Archive for the ‘epigenetics’ Category

meditation

With evidence growing that meditation can have beneficial health effects, scientists have sought to understand how these practices physically affect the body.

A new study by researchers in Wisconsin, Spain, and France reports the first evidence of specific molecular changes in the body following a period of mindfulness meditation.

The study investigated the effects of a day of intensive mindfulness practice in a group of experienced meditators, compared to a group of untrained control subjects who engaged in quiet non-meditative activities. After eight hours of mindfulness practice, the meditators showed a range of genetic and molecular differences, including altered levels of gene-regulating machinery and reduced levels of pro-inflammatory genes, which in turn correlated with faster physical recovery from a stressful situation.

“To the best of our knowledge, this is the first paper that shows rapid alterations in gene expression within subjects associated with mindfulness meditation practice,” says study author Richard J. Davidson, founder of the Center for Investigating Healthy Minds and the William James and Vilas Professor of Psychology and Psychiatry at the University of Wisconsin-Madison.

“Most interestingly, the changes were observed in genes that are the current targets of anti-inflammatory and analgesic drugs,” says Perla Kaliman, first author of the article and a researcher at the Institute of Biomedical Research of Barcelona, Spain (IIBB-CSIC-IDIBAPS), where the molecular analyses were conducted.

The study was published in the journal Psychoneuroendocrinology.

Mindfulness-based trainings have shown beneficial effects on inflammatory disorders in prior clinical studies and are endorsed by the American Heart Association as a preventative intervention. The new results provide a possible biological mechanism for therapeutic effects.

The results show a down-regulation of genes that have been implicated in inflammation. The affected genes include the pro-inflammatory genes RIPK2 and COX2 as well as several histone deacetylase (HDAC) genes, which regulate the activity of other genes epigenetically by removing a type of chemical tag. What’s more, the extent to which some of those genes were downregulated was associated with faster cortisol recovery to a social stress test involving an impromptu speech and tasks requiring mental calculations performed in front of an audience and video camera.

Perhaps surprisingly, the researchers say, there was no difference in the tested genes between the two groups of people at the start of the study. The observed effects were seen only in the meditators following mindfulness practice. In addition, several other DNA-modifying genes showed no differences between groups, suggesting that the mindfulness practice specifically affected certain regulatory pathways.

However, it is important to note that the study was not designed to distinguish any effects of long-term meditation training from those of a single day of practice. Instead, the key result is that meditators experienced genetic changes following mindfulness practice that were not seen in the non-meditating group after other quiet activities — an outcome providing proof of principle that mindfulness practice can lead to epigenetic alterations of the genome.

Previous studies in rodents and in people have shown dynamic epigenetic responses to physical stimuli such as stress, diet, or exercise within just a few hours.

“Our genes are quite dynamic in their expression and these results suggest that the calmness of our mind can actually have a potential influence on their expression,” Davidson says.

“The regulation of HDACs and inflammatory pathways may represent some of the mechanisms underlying the therapeutic potential of mindfulness-based interventions,” Kaliman says. “Our findings set the foundation for future studies to further assess meditation strategies for the treatment of chronic inflammatory conditions.”

Study funding came from National Center for Complementary and Alternative Medicine (grant number P01-AT004952) and grants from the Fetzer Institute, the John Templeton Foundation, and an anonymous donor to Davidson. The study was conducted at the Center for Investigating Healthy Minds at the UW-Madison Waisman Center.

http://www.news.wisc.edu/22370

Thanks to Dr. D for bringing this to the attention of the It’s Interesting community.

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sanger

By DENISE GELLENE

Frederick Sanger, a British biochemist whose discoveries about the chemistry of life led to the decoding of the human genome and to the development of new drugs like human growth hormone and earned him two Nobel Prizes, a distinction held by only three other scientists, died on Tuesday in Cambridge, England. He was 95.

His death was confirmed by Adrian Penrose, communications manager at the Medical Research Council in Cambridge. Dr. Sanger, who died at Addenbrooke’s Hospital in Cambridge, had lived in a nearby village called Swaffham Bulbeck.

Dr. Sanger won his first Nobel Prize, in chemistry, in 1958 for showing how amino acids link together to form insulin, a discovery that gave scientists the tools to analyze any protein in the body.

In 1980 he received his second Nobel, also in chemistry, for inventing a method of “reading” the molecular letters that make up the genetic code. This discovery was crucial to the development of biotechnology drugs and provided the basic tool kit for decoding the entire human genome two decades later.

