Endophytes Help Poplar Trees Clean up Trichloroethylene (TCE)

This article (from the Superfund Diary this month) should be of interest to some of you. It turns out that a symbiotic microbe, living in the cells of poplar trees, is capable of very efficiently degrading a known human carcinogen, trichloroethylene (TCE) present in the soil. The process is termed phytoremediation.

Endophytes Help Poplar Trees Clean up TCE on Superfund Site

Poplar trees can capture and remove trichloroethylene (TCE) from the soil and degrade it. Now, a method using endophytes, symbiotic microbes that live within a plant, has been successfully shown to boost the speed and effectiveness of this natural degradation process.

At the Ames Research Center field site, the researchers observed visible differences between the poplar trees with the inoculated endophyte and the poplar trees without (control). Endophyte-assisted poplars experienced more robust growth and increased survival rates. (Reprinted with permission from Doty et al. 2017. Enhanced degradation of TCE on a Superfund site using endophyte-assisted poplar tree phytoremediation. Environ Sci Technol 51(17):10050-10058. Copyright 2017 American Chemical Society.)Researchers led by Edenspace Systems Corporation, a Superfund Research Program (SRP)-funded small business, conducted the first large-scale experiment on a Superfund site using poplar trees fortified with a microbial endophyte to clean up TCE-contaminated groundwater. TCE is a known human carcinogen that is widely used as a metal degreasing agent and has been found in groundwater at many military and Superfund sites.

After inoculating poplar trees with a specific endophyte strain, the researchers successfully showed that the endophyte-assisted poplars quickly and effectively removed TCE, decreasing concentrations in groundwater from 300 to 5 micrograms per liter.

According to the researchers led by Michael Blaylock, Ph.D., this method offers a readily deployable, cost-effective, and sustainable approach to degrade TCE and has the potential to make a huge impact on Superfund and other hazardous waste sites with TCE-contaminated groundwater. Endophytes live within the plant and, therefore, are expected to persist in the trees at the site, continuing to degrade TCE as long as their host plant survives.

Moving from the lab to the field

The strain of bacteria used in the new research was isolated by Sharon Doty, Ph.D., professor at the University of Washington and partner on the small business project. It was taken from poplar trees exhibiting high rates of TCE degradation on sites with TCE contamination. The first phase of the small business grant demonstrated the ability of this bacterial endophyte to persist in the poplar trees and significantly enhance degradation of TCE compared to poplars without the bacteria.

In the new work, the researchers tested the ability of poplar trees inoculated with microbes to clean groundwater from the Middlefield-Ellis-Whisman Superfund research area in California’s Silicon Valley after it had flowed into the NASA Research Park at NASA’s Ames Research Center. At the Ames Research Center, the researchers planted rows of young poplar trees — some inoculated with the specific microbe, and others without — on a field above a known groundwater plume contaminated with TCE.

The researchers found that TCE concentration decreased from 300 micrograms per liter upstream of the planted area to less than 5 micrograms per liter downstream from the test site. They also found evidence of a 50 percent increase in chloride in the soil around the poplar roots. Chloride is a harmless, naturally occurring element that remains after TCE is degraded by the bacteria inside the trees.

When trees take up and degrade chemicals, it often leads to stunted tree growth and withering leaves and can sometimes cause the plant to die. But, in this case, the trees degrading TCE that received the microbe were bigger and healthier, exhibiting a 32 percent increase in trunk diameter compared to poplar trees without inoculation of the endophyte. After three years, tree trunk samples also revealed greatly reduced levels of TCE inside the inoculated trees.

Building on previous SRP-funded research

In the 1990s, SRP-funded researchers led by Milt Gordon, Ph.D., pioneered the use of hybrid poplar trees to remove TCE and other chlorinated contaminants from groundwater. Their research was the first to show conclusively that plants are capable of the types of degradation of toxic compounds that was formerly seen primarily with microorganisms.

SRP-funded researchers, including Doty, later went on to develop and successfully field test transgenic poplar plants that could remove TCE at much faster rates. But, according to the authors, significant regulatory and breeding hurdles have prevented large-scale use of this technology.

The endophyte-assisted technology provides a simpler and cheaper approach that does not require special poplar breeding and can be introduced more quickly. The field trial demonstrates the effectiveness of this natural TCE-degrading endophyte strain, which was successfully shown to improve tree growth and pollutant degradation.

