‘Fast-forward Genetics’ Induces Mutations to Produce Higher-Yielding Crops

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 A new development in plant breeding may lead to some very fruitful results. This month, a team of scientists announced that they had identified and combined key genetic mutations to significantly increase fruit production in tomato plants. These results may be a first step towards increasing yield in other crops as well.
 

 To create their productive new plants, researchers used a technique called mutation breeding. They exposed tomato seeds to DNA-altering chemicals to induce random changes in the plant’s genetic code; the team then searched for new, desirable traits in the resulting plants. The new plants are genetically modified, but different from what people typically call genetically modified organisms in that they contain no artificially introduced foreign DNA, writes Zachary Lippman, a researcher at Cold Springs Harbor Laboratory and an author of the
 <a href="http://www.nature.com/ng/journal/v46/n12/full/ng.3131.html" target="_blank">
 new study
 </a>
 published in Nature Genetics.
 
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<figcaption>Using mutation breeding, researchers have
 
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 Mutation breeding has been carried out for decades, says Robert Paarlberg, a political science professor at Wellesley College who researches food and agricultural policy. “We have in our food supply right now varieties of wheat and peanuts and grapefruit that have been developed using induced mutation and then breeding,” he says. The technique can also be used to develop ornamental crops and flowers, Paarlberg says, but says it’s not a “very precise” strategy. Plant breeders call the process “spray and pray,” Lippman says. Once the plants are treated, “you pray that you find something that’s useful,” he says.
 

 Lippman and his team were praying for more flowers, which lead to more fruit. Plants like tomatoes naturally balance flowering activity with increasing leaf and plant size. Changing the behavior of only a few genes can profoundly alter how many flowers a plant produces or how bushy it becomes. Modern processing tomatoes, for example, have a mutated flower-repression gene; this results in bushy plants with bursts of flowers that produce easily harvestable fruit. Lippman and his colleagues sought new ways to modulate this system of flower production and repression.
 

 The team discovered several new mutations that improved productivity. But to maximize fruit yield, Lippman and his colleagues mixed and matched their new mutations. Like humans and many other organisms, tomatoes have two alleles, or forms, of every gene. The researchers discovered that changing only one allele in certain flower-production gene pairs was enough to change the plant’s growth. Lippman thinks this could be particularly useful in agriculture, where “hybrid” or cross-bred plant varieties with mixed allele pairs are common. Lippman and his colleagues paired different mutations to produce several new plants with high fruit yield. In some cases, these new hybrid plants produced twice as much fruit as currently bred processing tomatoes.
 

 The work shows promise in terms of both breeding applications and understanding regulation of plant architecture, says David Francis, a professor of horticulture and crop science at Ohio State University. But Francis has some doubts about the utility of mutation breeding. He notes that the process largely leads to lost functionality. Plant breeding also depends upon environmental conditions, he says. “I don’t believe that you can just build a perfect tomato in the lab and get it done in the field.”
 

 There are other potential concerns associated with mutation breeding; for example, the National Research Council noted in a 2004 report that the process is not regulated for food or environmental safety. Still, Paarlberg sees little cause for concern. “They’ve been doing mutation breeding now for eighty years, and I’m not aware of anybody who’s been harmed by any of the crops that have been put on the market as a result,” he says.
 

 Francis also questions the immediate utility of the new tomato plants: they are less compact than standard processing tomatoes, he says, which might make them difficult to harvest industrially. “This kind of work is only really a breakthrough if it goes hand in hand with changes in agronomic practices,” he says. “That said, the science is pretty cool.”
 

 Lippman says that the tomato is simply a model. Similar modifications can be extended into other crops, with the likely next candidate being soybeans. “The most exciting thing to all of this is that you can fine-tune crop productivity,” Lippman says. Current GMOs mainly try to limit crop losses, he says, instead of producing more food. “But in the future, we’re going to have to look beyond that,” he says. “It’s not just about this particular way boosting yield in tomato,” he says. It’s also about “the issue of needing to produce more food in the future.”
 
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 Photo credit: USDA

Bioinspired Underwater Glue Could Soon Replace Stitches

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 It’s a sticky situation—in the best possible way. By combining proteins that mussels and bacteria use to stick to surfaces, scientists at the Massachusetts Institute of Technology have created a strong new underwater glue. This adhesive could tackle an important challenge in various fields, including surgery, where repairing wet surfaces is essential.
 

 For years, scientists have used marine organisms for insight in producing underwater glues. Water forms a “weak boundary” on surfaces it contacts, which prevents adhesives from attaching, says Dr. Herbert Waite, Professor of Molecular, Cellular, and Developmental Biology at the University of California, Santa Barbara. This becomes a challenge in fields where wet surfaces need to be repaired—marine salvage, dentistry, surgery, and more. But organisms like mussels and barnacles regularly overcome this obstacle, binding easily to wet rocks.
 

