Publisher Health

Many genetic diseases are caused by diverse mutations spread across an entire gene, and designing genome editing approaches for each patient’s mutation would be impractical and costly.
Investigators at Massachusetts General Hospital (MGH) recently developed an optimized method that improves the accuracy of inserting large DNA segments into a genome.
This approach could be used to insert a whole normal or “wild-type” replacement gene, which could act as a blanket therapy for a disease irrespective of a patient’s particular mutation.
The work involves the optimization of a new class of technologies called CRISPR-associated transposases (CASTs), which are promising tools for large DNA insertions that can be easily targeted to a desired genomic site via a reprogrammable guide RNA.
However, in their natural state, CASTs have undesirable properties for genome editing applications — namely, suboptimal product purity (how often only the intended DNA sequence is inserted into the genome) and a relatively high rate of unwanted off-target integration at unintended sites in the genome.
In their research published in Nature Biotechnology, a team led by first author Connor Tou, a graduate student at MIT and MGH, and senior author Ben Kleinstiver, PhD, an Assistant Investigator in the Center for Genomic Medicine at MGH and an Assistant Professor at Harvard Medical School, addressed these shortcomings by using protein engineering approaches to modify the properties of CAST systems.

They found that adding a certain enzyme called a nicking homing endonuclease to CASTs resulted in a dramatic increase in product purity towards the intended insertion.
Further optimization of CASTs’ structure led to DNA insertions with high integration efficiency at intended genomic targets with vastly reduced insertions at unwanted off-targets sites.
The researchers called the new and improved system “HELIX,” which is short for Homing Endonuclease-assisted Large-sequence Integrating CAST-compleX.
“We demonstrated a generalizable approach that can be used to modify a variety of CAST systems into safer and more effective versions that have high product purity and genome-wide specificity,” says Tou.
“By combining our insights, we created HELIX systems with greater than 96% on-target integration specificity — increased from approximately 50% for the naturally occurring wild-type CAST system. We also determined that HELIX maintains its advantageous properties in human cells.”
Kleinstiver notes that the technology could have applications beyond the ability to restore normal healthy genes to individuals with disease-causing mutations.
“Additionally, programmable DNA integration can facilitate cell engineering efforts where installation of large genetic sequences at targeted locations could endow cells with new capabilities while obviating safety, efficacy, and manufacturing issues resulting from traditional random integration approaches,” he says.
The study is also co-authored by Benno Orr.
This work was supported by the National Science Foundation and MGH.

