Mapping regulatory variants in human induced pluripotent stem cells (hiPSCs)

This study [see attached] illustrates the mind-boggling power of the “human induced pluripotent stem cell (hiPSC) platform.” Authors studied hiPSC-derived sensory neurons from 107 individuals. In addition to identifying thousands of quantitative trait loci (QTL; segments of DNA (the loci) that correlate with variation in a phenotype or quantitative trait) influencing gene expression, chromatin accessibility and RNA splicing –– the work highlights several under-appreciated challenges in the hiPSC field –– particularly those underlying the processes of neurodevelopment. Authors present the first map of regulatory variants in hiPSC-derived neurons, based on differentiating a large cohort of hiPSCs undergoing a sensory neuronal fate (i.e. pluripotent cells that can result in many differentiated types are directionally regulated to form sensory neurons).

Genetic studies have increasingly demonstrated that a combination of rare and common variants underlies many complex diseases. Identifying, and functionally validating, these small and frequently context-dependent (cell-type-specific and/or treatment-dependent) effects is necessary to help untangle how common risk factors interact among diverse cell-types of the human body. On these GEITP pages, we have previously described the Genotype-Tissue Expression (GTEx) Project, which aims to explore the functional roles of common variants by characterizing variation in gene-expression levels across individuals and tissues. The CommonMind Consortium (CMC) is applying similar methodologies –– focused on understanding how genetic variation in the human brain contributes to psychiatric disease. These studies must be accompanied by hiPSC-derived strategies that can generate additional cell-types and/or developmental time-points relevant to disease predisposition that are not readily available in post-mortem data-sets.

Additional advantages of hiPSCbased strategies are that they avoid issues associated with post-mortem RNA decay and lifetime-donor-environmental exposures. Of course, hiPSC-based models are only as valuable as their ability to retain donor-gene-expression signatures. Authors studied 123 differentiations of iPSCs proceeding into a sensory neuronal fate. Using single-cell RNA-sequencing, they found that the number of neuronal versus contaminating cells was influenced by iPSC culture conditions before differentiation. Despite high differentiation-induced variability, authors estimated that recall-by-genotype studies that use iPSC-derived cells –– will require cells from at least 20–80 individuals –– in order to distinguish effects of regulatory variants having moderately large-effect sizes.

Nat Genet Jan 2o18; 50: 54–61 & News’N’Views pp 1–2

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One gene (LRRK2) associated with two very different diseases, Crohn disease and Parkinson disease

Crohn disease (CD) and ulcerative colitis are distinguished by the distribution of chronic inflammatory changes. In ulcerative colitis, the inflammation is relatively superficial and is confined to the colon. CD most commonly affects the terminal ileum (last part of the small intestine) and colon and is frequently associated with deep inflammation that invades the intestinal wall, often resulting in obstruction and abscess formation requiring resectional surgery. Approved medical therapies for moderate to severe CD and ulcerative colitis and include monoclonal antibodies against the proinflammatory tumor necrosis factor (TNF) cytokine and, more recently, antibodies against a4b7 integrin, which blocks leukocyte-trafficking to the intestine. Monoclonal antibodies blocking the interleukin-23 pathway have also shown efficacy in inflammatory bowel diseases.

Authors [see attached] hypothesized that uncommon CD-susceptibility high-effect alleles (i.e. larger odds ratios; ORs), which had eluded analysis in common variant-predominant genome-wide association studies (GWAS), might play an important role in genetic predisposition to CD. They sought to identify the strongest functionally relevant associations and to characterize their biological implications. Given that a major epidemiological feature of inflammatory bowel diseases is its several-fold higher prevalence in Ashkenazi Jewish cohorts, compared to non-Jewish Europeans, authors performed whole-exome sequencing (WES( of Ashkenazi Jewish CD cases, followed by custom array–based genotyping in a large case-control cohort.

Authors identified independent coding CD risk and protective alleles in LRRK2, a large multifunctional gene (encoding leucine-rich repeat kinase-2) that confers the greatest genetic effects reported thus far in Parkinson disease (PD), a neurodegenerative movement disorder affecting the basal ganglia and characterized by resting tremor, bradykinesia, rigidity, and postural instability. Presence of shared alleles in CD and PD provides refined insight into disease mechanisms that may have major implications for the treatment of these two seemingly unrelated diseases. In human genetics, this is an example of PLEIOTROPY –– when one gene will encode, and control, the phenotype or expression of several different and unrelated traits (in this case, CD in the bowel and PD in the brain).

Sci Transl Med 10: eaai7795 (10 Jan 2018)

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Mutations in SELENBP1 encoding methanethiol oxidase, cause extra-oral halitosis

As these GEITP pages have often discussed, the TRAIT (phenotype) being studied in human genetics can be almost anything. And –– if we’re dealing not with a Mendelian trait involving one or a few genes, but rather with a multifactorial trait –– this phenotype will likely reflect contributions from: [a] genetics (variants in DNA sequence); [b] epigenetics (variations due to chromosomal differences other than DNA sequence); and [c] the environment (which can include diet, lifestyle and occupation). Effects that affect the developing embryo and fetus in utero –– can also be considered “the environment”. In the present article [attached], “the environment” includes our microbiome (bacteria that live in the gut and all other orifices of the body).

