The 2020 Nobel Prize in Chemistry was awarded to Jennifer Doudna and Emmanuelle Charpentier for developing a groundbreaking yet simple way to edit DNA, the “blueprint” of living organisms. While their discovery opened new avenues for research, the accuracy of the method and safety concerns about “cutting” both strands of DNA limited its use for gene therapy treatments. As such, research has been underway to develop tools that do not have these drawbacks.

The prime editing system is one such tool, a molecule complex consisting of two components. One component is the prime editor, which combines a SpCas9 protein, used in the first CRISPR-Cas gene editing technology, and a reverse transcriptase, an enzyme that transcribes RNA into DNA. The second component is the prime editing guide RNA (pegRNA), a modified guide RNA that identifies the target sequence within the DNA and encodes the desired edit. In this complex, the prime editor works like a “word processor,” accurately replacing genomic information. The tool has already been successfully implemented in living cells of organisms such as plants, zebrafish, and mice. However, precisely how this molecule complex executes each step of the editing process has not been clear, mostly due to a lack of information on its spatial structure.

“We became curious about how the unnatural combination of proteins Cas9 and reverse transcriptase work together,” says Shuto, the first author of the paper.

The research team used cryogenic electron microscopy, an imaging technique that makes observations possible at a near-atomic scale. The method required samples to be in glassy ice to protect them from the potential damage by the electron beams, posing some additional challenges.

“We found the prime editor complex to be unstable under experimental conditions,” explains Shuto. “So, it was very challenging to optimize the conditions for the complex to stay stable. For a long time, we could only determine the structure of Cas9.”

Finally overcoming the challenges, the researchers succeeded in determining the three-dimensional structure of the prime editor complex in multiple states during reverse transcription on the target DNA. The structures revealed that the reverse transcriptase bound to the RNA-DNA complex that formed along the “part” of the Cas9 protein associated with DNA cleavage, the splitting of a single strand of the double helix. While performing the reverse transcription, the reverse transcriptase maintained its position relative to the Cas9 protein. The structural and biochemical analyses also indicated that the reverse transcriptase could lead to additional, undesired insertions.

These findings have opened new avenues for both basic and applied research. So, Shuto lays out the next steps.

“Our structure determination strategy in this study can also be applied to prime editors composed of a different Cas9 protein and reverse transcriptase. We want to utilize the newly obtained structural information to lead to the development of improved prime editors.”

The study will be published on May 29 in JAMA Network Open. It is the latest publication from the Apple Women’s Health Study, a longitudinal study of menstrual cycles, gynecological conditions, and overall women’s health conducted by Harvard Chan School, the National Institute of Environmental Health Sciences, and Apple.

“Our findings can lead to a better understanding of menstrual health across the lifespan and how our lived environment impacts this critical vital sign,” said co-principal investigator Shruthi Mahalingaiah, assistant professor of environmental, reproductive, and women’s health at Harvard Chan School.

While previous studies have shown trends towards earlier menarche over the past five decades, data has been limited on how these trends present within different racial groups and socioeconomic statuses. Additionally, few studies have had sufficient data to identify any trends regarding time to menstrual cycle regularity.

The researchers used the Apple Women’s Health Study’s large, diverse dataset to fill this research gap. Participants who enrolled in the study between November 2018 and March 2023 — 71,341 in total — self-reported the age at which they first began menstruating and their race and socioeconomic status. The researchers divided the participants into five age brackets: born between 1950-1969, 1970-1979, 1980-1989, 1990-1999, and 2000-2005. Ages of menarche were defined as early (younger than 11 years old), very early (younger than 9), and late (ages 16 and above). A subset of participants (61,932) self-reported the time it took for their menstrual cycle to become regular and were divided into five categories: up to two years, between three and four years, longer than five years, hasn’t become regular, or became regular with use of hormones. Another subset (9,865) provided their body mass index (BMI) at their age of menarche.

