org/wgbh/nova/media/images/4923866114_cf260d947e_o-e1404233687390.width-990_Xk7yCj4.jpg"/>
<figcaption>Unlike opiate addiction, there aren't any pharmaceutical treatments for cocaine addiction. A bacterial enzyme could change that.
        
    </figcaption>
</figure>
<p>
  So Lei Fang, a postdoctoral researcher at the University of Kentucky’s College of Pharmacy, turned to
  <em>
   S. maltophilia
  </em>
  , which produces an enzyme called cocaine esterase that breaks down cocaine into inactive molecules. Split up into its constituent parts, cocaine can’t provide its characteristic high—or the risks associated with it. You can’t just inject the bacterial enzyme into humans, though. Cocaine esterase molecules need to be in pairs to work, and because protein structure is so temperature-sensitive, the natural enzyme can’t stay paired up for longer than about 12 minutes at human body temperature.
 </p>
<p>
  Bethany Brookshire,
  <a href="https://www.sciencenews.org/blog/scicurious/mutated-bacterial-enzyme-gobbles-cocaine">
   writing
  </a>
  for Science News:
 </p>
<blockquote>
<p>
   Fang and colleagues set about trying to make cocaine esterase a more stable dimer at body temperature. They carefully switched out the building blocks of the protein, amino acids, at the site where two enzymes become a matched pair. The scientists have already been able to create a version of cocaine esterase that can withstand human body temperature for six hours. And it’s already in a
   <a href="https://clinicaltrials.gov/ct2/show/NCT01846481">
    phase II clinical trial
   </a>
   to treat cocaine overdose.
  </p>
</blockquote>
<p>
  But Fang was hoping to do more than just treat overdoses—he wanted to find a drug that could treat addiction. To do that, you’d need cocaine esterase to function for a lot longer than six hours. So he and his colleagues used computer models to watch exactly what happens when heat unravels the enzyme. That helped them find the enzyme’s weak spots, and with just two more mutations they produced a new form that can stay paired up and active for more than 100 days. Injecting mice with this reinforced enzyme protects them from lethal cocaine overdoses for more than three months—the longest lasting effect that’s ever been demonstrated.
 </p>
<p>
  The reinforced enzyme is more active, too—it metabolizes cocaine a thousand times faster than the human body does on its own. If cocaine esterase could digest cocaine faster than addicts could get high, it might be able to disrupt the reward circuits that feed addiction. It would be an entirely new tool for helping the country’s more than one million cocaine addicts get clean—all from a little bacterium that lives in dirt and wastewater.
 </p>
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</p>
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<p>
 Photo Credit:
 <a href="https://www.flickr.com/photos/spookman01/4923866114">
  Lee Morley / Flickr (CC BY-NC-ND 2.0)
 </a>
</p>

T-cells are integral parts of our immune system.

Drug-Toting Red Blood Cells Could Vanquish Allergies and Autoimmune Diseases

<p>
 It starts with a bite. Maybe a misjudged ice cream sundae. Or perhaps a cookie that was hiding a dangerous secret. Either way, once you ingest it, your body starts working against you. Once the proteins in the peanuts enter your blood stream, your immune system starts releasing volleys of chemicals. Your skin erupts in hives. Your body’s soft tissues and mucous membranes swell, constricting your airway and leaving you struggling for breath. Your stomach may start convulsing as your body tries to vomit out the offending substance. And if you’re one of a small percentage of people, your blood pressure may plummet and your heart could stop. It’s uncontrollable, often unexpected, and absolutely terrifying.
</p>
<p>
 Severe allergies—especially of the sort that require people to carry EpiPens—are on the rise. Peanut allergies, for example, affected only 0.4% of children in the U.S. in 1997; in 2010, a study estimated that number had risen to 1.4%. So are autoimmune diseases, such as type I diabetes, multiple sclerosis, or rheumatoid arthritis, which, like severe allergies, occur when the immune system reacts forcefully to something harmless. They affect as many as 8% of Americans, according to the NIH. Both severe allergies and autoimmune diseases exact a toll, racking up treatment expenses and diminishing patients’ quality of life.
</p>
<div class="related"></div>
<p>
 We don’t know exactly what’s causing the uptick in allergies or autoimmune disorders, but there’s hope of treating them by acclimating people’s bodies to whatever substance is setting off the alarm bells. A promising treatment may lie with our red blood cells. Or rather, what they can help us sneak into our bodies.
</p>
<p>
 We’re a step closer to pulling off that subterfuge. Researchers at the Massachusetts Institute of Technology have recently manipulated red blood cells to carry virtually any molecule your doctor might prescribe. The technique, a collaborative effort by biology professors Harvey Lodish and Hidde Ploegh, is new, but the idea of using red blood cells to deliver therapeutic compounds has, surprisingly, been around for decades. It’s just been waiting for the right technology to come along.
</p>
<p>
 Because your body is programmed to eliminate anything it identifies as “foreign,” even drugs that don’t attract the ire of the immune system are still quickly flushed out by other means, namely enzymes known as cytochrome P450s, which are tasked with neutralizing foreign molecules. But using red blood cells as couriers could allow drugs to sidestep both the immune system and P450s. Red blood cells have other advantages, too: They swish around the body for a long time—about 120 days in humans—and are invisible to the immune system’s scouts, thanks to what University of Chicago chemist Jeffrey Hubbell calls “don’t eat me” proteins on their surface.
</p>
<p>
 There’s also a pragmatic reason that red blood cells are an appealing way to deliver drugs: we’re good at delivering new red blood cells to our bodies. “The blood transfusion is an ancient technology,” Ploegh points out. The first successful human-to-human blood transfusion took place almost 200 years ago; animal-to-human transfusions had been going on (with variable results) for about 150 years before that. “So as a cell type to focus attention on,” he says, “it makes perfect sense.”
</p>
<h2>
<b>
  An Old Approach, Revived
 </b>
</h2>
<p>
 This isn’t the first time we’ve tried administering drugs using modified red blood cells, says Dr. Vladimir Muzykantov, a professor at the University of Pennsylvania’s medical school. In the early 1970s, researchers experimented with using enzyme-loaded red blood cells to treat Gaucher disease, a condition in which patients are missing an enzyme that helps digest a certain kind of fatty molecule, which then builds up in organs like the liver, spleen, or brain. Simply injecting the missing enzyme isn’t always effective: the immune system, unused to the molecule, sometimes reflexively unleashes the same type of dramatic assault that peanut proteins prompt in allergy sufferers.
</p>
<div class="ad"></div>
<p>
 So the researchers soaked red blood cells in an enzyme solution so salty that the cells burst open and swallowed the enzyme. Thus fortified, the red blood cells raised enzyme levels in cell cultures from Gaucher patients more effectively than the enzyme alone. But though the treatment seemed poised to take off, it was quickly dealt a blow when the HIV/AIDS epidemic hit in the 1980s. Suddenly, any treatment involving blood transfusions seemed too risky to pursue. Eventually, most researchers turned their attention to developing synthetic cell analogues: nanoscale medication packages made from polymers or fatty molecules.
</p>
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<img alt="" class="richtext-image full-width" src="https://staging.pbs.org/wgbh/nova/media/images/red-blood-cells.width-990_f3Pa5NA.jpg"/>
<figcaption>Red blood cells as seen under a scanning electron microscope
        