And the trait chosen to be studied by geneticists can be virtually everything, including HALITOSIS (bad breath). Volatile sulfur-containing compounds –– such as hydrogen sulfide (H2S), methanethiol (CH3-SH) and dimethylsulfide (DMS; CH3-S-CH3) –– have been identified as the key contributors to halitosis. The origin of halitosis can be intra- or extra-oral. Intra-oral halitosis, the most common form, is usually caused by methanethiol and H 2S produced by Gram-negative bacteria located on the tongue or in the gum (gingival) and periodontal crevices. On the other hand, extra-oral halitosis (bad smell outside the mouth) has an estimated prevalence of 0.5–3% in the general population, and its origin is not well understood. Extra-oral bad breath can be caused by conditions affecting the nose, sinuses, tonsils, and esophagus; in some cases, extra-oral halitosis is bloodborne. In bloodborne halitosis, malodorous compounds (most commonly DMS) are carried to the lungs, where they enter the breath. DMS concentrations in oral and nasal breath have been found to be 6-fold higher in people with extra-oral halitosis than in controls.

The cause of elevated DMS levels in these individuals is unknown. DMS is produced from methanethiol through methylation. Both DMS and methanethiol result from the microbiome and mammalian co-metabolism of volatile sulfur compounds. Under physiological conditions, methanethiol has three sources in the human body: [a] synthesis from sulfur-containing amino acids by intestinal bacteria; [b] synthesis in intestinal cells through methylation of H2S by thiol S-methyltransferase; and [c] synthesis from methionine through the trans-amination pathway in human endogenous metabolism. Interestingly, people with cancer produce methanethiol and DMS as prominent volatile organic compounds.

Selenium-binding protein-1 (SELENBP1) has inexplicably been associated with several cancers. Authors [see attached] show that SELENBP1 is a methanethiol oxidase (MTO), related to the MTO in methylotrophic bacteria, that converts methanethiol to hydrogen peroxide (H2O2), formaldehyde, and H2S (this enzymatic activity not previously known to exist in humans). Authors identified DNA variants in the SELENBP1 gene in five patients with “cabbage-like halitosis”. The malodor was attributable to high levels of methanethiol and dimethylsulfide in their breath. Elevated urinary excretion of dimethylsulfoxide was associated with MTO deficiency. Patient fibroblasts had low SELENBP1 protein levels and were deficient in MTO enzymatic activity; these effects were reversed by lentivirus-mediated expression of wild-type SELENBP1 in these fibroblasts. Selenbp1-knockout mice showed biochemical characteristics similar to those in humans. These data reveal a potentially frequent inborn error of metabolism that results from MTO deficiency and leads to a “malodor syndrome.”

Nat Genet Jan 2o18; 50: 120–129

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Coffee may come with a cancer warning in California; and a sobering reflection on Paracelsus

Here is yet another example in which Irrationality (disguised as ‘scientific studies’) supercedes Rationality –– leading to fear-mongering, anxiety, and inconvenience to the American consumer. As scientific instrumentation continues to become more precise, we can measure amounts of chemical contaminations at increasingly lower levels. Remember (from elementary chemistry class) that 1 mole of any chemical = 6.022 x 1023 molecules of any substance, and a 1 Molar solution = 6.022 x 1023 grams (divided by its molecular weight) in one Litre of water or other liquid.

So, technically, anything below Avogardo’s Number (6.022e–23, also written as 6.022 x 10–23) would mean less than one molecular of a chemical (such as, in the article below, acrylamide) per Litre. “Micromolar” denotes 10–6 moles/L.” “Picomolar” denotes 10–12 moles/L.” “Femtomolar” denotes 10–15 moles/L.” “Attomolar” denotes 10–18 moles/L.” Scientists can now detect attomolar concentrations of recreational drugs in creek or river samples. Given the new methodology of whole-genome analysis of single cells, we are now approaching attomolar concentrations and below. However, as Paracelsius (1493–1541) wrote, and it is never more true than today’s journalism’s hype and hysteria, “Alle Dinge sind Gift, und nichts ist ohne Gift; allein die dosis machts, daß ein Ding kein Gift sei.“ [Everything is poison, there is nothing that is not poison; the dose alone is what is important as to whether or not a substance is poison.]

In fact, the Bruce Ames lab (in the early 1970s) had already determied that the amount oof acrylamide in a piece of bread that had been toasted is able to be detected as mutations in a bacterial assay. So, here we are, 45+ years later, re-confirming in California, what Ames had already demonstrated (in California). What goes around, comes around. Journalists want to sell newspapers, but when this hype results in public regulations and policy that affect consumers and their pocketbooks –– this has gone from the ridiculous to the sublime. Yes, this is another example of the Linear-No-Threshold (LNT) Model that had been pushed through (way back in the 1940s by Mueller) in the absence of sufficient scientific fact to support such policy.

Coffee may come with a cancer warning in California
By Jen Christensen, CNN
Thurs February 1, 2018
· Roasting coffee beans creates acrylamide, a chemical linked to cancer in rodents
· A California judge will decide whether stores that sell coffee need to warn about the chemical

(CNN) California coffee shops may soon be forced to warn customers about a possible cancer risk linked to their morning jolt of java.

The state keeps a list of chemicals it considers possible causes of cancer, and one of them, acrylamide, is created when coffee beans are roasted.

A lawsuit first filed in Los Angeles County Superior Court in 2010 by the nonprofit Council for Education and Research on Toxics targets several companies that make or sell coffee, including Starbucks, 7-Eleven and BP. The suit alleges that the defendants “failed to provide clear and reasonable warning” that drinking coffee could expose people to acrylamide.