The study found that as birth year increased (meaning younger participants), average age at menarche decreased and time from menarche to menstrual cycle regularity increased. Among participants born from 1950-1969, the average age at menarche was 12.5 years, and the rates of early and very early menarche were 8.6% and 0.6%, respectively. Among participants born from 2000-2005, the average age of menarche was 11.9 years, and the rates of early and very early menarche were 15.5% and 1.4%, respectively. Across the two groups, the percentage of participants who reached menstrual cycle regularity within two years of menarche decreased from 76% to 56%. The researchers observed that these trends were present among all sociodemographic groups but were most pronounced among the participants who identified as Black, Hispanic, Asian, or mixed race, and who rated themselves as belonging to a low socioeconomic status.

The findings showed that BMI at age of menarche could explain part of the trend toward periods starting earlier — in other words, that childhood obesity, a risk factor for early puberty and a growing epidemic in the U.S., could be a contributing factor to earlier menarche. Other possible factors that might explain the trend include dietary patterns, psychological stress and adverse childhood experiences, and environmental factors such as endocrine-disrupting chemicals and air pollution.

“Continuing to investigate early menarche and its drivers is critical,” said corresponding author Zifan Wang, postdoctoral research fellow in Harvard Chan School’s Department of Environmental Health. “Early menarche is associated with higher risk of adverse health outcomes, such as cardiovascular disease and cancer. To address these health concerns — which our findings suggest may begin to impact more people, with disproportionate impact on already disadvantaged populations — we need much more investment in menstrual health research.”

The authors noted some limitations to the study, including that it relies heavily on retrospective self-reporting.

Other Harvard Chan School authors included Gowtham Asokan, Jukka-Pekka Onnela, Michelle Williams, Russ Hauser, and Brent Coull.

The study was made possible by funding from Apple, Inc. and the National Institutes of Health (grant Z01ES103333).

A new University of Michigan study concludes that nearly half of the food waste, about 620 million metric tons, could be eliminated by fully refrigerated food supply chains worldwide.

At the same time, fully refrigerated supply chains, or “cold chains,” could cut food waste-related emissions of climate-warming greenhouse gases by 41% globally, according to the study published online May 28 in the peer-reviewed journal Environmental Research Letters.

Sub-Saharan Africa and South and Southeast Asia have the greatest potential for reductions in both food losses and related emissions through increased cold-chain implementation, according to the study.

South and Southeast Asia could see a 45% reduction in food losses and a 54% decrease in associated emissions under an optimized refrigeration scenario. Sub-Saharan Africa has tremendous opportunities for both food loss (47%) and emissions (66%) reductions under optimized refrigeration conditions, the study shows.

And in many situations, developing more localized, less industrialized “farm-to-table” food supply chains may yield food savings comparable to optimized cold chains, according to the study.

“I was surprised to find the scale of our opportunity for reducing food loss and waste globally,” said study lead author Aaron Friedman-Heiman, a master’s student at U-M’s School for Environment and Sustainability and Ross School of Business. “Approximately half of the roughly 1.3 billion tons of food that goes to waste annually can be solved through food supply-chain optimization.”

The other author is Shelie Miller, a professor at U-M’s School for Environment and Sustainability and at the College of Engineering.

Food losses produce an estimated 8% of human-caused greenhouse gas emissions. The new U-M study focuses on food losses in the post-harvest to retail stages of the food supply chain and does not address on-farm or at-home losses.

The study accounts for the greenhouse gases emitted during food production. It does not include emissions tied to refrigeration or other supply-chain operations and does not include emissions from food waste in landfills.

The study, funded in part by Carrier Global Corp., found that:

• The greatest opportunity to improve food losses in less industrialized economies is the supply chain between the farm and the consumer. But in North America, Europe and other more industrialized regions, most food loss happens at the household level, so cold chain improvements would not have a major impact on total food losses.
• Reinforcing previous research, the U-M study highlights the importance of meat-related food losses. While the amount of fruit and vegetable losses is much higher, by weight, throughout the world, the climate-related emissions associated with meat losses are consistently greater than those associated with any other food type — due mainly to the high greenhouse gas intensity of meat production.
• Unlike previous studies of this topic, the U-M researchers compared the benefits of globalized, technologically advanced food-supply chains with those of localized “farm-to-table” food systems. “Hyper-localized food systems resulted in lower food losses than optimized global, refrigerated supply chains,” Friedman-Heiman said. “The results help quantify the value of maintaining and supporting local food chains.”