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Previously unappreciated form of cell-to-cell communication might be related to prions and may participate in cancer metastasis and infections

Scientists know that some cells build wire-like extensions as a kind of temporary foothold to move themselves from place to place. But these “extensions” might in fact be involved in something far more complex [see attached article]. In 1999, cell biologist Thomas Kornberg (Uni­v California, San Francisco) was studying how fly larvae develop wings, and he noticed a sea of filaments –– projecting from the wing buds toward the signaling center that is essential for their growth. He coined the term cyto­neme — or cell thread — to describe these fila­ments. In 2004, two research groups independently pub­lished observations of “nanotubes in mammalian cells” that seemed to move cargo (i.e. organelles and vesicles) back and forth. These accidental sightings grew into a Science paper that described the structures as “nano­tubular highways”. These researchers proceeded to describe different sorts of nanotubes –– some holding subcellular vesicles and mitochondria inside, and others holding bacteria.

Meanwhile, other labs have reported cell-connecting tubes in neurons, epithelial cells, mesenchymal stem cells, several types of immune cells, and multiple cancers. Some tubes end in gap junctions: gateways that bestow the neuron-like ability to send electrical signals, which can also pass along peptides and RNA molecules. There is speculation that such connections may be more than conceptually related to neuronal synapses. The strongest evidence for a role in disease came in 2015, when a team of researchers was watching human gliomas grow in culture. Cells derived from the tumors were injected into the brains of mice that had glass windows in their skulls — through which they could watch the cells. As tumor cells invaded, they sent tubular protrusions ahead of them; they saw many tubes connecting cells through gap junctions. Interconnected cells managed to survive doses of radiation that had killed isolated cells, apparently because the gap junctions helped to spread the load of toxic ions to neighbors.

When radiation did kill linked tumor cells, nuclei from those cells sometimes traveled down a nanotube, to form a vigorous new cancer cell. These ‘tumor micro­tubes’ were also found in biopsies from patients; denser longer tubes correlated with more resistant forms of cancer and a poorer progno­sis for the patient. It has been speculated that cancer drugs such as paclitaxel –– that appear to work by disrupting tumor microtubules –– might be keeping these tubes from sprouting or extending, leading to effective treatment against certain types of cancer. The entire field remains controversial at this moment, with some suggesting these nanotubes are artifacts seen only in cell culture, while others disagree with these suggestions. Stay tuned..!

Nature 21 Sept 2o17; 549: 322–324

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After 13 years of planetary exploration, Cassini was programmed to crash into Saturn’s atmosphere

Although this article [attached] is not exactly on the topic of “gene-environment interactions,” the Cassini Project should boggle the mind of anyone interested in science, as well as astronomy or reading Sci-Fi books. In mid-September, after 13 years of solar system exploration, NASA’s Cassini spacecraft plunged into the upper reaches of Saturn’s atmosphere at 123,000 kilometers per hour and melted. Beaming back its last measurements to Mission Control at the Jet Propulsion Laboratory (JPL) in Pasadena, California, the orbiter had remained intact for 30 seconds longer than expected, during its fiery plunge into the atmoshere. Finally, at 4:55 a.m. local time, the radio signals stopped: Cassini’s aluminum and polymer skeleton had likely vaporized.

The spacecraft’s demise –– necessitated by diminishing fuel and a need to protect two of Saturn’s 62 moons from potential microbial contamination from Earth –– was bitter-sweet news to the researchers who had worked on the project for a decade or longer. Before the final six orbits, Cassini had orbited Saturn only outside of the rings; thus, the scientists could not distinguish between masses of the planet and the rings. But, once it began threading the gap, scientists could untangle the two measures, which should help resolve a debate about the age of the rings and be informative to scientists about development of our Solar System.

The rings appear to be “young”, i.e. perhaps 100 million years old, because the constant rain of micrometeroid pollution would have darkened anything older. Other scientists had believed the rings might be “ancient”, i.e. billions of years old, developing during the early, chaotic days of the Solar System when large planetoids would have been present to collide and provide grist for the rings. These primordial collisions would have created massive rings. But Cassini is now finding hints of a relatively low mass, suggesting the rings were probably created more recently by the destruction of a comet or small moon. As scientists sift through data from the radio science experiment, their estimates of how mass is distributed throughout the planet itself should also improve.

Other data from the final plunge into the atmosphere have already made clear that the interior and exterior layers of the planet Saturn rotate with significantly different speeds. A similar pattern is seen with the sun –– but not with Jupiter –– where deep and shallow layers rotate with little difference in rotation speeds.