The court documents state that, under the California Safe Drinking Water and Toxic Enforcement Act of 1986, also known as Proposition 65, businesses must give customers a “clear and reasonable warning” about the presence of agents that affect health — and that these stores failed to do so.

Is coffee healthy?

In addition to paying fines, the lawsuit wants companies to post warnings about acrylamide with an explanation about the potential risks of drinking coffee. If the suit is successful, the signs would need to be clearly posted at store counters or on walls where someone could easily see them when making a purchase.

“I’m addicted to coffee, I confess, and I would like to be able to have mine without acrylamide,” Metzger said.

At a bench trial last fall, the coffee companies argued that the level of acrylamide in coffee should be considered safe under the law and that the health benefits of coffee essentially outweigh the risk.

At least 13 of the defendants have settled and agreed to give a warning, most recently 7-Eleven, according to Metzger. The convenience store chain did not respond to requests for comment.

The other manufacturers would have to follow suit if they don’t settle the lawsuit and if the judge finds that they violated state laws. Metzger said private mediation with the remaining retailers is set for February 8. It will include nine of the defendants, and the parties will try to come to an agreement about the case. Otherwise, a judge would probably reach a decision this year.

BP did not return requests for comment. Starbucks referred questions to the National Coffee Association, the industry’s trade association, which said it was not in a position to comment on the litigation.

Bill Murray, the association’s president and CEO, said in a statement, “Coffee has been shown, over and over again, to be a healthy beverage. The US Government’s own Dietary Guidelines state that coffee can be part of a healthy lifestyle. This lawsuit simply confuses consumers, and has the potential to make a mockery of Prop 65 cancer warning at a time when the public needs clear and accurate information about health.”
Health effects of coffee: Where do we stand?

Health effects of coffee: Where do we stand?

Coffee has been much studied over the years, and research has shown that it provides several health benefits, including lowering your risk of early death. It may reduce your risk of heart disease, multiple sclerosis, type 2 diabetes, Alzheimer’s and even some cancers like melanoma and prostate cancer. However, a review by the International Agency for Research on Cancer, a branch of the World Health Organization, found that drinking very hot beverages was “probably carcinogenic to humans” due to burns to the esophagus; there was no relation to the chemical acrylamide.

The science on human exposure to acrylamide still needs “future studies,” according to a 2014 review of scientific research on the chemical’s relationship to a wide variety of cancers in the Journal of Nutrition and Cancer.

In addition to coffee, acrylamide can be found in potatoes and baked goods like crackers, bread and cookies, breakfast cereal, canned black olives and prune juice, although its presence is not always labeled. It’s in some food packaging and is a component of tobacco smoke. According to the National Cancer Institute, people are exposed to “substantially more acrylamide from tobacco smoke than from food.”

In 2002, the International Agency for Research on Cancer classified acrylamide as a group 2A carcinogen for humans based on studies done in animals. Studies done on humans have found “no statistically significant association between dietary acrylamide intake and various cancers,” according to the 2014 research review.

8 of the world's best cities for coffee

A few additional studies have seen an increased risk for renal, ovarian and endometrial cancers; however, “the exposure assessment has been inadequate leading to potential misclassification or underestimation of exposure,” according to the 2014 research review.

Even the studies showing cancer links between acrylamide in rats and mice used doses “1,000 to 100,000 times higher than the usual amounts, on a weight basis, that humans are exposed to through dietary sources,” the research review said.

Humans are also thought to absorb acrylamide at different rates and to metabolize it differentlythan rodents, earlier research showed.The National Toxicology Program’s Report on Carcinogens considers acrylamide to be “reasonably anticipated to be a human carcinogen.”

The Food and Drug Administration website says it “is still in the information gathering stage” on the chemical, but the FDA gave consumers suggested ways to cut it out of their diet. The FDA also provided guidance to the industry intended to suggest a range of approaches companies could use to reduce acrylamide levels. The recommendations are only a guide and are “not required,” according to the website.

California added acrylamide to its carcinogen list in January 1990, and the state has successfully taken companies to court over it.

In 2008, the California attorney general settled lawsuitsagainst Heinz, Frito-Lay, Kettle Foods and Lance Inc. when the companies agreed to reduce the levels of acrylamide found in potato chips and French fries.

In 2007, fast-food restaurants in California posted acrylamide warnings about fries and paid court penalties and costs for not posting the warnings in prior years. “We have a huge cancer epidemic in this country, and about a third of cancers are linked to diet,” Metzger said. “To the extent that we can get carcinogens out of the food supply, logically, we can reduce the cancer burden in this country. That’s what this is all about.”

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Arno MOTULSKY (1923-2018)

This obituary (in The New York Times) is much more complete and accurate. Professor Arno Motulsky was one of my heroes in human/medical genetics, the other one being Victor McKusick. As the article below states, Arno was thinking about “interindividual genetic responses to drugs” and wrote about it (1957) –– even before the term “pharmacogenetics” was coined in 1959 by Friedrich Vogel.

Arno Motulsky, a Founder of Medical Genetics, Dies at 94


JANUARY 29, 2018
Dr. Arno G. Motulsky, a former refugee from Nazi Germany who became a founder of medical genetics, recognizing the connection between genes and health long before mainstream medicine did, died on Jan. 17 at his home in Seattle. He was 94.

