Gene Editing: Optimists and Skeptics

"We're excited by the possibility that you could develop a single editing agent into a drug that may help many different types of patients, circumventing the need to invest multiple years and millions of dollars to develop each new genetic medicine for each individual."

"We are purposefully forgoing what is the most obvious way to treat a patient -- fix  their individual mutation back to the normal sequence."

"[The vast majority of people with genetic diseases] suffer from diseases too rare for companies to be able to recoup the costs of drug development." 

"We hope this research will eventually pave the way for a clinical trial of PERT, and will inspire other broadly applicable, disease-agnostic gene-editing strategies. If you don’t have to target one mutation at a time, the size of the patient groups that could be treated with a single drug becomes much, much larger."

"We hope the result will be many more patients that benefit, as well as greater incentives to develop gene-editing drugs for rare diseases."

David R. Liu, biologist, Broad Institute/Harvard University 

KJ was only days old when he was diagnosed with a rare metabolic disorder and transferred to Children's Hospital of Philadelphia where doctors were actively researching new cell and gene therapies.

 

Gene-editing therapies for the treatment of rare diseases hold out great hope for the future, while facing some roadblocks comprised of time and resources committed to devise treatments that may be relevant to only a limited number of patients. A recently published study in the journal Nature sees a new approach outlined that has the potential to make the process more efficient and less costly, comprised of a gene-editing strategy that could over time be standardized for various rare diseases rather than personalized edits for each one.

 

Over 7,000 rare genetic diseases have been defined, affecting fewer than 200,000 people, in the United States alone. These are diseases that afflict some 400 million people globally. The focus on the study was on 'nonsense mutations' which have the effect of truncating proteins, similar to a sentence halted in its midst by a period inserted where it should not be. These erratic, out-of-place 'stop signs' are labelled as premature stop codons. Their effect is to stop truncated proteins operating as they should, causing or contributing to a number of rare genetic diseases.

 

A molecule identified as a suppressor tRNA which can insert an amino acid at the stop codon position allowing the cell to read through the area on the gene where it would have paused to produce the full protein was the key to the study. The research team engineered an optimal suppressor tRNA following exhaustive testing. With the use of a genetic search-and-replace method Dr. Liu's lab invented called prime editing, it was inserted into a cell's genome replacing an existing tRNA that had not served any purpose.

 

UdeMnouvelles, Universite de Montreal

 

The method was tested in human cell models of  four diseases -- Batten disease, Tay-Sachs disease, cystic fibrosis and Niemann-Pick disease type C1 -- as well as in a mouse engineered with another human disease, Hurler syndrome. Enough of the relevant protein's function in each case was restored to encourage the expectation that the change would alleviate symptoms of the diseases. The method did not create genetic or biological missteps, the team reported encouragingly. 

 

Dr. Liu explained there is variation within diseases. As a result ,truncated proteins are not the cause for every patient, though the out-of-place stop signs can lead to 30 percent of genetic diseases. The new method, he estimates, could apply to ten to 15 percent of patients with Duchenne muscular dystrophy or cystic fibrosis. The method, estimates Dr. Liu's team, might be of value to 252,000 people with Stargardt disease and 31,000 people with phenyelketonuria.

 

Funded by the U.S. National Institutes of Health and academic institutions, the study was spurred by a 'bottleneck' in the drive to make gene editing more available to desperate patients. Increased scientific capacity to fix disease-causing mutations aside, the very issue of the diseases' rarity among populations means the pharmaceutical producers would be expending great amounts of time and research to produce specific drugs, yet could only anticipate a limited distribution, making them unable to recoup the steep costs of production.  

"In some cases, the bottlenecks in genetic medicine aren’t the science anymore. They’re in meeting regulatory requirements, in the manufacturing costs associated with these treatments, and in the commercial challenges of drugs that treat very small numbers of patients."

"Witnessing gene-editing companies make the gut-wrenching decisions of which targets to pursue — synonymous with the gut-wrenching decisions of which patients are left behind — made it clear that we need creative scientific ways to help address some of these problems."

Dr. David R. Liu, Broad Institute  

Dr. Liu spoke from personal experience, having co-founded gene-editing companies that faced the situation of ebbing funds making it difficult to enable clinical trials treating a limited number of patients. Efforts in the creation of drugs based on suppressor tRNAs face challenges; among them that patients would require repeated dosages indefinitely at the risk of toxic effects over time. 

