genomics

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Possible Key To Weight Loss? Researchers Find ‘Master Switch’ To Crank Up Fat-Burning

Researchers say new science on a “metabolic master switch"  may hold the promise of someday making a dent in the obesity epidemic. (Courtesy UConn Rudd Center for Food Policy & Obesity)

Researchers say new science on a “metabolic master switch” may hold the promise of someday making a dent in the obesity epidemic. (Courtesy UConn Rudd Center for Food Policy & Obesity)

Here’s my fantasy: I’ve overindulged — let’s say, purely theoretically, on Cape Cod fried clams, french fries and beer — and would normally face the greasy regret and resign myself to extra carrots and cardio in the days to come.

But no. Instead, I simply pop a pill that cranks up my metabolism for a few hours so that I burn the extra calories instead of storing them as fat. I don’t gain an ounce.

That’s a very distant prospect. But new science on a “metabolic master switch,” just out in the New England Journal of Medicine, brings my dream one step closer to reality — and, researchers say, may hold the promise of someday making a dent in the obesity epidemic.

Until now, weight-loss treatments have focused on altering appetite and exercise, says MIT computer science professor Manolis Kellis, senior author on the paper. Now, “what we have in our hands is a third knob, if you wish, for controlling body fat,” he says. “It’s working directly on your fat cells to reprogram them to burn more energy rather than to store it as fat.”

In normal-weight mice, Kellis says, the effects of turning that knob are dramatic: “By changing the expression of one gene in these mice, they lose 50 percent of their body weight. You can feed them all the fat you want and they will not take on weight. They do not exercise more and they do not eat less, what they do is simply burn more energy when they’re awake, or even in their sleep.”

Dr. Melina Claussnitzer is lead author on the fat-burning paper just out in the New England Journal of Medicine. (Courtesy of Lovely Valentine)

Dr. Melina Claussnitzer (Courtesy of Lovely Valentine)

But mice are not men, of course. Could this work in humans?

“We experimented on human fat cells,” says Melina Claussnitzer, first author of the paper, a visiting professor at MIT and faculty member at Beth Israel Deaconess Medical Center. “And we found that we could flip them from energy-storing to energy-burning by altering the expression of a single gene — and, even more remarkably, by altering a single letter from our 3-billion-letter genome. And we could flip that switch back in either direction.”

Still, it’s a very long way from genetically editing human cells in a Petri dish to altering the metabolism of a breathing human, the researchers caution. The team has filed patents on their switch-flipping manipulations and are seeking to commercialize the approach and lead it into human clinical trials, Kellis says, but cannot speculate on a time frame.

So meanwhile, there’s no such thing as a free fried clam. But we can at least savor the story of how this cutting-edge science came to be.

Let’s begin in 2007, when researchers turned up the first genetic link to obesity, a region of the genome called FTO. To this day, it remains the strongest genome-obesity link: Some 44 percent of Europeans, it turns out, have a version that predisposes them to weigh more, on average five to seven pounds.

The natural next question was: How does it work? Does it make people eat more? Move less? Both?

Or neither, says Claussnitzer. “Despite seven years of intense efforts to hunt down a mechanism, no link has been made between the genetic differences in the region and altered functions in the brain.” Continue reading

Related:

Calling All Gene Detectives: Solve Diagnosis Mysteries To Win Contest, Play Role In Film

 

What in the world is wrong with Dr. Katia Moritz?

When she was 43, Moritz felt like she had life all figured out. Always a high-energy extrovert, she would begin her workdays as a clinical psychologist treating severely ill patients at 7:15 a.m., and get home in time to be with her three young children after school.

There was no time for slacking in a life so full, so when she was scheduled for a minor diagnostic procedure that involved inserting a tube down her throat to look into her stomach, she figured she’d recover from the sedation and come right back to work that afternoon.

But afterward, she felt so sick she went to bed and slept for three days. “I felt like I was poisoned,” she recalls. “It felt like the worst flu ever. I had a low grade fever, my body hurt, everything hurt. After a few days, I improved, but I never felt well. And then it became an episodic illness — a few days later I’d get it again, and a few weeks later I’d get it again.”