A trapped mountaineer survived after enduring 16 frigid hours wedged in a crevasse on Denali (Mount McKinley) in Alaska. His long and difficult rescue in frigid conditions and care in the critical aftermath are examined in the current issue of the Wilderness Medical Society’s official journal, Wilderness & Environmental Medicine, published by Elsevier. This compelling case study highlights the distinguishing factors that led to the successful outcome.
The mountaineer was wedged about 20 meters deep in the crevasse, waiting 4.5 hours for a rescue team to arrive, followed by an 11.5-hour extrication process. His condition deteriorated and he eventually lost consciousness. Even though the rescue team collectively felt there was little or no chance of survival, they continued rescue efforts until the victim was extricated from the crevasse. He was almost immediately placed in a hypothermia wrap with active warming, loaded onto a rescue helicopter, and transported to a hospital in Fairbanks, Alaska. He was released after 14 days and made a full recovery.
“This case documents the heroic, persistent and expert rescue efforts of a group of people dedicated to saving lives. After conferring with the chief rescuer and chief of medical personnel, we pulled together our collective insights about the challenges of extracting climbers from extremely confined spaces and providing medical care to those who have had extended cold exposure,” explained lead investigator Gordon G. Giesbrecht, PhD, Laboratory for Exercise and Environmental Medicine, Faculty of Kinesiology and Recreation Management, Departments of Emergency Medicine and Anesthesia, University of Manitoba, Winnipeg, MB, Canada.
Their recommendations build on lessons learned from a previously published case study of a helicopter pilot who died after being trapped in an icy crevasse for only four hours. In that paper, Dr. Giesbrecht identified the need to develop processes for search and rescue personnel to prevent circum-rescue collapse, which is a complex physiological response to extreme cold that is worsened by improper handling of the patient. He cautioned that rescuers should be trained with the principle that the colder the victim is, the more care is required to perform horizontal extrication as gently as possible. Adding a few minutes for gentle handling and to reposition will not significantly increase cold exposure, but will greatly minimize the chance of rescue collapse.
“Responders should be aware of the causes, symptoms, and prevention of rescue collapse. Training should include techniques for transitioning a victim gently from vertical to a horizontal supine or, for narrower passages, to a lateral decubitus position. Even if a victim has to be hauled up in a vertical position, a simple technique using a sling or rope under the knees allows a simple, gentle and horizontal extrication from the crevasse to the surface,” noted Dr. Giesbrecht.
This case emphasized the need to continue extrication and treatment efforts for a cold patient even when survival with hypothermia seems impossible. It also underscored the need for rescue teams to pre-plan equipment and procedures specific to crevasse rescue of potentially cold patients.
This case highlights an important mix of preventive and resuscitative lessons and recommendations regarding crevasse rescue in an isolated location: Urging climbers to rope up for glacier travel in areas with known and possible crevasses. Making sure that any rescuers who descend into crevasses are continuously observed by someone who remains on the surface and has radio contact to call for immediate assistance. Recognizing that respirations are often more easily detected than pulses. Trying unorthodox extrication methods when necessary. Rescue teams deployed for crevasse rescues should carry kits with a pneumatic hammer-chisel (important for extrication), a tripod and winch, a hypothermia wrap made of a sleeping bag and chemical heating blankets, onboard oxygen supply with an adapter that connects to nasal prongs or a patient’s mask, a mechanical chest compression device, an automated external defibrillator, and IV saline with a fluid warmer. The Denali National Park and Preserve mountaineering rangers now include such kits in their rescue aircraft.The investigators plan to submit a standardized rescue process based on these recommendations for publication after completing field testing in the summer of 2023.
When asked about what he considered the most crucial factor for survival, Dr. Giesbrecht stressed that rescuers should never give up even when the patient’s survival with hypothermia seems impossible.

Research on fungi underway at the University of Kansas has helped transform tough-to-recycle plastic waste from the Pacific Ocean into key components for making pharmaceuticals.
The chemical-biological approach for converting polyethylene uses an everyday soil fungus called Aspergillus nidulans that has been genetically altered. The results were reported recently in the paper “Conversion of Polyethylenes into Fungal Secondary Metabolites” published in Angewandte Chemie, a journal of the German Chemical Society.
“What we’ve done in this paper is to first digest polyethylenes using oxygen and some metal catalysts — things that are not particularly harmful or expensive — and this breaks the plastics into diacids,” said co-author Berl Oakley, Irving S. Johnson Distinguished Professor of Molecular Biology at KU.
Next, long chains of carbon atoms resulting from the decomposed plastics were fed to genetically modified Aspergillus fungi. The fungi, as designed, metabolized them into an array of pharmacologically active compounds, including commercially viable yields of asperbenzaldehyde, citreoviridin and mutilin.
Unlike previous approaches, Oakley said the fungi digested the plastic products quickly, like “fast food.”
“The thing that’s different about this approach is it’s two things — it’s chemical, and it’s fungal,” he said. “But it’s also relatively fast. With a lot of these attempts, the fungus can digest the material, but it takes months because the plastics are so hard to break down. But this breaks the plastics down fast. Within a week you can have the final product.”
The KU researcher added the new approach was “bizarrely” efficient.

“Of the mass of diacids that goes into the culture, 42% comes back as the final compound,” he said. “If our technique was a car, it would be doing 200 miles per hour, getting 60 miles per gallon, and would run on reclaimed cooking oil.”
Previously, Oakley has worked with corresponding author Clay Wang of the University of Southern California to produce about a hundred secondary metabolites of fungi for a variety of purposes.
“It turns out that fungi make a lot of chemical compounds, and they are useful to the fungus in that they inhibit the growth of other organisms — penicillin is the canonical example,” Oakley said. “These compounds aren’t required for the growth of the organism, but they help either protect it from, or compete with, other organisms.”
For a time, scientists thought they’d fully exploited the potential of fungi to produce these compounds. But Oakley said the age of genome sequencing has unlocked new possibilities for using secondary metabolites to benefit humanity and the environment.
“There was a realization there were lots and lots of clusters of genes that made secondary metabolites that nobody had discovered — and there are millions of species of fungi,” Oakley said. “A lot of companies have done good work over the years, but it was very much incomplete, because they were just growing things in the incubator and examining them for production of new compounds — but 95 percent of the gene clusters were just silent since they are not ‘turned on’ until needed. They weren’t doing anything. So, there are lots more things to discover.”
Oakley’s lab at KU has honed gene-targeting procedures to change the expression of genes in Aspergillus nidulans and other fungi, producing new compounds.