    </figcaption>
</figure>
<p>
 But designing artificial carriers isn’t easy, says Elena Batrakova, a University of North Carolina pharmacy professor whose work uses white blood cells that can cross the blood-brain barrier to deliver treatments for neurodegenerative diseases like Parkinson’s. “You can never do better than nature,” she says. Nanoparticle delivery systems, Batrakova explains, present a catch-22: as soon as you encapsulate drugs in particles large enough to survive for extended periods in the body, their size attracts the attention of the immune system. To an immune system macrophage, a cancer medicine wrapped up in a little plastic shell looks a lot like an invading bacterium.
</p>
<p>
 A few labs, including Dr. Muzykantov’s, kept pursuing red blood cell therapies. In the last decade or so, advances in medical technology have revived the possibility of using red blood cells to deliver drugs. Muzykantov, for example, has developed techniques to stick an anticoagulant to the outside of red blood cells and hitch a ride to dangerous blood clots, helping to break them down. The encapsulation method explored in the 1970s is alive and well, too, thanks in part to better screening for HIV-infected blood: several European companies have already started clinical trials.
</p>
<p>
 Still, neither of these methods is perfect: Drug-loaded cells tend not to last very long in the body because forcing a cargo inside inevitably damages them. And compounds attached to the outside of a blood cell that’s already in circulation might not be able to hang on for the cell’s entire lifetime, reducing their efficacy.
</p>
<h2>
<b>
  A New Take
 </b>
</h2>
<p>
 That’s where the work of Ploegh and Lodish come in. The pair, who work at MIT’s Whitehead Institute in immunology and red-blood-cell biology, respectively, think they have come up with a better way to use red blood cells to smuggle foreign substances past the body’s defenses.
</p>
<p>
 It works like this: Ploegh, Lodish, and their team begin by fiddling with the red blood cell genome so one of the cell’s surface proteins contain an additional five amino acids. Those added amino acids, known as a tag, attract specific a bacterial enzyme called sortase, which kicks off one specific amino acid in the tag, glycine, and latches on in its place. The beauty of sortase is it can then be exchanged for just about any other molecule you want the cell to carry, provided it has a glycine available: small drug molecules, other proteins, even pieces of DNA. “You’re essentially limited only by what your friend the organic chemist can come up with,” Ploegh says. (Normally, there’s a risk of cancer associated with treatments using genetically-modified cells, but since red blood cells have jettisoned their DNA by the time they’re mature, there is no risk in this case, Ploegh says.)
</p>
<div class="newsletter"></div>
<div class="pullquote">
<p>
 “You’re essentially limited only by what your friend the organic chemist can come up with.”
</p>
</div>
<p>
 Because sortase will only bind to that five-amino-acid tag but is unscrupulous about the molecules it will exchange with, you end up with a method that combines the innate specificity of large proteins with the versatility of well-understood small-molecule chemistry: any molecule you want, exactly where you want it.
</p>
<p>
 The attached compounds can do their work for as long as the red blood cell is circulating, which can be quite a long time compared with other treatments. That longevity could be a major advantage when trying to neutralize toxins, for example, like those in some biological weapons. Injecting an antitoxin using traditional techniques might buy you a couple weeks of prophylactic treatment, but using one bound to a red blood cell could soak up dangerous molecules for up to four months. This method, which Ploegh and his colleagues call “Sortagging,” after the tag and its associated bacterial enzyme, could also be used to develop treatments for chronic inflammation and other systemic problems, providing long-term exposure to medication throughout all 150 miles of the circulatory system.
</p>
<h2>
<b>
  Taming the Immune System
 </b>
</h2>
<p>
 Besides longevity, red blood cells have another superpower—one that suggests a whole different suite of intriguing applications. Millions of red blood cells get recycled every second, and the body is an expert at digesting them. Last year, Hubbell, the University of Chicago chemist, and his colleagues published a paper suggesting that anything attached to a red blood cell when it dies—even if it’s something that would normally cause an allergic reaction—gets marked as “friendly” by the cells responsible for cleanup. When that happens, the white blood cells that were previously programmed to attack it are destroyed—after all, since their original target is now considered harmless, they no longer serve any purpose. The next time the body encounters that allergen, the immune system doesn’t bat an eye. The therapy has extinguished a single, problematic immune response without dismantling the rest of the body’s defenses.
</p>
<p>
 That means that modified red blood cells might be able to treat allergies like the ones that make parents fear rogue peanut-butter crackers at preschool. No more panicked searches for EpiPens—just a few transfusions of allergen-flavored red cells could train your immune system to love peanut-butter, shellfish, or even the explosion of pollen in the spring.
</p>
<p>
 There are other possibilities, too. Some protein-based treatments, like the antibody therapies, have proven very successful in fighting certain cancers, though their utility is limited since they can also trigger allergic reactions. But give the patient a few shots of antibody-fortified red blood cells and, Ploegh says, “perhaps you might be able to blunt a possible immune response when you start the therapy.” Inducing a protein-specific tolerance could also dramatically change the way autoimmune diseases are treated, shutting down the pathway that causes the body to attack the cells that produce, say, insulin like in type I diabetes or myelin like in multiple sclerosis.
</p>
<h2>
<b>
  A Long Journey
 </b>
</h2>
<p>
 Pleogh is careful to stress that these applications are “fairly fanciful and very much in the distance,” but both he and Hubbell contend that using modified red blood cells to create a less excitable immune system could one day be a realistic possibility.
</p>
<p>
 Whether or not Ploegh and Lodish’s method will someday be a most practical way to do that isn’t clear yet. For one thing, it requires modifying cells’ DNA, which, Hubbell points out, “is a lot easier to do in the laboratory than it is to turn it into a pharmaceutical process.” That’s why Hubbell’s work currently focuses on designing antibodies that will bind with red blood cells inside the body—no genetic engineering or transfusion needed. In practice, “sortagging” would be, says Batrakova, the pharmacy professor, “basically personalized medicine,” which is challenging to implement on a grand scale. That’s not to say it’s impractical, Hubbell says. “One would just have to find the applications that warrant the complexity.”
</p>
<div class="pullquote">
<p>
 “The more approaches we have, the better.”
</p>
</div>
<p>
 Those applications are still far in the future, though. Ploegh and Lodish have only transplanted their modified cells in mice, and haven’t tested how efficiently they might carry drugs or suppress immune responses. Plus, the long-lived nature of these cells requires scientists be cautious when choosing applications to investigate. As Hubbell points out, “If you embark on a 120 day long journey without a stop, you make a big bet that everything’s going to turn out fine.” Clinical trials of this sort are complicated, so it will take a long time before we know whether sortagging or red blood cell encapsulation or even simple protein-binding strategies are best for any particular disease.
</p>
<p>
 Ultimately, though, Muzykantov thinks all these approaches are complementary, not mutually exclusive. Batrakova agrees: “I think that the more approaches we have, the better.”
</p>
<p>
 Using the body’s own cells as drug mules has the potential to change the way we deliver medicine. Scientists are just beginning to glimpse what that strategic shift could accomplish. Could we eliminate rheumatoid arthritis? Stop multiple sclerosis in its tracks? Reduce peanut allergies to a faint memory? “Your imagination is the limit, basically,” Ploegh says.
</p>
<p>
 Image credits: NSF/DARPA, NIH
</p>