For the study, the researchers built a food-loss estimation tool to assess how improved access to the cold chain could impact food loss and its associated greenhouse gas emissions for seven food types in seven regions. They used data from the U.N. Food and Agriculture Organization and other sources.

By modeling food losses at each stage of the supply chain, the study highlights where the cold chain can be optimized to reduce food losses and emissions. The researchers analyzed the effects of moving from the current state of inconsistent and variable-quality cold chains throughout the world to an optimized system, defined as one with high-quality refrigeration across all stages.

The study estimates that poor cold-chain infrastructure could be responsible for up to 620 million metric tons of global food loss annually, resulting in emissions of 1.8 billion tons of carbon dioxide equivalents, the equivalent of 28% of U.S. annual greenhouse gas emissions.

The researchers say their adaptable, easy-to-use tool will be of use to anyone involved in the food supply chain, including farmers, grocery retailers, government officials and nongovernmental organizations.

“Although cold chain infrastructure is rapidly increasing worldwide, an optimized cold chain will likely develop at different rates and in different ways across the globe,” Miller said. “This analysis demonstrates that while increased refrigeration should lead to improvements in both food loss and greenhouse gas emissions associated with food loss, there are important tradeoffs associated with cold chain improvements by food type and region.”

She said Investment decisions will need to be prioritized to maximize the desired outcomes and impacts. For example, if an NGO’s top priority is ending hunger, then cold-chain upgrades that provide the greatest overall food-loss reductions may best meet that objective.

But organizations that prioritize climate action may choose to focus on reducing meat losses specifically, rather than total food losses.

The study found that meat accounts for more than 50% of food loss-related greenhouse gas emissions, despite accounting for less than 10% of global food losses by weight. Optimized refrigeration of meat could result in the elimination of more than 43% of emissions associated with meat loss, according to the study.

The researchers emphasize that the actual amount of greenhouse gas emissions savings will depend on the efficiency of cold-chain technologies and the carbon intensity of local electrical grids, since climate emissions associated with refrigeration can be significant.

The U-M study was supported by the U.S. National Science Foundation and by Carrier Global Corp., a global leader in intelligent climate and energy solutions.

Growing evidence suggests air pollution, which comprises toxic gases and particulate matter, might contribute to the onset of mental health problems. It is thought that pollution could negatively affect mental health via numerous pathways, including by compromising the blood-brain barrier, promoting neuroinflammation and oxidative stress, and directly entering the brain and damaging tissue.

Despite youth being a key period for the onset of these problems, until now, relatively few studies have investigated the associations of air and noise exposure during early life with mental health.

In this new study, researchers sought to examine the long-term impact of air and noise pollution exposure during pregnancy, early childhood and adolescence on three common mental health problems: psychotic experiences (including hallucinations, such as hearing or seeing things that others cannot, and delusions, such as having very paranoid thoughts), depression and anxiety.

To investigate this, the team used data from over 9,000 participants from Bristol’s Children of the 90s birth cohort study (also known as the Avon Longitudinal Study of Parents and Children), which recruited over 14,000 pregnant women from the Bristol area between 1991 and 1992, and has followed the lives of the women, the children and their partners ever since.

By linking participants’ early childhood data with their mental health reports at the ages of 13, 18 and 24 years, researchers were able to use this to map against outdoor air and noise pollution in South West England at different time points.

Researchers found that relatively small increases in fine particulate matter during pregnancy and childhood were associated with more psychotic experiences and depression symptoms many years later in teenage years and early-adulthood. These associations persisted after considering many related risk factors, such as family psychiatric history, socioeconomic status, and other area-level factors such as population density, deprivation, greenspace and social fragmentation.

The team found that every 0.72 micrograms per cubic meter increase in fine particulate matter (PM_2.5) during pregnancy and childhood was associated with an 11 per cent increased odds and 9 per cent increased odds for psychotic experiences, respectively; while exposure in pregnancy was associated with a 10 per cent increased odds for depression. In contrast, higher noise pollution exposure in childhood and teenage years was subsequently associated with more anxiety symptoms.