“We’ve sequenced the genomes of a bunch of fungi now, and we can recognize the signatures of groups of genes that make chemical compounds,” he said. “We can change the expression of genes; we can remove them from the genome; we can do all kinds of things to them. We could see there were lots of these secondary metabolite gene clusters there and our gene-targeting procedures allowed us, at least in principle, to turn some of those clusters on.”
Oakley and Wang’s co-authors were Chris Rabot, Yuhao Chen, Swati Bijlani, Yi-Ming Chiang and Travis Williams of USC, and Elizabeth Oakley of KU.
The researchers focused on developing secondary metabolites to digest polyethylene plastics because those plastics are so hard to recycle. For this project, they harvested polyethylenes from the Pacific Ocean that had collected in Catalina Harbor on Santa Catalina Island, California.
“There’ve been a lot of attempts to recycle plastic, and some of it is recycled,” Oakley said. “A lot of it is basically melted and spun into fabric and goes into various other plastic things. Polyethylenes are not recycled so much, even though they’re a major plastic.”
The KU investigator said the long-term goal of the research is to develop procedures to break down all plastics into products that can be used as food by fungi, eliminating the need to sort them during recycling. He added the work is emblematic of KU’s Earth, Energy + Environment research theme, geared toward “increasing understanding to help sustain the life of our planet and its inhabitants.”
“I think everybody knows that plastics are a problem,” Oakley said. “They’re accumulating in our environment. There’s a big area in the North Pacific where they tend to accumulate. But also you see plastic bags blowing around — they’re in the rivers and stuck in the trees. The squirrels around my house have even learned to line their nest with plastic bags. One thing that’s needed is to somehow get rid of the plastic economically, and if one can make something useful from it at a reasonable price, then that makes it more economically viable.”

Nitrites and nitrates occur naturally in water and soil and are commonly ingested from drinking water and dietary sources. They are also used as food additives to increase shelf life. A study publishing January 17 in the open access journal PLOS Medicine by Bernard Srour of the Nutritional Epidemiology Research Team (EREN-CRESS) of Inserm, INRAE, Cnam, and Sorbonne Paris Nord University, Bobigny, France and colleagues suggests an association between dietary exposure to nitrites and risk of type 2 diabetes.
Some public health authorities have advocated for limiting the use of nitrites and nitrates as food additives. However, the role of dietary nitrites and nitrates in metabolic dysfunction and type 2 diabetes in humans remains unexplored. In order to investigate the relationship between dietary exposure to nitrites/nitrates type 2 diabetes risk, researchers accessed data collected from 104,168 participants in the prospective cohort NutriNet-Santé. The NutriNet-Santé study is an ongoing, web-based cohort study initiated in 2009. Participants aged fifteen and older enroll voluntarily and self-report medical history, sociodemographic, diet, lifestyle, and major health updates. The researchers used detailed nitrite/nitrate exposure, derived from several databases and sources, and then developed statistical models to analyze self-reported diet information with health outcomes.
The researchers found that participants in the NutriNet-Santé cohort reporting a higher intake of nitrites overall and specifically from food additives, and non-additives sources had a higher risk of developing type 2 diabetes. There was no association between nitrates and type 2 diabetes risk, and the findings did not support any potential benefits for dietary nitrites or nitrates in terms of protection against type 2 diabetes. The study had several limitations and additional research is required to validate the results. The data were self-reported and the researchers could not confirm specific nitrite/nitrate exposure using biomarkers due to the underlying biological challenges. Additionally, people in the cohort’s demographics and behaviors may not be generalizable to the rest of the population — the cohort included a greater number of younger individuals, more often women, who exhibited healthier behaviors. Residual confounding may also have impacted the outcomes as a result of the observational design of the study.
According to the authors, “These results provide a new piece of evidence in the context of current discussions regarding the need for a reduction of nitrite additives’ use in processed meats by the food industry, and could support the need for better regulation of soil contamination by fertilizers. In the meantime, several public health authorities worldwide already recommend citizens to limit their consumption of foods containing controversial additives, including sodium nitrite.”
Srour and Touvier add, “This is the first largescale cohort study to suggest a direct association between additives-originated nitrites and type-2 diabetes risk. It also corroborates previously suggested associations between total dietary nitrites and T2D risk.”