 The MIT team turned to these organisms for inspiration—and ingredients. “One of the promises in synthetic biology is to be able to mix and match and optimize biologically based materials,” says Dr. Timothy Lu, an associate professor in MIT’s Synthetic Biology group and an author of the study. Lu and his colleagues combined proteins from two different sources—the feet of mussels, and E. coli bacteria.
 
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<figcaption>By combining proteins that mussels and bacteria use to stick to surfaces, scientists at MIT have created a strong new underwater glue.
 
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 A good adhesive has two properties, Waite says: It has to be able to stick to other surfaces, and it also has to bind to itself. DOPA, the protein mussels use to adhere to surfaces, can do both, but its behavior depends upon the conditions of its environment. Mussels use various “tricks” to control their DOPA that aren’t fully understood, Waite says. If you’re not a mussel, it can be hard to manage DOPA’s behavior.
 

 That’s where the second protein helps. Amyloids are also adhesive, water-resistant, and link strongly to one another. Barnacles, algae, and bacteria use them to stick to surfaces. Lu and his team saw an opportunity: “[W]e thought by combining the bacteria with the mussels, we might be able to get some synergistic behavior,” says Lu.
 

 The result was a glue stronger than any other bio-derived or bio-inspired adhesive made to date. Waite, who was not involved with the study, says the results “really impressed” him. The researchers only asked DOPA to work in the form where it adheres to surfaces, he explains, while the amyloid proteins held the glue together. This joint behavior gives the glue its strength.
 

 Lu believes that this is only the beginning. “We only looked at two of the proteins that are involved in mussel adhesion…If we could combine multiple proteins on top of that, maybe we can even get stronger performance,” he says. While the group has been focused on adhesion alone, in the future, the group plans to explore potential underwater and biomedical uses, says Lu.
 

 These biomedical applications could be profound, especially in surgery. Waterproof glues could help seal internal wounds, even when drenched in blood and other fluids. Sutures or staples are currently used to close such holes, but these are hard to affix and can damage tissues, says Dr. Jeffrey Karp, an associate professor at Brigham and Women’s Hospital and Harvard Medical School. Karp, who was not involved in the MIT study.
 

 “There’s a huge unmet need for better adhesives,” says Karp, who is also a co-founder of Gecko Biomedical, which is developing medical adhesives. “There’s really nothing available in the clinic that works well and doesn’t have its drawbacks,” he adds, calling Lu’s team’s work “excellent and very promising.” The next step, Karp says, is to test the glue at larger scales.
 

 To work inside the human body, an adhesive must be biocompatible, or “cell-friendly.” But strong glues are often toxic. “We really don’t have anything that is strong and biocompatible,” says Dr. Pedro del Nido, a specialist in cardiac surgery at Boston’s Children’s Hospital who was not involved with the MIT study.
 

 Lu says his group is interested in testing for biocompatibility and believes that natural sources will yield better biocompatible materials. Looking to nature for advice has served him well so far. “[N]ature has solved a lot of the same problems that we deal with in pretty creative ways…Often times, borrowing upon nature and then applying the tools that we have in our arsenal to improve those properties, I think, is a really powerful way to go.”
 
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Insulin-Producing Stem Cells Could Provide Lasting Diabetes Treatments

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 Researchers have crafted what may be a powerful weapon in the fight against diabetes: A new line of insulin-producing cells that has been shown to reverse diabetes in mice within forty days. Scientists hope that these cells may someday do the same in humans.
 

 The new cells, called “Stage 7” or “S7” for their seven-step production process, are the
 <a href="http://dx.doi.org/doi:10.1038/nbt.3033" target="_blank">
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 </a>
 by researchers at the University of British Columbia and the pharmaceutical company Janssen. S7 cells are made to mimic human beta cells, which are damaged or destroyed in patients with diabetes. Healthy beta cells produce insulin and help regulate blood sugar; S7 cells are grown from human embryonic stem cells and are programmed to do the same.
 
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 “The advance that they have made is that they’ve got better cells in the test tube, cells that have more insulin and can secrete insulin in response to glucose,” said Dr. Gordon Weir, a physician and researcher at Joslin Diabetes Center and Harvard Medical School. “People haven’t been able to do that before.”
 

 Human embryonic stem cells, like those used to produce the S7 line, show great promise for producing beta cell replacements. Just last week, another team of researchers led by Dr. Douglas Melton at Harvard University
 <a href="http://dx.doi.org/10.1016/j.cell.2014.09.040" target="_blank">
 announced their own line of insulin-producing cells
 </a>
 , also produced from human embryonic stem cells. Like S7 cells, the Harvard team’s cells produce insulin in response to high blood sugar and can reverse diabetes symptoms in mice.
 

 The hope is that cells like these could be injected into diabetic patients, restoring normal beta cell function. Timothy Kieffer, head of the diabetes research group at University of British Columbia and a co-author of the S7 cell study, said that treatment with these cells could be curative, though other researchers caution that additional work has to be done before that’s the case.
 