Science 22 Sept 2o17; 357: 1219–1220 [just 2 pages]

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RE: The monarch butterfly’s epic 3,000-mile migration

Dear Doron,

The article I sent was describing a professor at Univ of Cincinnati, but I can’t say that his research was any “big breakthrough” in the field. Hundreds of biologists have studied this migratory phenomenon for decades. I recall reading that the “magnetic compass” (determining the insect’s geographical position relative to the sun) is located in their antennae, and I suspect epigenetic factors –– that sense the length of day, temperature of the air, and host plant quality –– must play a role in the generation 3-4 times removed from the original generation.

One could conclude “this is an example if imprinting,” except that’s just the name of a biological process and still there is little to nothing known about the molecular explanation of this magnificent phenomenon.

When the late summer and early fall monarchs emerge from their pupae, they are physically and behaviorally different from those emerging in the summer. The shorter days, cooler air, and milkweed senescence (aging) of late summer trigger changes. In the northern part of their range, this occurs around the end of August, when monarchs begin to emerge in reproductive diapause. Diapause is controlled by the nervous system and by hormones. Environmental factors signaling the onset of unfavorable conditions are involved in triggering this physiological response.

Genetics: Upon dispersal, the Central and South American, Atlantic, and Pacific populations lost the ability to migrate. This prompted researchers to identify the gene regions in North American monarchs that appeared highly differentiated from non-migratory populations. Kronforst et al. (2014) identified 536 genes significantly associated with migration. One single genomic segment appeared to be divergent in the non-migrating populations and was extremely different from the North American population. One gene, collagen IV alpha-1, showed high divergence between migrating and non-migrating populations. Collagen IV alpha-1 is an important gene for muscle function, and divergence of this gene implicates selection for different flight muscles between migrating and non-migrating populations. Surprisingly, Collagen IV alpha-1 was down regulated in migratory monarchs, perhaps preparing them for lengthy flight. Furthermore, migrating monarchs had low metabolic rates compared to non-migrants as a consequence of flight muscle performance, lowering energy expenditure in migrating monarchs’ muscles. This evidence led researchers to conclude that changes in muscle function afforded migrating monarchs the ability to fly farther and use their energy more efficiently. Dr. Kronforst used the analogy of a marathon runner vs. a sprinter, “Migrating butterflies are essentially endurance athletes, while others are sprinters.”

Genetics: Genetic analysis is becoming an increasingly popular method to investigate the molecular-genetic basis of migration. Kronforst et al. 2014 used gene sequencing to compare 101 Danaus genomes from around the world. Comparative genomics analysis using Single Nucleotide Polymorphisms (SNPs) revealed variation in Danaus genomes that illustrated a monarch evolutionary tree. This tree revealed that the North American migratory population resided at the base of the tree signifying it as the most closely related species to the common ancestor of all monarchs. Their results suggest the monarch began in the southern USA or northern Mexico, making annual migrations as glaciers receded. These genetic analyses also allowed researchers to infer the distribution patterns of non-migratory monarch populations. Genetic analysis was also utilized to identify genes involved in migration (see “How do monarchs find the overwintering sites?).

One can find much more information at this URL, but still I see no definitive answers. 🙁 DwN


Subject: RE: The monarch butterfly’s epic 3,000-mile migration

Dear Dan,

As always, a pleasure to get your literature choices! Would you do me a great favor and tell me what was the migratory mechanism discovered? (-:
Prof. Doron Lancet

Home: http://www.weizmann.ac.il/molgen/Lancet/home

From: Nebert, Daniel (nebertdw) [mailto:NEBERTDW@ucmail.uc.edu]
Sent: Friday, October 6, 2017 7:40 PM
Subject: The monarch butterfly’s epic 3,000-mile migration

This is a story of gene-environment interactions. Monarch butterflies winter over in the mountains of Mexico. Then they migrate as far north as southern Canada in late summer; however, because of their life span, it takes four generations to reach their destination 7-8 months later. And then, HOW do these great-grandchildren KNOW when to fly quicly all the way south and where to go –– to return to that same mountainside where their great-grandparents had been born?

Kings of navigation
Biologists are unravelling the mystery behind the monarch butterfly’s epic 3,000-mile migration.
By Michael Miller
Oct. 3, 2017

Monarch butterflies flutter to the same mountains in Mexico each winter even though neither they nor their parents or grandparents have ever been there. A University of Cincinnati biology professor is trying to unravel the mystery of the monarch’s multigenerational migration at UC’s Center for Field Studies. “What’s amazing about monarchs is they go to the same general area in Mexico year after year, but they’ve never been there before. It’s their great-grandparents who were last there,” said Patrick Guerra, assistant professor of biological sciences at UC’s McMicken College of Arts & Sciences.

