The most cost-effective method of stopping invasive species is to put a halt to their introduction. In order for this to happen, managers need to know exactly what plants are invasive. Existing lists of global invasive plants include species that have been reported by scientists, but species that haven’t yet been reported as invasive still pose a risk. the team at UMass Amherst, led by Brittany Laginhas, who completed the research as part of her graduate work at UMass, mined a database of 5,893 studies, stretching back to 1959, to paint the most complete picture of the world’s invasive species yet.

“Trade and climate change have facilitated the widespread movement of species around the globe,” says Brittany Laginhas, who completed this research as part of her graduate studies at UMass Amherst and is the paper’s lead author. “In some cases, these species will establish and spread in their new environment, causing devastating ecological and economic damages. Basic information on invasive species, including which species are invasive, where they have invaded, and their timing of invasion, is critical for developing strategies to prevent their spread and subsequent damages.”

And yet, one of the most basic pieces of information — how many invasive plant species are there in the world? — is not precisely known.

“We’re capturing about two-thirds of the invasives that have been reported in the literature,” says Bethany Bradley, professor of environmental conservation at UMass Amherst, and the paper’s senior author.

Perhaps the most shocking result is that the numbers of invasive species seem to be increasing exponentially, with no sign of starting to level off. Though the team uncovered 3,008 total invasive species reported in the 5,893 papers, their statistical modelling suggests that there should be 4,721 species — though the identity of those missing 1,713 species remains a mystery.

Though there could be many explanations for why so many invasive species are missing from the literature, it’s also clear that there has been a systemic and geographically uneven undercount. While North America has been relatively well studied, Central and South America and Oceania haven’t been given equal attention. “There are vast differences in the studies conducted across different continents,” says Matthew Fertakos, one of the paper’s co-authors and a graduate student in organismic and evolutionary biology at UMass Amherst. “We have statistical methods that can help tell us how many species there should be, but real data is always better than an estimation.”

And that leads to the paper’s final conclusion: a comprehensive map of the world’s invasive species can’t be generated in the lab alone. “We need floristic surveys,” says Bradley, “where researchers actually go out into the field, especially in the places that have been understudied, like Africa, Southeast Asia, and South America, and identify the exact species causing problems.”

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The finding resolves a controversy about the possible redundancy of ILC2s with other cells in the body. The study also suggests that a unique set of regulatory networks controlled by neurons in the gut may be viable targets for future drug therapies to combat chronic inflammatory diseases including asthma, allergy and inflammatory bowel disease (IBD).

The study, published Nov. 2 in Nature, shows that although ILC2s have many functional similarities to immune cells called T helper type 2 cells (Th2 cells), the latter cell type cannot adequately compensate for loss of the protective response of ILC2s against parasitic worm infection in the gut as well as gut inflammation. Underscoring the clinical relevance of the study, the researchers found evidence that ILC2s in humans respond in a manner similar to mouse ILC2s.

“This advances our understanding of the complexity of the immune system, and gives us a potential new set of targets for future therapies,” said study senior author Dr. David Artis, director of the Jill Roberts Institute for Research in Inflammatory Bowel Disease, director of the Friedman Center for Nutrition and Inflammation and the Michael Kors Professor of Immunology at Weill Cornell Medicine.

ILC2s are part of a family of cells, innate lymphoid cells, that were discovered by multiple groups only about 12 years ago. With their strong presence in barrier tissues, innate lymphoid cells are generally considered to serve as sentinels and first responders against various types of infection. But scientists also recognize that ILCs may hold the keys to understanding common inflammatory and autoimmune conditions such as asthma and IBD.

It is thought that both ILC2s and Th2 cells evolved at least in part to defend the body from parasitic worm infections, biting insects and other environmental triggers. When triggered by such challenges, both help marshal what is called a type 2 immune response. These similarities have led researchers to suggest that they are functionally almost the same but ILC2s specialize in earlier, more localized responses, whereas T cells are more blood-borne and mobile, concentrating in multiple tissues where needed. However, in the new study, the researchers found that ILC2s have an essential immune role rather than being redundant as type 2 immune responders.