Combining a map of gene regulatory sites with disease-associated loci has uncovered a new genetic risk factor of adult-onset macular degeneration (AMD), according to a new study publishing January 17 in the open access journal PLOS Biology by Ran Elkon and Ruth Ashery-Padan of Tel Aviv University, Israel, and colleagues. The finding advances the understanding of the leading cause of visual impairment in adults.
AMD is caused by dysfunction in the retinal pigmented epithelium (RPE), a layer of tissue sandwiched between the photoreceptors that receive light, and the choriocapillaris, which nourishes the retina. Because of the central importance of the RPE in AMD, the authors began by exploring a transcription factor (a protein that regulates specific genes) called LHX2 which, based on the team’s analysis of mouse mutants, is central to RPE development. Knocking down LHX2 activity in RPE derived from human stem cells, they found that most affected genes were down-regulated, indicating that LHX2’s role was likely that of a transcriptional activator, binding to regulatory sites on the genome to increase activity of other genes.
The authors found that one affected gene, called OTX2, collaborated with LHX2 to regulate many genes in the RPE. By mapping the genomic sites that OTX2 and LHX2 could bind to, they showed that 68% of those that bound LHX2 were also bound by OTX2 (864 sites in all), suggesting they likely work together to promote the activity of a large suite of genes involved in RPE development and function.
A common method for finding genes that may contribute to a disease is to perform a genome-wide association study (GWAS), which identifies genome sequence differences between individuals (termed single nucleotide polymorphisms, or SNPs) that co-occur with disease. Numerous such studies have previously been done in AMD. However, a GWAS by itself cannot uncover a causal mechanism. Here, the authors compared their LHX2/OTX2 binding data to GWAS data in order to home in on variations that affected binding of the transcription factors, and thus may contribute to disease.
One such binding site was located within the promoter region of a gene called TRPM1, which had been previously linked to AMD, and found that the sequence variant at that site altered the binding strength of LHX2; the so-called C version bound it more strongly than the T version, and activity of the TRPM1 gene was higher when the C allele was present instead of the T allele.
The results of the study indicate that the previously known increased risk of AMD from the variant identified in the GWAS was due to reduction in binding of the LHX2 transcription factor to the TRPM1 gene promoter, with a consequent reduction in activity of this gene. The gene encodes a membrane ion channel, and previous studies have shown that mutations in the gene also cause visual impairment.
“Our study exemplifies how delineation of tissue-specific transcriptional regulators, their binding sites across the genome, and their downstream gene-regulatory networks can provide insights into a complex disease’s pathology,” the authors said.
Ashery-Padan adds, “The findings reveal a regulatory module consisting of LHX2 and OTX2 that controls the development and maintenance of the retinal pigmented epithelium, an important tissue of visual function. The genomic analyses further link the genomic regions bound by the two developmental factors to the genetics of the common, multifactorial blinding disease age-related macular degeneration (AMD).”