Many creatures undergo epic migrations. Wildebeest travel 900 miles from the African Serengeti to the Maasai Mara and back in search of fresh pasture every year. Sea turtles return to the beaches where they hatched to lay their own eggs. And some shorebirds fly from the tip of South America to the high arctic and back every year in a 9,000-mile odyssey.

But Guerra said monarchs are special because their round-trip migration from the United States and southern Canada to central Mexico requires several generations to complete. “The butterflies have never been there before. Their sense of direction has to be hardwired,” he said.

Scientists know that monarchs navigate by the position of the sun in the sky — like an internal sundial. It’s the same way that ants and bees orient themselves. “We know they use the sun and the Earth’s magnetic field as guides. But we don’t know how they know when to stop,” Guerra said.

The mountains west of Mexico City are the perfect place for monarchs to spend the winter, he said. “They’ll roost in groups at these overwintering sites. It’s the perfect temperature,” Guerra said. “It’s neither too cold that they freeze to death nor too warm that their reproductive drive kicks in. When it gets hot, they turn to reproductive mode. So they’re trying not to be in that reproductive status to conserve their metabolic reserves.”

The butterflies cluster together on the pine and oyamel fir trees for warmth. Scientists estimated there were as many as 1 billion butterflies gathered in the mountains in 1996. That number has dropped precipitously since then. Last year, conservation groups estimated that 145 million butterflies roosted in the reserve, roughly an 85 percent decrease.

Scientists are trying to understand what’s behind the sharp decline. Possible culprits include ubiquitous pesticides used in agriculture and landscaping in North America and deforestation within the Mexican reserve. Some backyard gardeners plant nonnative milkweed that stays in flower longer in the fall, which could prompt some monarchs to linger in the north. A sudden cold snap could kill them.

“Its conservation status is either threatened or ‘species of concern,’ depending on whom you ask,” Guerra said. Today, western butterfly populations are most at risk. Conservation groups across North America are working to restore prairie habitat from Nova Scotia to California. Not all monarchs migrate. Populations in Florida remain in the Sunshine State year-round.

A monarch butterfly.

Guerra has studied a variety of insects prior to taking on butterflies. He has been studying monarchs for more than five years. “I was interested in dispersal, how insects disperse from certain areas and what they’re looking for,” he said. “But migration always interested me. This movement is more directed — they’re going to a place and back.” Guerra and his students are trying to determine what effect, if any, increasing urbanization has on the butterfly’s circadian rhythms and knack for navigation.

Students Alexis Moore and Jered Nathan captured monarchs at UC’s Center for Field Studies next to Miami Whitewater Forest in southwest Ohio. Butterflies were placed in mesh enclosures at nine places around the Tristate: three rural, three suburban and three urban. There the butterflies are subjected to the ambient light and noise of city life or the darkness and tranquility of rural living.

One site is a flower garden a few blocks from UC at the Cincinnati Zoo & Botanical Garden. Guerra’s students keep the monarchs in a three-foot-tall mesh box on a mulch bed next to the landscaping. Despite the busy city traffic just beyond the zoo security fence, monarchs and other butterflies flitted from flower to flower around the garden.

“Volunteers have adopted this garden. We have pollinator-friendly plants everywhere,” said Lyn Lutz, an exhibit manager at the zoo. The zoo has exhibits on native plants throughout its 69 acres to encourage and inspire people to plant their own butterfly gardens, she said. “Everyone should do their part,” she said. “You don’t need a big botanical garden. Anyone can do it.”

On a daily visit, students carefully removed a monarch from the enclosure. Each butterfly has its own identification number written in marker on a wing. The students feed their test subjects a honey solution each day while the butterflies get used to their new surroundings. After a few weeks, the monarchs will be released on a still afternoon at the UC field station to see how they orient themselves and whether researchers can discern any difference in flight trajectory among the city, suburban or urban groups, Guerra said.

“At this time of year, fall monarchs should always have the drive to fly south,” he said. “But if you live in the city, if your circadian clock is so disrupted that you can’t use [it] to keep track of the time of day, you might use the sun incorrectly. That’s our hypothesis. We’re predicting urbanization or its effects might affect their behavior.”