His son, Harvey, confirmed the death.

Dr. Motulsky also founded pharmacogenetics, which studies inherited differences in the way people respond to medications.

“It was his vision to study how heredity could be involved in practically everything,” Dr. Francis Collins, a geneticist and the director of the National Institutes of Health, said in an interview. “The relationship between heredity and the response to drug therapy — nobody was thinking about that until he started it, 60 years ago. He anticipated it decades before science made it possible to get the answers that he dreamed of.”

As technologies emerged to decode DNA, the fields that Dr. Motulsky helped originate came to the forefront of medicine, leading to improved diagnosis and treatments for a host of diseases. Research in medical genetics has led to cancer drugs that target specific genetic mutations in tumor cells, as well as statins, which are widely prescribed to prevent heart attacks and strokes by lowering blood cholesterol.

Dr. Motulsky’s path to prominence began in harrowing fashion. He had been one of more than 900 Jewish refugees aboard the German liner St. Louis, which reached the Miami coast in 1939 but was turned away by the United States and sent back to Europe. He then spent a year in internment camps in France, where many prisoners died from starvation or typhoid, before finally reaching the United States in 1941. Drafted, he was put through medical school by the Army.

Dr. Motulsky in an undated photograph. “The relationship between heredity and the response to drug therapy — nobody was thinking about that until he started, 60 years ago,” a colleague said.

In 1957, at the University of Washington’s medical school in Seattle, Dr. Motulsky started one of the first divisions of medical genetics in the United States. “There were very few medical centers that considered genetics as being all that relevant to human medicine,” Dr. Collins said. “Genetics was more a study of fruit flies and mice, not humans.”

Dr. Mary Claire King, geneticist at the University of Washington who discovered the role of certain genetic mutations in breast cancer, said that because of Dr. Motulsky’s work in medical genetics, “the field is now integrated into every other field of medical practice, and has become the soul of precision medicine.”

Dr. Motulsky’s research encompassed genetic contributions to a broad array of conditions, including heart disease, blood disorders, colorblindness, infections and immunity, hypertension and alcoholism. He studied genetic disorders linked to certain population groups, like Ashkenazi Jews, and considered the ethical issues raised by genetic testing and gene therapy.

He was also highly esteemed as a mentor, becoming the subject of a chapter in a 2009 book on mentoring in higher education.

One who studied with him was Joseph L. Goldstein. It was during a fellowship with Dr. Motulsky, beginning in 1968, that Dr. Goldstein laid the foundation for research on how the body processes cholesterol. The findings led to a Nobel Prize in Physiology or Medicine in 1985, which Dr. Goldstein shared with Michael S. Brown. Their work led to the development of cholesterol-lowering statin drugs.

“Arno was sort of a maestro of human genetics,” Dr. Goldstein, now chairman of the department of molecular genetics at the University of Texas Southwestern Medical Center in Dallas, said in an interview. He added in an email, “He gave me the confidence to design a large study on lipid levels in survivors of heart attacks and gave me support and resources — at a time when I was only 28 years old.”

Arno Gunther Motulsky was born on July 5, 1923, in Fischhausen, Germany, on the Baltic Sea, to Herman Motulsky, a shopkeeper, and the former Rena Sass. His parents tried to leave Germany with him and his younger siblings, Leah and Lothar, in 1939, before war broke out in Europe.

In an account he gave to the Annual Review of Genomics and Human Genetics in 2016, Dr. Motulsky said his family had hoped to join his father’s brother in Chicago, but headed for Cuba instead, after hearing that a United States quota system was causing long delays in granting visas.

His father left first. His mother followed soon afterward, taking young Arno and his brother and sister with her, aboard the St. Louis in Hamburg on May 13, 1939, bound for Havana. But Cuba refused to accept the refugees, as did other Caribbean countries.

“We asked to land in America, but were denied,” Dr. Motulsky said. “When we sailed close to Miami, U.S. Coast Guard cutters and planes shooed us off.”

The German liner St. Louis being denied entrance to Havana, Cuba, in June 1939. Dr. Motulsky was aboard the ship with his mother and siblings when it was sent back to Europe. Voyage of the Damned [available on Netflix] is a 1976 drama film, which was based on a 1974 book written by Gordon Thomas and Max Morgan-Witts with the same title. The story was inspired by true events concerning the fate of the MS St. Louis ocean liner carrying Jewish refugees from Germany to Cuba and Miami in 1939.

Its passengers filled with dread, the ship headed back to Europe on June 6. “Miraculously, a few days before we would have arrived back in Germany, four other countries — England, France, Holland and Belgium — each agreed to take one-fourth of the passengers,” Dr. Motulsky said.

His family was assigned to Belgium, and he began high school there in June 1939. On May 10, 1940, the Germans invaded. The family had just received United States visas, but it was too late to get away. “Since I was now 17, I was arrested by the Belgians as an enemy alien — ironically, as a German — and sent to an internment camp in France,” Dr. Motulsky said. Belgium surrendered a few weeks later.

No longer considered a child, Dr. Motulsky was separated from his mother and siblings, grouped with men and moved from one camp to another, each lacking food and sanitation and rife with disease. The last camp was controlled by Nazi collaborators, the Vichy French, who sent ethnic Germans back home but kept Jews imprisoned.