When ILC2s and Th2 cells are activated by a worm infection, they both produce an anti-worm, tissue-protecting protein called amphiregulin (AREG). To determine if Th2 cells can compensate for loss of this protein from ILC2s, the researchers engineered mice in which AREG production is selectively deleted in ILC2s, but not in Th2 cells. They found that these mice were more susceptible to parasitic worm infection in the gut due to reduced capacity to mount an anti-parasitic immune response, compared with mice with normal ILC2s. The mice lacking ILC2 AREG were also much more susceptible to gut damage from inflammation.

“This finding clarifies that ILC2s are playing the major role in this tissue protective response — without them the response is inadequate,” said study co-first author Dr. Hiroshi Yano, a postdoctoral research associate in the Artis laboratory.

Clarifying the functional importance of a major immune cell type is a significant achievement in basic immunology and the results of the study also suggest clinical applications. The researchers showed that the ILC2 immune response, either to worm infection or inflammatory gut damage, is selectively controlled by a signaling molecule produced by neurons in the gut. Giving the molecule to mice with experimental gut inflammation boosted AREG production in ILC2s and protected the animals from gut damage. Preliminary experiments with gut ILC2s taken from patients with inflammatory bowel disease showed that the molecule could boost the protective response in the human cells as well. These findings suggest that neurons in the gut communicate with ILC2s to generate a protective response that cannot be replaced by other immune cells, thus offering new therapeutic opportunities, Dr. Artis said.

This work was supported in part by the National Institutes of Health (DK126871, AI151599, AI095466, AI095608, AI142213, AR070116, AI172027, DK132244), a WCM Department of Pediatrics Junior Faculty Pilot Award, the Jill Roberts Center Pilot Award for Research in IBD, a Thomas C. King Pulmonary Fellowship, the LEO foundation, Cure for IBD, Jill Roberts Institute, the Sanders Family, and the Rosanne H. Silbermann Foundation.

The study, published Nov. 2 in Nature, found that dietary inulin fiber alters the metabolism of certain gut bacteria, which in turn triggers what scientists call type 2 inflammation in the gut and lungs. This type of inflammation is thought to have evolved in mammals chiefly to defend against parasitic worm (“helminth”) infections, and is also part of normal wound-healing, although its inappropriate activation underlies allergies, asthma and other inflammatory diseases.

“There’s a lot to think about here, but, in general, these findings broaden our understanding of the relationship between diet, immunity, and the normally beneficial microorganisms that constitute our microbiota and colonize our bodies,” said study co-senior author Dr. David Artis, director of the Friedman Center for Nutrition and Inflammation and the Michael Kors Professor of Immunology at Weill Cornell Medicine.

The study’s scientific participants reflect the Friedman Center’s highly cross-collaborative research mission, drawing on expertise in bacterial genetics, biochemistry and immunology at Weill Cornell Medicine in New York City and Cornell’s Ithaca campus. Dr. Chun-Jun Guo, assistant professor of immunology in medicine at Weill Cornell Medicine, and Dr. Frank Schroeder, professor at the Boyce Thompson Institute and in the Department of Chemistry and Chemical Biology in the College of Arts and Sciences on Cornell’s Ithaca campus teamed up with the Artis laboratory to gain a detailed understanding of how an important dietary component affects the microbiome and the immune response. The study’s first author is Dr. Mohammad Arifuzzaman, a postdoctoral researcher in the Artis laboratory.Dr. Artis is also director of the Jill Roberts Institute for Inflammatory Bowel Disease at Weill Cornell Medicine.

Small amounts of inulin are present in a wide variety of fruits and vegetables, including bananas, asparagus, and garlic. It is also frequently concentrated in commonly available high-fiber dietary supplements. Previous studies have found that inulin boosts populations of beneficial gut bacterial species which in turn boost levels of anti-inflammatory immune cells called regulatory T (Treg) cells.