<p>Hitching molecules to red blood cells could treat everything from peanut allergies to multiple sclerosis.</p>

Scientists have figured out how to use a cell's DNA repair mechanisms to spread traits throughout a population.

Genetically Engineering Almost Anything

<p>
 When it comes to genetic engineering, we’re amateurs. Sure, we’ve known about DNA’s structure for more than 60 years, we first sequenced every A, T, C, and G in our bodies more than a decade ago, and we’re becoming increasingly adept at modifying the genes of a growing number of organisms.
</p>
<p>
 But compared with what’s coming next, all that will seem like child’s play. A new technology just announced today has the potential to wipe out diseases, turn back evolutionary clocks, and reengineer entire ecosystems, for better or worse. Because of how deeply this could affect us all, the scientists behind it want to start a discussion now, before all the pieces come together over the next few months or years. This is a scientific discovery being played out in real time.
</p>
<div class="ad"></div>
<p>
 Today, researchers aren’t just dropping in new genes, they’re deftly adding, subtracting, and rewriting them using a series of tools that have become ever more versatile and easier to use. In the last few years, our ability to edit genomes has improved at a shockingly rapid clip. So rapid, in fact, that one of the easiest and most popular tools, known as CRISPR-Cas9, is just two years old. Researchers once spent months, even years, attempting to rewrite an organism’s DNA. Now they spend days.
</p>
<div class="pullquote">
<p>
 “This is one of the most exciting confluences of different theoretical approaches in science I’ve ever seen.”
</p>
</div>
<p>
 Soon, though, scientists will begin combining gene editing with gene drives, so-called selfish genes that appear more frequently in offspring than normal genes, which have about a 50-50 chance of being passed on. With gene drives—so named because they drive a gene through a population—researchers just have to slip a new gene into a drive system and let nature take care of the rest. Subsequent generations of whatever species we choose to modify—frogs, weeds, mosquitoes—will have more and more individuals with that gene until, eventually, it’s everywhere.
</p>
<p>
 Cas9-based gene drives could be one of the most powerful technologies ever discovered by humankind. “This is one of the most exciting confluences of different theoretical approaches in science I’ve ever seen,” says Arthur Caplan, a bioethicist at New York University. “It merges population genetics, genetic engineering, molecular genetics, into an unbelievably powerful tool.”
</p>
<p>
 We’re not there yet, but we’re extraordinarily close. “Essentially, we have done all of the pieces, sometimes in the same relevant species.” says Kevin Esvelt, a postdoc at Harvard University and the wunderkind behind the new technology. “It’s just no one has put it all together.”
</p>
<p>
 It’s only a matter of time, though. The field is progressing rapidly. “We could easily have laboratory tests within the next few months and then field tests not long after that,” says George Church, a professor at Harvard University and Esvelt’s advisor. “That’s if everybody thinks it’s a good idea.”
</p>
<p>
 It’s likely not everyone will think this is a good idea. “There are clearly people who will object,” Caplan says. “I think the technique will be incredibly controversial.” Which is why Esvelt, Church, and their collaborators are publishing papers now, before the different parts of the puzzle have been assembled into a working whole.
</p>
<p>
 “If we’re going to talk about it at all in advance, rather than in the past tense,” Church says, “now is the time.”
</p>
<h2>
 “Deleterious Genes”
</h2>
<p>
 The first organism Esvelt wants to modify is the malaria-carrying mosquito
 <i>
  Anopheles gambiae
 </i>
 . While his approach is novel, the idea of controlling mosquito populations through genetic modification has actually been around since the late 1970s. Then, Edward F. Knipling, an entomologist with the U.S. Department of Agriculture, published a substantial handbook with a chapter titled “Use of Insects for Their Own Destruction.” One technique, he wrote, would be to modify certain individuals to carry “deleterious genes” that could be passed on generation after generation until they pervaded the entire population. It was an idea before its time. Knipling was on the right track, but he and his contemporaries lacked the tools to see it through.
</p>
<p>
 The concept surfaced a few more times before being picked up by Austin Burt, an evolutionary biologist and population geneticist at Imperial College London. It was the late 1990s, and Burt was busy with his yeast cells, studying their so-called homing endonucleases, enzymes that facilitate the copying of genes that code for themselves. Self-perpetuating genes, if you will. “Through those studies, gradually, I became more and more familiar with endonucleases, and I came across the idea that you might be able to change them to recognize new sequences,” Burt recalls.
</p>
<p>