Moritz, now 48, has never been the same. For the last five years, she has seen dozens of doctors, trekked to leading medical centers around the country in search of a diagnosis and cure, to no avail. Her fevers come and go, and other symptoms; sometimes it’s hard to swallow, even walk.

Dr. Katia Moritz shares a happy post-interview moment with 5-year-old Jeremy, who is also undiagnosed. (Courtesy "Undiagnosed")

Dr. Katia Moritz shares a happy post-interview moment with 5-year-old Jeremy, who is also undiagnosed. (Courtesy “Undiagnosed”)

If this were the television show “House,” or the popular New York Times column “Think Like A Doctor,” her story would have a neat ending, a solution to her mystery. But as Moritz has learned in her exhaustive travels, in real life, a great many people — millions of them, she estimates — are clearly very sick but never get the answer that could help them get well. Call them “the undiagnosed.”

Now, she’s working on a documentary on their plight (see the trailer above) and — in a lucky convergence — she’s combining forces with the bright minds at the cutting edge of genomic research to seek answers.

Five undiagnosed patients from the documentary are the focus of a new contest run by Boston Children’s Hospital, titled “CLARITY Undiagnosed.” Aiming to advance the field of genomic medicine — using a patient’s gene information in the clinic — it offers a $25,000 prize to the research team that best solves the patients’ diagnostic mysteries.

In an unusual twist for such an exercise in competitive crowd-sourcing, the teams may also appear in the documentary that Moritz is creating. Titled simply “Undiagnosed,” It is still filming and thus far chronicles the patients’ struggles but has no happy endings. (The medical detectives can also opt out if they’re camera-shy.)

“The probability that we’re going to find something in any of these individuals is about 50 percent.”

– Dr. Isaac Kohane

Up to 30 competing teams in the CLARITY contest will be given each patient’s full medical record — no small file, given the medical odysseys they have endured. The contestants will also be given extensive data on the patients’ genes.

Teams have until June 25 to apply, says Dr. Isaac Kohane, chair of Harvard Medical School’s Department of Biomedical Informatics, and they will then have two months to work. Results will be announced in November.

“I would say that, based on the performance from the Undiagnosed Disease Program at the National Institutes of Health, the probability that we’re going to find something in any of these individuals is about 50 percent,” Kohane says. Continue reading

Why We Need To Talk Now About The Brave New World Of Editing Genes

Screen shot 2015-05-21 at 7.48.44 PM

(Image: NIH)

It was standing room only in the Harvard Medical School auditorium last week, the atmosphere electric as an audience of hundreds hummed with anticipation — for a highly technical talk by a visiting scientist, Dr. Jennifer Doudna of Berkeley. Near the front sat the medical school’s dean, Dr. Jeffrey Flier.

Dr. Jennifer Doudna (Vimeo screenshot)

Dr. Jennifer Doudna (Vimeo screenshot)

“I don’t believe in my years at Harvard Medical School I’ve ever seen a crowd of this magnitude for a lecture of this kind,” he said.

The draw?

“The draw is, this is one of the most exciting topics in the scene of biology today.”

That buzzworthy biology topic is a revolutionary new method to “edit” DNA that has spread to thousands of labs around the world just in the last couple of years.

Suddenly, it’s no longer purely science fiction that humankind will have the ability to tinker with its own gene pool. But should it?

Learn This Acronym: CRISPR

The hot new gene-editing tool is known by the acronym CRISPR, for “clustered regularly interspaced palindromic repeats.” It acts as a sort of molecular scissors that can be easily targeted to cut and modify specific genes.

(Source: NIH)

(Source: NIH)

CRISPR occurs naturally in bacteria, but scientists are now learning to harness its power to alter DNA for research across the board — cancer, HIV, brain disease — even to make better potatoes. Just this week, the journal Science published a paper on possibly using CRISPR to try to stop female mosquitoes from spreading deadly diseases.