In this new study, the researchers examined inulin’s effects more comprehensively. They gave mice an inulin-based, high-fiber diet for two weeks, and then analyzed the many differences between these mice and mice that had been fed a diet lacking inulin. A major difference was that the inulin diet, while increasing Treg cells, also induced markedly higher levels of white blood cells called eosinophils in the gut and lungs. A high level of eosinophils is a classic sign of type 2 inflammation and is typically seen in the setting of seasonal allergies and asthma.

Ultimately the researchers found that the eosinophil response was mediated by immune cells called group 2 innate lymphoid cells (ILC2s), which were activated by elevated levels of small molecules called bile acids in the blood. The bile acid levels were elevated due to the inulin-induced growth of certain bacterial species — a group called Bacteroidetes, found in both mice and humans — which have a bile acid-metabolizing enzyme.

“We were amazed to find such a strong association between inulin supplementation and increased bile acid levels,” Dr. Schroeder said. “We then found that deletion of the bile acid receptor abrogates the inulin-induced inflammation, suggesting that microbiota-driven changes in bile acid metabolism underlie the effects of inulin.”

“When we colonized germ-free mice (mice without microbiota) with one of these bacterial species, and then knocked out the gene for one bacterial enzyme that promotes bile acid production, the whole pathway leading from inulin to eosinophilia and allergic inflammation was blocked,” Dr. Guo said.

The finding that inulin promotes type 2 inflammation does not mean that this type of fiber is always “bad,” the researchers said. They found that inulin did worsen allergen-induced type 2 airway inflammation in mice. But the experiments also confirmed inulin’s previously reported effect at boosting anti-inflammatory Treg cells, which may in many cases, outweigh some pro-inflammatory impact. Moreover, a type 2 immune response, which in the gut and lungs involves an increased production of tissue-protecting mucus, is not necessarily harmful in healthy people — indeed, the researchers found in their mouse experiments that the inulin-induced type 2 inflammation enhances the defense against helminth infection.

“It could be that this inulin to type-2-inflammation pathway represents an adaptive, beneficial response to endemic helminth parasite infection, though its effects in a more industrialized, helminth-free environment are more complex and harder to predict,” said Dr. Arifuzzaman.

The researchers now plan to use their multi-disciplinary, multi-platform approach to study systematically the immune effects of the different types of dietary fiber as well as a range of other dietary supplements in different states of health and disease.

This work was supported in part by the National Institutes of Health (5T32HL134629, DP2 HD101401-01, AI140724, KL2 TR002385, R35 GM131877, DK126871, AI151599, AI095466, AI095608, AR070116, AI172027 and DK132244) the AGA Research Foundation, the WCM-RAPP Initiative, the W. M. Keck Foundation, the Howard Hughes Medical Institute, the LEO Foundation, CURE for IBD, the Jill Roberts Institute for Research in IBD, the Sanders Family Foundation and the Rosanne H. Silbermann Foundation.

“The Chestnut-bellied Flycatcher is not as well-known as Darwin’s finches,” said lead author Leonardo Campagna, an evolutionary geneticist at the Cornell Lab of Ornithology. “But this complex of birds has also gone through many evolutionary changes, many of which involve changes in the coloration and patterning of their plumage.”

The scenario: A large population of chestnut-bellied birds lives on one of the bigger islands in the Pacific chain. From there, some birds established new populations on a couple of smaller islands. Over time, birds on the two smaller islands lost their chestnut bellies and became all black. But the birds on each island developed black plumage at different times, from different genetic mutations which moved rapidly through the small island populations. One of these mutations spread during the last 1,000 years — a mere blink in evolutionary time.

“Clearly there’s something advantageous about having all-black plumage,” said Campagna. “We’ve traced this trait back through time by sequencing the entire Chestnut-bellied Flycatcher genome for the first time. The two mutations that lead to black plumage appeared at different times, on different islands, and on different genes related to melanin pigment production. That level of convergence is wild!”