 Cellular transplantation has already been shown to effectively combat diabetes. Since the late 1980s, beta cells extracted from cadaver pancreases have been used to normalize blood sugar in diabetics. But these treatments are not an option for many patients. In addition to the challenges of establishing a treatment program, Weir said, “there aren’t enough pancreatic donors to even scratch the surface.” These transplanted cells also tend to stop working over time, said Dr. David Nathan, the director of the Diabetes Center and Clinical Research Center at Massachusetts General Hospital. Whole organ pancreatic transplants usually last longer and have been increasingly successful in recent years, Nathan says. But both organ and cell transplants from cadavers require immunosuppressive treatments, which can cause tumors, skin cancers, and weakened immune systems.
 

 Beta cells grown from stem cells could solve some of these problems. It is possible that stem cells could be developed to reduce or eliminate the need for immunosuppression, Nathan said. Plus, their supply is theoretically unlimited. “If you can make them in a test tube, in a dish, whatever—well, that gets rid of the problem of donor pancreases,” Nathan said. While S7 cells are most efficient when made from human embryonic stem cells, they can also be made using induced pluripotent stem cells, which are reprogrammed adult cells. This, Weir noted, could eliminate “ethical issues” involved with embryonic stem cell use.
 

 Kieffer believes that a stem cell-based treatment would also be superior to insulin supplementation, the current standard of treatment for type 1 diabetes. In type 1 diabetes, which Kieffer’s research targets, beta cells are destroyed by an autoimmune attack, and patients require external insulin to survive. Even with advanced treatment options like insulin pumps, Weir said, it is challenging to keep blood sugar in a normal range. “And if you push hard enough to drive the blood sugar down, you end up getting into trouble with insulin reactions,” Weir said. “The blood sugar goes too low and that’s dangerous.”
 

 But S7 cells have some challenges to overcome before they can replace current treatments. For one, it can be difficult to control the development of stem cells, Nathan pointed out. Kieffer agreed that more research is needed to mature the cells, which are still not identical to human beta cells because they react more slowly to sugar and don’t release as much insulin. Kieffer’s collaborators are also working to scale up production of the S7 line. Meanwhile, the Harvard study uses a protocol that already seems to allow relatively large-scale development of insulin-producing cells.
 

 There are also other challenges to treating type 1 diabetes with cells like S7 because of the autoimmune nature of the disease. If beta cell transplants are injected into type 1 diabetics, Weir said, “those cells are still going to be subject to the immune problem that killed the cells in the first place.” Kieffer said that the “next hurdle” for his team is to see if S7 cells will work inside devices that prevent immune attack.
 

 These “immunobarrier” devices are essentially capsules that contain implanted stem cells, allowing the exchange of nutrients and insulin while blocking attacking immune cells. Nathan and Weir expressed reservations about these devices. Nathan wondered if they can be designed to allow sufficient blood flow and nutrients to all the cells inside, while Weir questioned whether there could be a device large enough to hold the number of cells needed to control the disease. Still, in August, the company Viacyte started clinical trials with such a device, using a line of cells less developed than S7. “We’ll have to wait and see,” Weir said.
 

 Because of the autoimmunity problem inherent in type 1 diabetes, Weir says that it may be easier to use beta cell transplantations to treat type 2 diabetes instead. Up to 95% of diabetic patients have this form of the disease, which involves no autoimmunity. Instead, in type 2, beta cells “wear out” such that the body stops responding to insulin.
 

 “You can take a type 2 diabetic and give them insulin injections and normalize the sugar if you do it carefully,” Weir said. “So, a beta cell transplant is just the same thing as giving an insulin injection.” He feels the effects of such treatment could be profound. “You can put cells in and normalize the blood sugar for years,” he said. “So if you want to call that a cure, I’d go along with that.” Nathan disagrees: because type 2 diabetics have some pancreatic function, it can be simpler and easier to treat their symptoms. Because of this, he believes that cellular transplantations will mostly be useful to combat type 1 diabetes.
 

 Nathan doesn’t think that beta cell transplantations are an “appropriate clinical option”—yet. “The balance between risk and benefit isn’t quite right,” he says. Still, he hopes that someday, a cellular treatment will be advanced enough to safely and effectively treat this disease. “To cure type 1 diabetes would be a godsend,” he says. “To actually do a single procedure that essentially takes away the disease at low risk would be great.”
 

 Though several questions must be answered before they start curing patients, S7 cells are a promising step in the fight against a disease that affects 347 million people worldwide. The field is moving quickly towards its goal; as Kieffer writes, “I am very optimistic that we are narrowing down on a cure for diabetes.”
 
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 Image credit: Doug Melton/Harvard

Sarah Schwartz

Articles

‘Fast-forward Genetics’ Induces Mutations to Produce Higher-Yielding Crops

Bioinspired Underwater Glue Could Soon Replace Stitches

Insulin-Producing Stem Cells Could Provide Lasting Diabetes Treatments

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