The ultraviolet nail polish drying devices used to cure gel manicures may pose more of a public health concern than previously thought. Researchers at the University of California San Diego studied these ultraviolet (UV) light emitting devices, and found that their use leads to cell death and cancer-causing mutations in human cells.
The devices are a common fixture in nail salons, and generally use a particular spectrum of UV light (340-395nm) to cure the chemicals used in gel manicures. While tanning beds use a different spectrum of UV light (280-400nm) that studies have conclusively demonstrated to be carcinogenic, the spectrum used in the nail dryers has not been well studied.
“If you look at the way these devices are presented, they are marketed as safe, with nothing to be concerned about,” said Ludmil Alexandrov, a professor of bioengineering as well as cellular and molecular medicine at UC San Diego, and corresponding author of the study published Jan. XX in Nature Communications. “But to the best of our knowledge, no one has actually studied these devices and how they affect human cells at the molecular and cellular levels until now.”
Using three different cell lines- adult human skin keratinocytes, human foreskin fibroblasts, and mouse embryonic fibroblasts- the researchers found that the use of these UV emitting devices for just one 20-minute session leds to between 20 and 30 percent cell death, while three consecutive 20-minute exposures caused between 65 and 70 percent of the exposed cells to die.
Exposure to the UV light also caused mitochondrial and DNA damage in the remaining cells and resulted in mutations with patterns that can be observed in skin cancer in humans.
“We saw multiple things: first, we saw that DNA gets damaged,” said Alexandrov. ” We also saw that some of the DNA damage does not get repaired over time, and it does lead to mutations after every exposure with a UV-nail polish dryer. Lastly, we saw that exposure may cause mitochondrial dysfunction, which may also result in additional mutations. We looked at patients with skin cancers, and we see the exact same patterns of mutations in these patients that were seen in the irradiated cells.”
The researchers caution that, while the results show the harmful effects of the repeated use of these devices on human cells, a long-term epidemiological study would be required before stating conclusively that using these machines leads to an increased risk of skin cancers. However, the results of the study were clear: the chronic use of these nail polish drying machines is damaging to human cells.

Maria Zhivagui, a postdoctoral scholar in the Alexandrov Lab and first author of the study, used to be a fan of gel manicures herself, but has sworn off the technique after seeing the results.
“When I was doing my PhD, I started hearing about gel manicures, which last longer than normal polish. I was interested in trying out gel nail polish, particularly in the setting of working in an experimental lab where I frequently put gloves on and off, to maintain a presentable appearance,” said Zhivagui. “So I started using gel manicures periodically for several years. Once I saw the effect of radiation emitted by the gel polish drying device on cell death and that it actually mutates cells even after just one 20-minute session, I was surprised. I found this to be very alarming, and decided to stop using it.”
Studying their effect on human cells
The idea to study these particular devices came to Alexandrov in a dentist’s office, of all places. As he waited to be seen, he read a magazine article about a young beauty pageant contestant who was diagnosed with a rare form of skin cancer on her finger.
“I thought that was odd, so we began looking into it, and noticed a number of reports in medical journals saying that people who get gel manicures very frequently- like pageant contestants and estheticians- are reporting cases of very rare cancers in the fingers, suggesting that this may be something that causes this type of cancer,” said Alexandrov. “And what we saw was that there was zero molecular understanding of what these devices were doing to human cells.”
To conduct the study, Zhivagui exposed the three cell types to two different conditions: acute exposure and chronic exposure to the UV light device. Under acute exposure, Petri dishes containing one of the cell types were placed in one of these UV curing machines for a 20-minute session. They were then taken out for an hour to repair or return to their steady state, and then given one more 20-minute exposure. Under chronic exposure, the cells were placed under the machine for 20 minutes a day for three days.

Cell death, damage and DNA mutations were seen under both conditions, with an elevation of reactive oxygen species molecules- known to cause DNA damage and mutations- and mitochondrial dysfunction in the cells. Genomic profiling revealed higher levels of somatic mutations in the irradiated cells, with patterns of mutations ubiquitously present in melanoma patients.
Is the risk worth the reward?
This data in human cells, coupled with a number of prior reports of cancers in people who get gel manicures very frequently, paint a picture of a purely cosmetic procedure that is riskier than previously believed. But is getting a gel manicure once a year really cause for concern, or should only those who get this done on a very regular basis be worried? Further studies are needed to quantify any increased risk of cancer and at what frequency of use, but with plenty of alternatives to this cosmetic procedure, the risk may not be worth it to some consumers.
“Our experimental results and the prior evidence strongly suggest that radiation emitted by UV-nail polish dryers may cause cancers of the hand and that UV-nail polish dryers, similar to tanning beds, may increase the risk of early-onset skin cancer,” they write. “Nevertheless, future large-scale epidemiological studies are warranted to accurately quantify the risk for skin cancer of the hand in people regularly using UV-nail polish dryers. It is likely that such studies will take at least a decade to complete and to subsequently inform the general public. ”
Though other consumer products use UV light in the same spectrum- including the tool used to cure dental fillings and some hair removal treatments- the researchers note that the regularity of use, plus the entirely cosmetic nature of nail dryers, sets them apart.