 Other scientists were investigating endonucleases, too, but not in the way Burt was. “The people who were thinking along those lines, molecular biologists, were thinking about using these things for gene therapy,” Burt says. “My background in population biology led me to think about how they could be used to control populations that were particularly harmful.”
</p>
<div class="pullquote">
<p>
 “There’s a lot to be done still, but on the scale of years, not months or decades.”
</p>
</div>
<p>
 In 2003, Burt penned an influential article that set the course for an entire field: We should be using homing endonucleases, a type of gene drive, to modify malaria-carrying mosquitoes, he said, not ourselves. Burt saw two ways of going about it—one, modify a mosquito’s genome to make it less hospitable to malaria, and two, skew the sex ratio of mosquito populations so there are no females for the males to reproduce with. In the following years, Burt and his collaborators tested both in the lab and with computer models before they settled on sex ratio distortion. (Making mosquitoes less hospitable to malaria would likely be a stopgap measure at best; the
 <i>
  Plasmodium
 </i>
 protozoans could evolve to cope with the genetic changes, just like they have evolved resistance to drugs.)
</p>
<p>
 Burt has spent the last 11 years refining various endonucleases, playing with different scenarios of inheritance, and surveying people in malaria-infested regions. Now, he finally feels like he is closing in on his ultimate goal. “There’s a lot to be done still,” he says. “But on the scale of years, not months or decades.”
</p>
<h2>
 Cheating Natural Selection
</h2>
<p>
 Cas9-based gene drives could compress that timeline even further. One half of the equation—gene drives—are the literal driving force behind proposed population-scale genetic engineering projects. They essentially let us exploit evolution to force a desired gene into every individual of a species. “To anthropomorphize horribly, the goal of a gene is to spread itself as much as possible,” Esvelt says. “And in order to do that, it wants to cheat inheritance as thoroughly as it can.” Gene drives are that cheat.
</p>
<p>
 Without gene drives, traits in genetically-engineered organisms released into the wild are vulnerable to dilution through natural selection. For organisms that have two parents and two sets of chromosomes (which includes humans, many plants, and most animals), traits typically have only a 50-50 chance of being inherited, give or take a few percent. Genes inserted by humans face those odds when it comes time to being passed on. But when it comes to survival in the wild, a genetically modified organism’s odds are often less than 50-50. Engineered traits may be beneficial to humans, but ultimately they tend to be detrimental to the organism without human assistance. Even some of the most painstakingly engineered transgenes will be gradually but inexorably eroded by natural selection.
</p>
<p>
 Some naturally occurring genes, though, have over millions of years learned how to cheat the system, inflating their odds of being inherited. Burt’s “selfish” endonucleases are one example. They take advantage of the cell’s own repair machinery to ensure that they show up on both chromosomes in a pair, giving them better than 50-50 odds when it comes time to reproduce.
</p>
<figure class="richtext-image full-width">
<img alt="" class="richtext-image full-width" src="https://staging.pbs.org/wgbh/nova/media/images/gene-drive-family-tree.width-990_NOqFEe4.png"/>
<figcaption>A gene drive (blue) always ends up in all offspring, even if only one parent has it. That means that, given enough generations, it will eventually spread through the entire population.
        
    </figcaption>
</figure>
<p>
 Here’s how it generally works. The term “gene drive” is fairly generic, describing a number of different systems, but one example involves genes that code for an endonuclease—an enzyme which acts like a pair of molecular scissors—sitting in the middle of a longer sequence of DNA that the endonculease is programmed to recognize. If one chromosome in a pair contains a gene drive but the other doesn’t, the endonuclease cuts the second chromosome’s DNA where the endonuclease code appears in the first.
</p>
<p>
 The broken strands of DNA trigger the cell’s repair mechanisms. In certain species and circumstances, the cell unwittingly uses the first chromosome as a template to repair the second. The repair machinery, seeing the loose ends that bookend the gene drive sequence, thinks the middle part—the code for the endonuclease—is missing and copies it onto the broken chromosome. Now both chromosomes have the complete gene drive. The next time the cell divides, splitting its chromosomes between the two new cells, both new cells will end up with a copy of the gene drive, too. If the entire process works properly, the gene drive’s odds of inheritance aren’t 50%, but 100%.
</p>
<figure class="richtext-image full-width">
<img alt="" class="richtext-image full-width" src="https://staging.pbs.org/wgbh/nova/media/images/gene-drive-schematic.width-990_QA5fNuP.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.
        