Light pollution interferes with wildlife in lots of ways. Turtle hatchlings on coastal beaches can mistake streetlights for the moon and scurry into traffic. Bright lights have been known to disorient migrating birds so badly that they fly into buildings. And when navigating such great distances, a couple degrees of navigation error could send the monarchs hundreds of miles off course. If the study determines that city monarchs are prone to disorientation, the next step will be to determine what it is about outdoor lights that disrupts their uncanny navigation system. “Is it the intensity of the light or is it LED versus incandescent or fluorescents?” Guerra said. “It could be that certain wavelengths of light matter. For example, a lot of moths and night insects use the moon to navigate at night.”

At the field station, researchers also harness butterflies and test them in a flight simulator, sort of a butterfly treadmill. Although flying in place, the butterflies can orient themselves 360 degrees. In flight-simulator trials, monarchs can be tested under various outdoor or indoor testing conditions, during which their flight behavior can be monitored and analyzed. The path of flight directionality they choose in the simulator trials helps researchers learn more about how butterflies orient themselves.

Student Moore, 21, is studying biomedical engineering. Her specialty is biomimicry or how engineers and designers can take natural cues molded by evolution to design better products. For example, the air intakes of fighter plane engines are shaped like the nares (or nostrils) of peregrine falcons, which can breathe even when stooping on prey at 200 mph. “These creatures have had hundreds of millions of years to evolve and find solutions to problems,” she said. “We can take those solutions and apply them to what we want to do.”

“The biggest surprise for me was just how big monarchs get. I’ve been dealing with the smaller summer monarchs in the lab,” Nathan said. “The migrating monarchs are much, much bigger.” Guerra plans to conduct the monarch study over several years to validate their findings. “I’m trying to understand how their brains work. What’s amazing is they have a brain the size of a pinhead, and they’re doing something that would take us all sorts of complex computations to do,” he said. “Monarchs are a cool model system.”

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Inactivation of a pig retrovirus using CRISPR/Cas9, which will improve success at pig organ transplants in humans

CRISPR/Cas9 is an efficient relatively quick method of gene-editing, and a use of this technique in farmyard animals is shown herein. Previous papers shared by GEITP emails included CRISPR/Cas technology employed in laboratory animals, human clinical experiments, plants of agricultural importance, and even insects.

“Xenotransplantation” describes the process whereby tissue from one species is transplanted into a different species. Xenotransplantation is currently under development to help alleviate the increasing shortage of human tissues and organs for transplantation to treat organ failure. For several reasons –– the size and physiology of the organs, the ease of genetic modification and cloning, and the large number of progeny and short reproduction cycle –– pig is the animal of choice for organ transplant in humans. Three major problems need to be solved, however, before xenotransplantation becomes a clinical reality: immunological rejection, physiological incompatibility, and risk of transmission of porcine microorganisms that are able to induce a disease (this process is called “zoonosis”) in the human recipient.

In the attached paper and editorial, authors describe how to increase safety of xenotransplantation. In addition to the well-known form of immune rejection that can occur after allotransplantation (transplant of non–genetically identical material between the same species), a new form of rejection is observed when using pig cells and organs: hyperacute rejection (HAR); this occurs because of preexisting antibodies in human recipients that recognize sugar molecules on the surface of bacteria as well as pig cells (but not human cells). These antibodies can lead to destruction of the transplant within minutes. In order to prevent immune rejection (including HAR), genetically modified pigs have been generated that lack enzymes responsible for expressing those sugars and that express human proteins that prevent rejection.

Authors previously have demonstrated the feasibility of inactivating porcine endogenous retrovirus (PERV) activity in a pig cell culture line. In the current attached article, authors confirm that PERVs do infect human cells, and they have detected/observed the horizontal gene transfer of PERVs among human cells. Using CRISPR/Cas9, authors inactivated all the PERVs in a porcine primary cell culture line and generated PERV-inactivated pigs via somatic cell nuclear transfer. This study underscores the value of PERV inactivation to prevent cross-species viral transmission. Furthermore, this report demonstrates the successful production of PERV-inactivated animals to address the safety concern in clinical xenotransplantation.

Science 22 Sept 2o17; 357: 1303–1307 plus editorial, pp 1238–1239

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No paper? No problem. Some of these “predatory online open-access journals” willll actually help you write a paper or will add your name as coauthor …!!