Dr. Sanger spent his entire career working in a laboratory, which is unusual for someone of his stature. Long after receiving his first Nobel, he continued to perform many experiments himself instead of assigning them to a junior researcher, as is typical in modern science labs. But Dr. Sanger said he was not particularly adept at coming up with experiments for others to do, and had little aptitude for administration or teaching.

“I was in a position to do more or less what I liked, and that was doing research,” he said.

Frederick Sanger was born on Aug. 3, 1918, in Rendcomb, England, where his father was a physician. He expected to follow his father into medicine, but after studying biochemistry at Cambridge University, he decided to become a scientist. His father, he said in a 1988 interview, “led a scrappy sort of life” in which he was “always going from one patient to another.”

“I felt I would be much more interested in and much better at something where I could really work on a problem,” he said.

He received his bachelor’s degree in 1939. Raised as a Quaker, he was a conscientious objector during World War II and remained at Cambridge to work on his doctorate, which he received in 1943.

However, later in life, lacking hard evidence to support his religious beliefs, he became an agnostic.

“In science, you have to be so careful about truth,” he said. “You are studying truth and have to prove everything. I found that it was difficult to believe all the things associated with religion.”

Dr. Sanger stayed on at Cambridge and soon became immersed in the study of proteins. When he started his work, scientists knew that proteins were chains of amino acids, fitted together like a child’s colorful snap-bead toy. But there are 22 different amino acids, and scientists had no way of determining the sequence of these amino acid “beads” along the chains.
In 1962, Dr. Sanger moved to the British Medical Research Council Laboratory of Molecular Biology, where he was surrounded by scientists studying deoxyribonucleic acid, or DNA, the master chemical of heredity.

Scientists knew that DNA, like proteins, had a chainlike structure. The challenge was to determine the order of adenine, thymine, guanine and cytosine — the chemical bases from which DNA is made. These bases, which are represented by the letters A, T, G and C, spell out the genetic code for all living things.

Dr. Sanger decided to study insulin, a protein that was readily available in a purified form since it is used to treat diabetes. His choice of insulin turned out to be a lucky one — with 51 amino acids, insulin has a relatively simple structure. Nonetheless, it took him 10 years to unlock its chemical sequence.

His approach, which he called the “jigsaw puzzle method,” involved breaking insulin into manageable chunks for analysis and then using his knowledge of chemical bonds to fit the pieces back together. Using this technique, scientists went on to determine the sequences of other proteins. Dr. Sanger received the Nobel just four years after he published his results in 1954.

Dr. Sanger quickly discovered that his jigsaw method was too cumbersome for large pieces of DNA, which contain many thousands of letters. “For a while I didn’t see any hope of doing it, though I knew it was an important problem,” he said.

But he persisted, developing a more efficient approach that allowed stretches of 500 to 800 letters to be read at a time. His technique, known as the Sanger method, increased by a thousand times the rate at which scientists could sequence DNA.

In 1977, Dr. Sanger decoded the complete genome of a virus that had more than 5,000 letters. It was the first time the DNA of an entire organism had been sequenced. He went on to decode the 16,000 letters of mitochondria, the energy factories in cells.

Because the Sanger method lends itself to computer automation, it has allowed scientists to unravel ever more complicated genomes — including, in 2003, the three billion letters of the human genetic code, giving scientists greater ability to distinguish between normal and abnormal genes.

In addition, Dr. Sanger’s discoveries were critical to the development of biotechnology drugs, like human growth hormone and clotting factors for hemophilia, which are produced by tiny, genetically modified organisms.

Dr. Sanger shared the 1980 chemistry Nobel with two other scientists: Paul Berg, who determined how to transfer genetic material from one organism to another, and Walter Gilbert, who, independently of Dr. Sanger, also developed a technique to sequence DNA. Because of its relative simplicity, the Sanger method became the dominant approach.

Other scientists who have received two Nobels are John Bardeen for physics (1956 and 1972), Marie Curie for physics (1903) and chemistry (1911), and Linus Pauling for chemistry (1954) and peace (1962).

Dr. Sanger received the Albert Lasker Basic Medical Research Award, often a forerunner to the Nobel, in 1979 for his work on DNA. He retired from the British Medical Research Council in 1983.

Survivors include two sons, Robin and Peter, and a daughter, Sally.

In a 2001 interview, Dr. Sanger spoke about the challenge of winning two Nobel Prizes.