Finally, in June 1941 — 10 days before his 18th birthday — Dr. Motulsky, carrying an American visa, left France and traveled through Spain to Portugal, where he boarded a ship to the United States. “Ten days later and I wouldn’t have made it, because Franco did not allow males 18 or older to pass through Spain,” he said, referring to the Spanish dictator. “A few months later, the Vichy French turned over all their internment camps to the Gestapo.”

He joined his father in Chicago in 1941. Two years passed before they learned that his mother, brother and sister had also survived, in Switzerland. The family was not reunited until 1946. Only Dr. Motulsky kept the original family surname; his parents and siblings changed it to Molton. “They were told that they couldn’t possibly succeed in the U.S. with a name like Motulsky,” Harvey Motulsky said.

Though he had not finished high school in Europe, Dr. Motulsky had managed to study even while he interned, which helped him pass high school equivalency tests in Chicago 1942. He worked days and began taking college courses at night and on Saturdays at Central Y.M.C.A. College.

By 1943, he had been accepted to medical school at the University of Illinois at Chicago. But then he was drafted. The Army needed doctors and sent him to Yale to finish his premedical courses. There, he took a genetics course and, he said, was “hooked forever.”

He returned to the University of Illinois for medical school, entering as a private first class. In 1945 he married Gretel Stern, an accountant, who had left Germany in 1938 and whom he had met at the Y.M.C.A. College. He graduated in 1947 and took further training in internal medicine and hematology.

In 1951, during the Korean War, Dr. Motulsky was called back into the Army and assigned to Walter Reed Army Medical Center in Washington, where he studied inherited blood disorders.

Discharged in 1953, he became an instructor at the University of Washington’s new medical school, in Seattle, assigned to teach internal medicine and hematology. That same year, James Watson and Francis Crick determined the structure of DNA. Dr. Motulsky began to slip what he called “bootleg medical genetics” into his lectures. Interest grew, and by 1957 he was leading the new division in medical genetics.

Dr. Motulsky was an author of more than 400 scientific articles and, with Friedrich Vogel, of a leading textbook, “Human Genetics: Problems and Approaches” (1979). His many scientific honors included induction into the National Institute of Medicine, the National Academy of Sciences, and the American Philosophical Society.

In addition to his son, Dr. Motulsky is survived by his daughters, Judy Walker and Arlene Audergon; a sister, Leah Kadden; six grandchildren; and two great-grandchildren. His wife died in 2009. When Dr. Motulsky talked about the St. Louis and the aftermath of its ill-fated voyage, he “often spoke about luck, the sheer luck to be alive, when you think of the events of the Holocaust,” Ms. Audergon wrote in an email.

“He’d speak so passionately about how these events had shaped him, made him the man that he is,” she added. “And he was passionate about trying to contribute something with his life, to make a difference.”

A version of this article appears in print on January 30, 2018, on Page B12 of the New York edition with the headline:

“Arno Motulsky, a Founder of Medical Genetics 60 Years Ago, Dies at 94”

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kids aged 4-6 perform better during boring tasks when dressed as Batman

Okay, okay. Some of you are going to question this topic. Let’s just say it has been a very slow ~2 weeks in trying to find “cutting-edge/fascinating” articles pertaining to Gene-Environment Interactions. But –– with some stretch of the imagination –– one could see that “the genome” (chromosomes of these kids) is interacting with “the environment” (these kids being forced to perform boring tasks). 😉

This article was contributed (anonymously) by one of the GEITP-ers. If you wonder who in the world would FUND this kind of research –– that information is given below this article.

New research finds that kids aged 4-6 perform better during boring tasks when dressed as Batman
his article is published in collaboration withQuartz

04 Dec 2017

1. Jenny Anderson, Journalist, Quartz – Atlantic Media

Perseverance, or the ability to stick with something, is critical to success in life, from academics and sports to music and getting around to that presentation for tomorrow’s meeting. But life is increasingly distracting, especially for kids, with the allure of technology and the ability to access just about any form of entertainment on demand.

So what gives a child the right grit? Six researchers, building on past studies, designed an experiment to see what makes kids stay on task when presented with the very real-world temptation of an iPad.

Rachel E. White, from Hamilton College, and Emily Prager and Catherine Schaefer from the University of Minnesota, tested four and six-years-olds by giving them a boring computer task and asking them to do it for 10 minutes. They also offered the kids an out: If they got bored, they could play a game on the iPad, located nearby in the testing room.

Could kids actually resist the temptation?

There was a twist. The 180 kids were assigned to one of three conditions: a control group, which asked the children to think about their thoughts and feelings as they went through the task and ask themselves “Am I working hard?” The second group was asked to think of themselves in the third-person, for example (if the kid’s name is Hannah), “Is Hannah working hard?”

In the third condition, the kids were asked to think about someone else who is really good at working hard. They could pick from some well-known superhero types: Batman, Bob the Builder, Rapunzel, and Dora the Explorah. The kids got to dress up as the character they picked and then were asked, “Is Batman working hard?”

For 10 minutes the kids could move between the “work” and iPad. They were reminded every minute, through a loud speaker, of their “condition” (“Is Dora working hard?”). All the kids were told, “This is a very important activity and it would be helpful if you worked hard on this for as long as you could.” Perseverance was measured as time spent on the ‘work’ task.

Not surprisingly to anyone who has kids, and iPads, the kids spent 37% of their time on the ‘work’ task, and 63% on the iPad.