CRISPR looks particularly promising for human diseases that hinge on just one gene, like sickle-cell anemia or cystic fibrosis. Someday, the hope is, CRISPR and gene-editing tools like it will let us cure what are now lifelong diseases by simply deleting and replacing a baby’s “broken” gene. Continue reading

Q&A: A Taste Of The Looming Ethical Debate On Gene-Editing Humans

Boston University bio-ethicist George Annas discusses the ethical issues raised by new gene-editing tools that may eventually allow humankind to control its own genetic legacy. (Courtesy)

Boston University bio-ethicist George Annas discusses the ethical issues raised by new gene-editing tools that may eventually allow humankind to control its own genetic legacy. (Courtesy)

The powerful new gene-editing tool CRISPR is sparking excitement in biology labs — but also calls for a broad discussion about limits, and whether we should ever meddle with the human gene pool. I asked Boston University bio-ethicist Prof. George Annas for his take. Our conversation, edited:

CG: So scientists are saying we should start talking about using CRISPR to alter the human gene pool. What would a conversation like that even sound like?

GA: The conversation is not about CRISPR per se. It’s about: Now that we have techniques to edit the human genome, should we edit the human genome, and if so, for what purposes?

We’ve had this conversation around cloning in the mid-1990s. Most but not all scientists, and almost everyone in the public, agreed we should not try to clone a human being, use our genetic knowledge to make a genetic duplicate human being. And we’ve had very good luck: it’s turned out not to be possible to clone a human being. At least, we don’t know how to do it yet.

But with CRISPR, it seems much more likely that sometime in the not-too-distant future — though it may be decades, this gene editing technology will be dependable enough that someone is likely to try to use it on a human embryo.

This will be a big and dangerous step—dangerous for sure to the resulting child. Many people have no trouble with using genome editing on animals and plants, so long as you’re not harming the animal in a way that makes it suffer. But children do suffer. So the first question is: Should we ever try to edit the genomes of human embryos that are destined to become children? I think the answer is no.

I agree with the scientists who say that it’s definitely not safe to do it now because we can’t predict what other things CRISPR will do to the rest of the genome. We know very little about the genome, and what impact taking out one or a series of base pairs — with CRISPR, you can take a series out — is going to do to the rest of the genome, and hence to the whole organism as it develops.

And the problem with germ-line genetic engineering at the level of the embryo —

— Making genetic changes that will be passed on forever —

Potentially, yes. First they will be passed on to this baby, and this baby will become an adult. And if this “engineered” baby has children, the new traits will be passed on to the next generation, and so on.

So an initial question — and scientists agree with this — is, how many generations do you need to prove that a particular method of genome editing is safe? I would guess most scientists would say, at least four or five. Well, we can do four or five generations in zebrafish or in rats or in fruit flies pretty quickly.. In humans, however, it’s going to take you probably 100 years. So, how many children would you want to follow, and their offspring, for 100 years before you are ready to conclude that editing the human genome is safe for children?

That strikes me as a question that we can’t answer. Because we cannot prove it safe without putting human children at terrible risk of harm, we can’t subject any human child to this experiment. That’s because children can’t consent, and their consent is necessary as a matter of ethics because there are good reasons to anticipate that something will go horribly wrong.

And more broadly, there are potential implications for the whole human race, if we start engineering evolution — ? Continue reading

Biggest Gene Study Finds New Clues To Obesity, Apple Vs. Pear Shapes

(Wikimedia Commons)

(Wikimedia Commons)

You might think the link between genes and weight is simple: Fat tends to run in families, right? But as researchers tease apart the underlying genetics of body weight, it becomes ever clearer that it is a complex trait. Very complex, with ultimately perhaps hundreds of genes involved in what you see when you step on the scale.

Today, the biggest-ever study of the genetics of obesity, involving genetic samples from nearly 350,000 people, reveals dozens of new spots on the human genome that are involved with body weight and body shape, according to two papers (here and here) published in the journal Nature.

My dominant impression: The data tend to implicate the brain as a powerful influence on overall body weight, but point more towards hormones and the fat cells themselves as strong determinants of whether we’re shaped like “apples” — with more upper body fat — or “pears,” with more fat concentrated below the waist.