“It’s much more difficult to get the first prize than to get the second one,” he said, “because if you’ve already got a prize, then you can get facilities for work and you can get collaborators, and everything is much easier.”

http://www.nytimes.com/2013/11/21/us/frederick-sanger-two-time-nobel-winning-scientist-dies-at-95.html?pagewanted=2&_r=1&hp

File photo of Watson receiving data encompassing his personal genome sequence in Houston

James Watson, co-discoverer of the double helix structure of DNA, lit into targets large and small. On government officials who oversee cancer research, he wrote in a paper published on Tuesday in the journal Open Biology, “We now have no general of influence, much less power … leading our country’s War on Cancer.”

On the $100 million U.S. project to determine the DNA changes that drive nine forms of cancer: It is “not likely to produce the truly breakthrough drugs that we now so desperately need,” Watson argued. On the idea that antioxidants such as those in colorful berries fight cancer: “The time has come to seriously ask whether antioxidant use much more likely causes than prevents cancer.”

That Watson’s impassioned plea came on the heels of the annual cancer report was coincidental. He worked on the paper for months, and it represents the culmination of decades of thinking about the subject. Watson, 84, taught a course on cancer at Harvard University in 1959, three years before he shared the Nobel Prize in medicine for his role in discovering the double helix, which opened the door to understanding the role of genetics in disease.

Other cancer luminaries gave Watson’s paper mixed reviews.

“There are a lot of interesting ideas in it, some of them sustainable by existing evidence, others that simply conflict with well-documented findings,” said one eminent cancer biologist who asked not to be identified so as not to offend Watson. “As is often the case, he’s stirring the pot, most likely in a very productive way.”

There is wide agreement, however, that current approaches are not yielding the progress they promised. Much of the decline in cancer mortality in the United States, for instance, reflects the fact that fewer people are smoking, not the benefits of clever new therapies.

“The great hope of the modern targeted approach was that with DNA sequencing we would be able to find what specific genes, when mutated, caused each cancer,” said molecular biologist Mark Ptashne of Memorial Sloan-Kettering Cancer Center in New York. The next step was to design a drug to block the runaway proliferation the mutation caused.

But almost none of the resulting treatments cures cancer. “These new therapies work for just a few months,” Watson told Reuters in a rare interview. “And we have nothing for major cancers such as the lung, colon and breast that have become metastatic.”

The main reason drugs that target genetic glitches are not cures is that cancer cells have a work-around. If one biochemical pathway to growth and proliferation is blocked by a drug such as AstraZeneca’s Iressa or Genentech’s Tarceva for non-small-cell lung cancer, said cancer biologist Robert Weinberg of MIT, the cancer cells activate a different, equally effective pathway.

That is why Watson advocates a different approach: targeting features that all cancer cells, especially those in metastatic cancers, have in common.

One such commonality is oxygen radicals. Those forms of oxygen rip apart other components of cells, such as DNA. That is why antioxidants, which have become near-ubiquitous additives in grocery foods from snack bars to soda, are thought to be healthful: they mop up damaging oxygen radicals.

That simple picture becomes more complicated, however, once cancer is present. Radiation therapy and many chemotherapies kill cancer cells by generating oxygen radicals, which trigger cell suicide. If a cancer patient is binging on berries and other antioxidants, it can actually keep therapies from working, Watson proposed.

“Everyone thought antioxidants were great,” he said. “But I’m saying they can prevent us from killing cancer cells.”

Research backs him up. A number of studies have shown that taking antioxidants such as vitamin E do not reduce the risk of cancer but can actually increase it, and can even shorten life. But drugs that block antioxidants – “anti-antioxidants” – might make even existing cancer drugs more effective.

Anything that keeps cancer cells full of oxygen radicals “is likely an important component of any effective treatment,” said cancer biologist Robert Benezra of Sloan-Kettering.

Watson’s anti-antioxidant stance includes one historical irony. The first high-profile proponent of eating lots of antioxidants (specifically, vitamin C) was biochemist Linus Pauling, who died in 1994 at age 93. Watson and his lab mate, Francis Crick, famously beat Pauling to the discovery of the double helix in 1953.

One elusive but promising target, Watson said, is a protein in cells called Myc. It controls more than 1,000 other molecules inside cells, including many involved in cancer. Studies suggest that turning off Myc causes cancer cells to self-destruct in a process called apoptosis.

“The notion that targeting Myc will cure cancer has been around for a long time,” said cancer biologist Hans-Guido Wendel of Sloan-Kettering. “Blocking production of Myc is an interesting line of investigation. I think there’s promise in that.”