As we’ve discussed in these GEITP pages a number of times before, approximately 15,000 “predatory online open-access journals” have popped up during these past 6-8 years, with their primary goal to make a lot of money –– whether or not any solid science is ever published in their “journal”. These “journals” will publish almost any paper –– if scientists are willing to pay. However, some of these “journals” [see attached brief note] also seem happy to help researchers who have nothing to publish at all. 🙂

Pravin Bolshete (a medical writer at Tata Consultancy Services in Thane, India) decided to send hundreds of such journals and publishers an email from a fictitious researcher, simply asking to become coauthor on an existing manuscript. Alternatively, was there any way for him to have the entire paper written for him? Of the 117 publishers that responded, 19 said they would add his name; and so did the editors of three out of 35 stand-alone journals. Some offered to write a paper and publish it for this fictitious author, while others promised to publish one on any subject if he wrote it himself.

At least 54% of the publishers, and 49% of the journals, behaved “unethically,” concluded Bolshete. He presented his work, surveying more than one hundred journals and publishers, as a poster at the Eighth International Congress on Peer Review and Scientific Publication in Chicago, Illinois, on 11 September.

Science 22 Sept 2o17; 357: 1218

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Why do redheaded people have increased risk of maglignant melanoma ??

Of special interest to Zalfa Abdel-Malik, melanocyte cells in the skin and hair follicles make a pigment called melanin, and these cells can give rise to the deadly skin cancer mela­noma. Melanin protects the skin against ultraviolet (UV) radiation from sunlight, which are able to cause DNA damage including harmful mutations. The type of this pigment made by melanocytes is controlled by the melanocortin-1 receptor (MC1R) protein. MC1R up-regulation results in production of a dark form of melanin called eumelanin; however, if MC1R signalling is low or absent, the primary type of melanin that is produced is a red or orange form called phaeomelanin. Virtually all red-haired individuals have a version of MC1R with diminished or absent signaling capacity, and most of these individuals have fair skin that doesn’t tan easily.

The Mc1r gene was first identified in mice in which a loss-of-function mutation of the gene causes yellow fur. Many other species (e.g. dogs with red or yellow hair) also have pigment alterations associated with specific versions of MC1R. Humans of ancient European ancestry often have variant forms of MC1R, which differ in the level of their association with red hair. MC1R variation is necessary, but not always sufficient, to produce red hair –– sug­gesting that most variants retain some signaling activity that may be masked or enhanced, depending on modifier genes or other cellular factors. In the attached article and editorial, authors studied mouse models and human cells show­ing that risk of skin cancer associated with certain versions of MC1R, linked to red hair, can be lowered by increasing the degree to which this protein is modified by a lipid.

Authors screened human melanocytes grown in cell culture and identified palmitate as a lipid molecule that enhances downstream MC1R signaling –– in mutant MC1R pro­teins associated with red hair. Moreover, red and yellow dogs that lack MC1R signaling were found to have a muta­tion that removes the palmitate-binding site from the protein, suggesting this site might be important for MC1R function. Authors then showed that MC1R is palmitoylated in human cells grown in culture, and that the degree of palmitoylation increases in response to UV treatment and stimulation of the receptor by the peptide hormone α-MSH (a protein produced by nearby keratinocyte cells after UV damage). Rises in the level of palmitoylation of MC1R led to an increase in MC1R-mediated signaling and activation of the melanin-production pathway. Authors also tested an MC1R variant (in mice that are yellow, indicating absence of MC1R function) that cannot be palmitoylated; this receptor lacked signaling activity, whether or not it was stimulated by UV light. This elegant study therefore highlights a central role for MC1R palmitoylation in pigmentation and protection against melanoma.

Nature 21 Sept 2o17; 549: 399–403 and News’N’Views editorial pp 337–339

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Circadian Biology Scientists Win Nobel Prize

This year’s Nobel award is thoroughly focused on the theme of Gene-Environment Interactions. 🙂

The 2017 Nobel Prize in Physiology or Medicine has been jointly awarded to Jeffrey Hall, Michael Rosbash, and Michael Young for their work on circadian rhythms. The trio is recognized for research on the period gene in Drosophila—a central regulator of the circadian clock whose discovery led to the identification of such genes in humans and other animals—plus the protein machinery governing the timing of biological rhythms.

In the course of their research, collaborators Rosbash and Hall at Brandeis University and Young independently at Rockefeller University, “solved the mystery of how an inner clock in most of our cells in our bodies can anticipate daily fluctuations between night and day to optimize our behavior and physiology,” Thomas Perlmann, secretary general for the Nobel Assembly and Nobel Committee, says in a statement.