 

Credit: Agnieszka Grosso, Broad Communications

PERT, the reprogramming of cells by a process of a single prime editing system could potentially treat multiple genetic diseases. Dr. Liu's method would result in a one-time edit, producing no toxicity nor errors in other proteins. His study was not universally acclaimed, however. Several experts in gene-editing cautioned considerable further testing and other steps must be considered before the new approach could represent a trusted protocol to meet patients' medical needs. 

 

"[While the new approach is years away from potential use, it might ultimately apply to] a significant fraction [of those patients; conservatively about ten percent]."

"How do you deliver this to all cells in the body that would need to be corrected to prevent the worse outcomes from the disease?" 

Dr. Richard P. Lifton, president, Rockefeller University, head, laboratory of human genetics and genomics

BMI or BIA Predictive of future Health Risks?

"Body mass index has no statistically significant relationship with all-cause mortality."

"[The study used BIA -- bioelectrical impedance analysis -- technology decades old] and that still had stronger associations with mortality when compared with the BMI [body mass index]."

"Current BIA models provide reproducible results in less than one minute [making their adoption easy for busy family medicine clinics." 

"[While] this is the strongest and most definitive health outcome [the researchers bypassed morbidity; other health complications other than death, in their study]."

University of Florida research team

 

"This is the ultimate Coke versus Pepsi test. And BMI failed."

"BMI is just so ingrained in how we think about body fat. I think the study shows it's time to go to an alternative that is now proven to be far better [risk-predictive]."

"For essentially the same price as a scale to weigh newborns or a machine to sterilize instruments, a machine to reliably and validly assess body fat percentage will allow a practise to accurately target the patient who can benefit most from obesity and body fat reduction strategies to prevent a wide variety of diseases."

Professor Arch Mainous, vice-chair, research in community health and family medicine, University of Florida

 

"Now remember, using BMI did not flag any risk at all in this younger population, which isn't one we typically consider to be at high risk for heart disease."

"Think of the interventions we can do to keep them healthy when we know this early. I think it's a game-changer for how we should look at body composition." 

Dr. Frank Orlando, study senior author 

Cleveland Clinic

 

A study questioning the utility of the long-relied-upon body mas index to project injurious health outcomes recently published in the July edition of the journal Annals of Family Medicine, reflects the outcome of the research where adults with a high body-fat percentage were found to be close to twice as likely to die from any cause over 15 years, in comparison with others that have a healthy body fat range...and over three times likelier to die from heart disease.

 

The researchers found that a BMI indicating overweight or higher, not to be associated with a statistically significant higher risk of death from any cause. Body mass index has been the subject of growing criticism with the realization that the body composition measure is flawed and overrated for determining anyone's health. A person's weight is divided by the square of his/her height, then based on a range of numbers, places people into one of four subsequent categories: underweight, healthy weight, overweight or obese, in arriving at results for body mass index.

 

The World Health Association along with other health associations globally has endorsed the BMI as representing the standard measure for body composition. People with muscular physiques, however, can be classified as overweight or obese, since the BMI fails to account for bone or muscle. Nor does it take into account where excess fat is deposited; visceral or belly fat that wrap around internal organs, increasing the risk of diabetes and heart disease is in fact more dangerous than fat acquired around the hips. 

 

The researchers analyzed data taken from 4,252 people age 20 to 49 who were enrolled in a national U.S. health and nutrition survey, all of whom had a technician measure height, weight and waist circumference. Body-fat percentage was assessed via 'bioelectrical impedance analysis" (BIA), applying a light, harmless current through the body to measure resistance as it passes through bodily tissues to estimate total body composition including fat-free mass and total body water. Collected data from the health survey were then linked to records of death certificates.

 

After a fifteen year period, the researchers examined "mortality status" of each participant. Those adults with a higher body-fat percentage (27 percent or more in men; 44 percent or greater in women) were 78 percent more likely to die from any cause than those people with lower body-fat percentages. Any with a high body-fat count were also 3.62 times likelier to die from heart disease.

 

A BMI in the unhealthy range, on the other hand -- 25 or higher -- was not associated with a statistically significant higher risk of death from any cause, in comparison with adults in the healthy BMI range. At-home bathroom scales, fitness apps and smartwatches have begun to incorporate BIA technology. A high waist circumference of over 44 inches for men and more than 35 inches in women independent of height or weight, also performed more meaningfully than BMI in predicting risks.