Targeting Myc, however, has been a backwater of drug development. “Personalized medicine” that targets a patient’s specific cancer-causing mutation attracts the lion’s share of research dollars.

“The biggest obstacle” to a true war against cancer, Watson wrote, may be “the inherently conservative nature of today’s cancer research establishments.” As long as that’s so, “curing cancer will always be 10 or 20 years away.”

http://www.reuters.com/article/2013/01/09/us-usa-cancer-watson-idUSBRE90805N20130109

sn-epigenetic

Cigarettes leave you with more than a smoky scent on your clothes and fingernails. A new study has found strong evidence that tobacco use can chemically modify and affect the activity of genes known to increase the risk of developing cancer. The finding may give researchers a new tool to assess cancer risk among people who smoke.

DNA isn’t destiny. Chemical compounds that affect the functioning of genes can bind to our genetic material, turning certain genes on or off. These so-called epigenetic modifications can influence a variety of traits, such as obesity and sexual preference. Scientists have even identified specific epigenetic patterns on the genes of people who smoke. None of the modified genes has a direct link to cancer, however, making it unclear whether these chemical alterations increase the risk of developing the disease.

In the new study, published in Human Molecular Genetics, researchers analyzed epigenetic signatures in blood cells from 374 individuals enrolled in the European Prospective Investigation into Cancer and Nutrition. EPIC, as it’s known, is a massive study aimed at linking diet, lifestyle, and environmental factors to the incidence of cancer and other chronic diseases. Half of the group consisted of people who went on to develop colon or breast cancer 5 to 7 years after first joining the study, whereas the other half remained healthy.

The team, led by James Flanagan, a human geneticist at Imperial College London, discovered a distinct “epigenetic footprint” in study subjects who were smokers. Compared with people who had never smoked, these individuals had fewer chemical tags known as methyl groups—a common type of epigenetic change—on 20 different regions of their DNA. When the researchers extended the analysis to a separate group of patients and mice that had been exposed to tobacco smoke, they narrowed down the epigenetic modifications to several sites located in four genes that have been weakly linked to cancer before. All of these changes should increase the activity of these genes, Flanagan says. It’s unclear why increasing the activity of the genes would cause cancer, he says, but individuals who don’t have cancer tend not to have these modifications.

The study is the first to establish a close link between epigenetic modifications on a cancer gene and the risk of developing the disease, says Robert Philibert, a behavioral geneticist at the University of Iowa in Iowa City. “To the best of my knowledge, no previous genome-wide epigenetics study has taken such efforts from initial discovery to replication to experimental validation,” adds Lutz Breitling, an epidemiologist at the German Cancer Research Center in Heidelberg, Germany.

The work may lead to new ways to asses cancer risks from smoking. “Previous research into smoking has often asked people to fill out questionnaires, … which have their obvious drawbacks and inaccuracies,” Flanagan says. The new study, he says, may make it possible for doctors to quantify a person’s cancer risk simply through an epigenetic analysis of their DNA.

http://news.sciencemag.org/sciencenow/2012/12/smoking-smothers-your-genes.html

Thanks to Dr. Rajadhyaksha for bringing this to the attention of the It’s Interesting community.

bull

A recent study by a researcher at the Centre for Studies on Human Stress (CSHS) at the Hôpital Louis-H. Lafontaine and professor at the Université de Montréal suggests that bullying by peers changes the structure surrounding a gene involved in regulating mood, making victims more vulnerable to mental health problems as they age.

The study published in the journal Psychological Medicine seeks to better understand the mechanisms that explain how difficult experiences disrupt our response to stressful situations. “Many people think that our genes are immutable; however this study suggests that environment, even the social environment, can affect their functioning. This is particularly the case for victimization experiences in childhood, which change not only our stress response but also the functioning of genes involved in mood regulation,” says Isabelle Ouellet-Morin, lead author of the study.

A previous study by Ouellet-Morin, conducted at the Institute of Psychiatry in London (UK), showed that bullied children secrete less cortisol — the stress hormone — but had more problems with social interaction and aggressive behaviour. The present study indicates that the reduction of cortisol, which occurs around the age of 12, is preceded two years earlier by a change in the structure surrounding a gene (SERT) that regulates serotonin, a neurotransmitter involved in mood regulation and depression.