    </figcaption>
</figure>
<p>
 Most natural gene drives are picky about where on a strand of DNA they’ll cut, so they need to be modified if they’re to be useful for genetic engineering. For the last few years, geneticists have tried using genome-editing tools to build custom gene drives, but the process was laborious and expensive. With the discovery of CRISPR-Cas9 as a genome editing tool in 2012, though, that barrier evaporated. CRISPR is an ancient bacterial immune system which identifies the DNA of invading viruses and sends in an endonuclease, like Cas9, to chew it up. Researchers quickly realized that Cas9 could easily be reprogrammed to recognize nearly any sequence of DNA. All that’s needed is the right RNA sequence—easily ordered and shipped overnight—which Cas9 uses to search a strand of DNA for where to cut. This flexibility, Esvelt says, “lets us target, and therefore edit, pretty much anything we want.” And quickly.
</p>
<p>
 Gene drives and Cas9 are each powerful on their own, but together they could significantly change biology. CRISRP-Cas9 allows researchers to edit genomes with unprecedented speed, and gene drives allow engineered genes to cheat the system, even if the altered gene weakens the organism. Simply by being coupled to a gene drive, an engineered gene can race throughout a population before it is weeded out. “Eventually, natural selection will win,” Esvelt says, but “gene drives just let us get ahead of the game.”
</p>
<h2>
 Beyond Mosquitoes
</h2>
<p>
 If there’s anywhere we could use a jump start, it’s in the fight against malaria. Each year, the disease kills over 200,000 people and sickens over 200 million more, most of whom are in Africa. The best new drugs we have to fight it are losing ground; the
 <i>
  Plasmodium
 </i>
 parasite is evolving resistance too quickly. And we’re nowhere close to releasing an effective vaccine. The direct costs of treating the disease are estimated at $12 billion, and the economies of affected countries grew 1.3% less per year, a substantial amount.
</p>
<p>
 Which is why Esvelt and Burt are both so intently focused on the disease. “If we target the mosquito, we don’t have to face resistance on the parasite itself. The idea is, we can just take out the vector and stop all transmission. It might even lead to eradication,” Esvelt says.
</p>
<p>
 Esvelt initially mulled over the idea of building Cas9-based gene drives in mosquitoes to do just that. He took the idea to to Flaminia Catteruccia, a professor who studies malaria at the Harvard School of Public Health, and the two grew increasingly certain that such a system would not only work, but work well. As their discussions progressed, though, Esvelt realized they were “missing the forest for the trees.” Controlling malaria-carrying mosquitoes was just the start. Cas9-based gene drives were the real breakthrough. “If it let’s us do this for mosquitos, what is to stop us from potentially doing it for almost anything that is sexually reproducing?” he realized.
</p>
<div class="pullquote">
<p>
 “What is to stop us from potentially doing it for almost anything that is sexually reproducing?”
</p>
</div>
<p>
 In theory, nothing. But in reality, the system works best on fast-reproducing species, Esvelt says. Short generation times allow the trait to spread throughout a population more quickly. Mosquitoes are a perfect test case. If everything were to work perfectly, deleterious traits could sweep through populations of malaria-carrying mosquitoes in as few as five years, wiping them off the map.
</p>
<p>
 Other noxious species could be candidates, too. Certain invasive species, like mosquitoes in Hawaii or Asian carp in the Great Lakes, could be targeted with Cas9-based gene drives to either reduce their numbers or eliminate them completely. Agricultural weeds like horseweed that have evolved resistance to glyphosate, a herbicide that is broken down quickly in the soil, could have their susceptibility to the compound reintroduced, enabling more farmers to adopt no-till practices, which help conserve topsoil. And in the more distant future, Esvelt says, weeds could even be engineered to introduce vulnerabilities to completely benign substances, eliminating the need for toxic pesticides. The possibilities seem endless.
</p>
<h2>
 The Decision
</h2>
<p>
 Before any of that can happen, though, Esvelt and Church are adamant that the public help decide whether the research should move forward. “What we have here is potentially a general tool for altering wild populations,” Esvelt says. “We really want to make sure that we proceed down this path—if we decide to proceed down this path—as safely and responsibly as possible.”
</p>
<p>
 To kickstart the conversation, they partnered with the MIT political scientist Kenneth Oye and others to convene a series of workshops on the technology. “I thought it might be useful to get into the room people with slightly different material interests,” Oye says, so they invited regulators, nonprofits, companies, and environmental groups. The idea, he says, was to get people to meet several times, to gain trust and before “decisions harden.” Despite the diverse viewpoints, Oye says there was surprising agreement among participants about what the important outstanding questions were.
</p>
<p>
 As the discussion enters the public sphere, tensions are certain to intensify. “I don’t care if it’s a weed or a blight, people still are going to say this is way too massive a genetic engineering project,” Caplan says. “Secondly, it’s altering things that are inherited, and that’s always been a bright line for genetic engineering.” Safety, too, will undoubtedly be a concern. As the power of a tool increases, so does its potential for catastrophe, and Cas9-based gene drives could be extraordinarily powerful.
</p>
<p>
 There’s also little in the way of precedent that we can use as a guide. Our experience with genetically modified foods would seem to be a good place to start, but they are relatively niche organisms that are heavily dependent on water and fertilizer. It’s pretty easy to keep them contained to a field. Not so with wild organisms; their potential to spread isn’t as limited.
</p>
<div class="pullquote">
<p>
 There’s little in the way of precedent that we can use as a guide.
</p>
</div>
<p>
 Aware of this, Esvelt and his colleagues are proposing a number of safeguards, including reversal drives that can undo earlier engineered genes. “We need to really make sure those work if we’re proposing to build a drive that is intended to modify a wild population,” Esvelt says.
</p>
<div class="newsletter"></div>
<p>
 There are still other possible hurdles to surmount—lab-grown mosquitoes may not interbreed with wild ones, for example—but given how close this technology is to prime time, Caplan suggests researchers hew to a few initial ethical guidelines. One, use species that are detrimental to human health and don’t appear to fill a unique niche in the wild. (Malaria-carrying mosquitoes seem fit that description.) Two, do as much work as possible using computer models. And three, researchers should continue to be transparent about their progress, as they have been. “I think the whole thing is hugely exciting,” Caplan says. “But the time to really get cracking on the legal/ethical infrastructure for this technology is right now.”
</p>
<p>
 Church agrees, though he’s also optimistic about the potential for Cas9-based gene drives. “I think we need to be cautious with all new technologies, especially all new technologies that are messing with nature in some way or another. But there’s also a risk of doing nothing,” Church says. “We have a population of 7 billion people. You have to deal with the environmental consequences of that.”
</p>
<p>
 Image credits: Tom Ellenberger, Washington University School of Medicine/NIH, Esvelt et al 2014
</p>
<p>
 Sources:
</p>
<p>
 Burt, Austin. 2003. "Site-specific selfish genes as tools for the control and genetic engineering of natural populations."
 <i>
  Proceedings of the Royal Society of London B
 </i>
 270: 921-928. DOI:
 <a href="http://dx.doi.org/10.1098/rspb.2002.2319">
  10.1098/rspb.2002.2319
 </a>
</p>
<p>
 Esvelt, Kevin M., Andrea L. Smidler, Flaminia Catteruccia, and George M. Church. 2014. "Concerning RNA-Guided Gene Drives for the Alteration of Wild Populations."
 <i>
  eLife
 </i>
 . DOI:
 <a href="http://dx.doi.org/10.7554/eLife.03401">
  10.7554/eLife.03401
 </a>
</p>
<p>
 Oye, Kenneth A., Kevin Esvelt, Evan Appleton, Flaminia Catteruccia, George Church, Todd Kuiken, Shlomiya Bar-Yam Lightfoot, Julie McNamara, Andrea Smidler, and James P. Collins. 2014. "Regulating gene drives."
 <i>
  Science
 </i>
 DOI:
 <a href="http://dx.doi.org/10.1126/science.1254287">
  10.1126/science.1254287
 </a>
</p>