But those kids pretending to be superheroes ‘worked’ more than those who thought of themselves in the third person, and both of those groups did better than the kids who just thought of themselves as ‘me’.

In other words, the more the child could distance him or herself from the temptation, the better the focus. “Children who were asked to reflect on the task as if they were another person were less likely to indulge in immediate gratification and more likely to work toward a relatively long-term goal,” the authors wrote in the study called “The “Batman Effect”: Improving Perseverance in Young Children,” published in Child Development.

This is not a new finding. In the 1960s, Walter Mischel’s did his famous marshmallow test at the Bing nursery school at Stanford which cleverly put kids roughly 3.5 to 5 years old in a room with a treat (marshmallows were one) and told them they could eat it, or wait, and get two. Those kids who were able to delay their gratification, or who exhibited high levels of self control fared far better in life; they did better academically, earned more money, and turned out to be healthier and happier. They were less likely than those who could not resist to be obese, do drugs or go to jail.

The key to superior executive function, or self-control, Mischel and Patterson concluded, was the ability to reframe the object of temptation into something more abstract. One boy told Mishel he imagined the marshmallow was a picture and not a treat, according to this New Yorker profile. “You can’t eat a picture.” The secret to reframing is learning how to mentally “cool” the “hot” aspects of an environment which tempt you. Maria Konnikova, explains it this way in the New Yorker:

“Cooling can be accomplished by putting the object at an imaginary distance (a photograph isn’t a treat), or by re-framing it (picturing marshmallows as clouds not candy). Focussing on a completely unrelated experience can also work, as can any technique that successfully switches your attention.”

—Maria Konnikova

Donning a cape and mask, the kids from the recent study were better at what psychologists call ‘self-distancing’. One reason the kids engaged in imaginary play had better focus might be that pretending to be another person allowed the greatest separation from the temptation. A second potential explanation is that the kids in costume identified with the powerful character traits of the superhero and wanted to imitate them. Whatever the cause, the superheroes showed more grit.

The study also showed something that parents know, but often forget: Kids change dramatically in a short period of time. Six-year-olds spent about half their time on the task compared to four-year-olds who spent about a quarter of their time on it. This is not surprising –– considering how kids develop from preschool to school-aged. Like most skills, executive function is one that develops as kids grow, though sometimes not fast enough for parents. More time spent as superheroes might help.
This research was funded by the John F. Templeton Foundation [21564] to Angela L. Duckworth, Ethan Kross, and Stephanie M. Carlson, by the National Institutes of Health under Ruth L. Kirschstein National Research Service Award [5T32HD007151] from the NICHD to Rachel E. White and Emily O. Prager, and by an NSF Graduate Research Fellowship [00039202] to Emily O. Prager.

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Target gene activation via CRISPR/Cas9-mediated trans-epigenetic modulation in the intact animal

In these GEITP pages, we have often discussed that any phenotype (trait) can be Mendelian or multifactorial. Mendelian inheritance involves the contribution from one or a relatively small number of genes –– and manifestations can occur at birth or later in life. Multifactorial traits include contributions from genetics (differences in DNA sequence), plus epigenetics (differences in the chromosome other than DNA variants), plus environmental effects (adverse insults that can alter either DNA sequence or epigenetic factors), plus even transgenerational effects (still poorly understood, a stimulus in the grandparent that affects the parent and can even affect the grandchild). Epigenetics classically has included DNA-methylation, RNA-interference, histone modifications, and chromatin remodeling.

The topic of the attached publication represents epigenetic effects, which can cause certain disorders also has been used as therapy to treat certain complex diseases –– such as cancer, type-2 diabetes, autoimmunity, and some Mendelian disorders. Most of these approaches have relied on drugs that ubiquitously alter epigenetic marks (e.g. DNA-methylation or histone modifications). These “epi-drugs” cause many side-effects, because ”off-target genes” can also be affected. Therefore, it is important to establish new methods for generating targeted epigenetic modifications that alter only the expression of specific genes.

Also discussed on these pages numerous times, CRISPR/Cas9 methodology has led to the development of tools for rapid and efficient RNA-based, sequence-specific genome editing. In addition to enabling the engineering of genomes, recent alterations to the CRISPR/Cas9 system have provided opportunities for regulating gene expression and for creating epigenetic alterations –– without introducing DNA double-strand breaks (this circumvents concerns of creating undesirable permanent mutations in target genomes).

Authors [see attached] describe a robust system for in vivo activation of endogenous target genes through trans-epigenetic remodeling. The system relies on recruitment of Cas9 and transcriptional activation complexes to target loci by modified single-guide RNAs. As proof-of-principle, authors used this technology to treat mouse models of type-2 diabetes, muscular dystrophy, and acute kidney disease. Their data show that CRISPR/Cas9-mediated target gene activation can be achieved in the intact animal, leading to quantifiable phenotypes and amelioration of disease symptoms. This breakthrough should establish new avenues for developing targeted epigenetic therapies against human diseases.

Cell 14 Dec 2017; 171, 1495–1507

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The very mysterious ailment, chronic fatigue syndrome, is more common than one might think

Chronic fatigue syndrome (CFS) — also known as myalgic encephalomyelitis or ME/CFS –– is a somewhat vague disorder that causes extreme fatigue and is more common than many people might think. The fatigue is not the kind of tired feeling that goes away after you rest; rather, the tiredness can last many months or years, limiting one’s ability to do ordinary daily activities. The main symptom of CFS can sometimes include: [a] feeling unwell for more than 24 hours after physical activity; [b] chronic muscle pain; [c] memory problems; [d] frequent headaches; [e] pain in multiple joints; [f] sleep problems; [g] sore throat; and [h] tender lymph nodes.