To achieve these results, 28 pairs of identical twins with a mean age of 10 years were analyzed separately according to their experiences of bullying by peers: one twin had been bullied at school while the other had not. “Since they were identical twins living in the same conditions, changes in the chemical structure surrounding the gene cannot be explained by genetics or family environment. Our results suggest that victimization experiences are the source of these changes,” says Ouellet-Morin. According to the author, it would now be worthwhile to evaluate the possibility of reversing these psychological effects, in particular, through interventions at school and support for victims.

Journal Reference:

1.I. Ouellet-Morin, C. C. Y. Wong, A. Danese, C. M. Pariante, A. S. Papadopoulos, J. Mill, L. Arseneault. Increased serotonin transporter gene (SERT) DNA methylation is associated with bullying victimization and blunted cortisol response to stress in childhood: a longitudinal study of discordant monozygotic twins. Psychological Medicine, 2012; DOI: 10.1017/S0033291712002784

http://www.sciencedaily.com/releases/2012/12/121218081615.htm

sn-homosexuality

 

From a strictly Darwinian viewpoint, homosexuality shouldn’t still be around. It isn’t the best way to pass along one’s genes, and to complicate the picture further, no “gay genes” have even been identified. According to a newly released hypothesis, the explanation may not lie in DNA itself. Instead, as an embryo develops, sex-related genes are turned on and off in response to fluctuating levels of hormones in the womb, produced by both mother and child. This tug of war benefits the unborn child, keeping male or female development on a steady course even amid spikes in hormones. But if these so-called epigenetic changes persist once the child is born and has children of its own, some of those offspring may be homosexual, the study proposes.

Evolutionary geneticist William Rice of the University of California, Santa Barbara, felt there had to be a reason why homosexuality didn’t just fade away down the generations. Research estimates that about 8% of the population is gay, and homosexuality is known to run in families. If one of a set of identical twins is gay, there’s a 20% probability that the other will be, too.

Furthermore, Rice notes, “homosexuality isn’t just a human thing.” Among California gulls, which he watches from his office window, about 14% of pairs are female-female. In Australian black swans, some 6% of pairs are male-male, and 8% of male sheep are attracted exclusively to male partners.

But many genetic screens have failed to turn up genes that are responsible for sexual orientation. So to find out what makes homosexuality persist, Rice and colleagues began a comprehensive survey of the literature.

According to conventional wisdom, an embryo becomes a boy when a gene on the Y chromosome triggers the development of testes, which then begin to produce male sex hormones, including testosterone, at about the 8th week of gestation. With no Y chromosome and hence no testosterone, the embryo becomes a girl.

But testosterone doesn’t explain everything, the researchers found. For one thing, female fetuses are exposed to small amounts of the hormone from their adrenal glands, the placenta, and the mother’s endocrine system. At many key points of gestation, male and female fetuses are often exposed to similar amounts of testosterone. Levels of the hormone can even be higher than normal in females and lower than normal in males without any effect on genital or brain structure.

Rice and his co-workers were more intrigued by studies showing that male and female fetuses respond differently to the hormones that surround them, even when one hormone is temporarily higher. In their study, published online today in The Quarterly Review of Biology, the authors propose that differences in sensitivity to sex hormones result from “epigenetic” changes. These are changes that affect not the structure of a gene but when, if, and how much of it is activated—by chemically altering a gene’s promoter region or “on” switch, for example. Epigenetic changes at key points in the pathway through which testosterone exerts its effects on the fetus could blunt or enhance the hormone’s activity as needed, the authors suggest.

Although epigenetic changes are usually temporary, they involve alterations in the proteins that bind together the long strands of DNA. Thus, they can sometimes be handed down to offspring. According to the hypothesis, homosexuality may be a carry-over from one’s parents’ own prenatal resistance to the hormones of the opposite sex. The “epi-marks” that adjusted parental genes to resist excess testosterone, for example, may alter gene activation in areas of the child’s brain involved in sexual attraction and preference. “These epigenetic changes protect mom and dad during their own early development,” Rice says. The initial benefit to the parents may explain why the trait of homosexuality persists throughout evolution, he says.

“The authors have done a terrific job providing a mechanism for genetic variation, especially a variation that might not be expected to persist because it’s so tightly bound to reproduction,” says evolutionary biologist Marlene Zuk of the University of Minnesota, Twin Cities. But she adds that to go from changes in gene expression to why someone is attracted to a person of the same sex is a question for which science may never fill in all the blanks.

http://news.sciencemag.org/sciencenow/2012/12/homosexuality-may-start-in-the-w.html?ref=hp