Russell Foster, head of the Sleep and Circadian Neuroscience Institute at the University of Oxford, tells The Scientist that he’s “thrilled and delighted” by the news. “These are the people who gave us our first working model of how the molecular clock might tick. The three of them . . . have formed the platform of our understanding of the molecular basis of circadian rhythms, not only in flies, but it’s informed the work in mice and humans.”

Retired since 2008, Jeffrey Hall was at Brandeis University from 1974, where he took an early interest in the biology of circadian rhythms in Drosophila. His initial work with period showed that the gene played an important role in regulating the rhythm of courtship song cycles produced by male fruit flies (PNAS, 77: 6729-33, 1980). This work expanded upon the original discovery by Knopke and Benzer (PNAS, 68: 2112–16, 1971), both of whom are deceased.

Hall later began collaborating with Brandeis colleague Michael Rosbash—a neuroscientist he got to know primarily through sport, colleagues say. The pair went on to isolate the period gene—which had been described in the 1970s by Seymour Benzer and Ronald Konopka—and showed that it produced a protein, PER, that cycles on a daily rhythm (Cell, 39: 369-76, 1984). Rockefeller’s Michael Young and colleagues simultaneously isolated period, publishing the findings in Nature the same year (312: 752-54).

The research laid the groundwork for other researchers to map similarly essential circadian genes in mice and other animals. “What’s extraordinary is that the basic building blocks of the clock discovered in flies are very similar in mice and humans,” says Foster. “It’s broadly the same genes and broadly the same proteins.”

The trio went on to pin down the details of the protein machinery governing circadian rhythms. Working with postdoctoral researcher Paul Hardin, Hall and Rosbash showed that mRNA transcripts from the period gene also cycle, allowing the PER protein to regulate its own production via a feedback loop (Nature, 343: 536-40, 1990). “It was a great experience working as a postdoc,” Hardin tells The Scientist, adding that he is pleased and not overly surprised about today’s news. “Their work for a number of years has merited an award of this magnitude. I was so happy to hear the news this morning.”

Young, meanwhile, discovered a number of other genes influencing period protein dynamics. In 1994, his group identified timeless, a clock gene that produces a protein, TIM, that binds to PER, and is required for the latter’s entry into the nucleus to regulate period gene expression (Science, 263:1603-6). A few years later, the team described another gene, double-time, which regulates the accumulation of the period protein (Cell, 94: 83-95, 1998). “He’s just a terrific scientist,” says collaborator Brian Crane, a biochemist at Cornell University. “His impact is huge. I figured that sooner or later this would happen, but it’s nice to see it materialize.”

It’s not the first time the laureate trio has been recognized for contributions to biology and the research into human circadian rhythms that has followed. In 2009, the Gruber Foundation awarded the Neuroscience Prize to Hall, Rosbash, and Young for the establishment of “a direct link between genes and behavior” that could later be extended beyond fruit flies into humans and, indeed, “all living organisms.”

In 2012, the three were recognized again with the Canada Gairdner International Award for pioneering science’s understanding of the circadian rhythm. “The medical relevance of these findings has become apparent as it was found that changes in these clock genes are associated with a series of sleep disorders in humans,” Young said in an interview at the time. “There are strong indications that some forms of depression are linked to the control of circadian rhythms.”

All three have made an impression inside and outside the lab. “Being in the room with them, you realize you have to keep concentration to keep up with the discussion,” notes Michael Hastings, a molecular neurobiologist working on circadian rhythms at the University of Cambridge, who sees both Rosbash and Young frequently at research gatherings. “[They have] an enormous intellectual appetite and curiosity.

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Strong evidence of an epigenetic effect on mRNA that modulates hematopoietic stem cell fate and progenitor cell specification

In previous GEITP emails, we have emphasized the importance of genetics, epigenetic effects, AND environmental factors –– all contributing to a phenotype (trait) –– whether the trait is a complex disease, drug efficacy or toxicity, or some metric (quantitative measurement) such as height or body mass index. Classically, “epigenetic effects” include nucleic acid-methylatiion, RNA-interference, histone modifications, and chromatin remodeling. This article [attached] describes nucleic acid (RNA)-methylation, and the trait being measured is determination of cell fate during the endothelial-to-hematopoietic transition (EHT) to specify the earliest hematopoietic (blood cell-forming) stem/progenitor cells (HSPCs) during zebrafish embryogenesis.