There are no tests for diagnosing or confirming ME/CFS, and other illnesses can mimic these symptoms. Therefore, physicians must first rule out other diseases before making a diagnosis of ME/CFS. No one knows what causes CFS; the etiology remains unknown. It is most common in women in their 40s and 50s, but it is possible to happen to anyone in any age group. Consequently, there is no unequivocal cure for ME/CFS –– thus, the goal of treatment has been simply to improve symptoms. It also comes as no surprise that many regard ME/CFS as a psychological or hysterical mindset in the afflicted patient. From 1994 until 2oo6 we published a Center for Environmental Genetics (CEG) NewsLetter, Interface (written in semi-lay language) that had a circulation of several hundred recipients. One of the most popular segments of Interface was called “Question & Answer” in which Readers were invited to inquire about anything involving health and the environment; the overwhelming topic (80-90% of questions) being asked about involved ME/CFS and related symptoms.

The attached article summarizes the latest news in the ME/CFS field. Patients having CFS have finally caught the attention of mainstream science, and dozens of exploratory studies are now under way. Scientists entering the field are beginning to use the powerful tools of modern molecular biology to search for any genes, proteins, cells and/or possible infectious agents involved. The goal of course is to develop a laboratory test to diagnose ME/CFS, and they want to identify molecular pathways to target with drugs. The US National Institutes of Health (NIH) in Bethesda, Maryland, bolstered the field last year by more than doubling spending for research into this condition. Included in this effort are funds for four ME/CFS research hubs in the United States that between them will receive $36 million over the next 5 years.

Nature 4 Jan 2o18; 553: 14–17
At the bottom of this email is my Jan 16th article shared among all of GEITP. Below is a response –– by a practicing physician who commonly sees these types of problems in the clinic, and who wishes to remain anonymous. The first five attached articles pertain to this response; the last article is the one originally shared by all of GEITP.

Sent: Tuesday, January 16, 2018 11:03 AM

Syndromic medicine is a real challenge. This two-sided problem in the clinic is currently manifested by: [a] an overabundance of “syndromes”, and [b] an equally overabundant number of practitioners quite happy to proceed with any form of intervention (usually invasive, and involving polypharmacy and multiple but unproven diagnostics). In the case of ME/CFS, the situation is obtunded by a very simple yet often overlooked fact: there is no true positive to address this as a scientifically valid or testable condition. It should be emphasized that no pathophysiology is known and no diagnostic tests exist.

This is not to say or imply that there is nothing wrong with these people; to the contrary, there clearly is some factor affecting them. However, referring to this in syndromic terms remains problematic and condescending. Commonly encountered overlapping conditions include fibromyalgia, complex regional pain syndrome (CRPS), cervical (or low back or shoulder, etc) syndrome, restless legs syndrome, etc. The list is endless.

It must be recalled that the term “syndrome” refers to a “collection of subjective complaints often seen together” (Stedman’s Medical dictionary). In practice, this definition is usually ignored, and all established scientific or medical boundaries are evanescent. These terms assume a clinical meaning roughly resembling the shape of water. From a practical perspective –– the term CE/CFS, when it appears in the literature, is so loosely defined as to have no meaning.

Sadly, the end result is that the poor patient is saddled with a syndromic assessment that is meaningless to anyone other than its author (who is the “treating doctor” trained in whatever background. Our medical profession is now seriously diluted by “para-professionals” who use such terms with no knowledge or understanding of the science which may, or may not, support those terms as meaningful.

The first of the above attached Articles (#1) describes N=41 patients and focuses on these unfortunate cornerstones of ignorance. Article #2 examines N=100 randomly-selected patients and finds no cause-and-effect between serum vitamin D levels and autoimmune disease or chronic syndromes. Article #3 describes a randomized double-blind study (N=50), concluding that high-dose oral vitamin D3 did not improve markers of vascular health or fatigue in patients having ME/CFS. Article #4 represents a literature search, finding 56 articles that met authors’ criteria; yet, their conclusions (that “classification of patients according to severity and symptom patterns, aiming to predict prognosis or effectiveness of therapy, seems useful”) seems as vague as the ME/CFS disorder itself. Finally (Article #5), summarizes N=92 patients and N=94 matched controls, concluding that low serum vitamin D status did not appear to be a contributing factor to the level of fatigue in ME/CFS patients.

There exist many other studies in the medical literature. Many studies describe patients having subjective complaints of fatigue, others sound vaguely like some patients such from a severe psychiatric disturbance. No clinical data are provided to permit any form of scientific assessment. All physicians must learn to adhere to our Hippocratic Oath, “Primum non nocere” (“First, do no harm”). However, like Sherlock Holmes, we must investigate the patient and provide appropriate intervention, while we continue to question and logically pursue the cause of the problem.

