Unexpected outcomes: a warning for gene editing in embryos

Researchers from the South Australian Health and Medical Research Institute (SAHMRI) and the University of Adelaide have uncovered a significant hurdle to realising the potential benefits of gene editing in embryos. North American research published in 2017 seemed to demonstrate that gene editing in human embryos using molecular scissors, or CRISPR-Cas9, to cut specific regions of a cell’s genetic material was highly effective in repairing a defective gene in a majority of the embryos; however, the SAHMRI team says their research provides an alternative explanation for the apparent gene correction, suggesting that rather than the gene editing technology fixing small errors, much larger errors were being created. The researchers replicated the North American study with preclinical animal models — Australia has strict legislation restricting gene editing in human embryos. “We looked beyond the small deletions, exploring larger areas of DNA,” the researchers wrote. “When we searched a wider area, we found that repair of the DNA break generated by ‘molecular scissors’ resulted in deletion of large stretches of DNA.” The molecular scissors, or CRISPR-Cas9, are a tool used by scientists to cut specific regions of a cell’s DNA. Repair of the cut can alter the target DNA sequence, resulting in a specific change or “edit”. Faulty genes can theoretically be repaired by cutting them using CRISPR. However, as the SAHMRI researchers have shown, DNA can sometimes be lost during the repair process, resulting in large deletions that would not restore function to the faulty gene. “Understanding the fundamental mechanisms by which these tools work [is an important advancement] for research and for clinical translation to treat a host of genetic diseases.” The SAHMRI research findings were published in Nature.

Revolutionary new view of how cells make energy

Researchers at the University of Western Australia and the Harry Perkins Institute of Medical Research have made a discovery about the atomic structure and function of cell mitochondria, providing a new means to target them for drug treatments. The research is published in Nature. “Mitochondria contain a set of genes that are used to make key protein building blocks that enable mitochondria to produce energy,” the researchers wrote. “These proteins are essential for energy production; however, little is known about how they are made. The recent discovery of the atomic structure of the mitochondrial ribosome, the machine that makes these proteins, has revealed how they are made. Surprisingly, the ribosome blocks itself from making the proteins until it is precisely located where these proteins are required within mitochondria. This is highly unusual and previously not found in nature.” As well as providing a new means to target the ribosome for drug treatments, the discovery also demonstrated the power of cutting-edge technology to reveal how living systems had evolved to function under different energy requirements. “Defects in mitochondrial function underlie many common diseases such as neurodegenerative, metabolic and heart diseases; cancer; diabetes and ageing. Therefore, molecular discoveries provide the much-needed knowledge that enables us to make the leap to disease treatments and drug discoveries.” The next step was to delve deeper into the role of the mitochondrial ribosome to understand how its defects could cause disease, the researchers wrote. “We are now working on developing models of disease to study these defects. We are using our models to screen for drugs that can selectively rescue defects in protein synthesis and energy production.”

Largest study yet shows boxers better than briefs for sperm quality

Men who wear boxer shorts have higher sperm concentrations than men who wear tighter fitting underwear, according to new US research published in Human Reproduction. The researchers also found that men who wore boxer shorts had lower levels of follicle-stimulating hormone (FSH) compared with men who most frequently wore briefs, “bikinis” (very brief briefs), “jockeys” (underwear that finishes just above the knee) or other tight-fitting underwear. FSH stimulates sperm production, and the researchers say that these findings suggest that it kicks into gear when it needs to compensate for testicular damage from increasing scrotal temperatures and decreasing sperm counts and concentration. The study differs from previous research on this topic because it includes a larger number of men (656) than previous studies, and because it is the first to go beyond the traditional, narrow focus on semen quality and include information on a variety of indicators of testicular function, such as reproductive hormones and sperm DNA damage. The researchers recruited the male partners of couples who were seeking infertility treatment at the Massachusetts General Hospital between 2000 and 2017. The men were aged between 18 and 56 years, had an average body mass index (BMI) of 26, and had not had vasectomies. Each of them provided a semen sample and blood sample on the same day, and they answered a questionnaire that asked about the style of underwear they wore most frequently in the preceding 3 months. Among the 656 men, 53% (345) reported that they usually wore boxer shorts. They tended to be younger, slimmer and more likely to take hot baths or jacuzzis than the men who wore more tightly fitting underwear. Men who primarily wore boxer shorts had a statistically significant 25% higher sperm concentration, 17% higher total sperm count, 33% more swimming sperm in a single ejaculate and 14% lower FSH levels than men who did not usually wear boxers, after adjusting for factors that might affect the results, such as BMI, physical activity, hot baths and jacuzzis, smoking, and the year the sample was taken. In addition, more sperm were correctly shaped, although this result was not statistically significant. The greatest difference in sperm concentration was found between men wearing boxer shorts most frequently and men wearing jockeys or briefs. There were no significant differences in other reproductive hormones or damage to the DNA of the sperm. When the researchers adjusted their results to take account of reproductive hormones, apart from FSH, they found the adverse effect of tighter underwear on sperm quality remained. However, when they adjusted for FSH levels, the effect was no longer significant. This suggested to them that it was the damage to sperm concentrations and total sperm count associated with wearing tighter underwear that could be responsible for the changes in FSH levels. The researchers point out that it may not be possible to generalise the findings of their study to all men, as the study focused on men attending a fertility centre. Moreover, the study only shows an association between type of underwear and semen quality and FSH levels, it does not confirm causality.

Exercise for mental health: more may not be better

A study of 1.2 million Americans has found that people who exercise report having 1.5 fewer days of poor mental health a month, compared with people who do not exercise. The study found that team sports, cycling, aerobics and going to the gym were associated with the biggest reductions, according to the largest observational study of its kind published in The Lancet Psychiatry. More exercise was not always better, and the study found that exercising for 45 minutes three to five times a week was associated with the biggest benefits. Small reductions were still seen for people who exercised more than 90 minutes a day, but exercising for more than 3 hours a day was associated with worse mental health than not exercising at all. The authors noted that people doing extreme amounts of exercise might have obsessive characteristics, which could place them at greater risk of poor mental health. The researchers used data from 1.2 million adults who completed the Behavioural Risk Factor Surveillance System survey in 2011, 2013 and 2015. This included demographic data and information about their physical health, mental health, and health behaviour. Participants were asked to estimate how many days in the past 30 days they would rate their mental health as “not good” based on stress, depression and emotional problems. They were also asked how often they took part in exercise in the past 30 days outside of their regular job, as well as how many times a week or month they did this exercise and for how long. Compared with people who reported doing no exercise, people who exercised reported 1.5 fewer days of poor mental health each month – a reduction of 43.2% (2.0 days for people who exercised v 3.4 days for people who did not exercise). The reduction in number of poor mental health days was larger for people who had previously been diagnosed with depression, for whom exercise was associated with 3.75 fewer days of poor mental health compared with people who did not exercise – equivalent to a 34.5% reduction (7.1 days for people who exercised v 10.9 days for people who did not exercise). Even completing household chores was associated with an improvement (reduction in poor mental health days of around 10% or around half a day less each month).

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