<p>Scientists are proposing a technology that could change nearly any sexually reproducing species anywhere.</p>

Galactic Collision with Power of One Million LHCs Spawns Massive Gravitational Lens

<section class="entry-content instapaper_body clearfix" itemprop="articleBody">
<div class="add-container clearfix" id="add-block-placer">
</div>
<p>
  Five billion light-years from earth, there’s a massive galactic pileup unfolding in slow motion. As four clusters of galaxies plow into each other, thousands of individual galaxies are colliding—creating huge amounts of cosmic chaos and a lot of energy.
 </p>
<p>
  New images of this phenomenon—one of the largest galactic mergers on record—suggest it’s also producing more than just pretty pictures. It’s also serving as quite possibly the largest particle accelerator of all time, besting the exquisitely engineered Large Hadron Collider one million times over.
 </p>
<figure class="richtext-image full-width">
<img alt="" class="richtext-image full-width" src="https://staging.pbs.org/wgbh/nova/media/images/macsj0717.width-990_4rajjHG.jpg"/>
<figcaption>Colliding galaxy clusters MACS J0717+3745 are seen here in this composite image. The background is a Hubble Space Telescope image, blue is an X-ray image from Chandra, and red is a VLA radio image.
        
    </figcaption>
</figure>
<p>
  The discovery of the power of the collision, endearingly named MACSJ0717.5+3745, was revealed at a recent American Astronomical Society meeting by Reinout van Weeren of the Harvard-Smithsonian Center for Astrophysics. He and his team observed different types of radiation to peer into the complex interactions.
 </p>
<p>
  Radio-wave data from the Very Large Array show what seems to be radiation emitted by high-energy charged particles. According to X-ray data from the Chandra Observatory, there’s extremely hot (hundred-million-Kelvin-hot) gas in the same place the radiation is coming from. That combination of energetic particles and super-heated gas suggests that gases are colliding and spewing out high-energy particles.
 </p>
<p>
  Galaxies are mostly empty space, of course, and the likelihood of stars colliding is relatively small. But as Clara Moskowitz, writing for Scientific American, explains that the gases in galaxies’ interstellar spaces can interact violently:
 </p>
<blockquote>
<p>
   When clouds of gas slam into one another, they warm up, causing a shock front where magnetic fields get compressed. These fields cause particles to travel back and forth over the front, picking up energy from the heat of the gas during every crossing. Eventually, the particles become so energetic that they escape and fly out into space.
  </p>
</blockquote>
<p>
  This isn’t the first natural particle accelerator we’ve observed—supernova debris can create the same energy-amping shock fronts—but it seems to be one of the strongest. In millions of years, some of the particles could wind up as the cosmic rays that pelt the Earth.
 </p>
<p>
  The colossal mass of the four clusters has also created a very large gravity lens. The gravity the clusters exert bends the light originating from other galaxies, allowing us to see distant galaxies that would otherwise be invisible, just like a glass lens in a standard telescope. Later this year, in fact, astronomers will use another giant lens, the Hubble Space Telescope, which took the first optical images of this collision, to take advantage of the gravitational lensing to produce long-exposure images which peer deep into the cosmos. The combined powers of Hubble and MACSJ0717.5+3745 will produce what is “probably the best cosmic telescope on our sky,” Dan Coe of the Space Telescope Science Institute told Moskowitz.
 </p>
<div class="cove-box flex-video" data-cove-id="1463392610" data-cove-params="&amp;topbar=false">
</div>
<div class="inline-caption">
  Learn more about telescopes that are expanding our view of the universe.
 </div>
</section>
<p>
 Photo credit: Van Weeren, et al.; Bill Saxton, NRAO/AUI/NSF; NASA
</p>