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Evidence of convergent evolution of the central nervous system (CNS)

The nervous systems of animals come in many shapes and sizes, ranging from a handful of neurons to large, complex brains. A basic evolutionary question has been whether the centralized nervous systems –– found in many bilaterally symmetrical animals (bilaterians, i.e. having a left and right ‘side’), which include vertebrates (animals having a spine) and insects –– share a common evolutionary origin, or have evolved more than once. In terms of “evolution of the eye”, (i.e. any living thing’s perception of light vs darkness vs motion, which obviously has a survival advantage for finding food and avoiding prey), there is evidence that such a structure has spontaneously independently evolved at least 64 times..!!

At a superficial level, both flies and vertebrates boast a brain connected to a single nerve cord that extends into the trunk. In addition, molecular biology data indicate that key regulatory genes are deployed simi­larly during nervous-system development in vertebrates, flies, and another bilaterian, a seg­mented worm (an annelid). These similarities have been interpreted as evidence for evolu­tionary conservation of an ancient bilaterian developmental program for centralized nerv­ous systems. However, in the [attached] paper, authors provide evi­dence for the independent evolution of such nervous systems. In the mid-1980s, the ability to study this process received a boost, thanks to the discovery of a large family of genes that encode transcription factors con­taining a DNA-binding homeobox domain. Members of this homeobox-gene family, including the Hox complex, are expressed in the same order along the head-to-tail (anterior–posterior) axis during devel­opment in many distantly-related bilaterians, including flies and vertebrates. It was also shown that another signaling pathway –– genes that encode bone morphogenetic pro­teins (BMPs) is needed to establish the dor­sal–ventral (back-to-belly) body axis in amazingly diverse bilaterians.

It was therefore not surprising to find that a suite of homeobox genes is also expressed in strikingly similar patterns along the dorsal–ventral axis of the developing nervous systems of vertebrates and fruit flies. Along this axis, staggered homeobox-gene expression correlates with development of specific neuron types in different regions. The discovery that these genes are also expressed along the dorsal–ventral nervous-system axis in Platynereis dumerilii (an annelid distantly related to flies and vertebrates) was seen as evidence that bilaterian nerve cords are evolutionarily conserved.

Authors [attached article] studied representatives of Xenacoelomorpha, Rotifera, Nemertea, Brachiopoda, and Annelida (each one of these six represents a different Phylum in the Animal Kindgom) to assess the evolutionary conservation of the dorsoventral nerve cord patterning. None of the studied species shows a conserved dorsoventral molecular regionalization of their nerve cords –– not even the annelid Owenia fusiformis, whose trunk neuroanatomy parallels that of vertebrates and flies. These (pretty cool) data limit the use of molecular patterns to explain nervous system evolution, and suggest that similarities in dorsoventral patterning and trunk neuroanatomies evolved independently in these Bilateria.

Nature 4 Jan 2o18; 553: 45-50 & pp 34-36 [News-N-Views]

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FW: High-throughput annotation of full-length long noncoding RNAs (lncRNAs) — success using RNA Capture Long Seq (CLS)

Long noncoding RNAs (lncRNAs), formerly called “long intergenic noncoding RNAs” (lincRNAs), represent a vast and relatively unexplored component of the mammalian genome. They are defined as “>200 nucleotides, and up to many thousands of nucleotides, that are transcribed into RNA but not translated in a protein product.” LncRNAs have been implicated in associations with certain human complex diseases (e.g. schizophrenia, autism spectrum disorder, and cancers) and therefore are relevant to “gene-environment interactions” because LncRNAs are yet-another form of GENOTYPE that influences/affects the PHENOTYPE (multifactorial trait).

Assignment of lncRNA functions depends on the availability of high-quality transcriptome (mRNAs, coding RNA, transcribed from DNA) annotations. At present, such annotations are still rudimentary: we have little idea of the total number of lncRNAs, and for those that have been identified, transcript structures remain largely incomplete. Projects –– using diverse approaches –– have helped to increase both the number and size of available lncRNA annotations. Early gene sets, derived from a mixture of FANTOM cDNA sequencing efforts and public databases, were combined with lncRNA sets discovered through chromatin signatures. More recently, researchers have applied transcript-reconstruction software, but annotation efforts continue to face a necessary compromise between throughput and quality. Hence, there is growing divergence between large automated annotations of uncertain quality (e.g. 101,700 genes for NONCODE versus 15,767 genes for GENCODE version 25).

Annotation incompleteness takes two forms. First, genes may be entirely missing from an annotation; many genomic regions are suspected to transcribe RNA but contain no annotation, including ‘orphan’ small RNAs with presumed long precursors, enhancers, and ultra-conserved elements. Second, annotated lncRNAs may represent partial gene structures. Start- and end-sites frequently lack independent supporting evidence, and lncRNAs are shorter and have fewer exons than mRNAs. To accelerate lncRNA annotation, the GENCODE consortium has developed RNA Capture Long Seq (CLS), which combines targeted RNA-capture with third-generation long-read sequencing. Authors [attached article] present an experimental reannotation of the GENCODE intergenic lncRNA populations in matched human and mouse tissues –– that resulted in novel transcript models for 3,574 and 561 gene loci, respectively.

CLS approximately doubled the annotated complexity of the targeted loci, outperforming existing short-read techniques. Full-length transcript models produced by CLS enabled these authors definitively to characterize the genomic features of lncRNAs –– including promoter and gene structure, and protein-coding potential. Therefore, CLS can remove a long-standing bottleneck in transcriptome annotation, by generating manual-quality full-length transcript models at high-throughput scales.

Nat Genet Dec 2o17; 49: 1731–1740

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