The various flycatcher populations are in the early stages of speciation — splitting off to form new species — but they have not yet diverged much genetically and they can interbreed. But they rarely do, producing a few hybrids. Field experiments have shown the chestnut-bellied birds and the all-black birds each react aggressively toward a perceived interloper with their own plumage color, but do not respond the same way to the members of their species with a different color.

And it turns out Mother Nature is not done tinkering with the flycatcher genome.

“We’re finding there’s a third melanic (all black) population of flycatchers among islands about 300 miles away from the original island,” said senior co-author Al Uy, a biology professor at the University of Rochester. “The mutation governing their plumage color is different yet again from those on the other two islands we studied.”

Uy has been studying the Solomon Islands flycatchers for about 15 years, aided by a trusted group of indigenous islanders he says have been “instrumental” in his work.

“I think the emerging pattern is that there’s something about small islands that’s favoring these all-black birds — in the more distant archipelago were melanism has evolved for the third time, we found that melanic and chestnut-bellied birds still coexist within each island but as islands get smaller, the frequency of melanic birds goes up.”

There are multiple theories about what’s driving the switch to back plumage, including female preference, the greater durability of black feathers, and even a possible link to genes that govern other advantageous behaviors.

The study authors include computer scientists Ziyi Mo and Adam Siepel from Cold Spring Harbor Laboratory who wrote the machine learning program that helped the researchers dig deeper into the past and measure mutation patterns in the flycatcher “family tree.”

“The use of machine learning is an exciting new development in the field of population genetics,” said Campagna. “We train the computer to recognize specific evolutionary patterns for when a particular genetic trait started, how strong natural or sexual selection was, and how quickly it moved through a population. We can then ask the trained algorithm to tell us the most likely scenario that generated the data that we observe in the present populations. It’s like going back in time.’

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“For the first time, we have identified a root cause of chronic heart failure following a heart attack,” Dharmakumar said.

Dharmakumar is executive director of IU’s Krannert Cardiovascular Research Center and associate director for research at the Cardiovascular Institute, a joint enterprise between IU School of Medicine and IU Health.

“While advances across populations have made survival after a heart attack possible for most, too many survivors suffer long-term complications like heart failure,” said Subha Raman, MD, who is physician director of the Cardiovascular Institute. “Dr. Dharmakumar’s breakthrough science illuminates who is at risk and why and points to an effective way to prevent these complications.”

The multi-million-dollar study, which involved collaborators from institutions in the United States and Canada, followed large animal models over six months. It found that in heart attacks that result in bleeding within the heart muscle — which is about half of them — scar tissue is slowly replaced by fat. Fatty tissue can’t push blood from the heart effectively, and this is what leads to heart failure and eventually to death in many survivors of hemorrhagic heart attacks, Dharmakumar said.

“Using noninvasive imaging, histology and molecular biology techniques, and various other technologies, we have shown that iron from red blood cells is what drives this process,” he explained. “When we removed the iron, we reduced the amount of fat in the heart muscle. This finding establishes a pathway for clinical investigations to remedy or mitigate the effects associated with iron in hemorrhagic myocardial infarction patients.”

Dharmakumar’s team is currently testing iron chelation therapy to do just that in a just-launched clinical trial.

“Thanks to a clinical trial underway being led by his team at Indiana University, I’m excited to see this treatment improve the lives of millions of heart attack survivors worldwide,” said Raman.

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This technique could be used to finely tune the production of useful proteins, such as the monoclonal antibodies used to treat cancer and other diseases, or other aspects of cellular behavior. In their new study, which appears in Nature Communications, the researchers showed that this system can work in a variety of mammalian cells, with very consistent results.

“It’s a highly predictable system that we can design up front and then get the expected outcome,” says William C.W. Chen, a former MIT research scientist. “It’s a very tunable system and suitable for many different biomedical applications in different cell types.”