Dr Joanne Newbury, Sir Henry Wellcome Postdoctoral Research Fellow in the University’s Bristol Medical School: Population Health Sciences (PHS) and the study’s lead author, said: “Childhood, adolescence, and early adulthood are critical periods for the development of psychiatric disorders: worldwide, nearly two-thirds of those affected become unwell by the age of 25. Our findings add to a growing body of evidence — from different populations, locations, and using different study designs — suggesting a detrimental impact of air pollution (and potentially noise pollution) on mental health.

“This is a major concern, because air pollution is now such a common exposure, and rates of mental health problems are increasing globally. Given that pollution is also a preventable exposure, interventions to reduce exposure, such as low emissions zones, could potentially improve mental health. Targeted interventions for vulnerable groups including pregnant women and children could also provide an opportunity for more rapid reductions in exposure.

“It is important to emphasise that these findings, by themselves, do not prove a causal association. However, other recent studies have shown that low emissions zones appear to have a positive impact on mental health.”

The research, which involved researchers from King’s College London, University College London and Cardiff University, was funded by the University of Bristol, Wellcome, Economic and Social Research Council (ESRC), Medical Research Council (MRC), National Institute for Health and Care Research (NIHR), and the Natural Environment Research Council (NERC).

The researchers’ findings, which were recently published in Nature Communications Biology, highlight their discovery of the lipid-lowering effects of nesfatin-1-like peptide (NLP). This newly identified peptide — or small protein — is a close relative of nesfatin-1 (NESF-1), which regulates feed intake and body weight.

“We found that both NESF-1 and NLP lower lipid (fat) accumulation in human liver cells,” said research team member Dr. Suraj Unniappan (PhD), the university’s Centennial Enhancement Chair in Comparative Endocrinology and a professor at the Western College of Veterinary Medicine (WCVM). The collaborative study involved researchers at the WCVM and USask College of Medicine.

While the lipid-lowering effect of nesfatin-1 was previously reported, Unniappan said identifying NLP and understanding its lipid-lowering capabilities in human cells represent new advancements in the field of endocrinology.

“We are far away from bringing these findings to bedside,” said Unniappan. “But we now have additional multiple targets available that could be explored for lipid disease treatment and therapeutic advancements.”

The research team’s discovery is hopeful news since there’s a lack of new therapies for many metabolic diseases — including non-alcoholic fatty liver disease (recently renamed as metabolic dysfunction-associated steatotic liver disease or MAFLD), which affects about 20 per cent of Canadians. A hormone-based drug was approved in the United States in March 2024, but so far, there are no drugs currently available in Canada exclusively for treating this disease.

Typical treatment plans for both humans and animals suffering from metabolic disease generally consist of diet and exercise changes to gradually lower body weight and reduce fat accumulation.

Unniappan and his research team have been at the forefront of nesfatin-1 research. Discovered in 2006 by a group of researchers in Japan, nesfatin-1 was initially recognized for its ability to suppress food intake.

The USask team went a step further than previous studies and successfully verified that genetic disruption of NLP leads to changes in genes involved in lipid metabolism in mice.

“We found that if you disrupt the gene that is the source of that protein [NLP] naturally present in these animals, then that actually leads to changes in lipid metabolism-associated genes,” said Unniappan.

Discovering such results — that administering NLP reduces lipid levels, while disrupting its production alters lipid metabolism — reinforces its pivotal role in metabolic regulation.

Unniappan and Dr. Atefeh Nasri (PhD), who completed her doctoral program at USask in 2023 and is now a post-doctoral fellow at Dalhousie University, collaborated with Dr. Scott Widenmaier (PhD), an assistant professor of anatomy, physiology and pharmacology, and an expert in metabolic disease at the USask College of Medicine. The team’s fourth member was undergraduate student Mateh Kowaluk.

Unniappan hopes that this new research can pave the way for further exploration of treatment options. He plans to work with collaborators to extend this research to more complex animal models — including rodents — and eventually studying larger animals such as cats and dogs. Like humans, these species also suffer from obesity and related metabolic disorders.

“It’s beautiful to know the same peptide can achieve so many meritorious health effects, that in combination have the potential to help both human and animal patients,” said Unniappan.

This research was supported by the Canadian Institutes of Health Research (CIHR) and the USask Centennial Enhancement Chair in Comparative Endocrinology.