Scientists continue to expand the technological frontiers of CRISPR, along with its enormous potential, in areas ranging from human health to global food supplies. Such is the case with CRISPR-based gene drives, a genetic editing tool designed to influence how genetic elements are passed from one generation to the next.
Gene drives designed for mosquitoes have the potential to curb the spread of malarial infections that cause hundreds of thousands of deaths each year, yet safety issues have been raised since such drives can spread quickly and dominate entire populations. Scientists have explored the principles governing the spread of gene-drive elements in targeted populations such as mosquitoes by testing many different combinations of components that constitute the drive apparatus. They have found, however, that there’s still more to explore and key questions remain.
In the journal Nature Communications, University of California San Diego researchers led by former Postdoctoral Scholar Gerard Terradas together with Postdoctoral Scholar Zhiqian Li and Professor Ethan Bier, in close collaboration with UC Berkeley graduate student Jared Bennett and Associate Professor John Marshall, describe the development of a new system for testing and developing gene drives in the laboratory and safely converting them into tools for potential real-world applications.
“These studies both empower new engineering of gene-drive systems while providing important information regarding how to assess and analyze key interactions between their most important moving parts,” said Bier, a faculty member in the School of Biological Sciences, Department of Cell and Developmental Biology.
CRISPR-based gene drives feature a protein called a Cas9 endonuclease and a guide RNA molecule that join forces to direct DNA cuts to specific sites in the genome where new genetic elements can be inserted. As the DNA repairs these cuts, the new genetic elements are copied from one chromosome to another, resulting in offspring that exceed the standard 50-50 percent inheritance, instead favoring the newly inserted genetic elements.
Gene drives come in two “flavors.” Full gene drives (fGDs) carry both the Cas9 and guide RNA components in a linked unitary package. In contrast, split drives (sGDs) consist of two genetic elements that separately carry the Cas9 and guide RNA components and are inserted at different sites in the genome. sGDs are considered to be safer than fGDs since it is possible to control and test the components carried by each of the elements separately or under conditions where they gradually amplify the frequency of the gRNA component. Researchers design the two elements to eventually reconnect in order to deliver the effects of a full gene drive.

In the case of eradicating malaria, full gene drives have created considerable enthusiasm due to their potential as vehicles to transfer elements that halt the transmission of malarial parasites that cause infection. But fGDs have also raised concerns due to their potential to rapidly spread and potentially alter the genetic makeup of entire mosquito populations. Experimenting with fGDs requires high-security barriers and restrictions to prevent unintended escape of insects carrying such drives into the open environment.
This is not the case with split gene drives. Because the key elements are separate, sGDs carry far less risk of unintentional spread and researchers hold much more control for their safe manipulation. Experiments with sGDs can be conducted in traditional lab facilities, thus allowing much more flexibility for testing their potential.
Scientists have been challenged, however, in developing systems that effectively convert sGDs into fully functioning fGDs. One challenge faced by current conversion of sGD systems into fGDs is that they rely on two separate genetic components, each of which must manifest efficient drive properties.
Now, UC San Diego scientists who have recently pioneered gene drive development and related technologies have created a flexible genetic “hacking” system for converting sGDs into fGDs. Working in fruit flies, the researchers developed a novel genetic strategy that employs a specially designed guide RNA carried by the Cas9 part of the sGD. This hacking tool cuts the copying component of the sGD and triggers a genetic exchange, or “recombination event,” that inserts the Cas9 into the element carrying the guide RNA, resulting in the creation of a fully functioning fGD.
“First, and most importantly, the study provides proof-of-principle for the agile genetic conversion of an sGD into an fGD, which should greatly aid in the testing and development of new optimized gene-drive systems,” said paper first author Terradas, who is now based at Penn State University.
Once the researchers developed their new sGD-to-fGD hacking system, some surprising results began to emerge. The newly hacked fGD spread through populations of flies in cage experiments, as expected. However, the rate at which it spreads was unexpectedly slower than models had predicted for a traditional fGD.
Research collaborators Bennett and Marshall developed a mathematical model that provided an explanation. Their model revealed that during the hacking conversion, fGDs impose a greater fitness cost on individual flies than sGDs alone. This fitness cost, which unfolds when the drive element copies itself, vanished after acting on all potential target chromosomes in the population.
“The study reveals unanticipated complexities in how gene-drive components work together, revealing that one cannot simply assume how separate components may interact when brought together,” said Bennett.
The Nature Communications paper’s full author list: Gerard Terradas, Jared Bennett, Zhiqian Li, John Marshall and Ethan Bier.