Chen, who is now an assistant professor of biomedical sciences at the University of South Dakota, is one of the lead authors of the new study, along with former MIT Research Scientist Leonid Gaidukov and postdoc Yong Lai. Senior author Timothy Lu led the research as an MIT associate professor of biological engineering and of electrical engineering and computer science.

Gene control

Many therapeutic proteins, including monoclonal antibodies, are produced in large bioreactors containing mammalian cells that are engineered to generate the desired protein. Several years ago, researchers in MIT’s Synthetic Biology Center, including Lu’s lab, began working with Pfizer Inc. on a project to develop synthetic biology tools that could be used to boost the production of these useful proteins.

To do so, the researchers targeted the promoters of the genes they wanted to upregulate. In all mammalian cells, genes have a promoter region that binds to transcription factors — proteins that initiate the transcription of the gene into messenger RNA.

In previous work, scientists have designed synthetic transcription factors, including proteins called zinc fingers, to help activate target genes. However, zinc fingers and most other types of synthetic transcription factors have to be redesigned for each gene that they target, making them challenging and time-consuming to develop.

In 2013, researchers in Lu’s lab developed a CRISPR-based transcription factor that allowed them to more easily control transcription of naturally occurring genes in mammalian and yeast cells. In the new study, the researchers set out to build on that work to create a library of synthetic biological parts that would allow them to deliver a transgene — a gene not normally expressed by the cell — and precisely control its expression.

“The idea is to have a full-spectrum synthetic promoter system that can go from very low to very high, to accommodate different cellular applications,” Chen says.

The system that the researchers designed includes several components. One is the gene to be transcribed, along with an “operator” sequence, which consists of a series of artificial transcription factor binding sites. Another component is a guide RNA that binds to those operator sequences. Lastly, the system also includes a transcription activation domain attached to a deactivated Cas9 protein. When this deactivated Cas9 protein binds to the guide RNA at the synthetic promoter site, the CRISPR-based transcription factor can turn on gene expression.

The promoter sites used for this synthetic system were designed to be distinct from naturally occurring promoter sites, so that the system won’t affect genes in the cells’ own genomes. Each operator includes between two and 16 copies of the guide RNA binding site, and the researchers found that their system could initiate gene transcription at rates that linearly correspond to the number of binding sites, allowing them to precisely control the amount of the protein produced.

High consistency

The researchers tested their system in several types of mammalian cells, including Chinese hamster ovary (CHO) cells, which are commonly used to produce therapeutic proteins in industrial bioreactors. They found very similar results in CHO cells and the other cells they tested, including mouse and rat myoblasts (precursors to muscle cells), human embryonic kidney cells, and human induced pluripotent stem cells.

“The system has very high consistency over different cell types and different target genes,” Chen says. “This is a good starting point for thinking about regulating gene expression and cell behavior with a highly tunable, predictable artificial system.”

After first demonstrating that they could use the new system to induce cells to produce expected amounts of fluorescent proteins, the researchers showed they could also use it to program the production of the two major segments of a monoclonal antibody known as JUG444.

The researchers also programmed CHO cells to produce different quantities of a human antibody called anti-PD1. When human T cells were exposed to these cells, they became more potent tumor cell killers if there was a larger amount of the antibody produced.

Although the researchers were able to obtain a high yield of the desired antibodies, further work would be needed to incorporate this system into industrial processes, they say. Unlike the cells used in industrial bioreactors, the cells used in this study were grown on a flat surface, rather than in a liquid suspension.

“This is a system that is promising to be used in industrial applications, but first we have to adapt this into suspended cells, to see if they make the proteins the same way. I suspect it should be the same, because there’s no reason that it shouldn’t, but we still need to test it,” Chen says.

The research was funded by the Pfizer-MIT RCA Synthetic Biology Program, the National Science Foundation, the National Institutes of Health, the University of South Dakota Sanford School of Medicine, an NIH Ruth L. Kirschstein NRSA postdoctoral fellowship, and the U.S. Department of Defense.