 

Victoria State Government, Department of Health

 

A Pig's Ear Really Is a Silk Purse ... Social Harmony in the Pigsty

"Pigs are highly social, and they have a very complex and high cognitive capacity to recognize familiar individuals."

"The nose is very important for pigs not just for communication and exploration, but for social interaction."

"[A victim['s anxiety levels notably decreased after contact, whereas] when the third party contacted the aggressor, we can detect a reduction in the frequency of the aggression directed at the other victim."

Giada Cordoni, PhD in Evolutionary Biology, University of Turin

"When a third person comes in, it's an opportunity for someone to hear you. In a conflict, the other person isn't understanding your perspective. The third party is going to at least understand your perspective."

"The third party contains the conflict and the emotions associated with it ... We automatically regulate and behave better when someone else is there."

Louisa Weinstein, conflict mediation specialist, Conflict Resolution Centre, London

Piggy in the Middle! A bizarre new study has revealed that when two porkers are fighting, a third bystander pig can intervene to cut the tension

 

It is no secret that in the animal kingdom some animals are seen to be more intelligent than others. Pigs are among the intelligent groups. And now a recently published study confirms that they're also empathetic conflict interveners. Pigs, according to the study, appear to possess cognitive capacity sufficient in measure to be aware of and empathize when two other pigs reach a disagreement. Upon which the third pig will intervene to reduce tension levels.

It was observed by the study participants that bystander pigs occasionally intervene following a conflict through approaching one of the two disagreeing parties to initiate physical contact by the calming effect of their snouts, rubbing either of the parties with their ears or sitting up against one of the opponents. A pig was also seen to place its entire head over the body of one of the two combatants, an effective calming affect.

Anxiety levels  diminish when a victim is given physical contact following a fight, while aggressors that might be approached are then less likely to attack the victim -- or other members of the group -- again. This resolution strategy involving a third pig is described as a "triadic conflict mechanism". This is the first time such intervention has been observed in the species. Though the propensity to intervene in disputes has been identified previously in humans, wolves, primates and birds.

Researchers observed and recorded interactions between pigs from June to November 2018 and noted aggressive behaviours such as head-knocking, pushing, biting and lifting of a victim

 

Italian researchers in 2018 observed 104 pigs for six months on a farm near Turin in northern Italy. There, the pigs were free to forage through a 213-hectare woodland area where they could move and behave naturally. In the process, hours of video data were collected and analyzed. It was found that domestic pigs can take to a wide array of post-conflict strategies minutes following a fight.

This leads the two fighting pigs to engage in reconciliation or a third pig not involved in the conflict can provide unsolicited physical contact with the aggressor or the victim, most frequently with the use of the snout. Bystander pigs clearly have the cognitive and empathetic skills to detect emotions such as anxiety in other pigs. It also suggests that the third pig knows when the moment is right to intervene, how to do it effectively. Although physical contact while not solicited by either of the antagonistic animals, proves an effective remedy to conflict.

Pigs on a farm, Deposit Photos

More Sleep, Less Exercise in Retirement

"Transition to retirement is shown to affect sleep, sedentary time and physical activity, but no previous studies have examined how retirement changes the distribution of time spent daily in these movement behaviours."

"Manual workers' daytime hours were more sedentary after retirement compared to work-days before retirement."

"Thus, physical activity at work may have been partly replaced with sedentary activities like watching TV after retirement."

"Non-manual workers seemed to replace some sedentary time with sleep, which may benefit health for those with inadequate sleep before retirement."

Finnish researchers, International Journal of Behavioral Nutrition and Physical Activity

NCO

 

Some insight has been gathered into trends in activity in older adults with studies monitoring lifestyle habits of recent retires. It is well enough known that a sedentary lifestyle helps to degrade health in the long term, particularly as people age. As well known is that physical activity on a regular basis can have the effect of delaying some physical and mental decline in conjunction with aging. As well as boosting health, mood, energy levels and social engagement.

A new finding, linking work-occupation with physical activity behaviours in retirement is quite interesting. Where people engaged in manual labour employment have a tendency to become, on retirement, more sedentary while those whose workplace tended to be an office environment, become more active during the retirement years. Researchers of the newly published study in the International Journal of Behavioral Nutrition and Physical Activity evaluated lifestyle habits of 551 public-sector employees.