In vertebrates, which include zebrafish, HSPCs are derived from hemogenic endothelium –– a subset of endothelial cells in the ventral wall of dorsal aorta, by means of endothelial-to-hematopoietic transition (EHT) during embryogenesis. Previous studies have suggested the role of N6-methyladenosine (m6A) modification in cell fate determination and lineage transition in embryonic stem cells. However, the exact physiological function of m6A modification in vertebrate definitive hematopoiesis remains unknown. Given the early embryolethality of mice having the complete knockout of the m6A methyltransferase catalytic subunit Mettl3, authors herein chose to investigate the m6A methylome during embryogenesis of zebrafish.

The m6A appears to be the most abundant modification of messenger RNA (mRNA) in animals having pairs of chromosomes (eukaryotes). Herein authors show that m6A determines cell fate during the EHT, to specify the earliest HSPCs during zebrafish embryogenesis. In Mettl3-deficient embryos, levels of m6A are significantly decreased, and emergence of HSPCs is blocked. Mechanistically, authors determined that the YTH N6-methyladenosine RNA-binding protein-2 (YTHDF2)-mediated mRNA decay of the arterial endothelial genes Notch1a and Rhoca contributes to this deleterious effect. The continuous activation of Notch-signaling in arterial endothelial cells of Mettl3-deficient embryos blocks the EHT, thereby repressing generation of the earliest HSPCs. Furthermore, knockdown of Mettl3 in mice confers a similar phenotype. Collectively, the exciting findings in the attached paper demonstrate the critical function of m6A modification in the fate determination of HSPCs during vertebrate embryogenesis.

Nature 14 Sept 2o17; 549: 273–276

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DNA surgery on embryos removes disease

This article is from BBC News this morning.

DNA surgery on embryos removes disease

By James Gallagher, BBC News

· 28 September 2017

Precise “chemical surgery” has been performed on human embryos to remove disease

A research team at Sun Yat-sen University used a technique called base editing to correct a single error out of the three billion “letters” of our genetic code. They altered lab-made embryos to remove the disease beta-thalassemia. The human embryos were not implanted. The team says the approach may one day treat a range of inherited diseases.

Base editing alters the fundamental building blocks of DNA: the four bases adenine, cytosine, guanine and thymine (A, C, G, & T). Many of the “instructions” for building and running the human body are encoded in combinations of those four bases.


The potentially life-threatening blood disorder beta-thalassemia is caused by a change to a single base in the genetic code –– known as a point mutation. The team in China edited it back (to the normal base). They scanned DNA for the error, and then converted a G to an A, correcting the fault. Junjiu Huang, one of the researchers, told the BBC News website: “We think we are the first to demonstrate the feasibility of curing genetic disease in human embryos by base editor system.”

He said their study opens new avenues for treating patients and preventing babies being born with beta-thalassemia, “and even other inherited diseases”. The experiments were performed in tissues taken from a patient with the blood disorder and in human embryos made by means of cloning.
Genetics revolution

Base editing is an advance on a form of gene-editing known as CRISPR/Cas9, which is already revolutionizing science. CRISPR breaks the DNA at a selected location. When the body tries to repair the break, it deactivates a set of instructions called a gene. It is also an opportunity to insert new genetic information.

Base editing works on the DNA bases themselves to convert one into another. Prof David Liu, who pioneered base-editing at Harvard University, describes the approach as “chemical surgery”. He says the CRISPR technique is more efficient and has fewer unwanted side-effects than previous methods.

He told the BBC: “About two-thirds of known human genetic variants associated with disease are point mutations. So base editing has the potential to directly correct, or reproduce for research purposes, many pathogenic mutations.”


The research group at Sun Yat-sen University in Guangzhou had hit the headlines previously, when they were the first to use CRISPR on human embryos. Prof Robin Lovell-Badge, from the Francis Crick Institute in London, described parts of their latest study as “ingenious”. But he also questioned why they did not do more animal research before jumping to human embryos and said the rules on embryo research in other countries would have been “more exacting”.

The study, published in Protein and Cell, is the latest example of the rapidly growing ability of scientists to manipulate human DNA. The technique obviously is provoking deep ethical and societal debate about what is, and what is not, acceptable in efforts to prevent disease.

Prof Lovell-Badge predicted that these approaches are unlikely to be used, clinically, anytime soon. “There would need to be far more debate, covering the ethics, and how these approaches should be regulated. And in many countries, including China, there needs to be more robust mechanisms established for regulation, oversight, and long-term follow-up.”

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