A recent paper published in the Journal of Physiology deepened the case for the youthfulness-promoting effects of exercise on aging organisms, building on previous work done with lab mice nearing the end of their natural lifespan that had access to a weighted exercise wheel.
The densely detailed paper, “A molecular signature defining exercise adaptation with ageing and in vivo partial reprogramming in skeletal muscle,” lists a whopping 16 co-authors, six of whom are affiliated with the U of A. The corresponding author is Kevin Murach, an assistant professor in the U of A’s Department of Health, Human Performance and Recreation, and the first author is Ronald G. Jones III, a Ph.D. student in Murach’s Molecular Muscle Mass Regulation Laboratory.
For this paper, the researchers compared aging mice that had access to a weighted exercise wheel with mice that had undergone epigenetic reprogramming via the expression of Yamanaka factors.
The Yamanaka factors are four protein transcription factors (identified as Oct3/4, Sox2, Klf4 and c-Myc, often abbreviated to OKSM) that can revert highly specified cells (such as a skin cell) back to a stem cell, which is a younger and more adaptable state. The Nobel Prize in Physiology or Medicine was awarded to Dr. Shinya Yamanaka for this discovery in 2012. In the correct dosages, inducing the Yamanaka factors throughout the body in rodents can ameliorate the hallmarks of aging by mimicking the adaptability that is common to more youthful cells.
Of the four factors, Myc is induced by exercising skeletal muscle. Myc may serve as a naturally induced reprogramming stimulus in muscle, making it a useful point of comparison between cells that have been reprogrammed via over expression of the Yamanaka factors and cells that have been reprogrammed through exercise — “reprogramming” in the latter case reflecting how an environmental stimulus can alter the accessibility and expression of genes.
The researchers compared the skeletal muscle of mice who had been allowed to exercise late in life to the skeletal muscle of mice that overexpressed OKSM in their muscles, as well as to genetically modified mice limited to the overexpression of just Myc in their muscles.
Ultimately, the team determined that exercise promotes a molecular profile consistent with epigenetic partial programming. That is to say: exercise can mimic aspects of the molecular profile of muscles that have been exposed to Yamanaka factors (thus displaying molecular characteristics of more youthful cells). This beneficial effect of exercise may in part be attributed to the specific actions of Myc in muscle.
While it would be easy to hypothesize that someday we might be able to manipulate Myc in muscle to achieve the effects of exercise, thus sparing us the actual hard work, Murach cautions that would be the wrong conclusion to draw.
First, Myc would never be able to replicate all the downstream effects exercise has throughout the body. It is also the cause of tumors and cancers, so there are inherent dangers to manipulating its expression. Instead, Murach thinks manipulating Myc might best be employed as an experimental strategy to understand how to restore exercise adaptation to old muscles showing declining responsiveness. Possibly it could also be a means of supercharging the exercise response of astronauts in zero gravity or people confined to bed rest who only have a limited capacity for exercise. Myc has many effects, both good and bad, so defining the beneficial ones could lead to a safe therapeutic that could be effective for humans down the road.
Murach sees their research as further validation of exercise as a polypill. “Exercise is the most powerful drug we have,” he says, and should be considered a health-enhancing — and potentially life-extending — treatment along with medications and a healthy diet.
Murach and Jones’ co-authors at the U of A included exercise science professor Nicholas Greene, as well as contributing researchers Francielly Morena Da Silva, Seongkyun Lim and Sabin Khadgi.