Editing Stem Cell Genomes to Lock Out HIV

<section class="entry-content instapaper_body clearfix" itemprop="articleBody">
<div class="add-container clearfix" id="add-block-placer">
</div>
<p>
  In the span of a few decades, HIV has gone from a death-sentence to a manageable illness—provided a patient has access to the right drugs. But even then, drug therapies for HIV are notoriously toxic, with heart disease, nausea, and liver damage among their side effects. That has some researchers wondering, what if they could rid the body of the virus by reprogramming a patient’s own white blood cells—the ones ravaged by HIV—to keep the virus from ever getting in?
 </p>
<figure class="richtext-image full-width">
<img alt="" class="richtext-image full-width" src="https://staging.pbs.org/wgbh/nova/media/images/t-cell.width-990_JHhmDMo.jpg"/>
<figcaption>Human T cells are attacked by HIV, but specific mutation can make them resistant to the virus.
        
    </figcaption>
</figure>
<p>
  A small percentage of people are already naturally resistant to HIV thanks to two copies of a mutation that knocks out the receptors HIV uses to enter the body’s T-cells—something like locking the virus out and throwing away the key. This is the mutation that seems to have cured “Berlin Patient” Timothy Ray Brown, after a transplant of HIV-resistant bone marrow in 2008.
 </p>
<p>
  But a bone marrow transplant is no walk in the park, either: to keep the body from attacking the new marrow, the patient’s own immune system has to be demolished before the transplant, and subjected to a regimen of immunosuppressants afterward.
 </p>
<p>
  That’s where this new technique comes in. Yuet Kan, a hematology professor at the University of California, San Francisco, and his team started with induced pluripotent stem cells, known as iPSCs, which are adult cells that have been retroengineered to act like embryonic stem cells. Made from the patient’s own cells, they would be less likely to trigger rejection. Peter Aldhous,
  <a href="http://www.newscientist.com/article/dn25698-gene-editing-tool-can-write-hiv-out-of-the-picture.html#.U5ck-BZgvwI">
   writing
  </a>
  for NewScientist, explains:
 </p>
<blockquote>
<p>
   It’s fairly easy to make iPSCs from a person’s cells, which then have the potential to grow into any type of cell in the body. So if iPSCs could be given two copies of the protective mutation, it should be possible to make personalized versions of the therapy that cleared HIV from Brown’s body.
  </p>
</blockquote>
<p>
  To create that mutation, Kan used a genomic editing technique called CRISPR-Cas9 that can target precise sequences of DNA. CRISPR snips out the receptor-coding gene while leaving the rest of the cell’s genome alone. After their genetic revision, the stem cells were transformed into white blood cells. Ten days after those white blood cells were exposed to HIV, they didn’t show any sign of the virus. The mutation had made them resistant.
 </p>
<p>
  Kan hopes to further transform the iPSCs into blood-forming stem cells, which would produce white blood cells that carry the resistance mutation. The concept has promise and some precedent. Research published earlier this year in the New England Journal of Medicine showed that extracting and gene-editing just the white blood cells alone could reduce the viral load in HIV patients. That method, though, would require repeated transfusions. The stem cells Kan’s method could make would live and multiply in the bone marrow, generating a constant supply of HIV-resistant white blood cells.
 </p>
<p>
  The research isn’t ready for clinical application yet; creating cells that can be transplanted into the body without being rejected or causing other problems remains a significant challenge. Encouragingly, however, the natural mutation doesn’t seem to have any medical effects other than the fortuitous HIV resistance. If the engineered solution turns out to be just as innocuous, HIV treatments could become a lot more effective and lot less taxing.
 </p>
</section>
<p>
 Photo Credit:
 <a href="https://www.flickr.com/photos/niaid/5950870236">
  NIAID / Flickr (CC BY 2.0)
 </a>
</p>

Just one bite of this granola will unlock your body's energy reserves.