The study participants' average age was 63. With the use of a wrist-worn accelerometer, during the first year of retirement, subjects' movement habits were recorded 24 hours daily, for a week both before and following their last day at work, about a year apart. Data was then divided by occupation and gender. Nurses' aides, cooks, cleaners and maintenance workers were included as manual workers for the purpose of the study. While teachers, physicians, registered nurses and technicians were classified as non-manual workers.

 

The study recorded the proportion of time in a day spent on sleep, on light physical activity, on moderate-to-vigorous physical activity, and on sedentary activities; then tallied the results of the data collected by the accelerometers.

Women, who represented 86 percent of the study subjects were spending eight hours nightly before retirement, 11 hours in sedentary pursuits, four hours performing light physical activity and 50 minutes in moderate-to-vigorous activity on a daily basis. Men, on the other hand, logged 16 minutes less sleep, 60 minutes of more sedentary time, and 46 minutes of less light activity than women. Both, on the other hand, logged a similar number of minutes on moderate-to-vigorous daily activity.

Manual workers logged less sedentary time and more physical activity than desk-bound counterparts before retirement in a pattern reflecting both men and women. The first year of retirement saw this group in reversal. Non-manual workers' lifestyle habits took a different turn, where sleep improved and time being sedentary diminished, while an increase in physical activity was seen, attributable to fewer hours spend behind a desk.

The greatest change in post-retirement daily lifestyle habits was seen in women with manual occupation backgrounds, who slept 45 minutes longer and spent 64 fewer minutes in light physical activity and 17 minutes less in moderate-to-vigorous activity; seeing sedentary time increase by 36 minutes. Retired from manual occupations, men experienced a lesser increase in sleep and sedentary activities in opposition to physical activity. 

Both types of workers saw a decrease in moderate-to-vigorous activity up to 17 inutes daily. Interpreted by the researchers in relation to a change in commuting habits; no bus or train to catch and no clock to punch -- seeing retirees sleep a bit longer, enjoying a slower and less active start to their days. The gathered data indicated for a large subset of the population, retirement results in a more sedentary lifestyle with a larger drop in moderate-to-vigorous activity than in light activity, both of which changes could result in negative consequences on health.

Outcome of Banning the Veil in French Schools

"For students who wore the veil, the ban may have had a negative effect on those who were most attached to it, as it may have led them to drop out of school."

"But the ban may also have had a positive effect on students who were forced to wear the veil, and on students suffering from stigmatization and discrimination in school because of it."

"When comparing women in the Muslim group to those in the non-Muslim group, the data reveal a very significant increase in educational attainment in the Muslim group for the cohorts that attended middle school and reached puberty after the ban."

"This increase clearly coincides with the implementation of the circular – the more years the Muslim group women spent in middle school after the circular, the higher their educational attainment."

Eric Maurin, Paris School of Economics, study co-author

State schools in France were asked to ban "ostentatious religious signs" -including Islamic veils - in 1994, but it was not forbidden by law until 2004. Photo by FRED DUFOUR/AFP via Getty Images

Im 1994 the government of France emphatically recommended that state schools ban "ostentatious religious signs", the customary Muslim girls' veils included. This was not a mandatory order but a recommendation. It became law in 2004 however, when despite warning from religious leaders that the law would persecute Muslims and encourage fundamentalism, it became lawfully illegal for French Muslim girls to wear the veil while attending state schools.

Now, researchers have produced results from a decades-long study with the finding that positive effects resulted after all, from the state initiative of removing the veil in schools. It was found that educational outcomes for Muslim girls were significantly improved once the law was formally implemented. There was also seen to have been an increase in mixed marriages.

Academic accomplishments of Muslim and their non-Muslim female counterparts in France were compared with the use of data extracted from the French Labour Force Survey which had been conducted between the years 2005 to 2019. Born between 1970 to 1974, Muslim women who completed school before the 1994 guideline on veils were 12 percent less likely to graduate from high school in comparison with their non-Muslim coevals.

Among women born between 1980 to1984 that gap in school completion was seen to shrink to 7 percent. For those who spent their education with some form of veil ban in place between 1990 to 1994 the gap in high school completion was seen to shrink once more to 6.5 percent. As well, the number of Muslim women marrying non-Muslim men increased from 13 to 22 percent, during that same period.