Acute Graft-versus-host disease (GvHD) is a life-threatening complication after leukemia treatment with allogeneic stem cell transplantation, i.e. the transplantation of cells from another person. GvHD occurs when the transplanted immune cells are overly active and damage the receiving patient’s healthy tissue. Researchers from the University Medical Center Freiburg and the Cluster of Excellence CIBSS of the University of Freiburg found that an endogenous molecule can mitigate this misdirected immune response.
For many leukemia patients, receiving a bone marrow or blood stem cell transplantation is essential for survival. This treatment, however, results in complications in almost every second patient: The transplanted immune cells, especially T cells, not only attack the cancer cells but also healthy tissue. This leads to severe inflammatory reactions, especially of the skin and intestine. Even with drug prophylaxis and treatment, acute GvHD often is fatal.
In other inflammatory diseases of the gut, such as ulcerative colitis, epithelial cells of the gut release increased amounts of the molecule human beta-defensin 2 (hBD-2). This defensin has antimicrobial properties and can prevent infections. Recent studies also suggest that the molecule can also have a regulatory effect on immune cells. A team led by Junior Professor Dr. Natalie Köhler, researcher at the University Medical Center Freiburg and the Cluster of Excellence CIBSS — Centre for Integrative Biological Signalling Studies of the University of Freiburg, now investigated whether hBD-2 impacts inflammation in GvHD. They found that administration of hBD-2 significantly improved severity of disease and mortality in mice with acute GvHD. The promising results have been published in the journal Science Translational Medicine.
Low hBD-2 levels in patients with acute GvHD
The researchers first compared hBD-2 levels in the intestinal tissue of patients with acute GvHD with those of patients with ulcerative colitis and healthy volunteers. “Although both diseases are characterized by inflammatory processes in the intestine, hBD-2 was only increased in patients with ulcerative colitis, not in patients with acute GvHD,” says Köhler, describing the observations from gene expression analyses and microscopic examinations.
Lower T cell activity and fewer immune cells in the gut under treatment with hBD-2
The researchers then tested whether the administration of hBD-2 has an effect on the course of acute GvHD in mice. Indeed, the allogeneic T cell response was reduced in the gut of mice that received hBD-2. The researchers attributed this effect to the molecule’s influence on signalling pathways that trigger the activation of resting T cells. Furthermore, they found that the administration of hBD-2 changed the composition of the bacterial flora in the mice’s intestines and decreased the number of neutrophil immune cells migrating into the intestinal tissue, reducing their contribution to the inflammatory reaction there. “In summary, our study shows that prophylactic treatment with hBD-2 inhibits the allogeneic T cell response and influences the intestinal microbiome, thereby reducing acute GvHD severity.” says Köhler. “At the same time, the T cells’ effect against the leukemia cells is maintained.” This makes hBD-2 an interesting candidate for further investigation and clinical trials, and might be used as a prophylactic in allogeneic stem cell transplantation in the future, the researchers say.

The cerebellum, or our little brain, is mainly responsible for our motor skills. Furthermore, the structure is important for behavior and cognition. The cerebellum is a part of your brain located at the back of your head, just above and behind where your spinal cord connects to your brain itself. Although this part only accounts for 10 percent of the volume of our brain, the cerebellum contains more brain cells than the rest of our brain, and is therefore an important area that we want to map out properly.
The cerebellum is highly folded in humans compared to other mammals. This makes it a difficult structure to fully visualize and therefore study, because of the condensed layers. To really properly image it, you need high resolution imaging. Using current imaging techniques, only a small portion of the cerebellar anatomy could be visualized, leaving the remaining details ignored. The ingenious structure is therefore still largely undiscovered. Until now.
High resolution
Researchers at the Spinoza Center have developed a method to look at the cerebellum using a powerful 7-Tesla MRI scanner. By correcting for movements during, for example, the subjects’ breathing, the team succeeded in achieving a resolution of 1/5th of a millimetre. In addition, the researchers can use this data to reconstruct and digitally inflate the cerebellum, making the patterns and layers clearly visible. The cerebellum can also be viewed ‘live’ while performing various tasks.
Researcher Nikos Priovoulos: ‘We can do this specifically because we have a very high field magnet (which is expensive and hard to build) and also motion correction because people, tend to move during the scans. We can now look at the cognitive role of the cerebellum and the clinical aspects related to the cerebellum. We hope that using this technique we can look more in depth at neurodegenerative disorders. This is the first time that we can view the human cerebellum directly, with this much detail.’
‘In multiple sclerosis (MS) the cerebellum plays an important role. MS patients have motor lesions, which means that they have damage to the nerve cells involved in movement. We already know from ex vivo studies, experiments outside the body, that degeneration of these cells takes place in case of MS. Right now we are scanning MS patients and we hope to look at other clinical groups as well. Based on previous findings we know for MS specifically that we could benefit from high resolution imaging in the cerebellum. We don’t know what the exact impact will be on the longer term. Hopefully it has some predictive value for these patients.’