Sixth Taste on Our Tongues May Unleash Our Energy Reserves

<div class="related"></div>
<p>
 If you think a quick carb hit will boost your energy during a workout, your tongue is way ahead of you.
</p>
<p>
 Lots of people rely on sugar as a quick source of energy. Just sipping on Gatorade can be enough to lift you out of a slump. Except it shouldn’t be, at least not directly. Your body won’t actually start using that glucose for energy until after you’ve been exercising for about an hour.
</p>
<p>
 Recently scientists have been learning that the near-instant energy burst may not come from our stomachs, but our tongues. A 2004 study showed that intravenously-injected carbohydrates didn’t help cyclists complete a 1-hour time trial any faster, but, amazingly, just rinsing their mouths with a carbohydrate solution did. Since then, evidence has been piling up that the immediate energy jolt we get from sugar and carbs has more to do with our senses than with digestion.
</p>
<p>
 Now, a new study from the University of Auckland researcher Dr. Nicholas Gant shows what happens in the brain when you combine physical activity with a tongue that’s tasting carbohydrates.
</p>
<p>
 Gant and his colleagues used fMRI to watch how people’s brains responded when they performed a simple motor task—gripping a sensor when they saw a visual cue—while having their mouths rinsed with various solutions. One portion of the subjects received a carbohydrate solution consisting of maltodextrin.
</p>
<div class="ad"></div>
<p>
 Ian Randall, writing for
 <i>
  Science
 </i>
 :
</p>
<blockquote>
<p>
 When the carbohydrate solution was used, the researchers observed
 <a href="http://www.sciencedirect.com/science/article/pii/S0195666314002281">
  a 30% increase in activity for the brain areas that control movement and vision
 </a>
 . This reaction, they propose, is caused by our mouths reporting that additional energy in the form of carbs is coming.
</p>
</blockquote>
<p>
 The tongue, apparently, tastes the carbohydrates and signals the brain to rev up motor function. It knows the body will be getting extra energy to replenish the reserves once the sugars are processed. It wasn’t just a sweet taste that triggered the rush of energy either. Swishing with an artificially-sweetened liquid had no effect. Plus, the brain’s reward centers only lit up when the tongue sensed real carbohydrates, not artificial sweeteners. These findings suggest that the presence of carbohydrates triggers a sixth taste in addition to the existing five—sweet, salty, sour, bitter, and umami.
</p>
<p>
 Other studies had shown that carb-on-tongue action increased performance in endurance sports (like riding a bike for an hour), and that it seemed to prompt activity in areas of the brain associated with motor control. But Gant’s study is the first to link carbohydrate exposure on the tongue with increased brain performance during a physical task, helping to explain just how an energy bar can boost your 5k time before its sugars ever reach your muscles.
</p>
<p>
 Learn more about the neuroscience of taste in "Can I Eat That?"
</p>
<p>
 Photo credit:
 <a href="https://www.flickr.com/photos/lunaspin/4943431344">
  Melissa/Flickr (CC BY-NC-SA)
 </a>
</p>

<p>Recently, scientists have been learning that the near-instant energy burst of something sweet may not come from our stomachs, but our tongues.</p>

The planet looks blue from space, but new research shows that most of Earth's water may actually be deep underground.

Huge Underground Reservoir Holds Three Times as Much Water as Earth’s Oceans

<p>
</p>
<p>
 Earth is a jewel of the solar system, painted blue by the vast oceans that hold the majority of our planet’s water—or so we thought. Most of Earth’s water, according to a new study, may actually be locked in a reservoir 400 miles underground.
</p>
<p>
 That Earth, for much of its history, has been covered by water isn’t much of surprise. But how so much water ended up on a planet that, at its birth, was boiling hot has puzzled scientists for decades. Previous theories had assumed that Earth had picked up its water when it collided violently with icy comets and asteroids. But an alternate hypothesis just received a boost courtesy of a new study published in
 <i>
  Science
 </i>
 : Earth’s water may have been here all along, oozing out gradually as rock deep in the crust was pressed by the intense heat and pressure below the surface.
</p>
<div class="related"></div>
<p>
 The idea of water trapped in solid rock isn’t as unlikely as it sounds. Minerals can trap molecules of water in their metals and metal oxides like a sponge. If the pressure gets high enough, the trapped water can get squeezed out.
</p>
<p>
 Steven Jacobsen, the Northwestern University professor who led the study, found water in subterranean ringwoodite, a deep blue mineral chemically similar to peridot, a green mineral often used in jewelry. Until a sample turned up in 2008 in a diamond coughed up from a volcano,
 <a href="http://www.pbs.org/wgbh/nova/next/earth/a-diamonds-journey-from-the-center-of-the-earth-brings-news-of-a-secret-water-reserve/">
  ringwoodite had only been found in meteorites
 </a>
 . The ringwoodite came from the “transition zone” between the upper and lower mantle, about 400 miles below the Earth’s surface, and about 1.5% of its weight turned out to be water. If a lot of this water-heavy mineral existed underground, scientists reasoned, that might be enough to explain where Earth’s oceans came from.
</p>
<div class="ad"></div>
<p>
 So Jacobsen and his team went looking for dampness lurking deep underground by monitoring the seismic waves generated by earthquakes. Because the velocity of these waves changes depending on what kind of material they’re passing through—like, for example, if a mineral is wet or dry—measuring that speed can give geologists a map of what’s below the Earth’s surface.
</p>
<p>
 Andy Coghlan, writing for
 <a href="http://www.newscientist.com/article/dn25723-massive-ocean-discovered-towards-earths-core.html#.U5skchZgvwI">
  NewScientist
 </a>
 :
</p>
<blockquote>
<p>
 Sure enough, they found signs of wet ringwoodite in the transition zone 700 kilometres [400 miles] down, which divides the upper and lower regions of the mantle. At that depth, the pressures and temperatures are just right to squeeze the water out of the ringwoodite. “It’s rock with water along the boundaries between the grains, almost as if they’re sweating,” says Jacobsen.
</p>
</blockquote>
<p>
 If all the ringwoodite in the transition zone is as damp as the samples that Jacobsen and his team detected, that layer would hold three times as much water as all of the Earth’s oceans combined, reducing their share from 96.5% of all known water to a relatively paltry 24.8%. In other words, the ringwoodite discovery could quadruple the amount of water found on Earth. A blue planet, indeed.
</p>
<div class="newsletter"></div>
<p>
 Photo Credit:
 <a href="http://commons.wikimedia.org/wiki/File:Earth_Pacific_jul_30_2010.jpg">
  NASA/Wikimedia Commons
 </a>
</p>

<p>Most of Earth’s water, according to a new study, may actually be locked in a reservoir 400 miles underground.</p>

Eleanor Nelson

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