Dr. Joel Hirschhorn, of Boston Children’s Hospital, the Broad Institute and Harvard Medical School, leads the Genetic Investigation of Anthropometric Traits consortium, or GIANT, the friendly collaborative of hundreds of researchers around the world who contributed to the studies. Our conversation, lightly edited:

How would you sum up the findings that come out in “Nature” today?

We did a very large genetic study looking at two different kinds of obesity: Overall obesity measured by body mass index and central obesity — fat around the belly — measured by waist circumference and hip circumference. And what we found was that there are a lot of genes that influence both types of obesity, but, really interestingly, the types of genes that influence overall obesity are actually quite different than the types of genes that influence where the fat goes on the body.

Interesting. So what does that tell us?

That tells us that even though both types of obesity are bad for your health, that it may be very important to understand what kind of obesity you have, because if the biology is different, that means the way we can treat that obesity, or prevent it effectively, is probably going to be different for the two kinds of obesity.

So it may matter even more than we thought whether you’re shaped like an ‘apple or a ‘pear’?

That’s right. It matters both whether you’re an apple or a pear and it matters just how big you are in general. But the way you get to be big in general is probably different than the way you get to be an apple or a pear.

So it’s different pathways? Perhaps whole different mechanisms at work?

That’s right. The overall obesity seems to have more to do with what’s going on in the brain, maybe controlling appetite or whether you get full or how quickly you get full. And the apple vs. pear seems to have more to do with your fat cells and hormones that your body makes, things like insulin.

So does all this translate into any action points for the general public? Continue reading

Study: Do You Really Need Counseling On Your Alzheimer’s Gene Test?

Today on Radio Boston: A new Brigham and Women’s Hospital study finds that we may not need quite as much genetic counseling as we’d thought. Particularly on relatively cut-and-dried findings, like test results on a common gene that raises the risk of Alzheimer’s disease. Listen to host Anthony Brooks speak with Dr. Robert C. Green in the segment above.

From the Brigham’s press release:

A new study led by researchers at Brigham and Women’s Hospital (BWH) has found that people who received a written brochure instead of time-intensive genetic counseling about their genetic risk for Alzheimer’s disease did not experience greater anxiety or symptoms of depression than their counterparts a year later. The results of the randomized controlled study were published online in the journal Alzheimer’s and Dementia.

“As genetic testing of all kinds becomes commonplace, one of the primary challenges will be determining how to share this information with individuals seeking it in a way that limits the burden on health care providers but still puts the well-being of patients first,” said Robert C. Green, MD, MPH, a medical geneticist and researcher at BWH and Harvard Medical School and lead investigator of the study. “These new results show that for individuals seeking genetic risk information, we can use written material, rather than genetic counseling, to prepare them without causing greater long-term anxiety or distress.” Continue reading

Boston Survey: Most Parents Say Sure, I’d Like To Know My Newborn’s Genes

(Wikimedia Commons)

(Wikimedia Commons)

For years, futurists have foreseen an era when all newborn American babies would be sent home with a supply of self-knowledge: a readout of their full set of genes, with all it may imply about heightened chances for disease or health.

So how would you feel about that, as a new parent? Eager to absorb any possible indicator of your child’s potential future? Or wary that genes are not destiny, and you may spend a lifetime fearing something that never comes to pass?

If you answer, “I’d want to know about my baby’s genetic makeup,” your sentiments are in line with the majority of parents surveyed in the first poll of new parents about genomic screening, just out in the journal Genetics In Medicine. Researchers from Brigham and Women’s Hospital and Boston Children’s Hospital led the study. From the press release:

“Several other studies have measured parents’ interest in newborn genomic screening, but none focused on new parents in the first 48 hours,” said Robert C. Green, MD, MPH, a geneticist and researcher at BWH and Harvard Medical School and senior author of the study. “Since this is when genomic testing would be of the greatest value, it is especially important to study parents’ attitudes immediately post-partum.”

The researchers surveyed 514 parents at the well baby nursery at BWH within 48 hours of their child’s birth. After receiving a brief orientation to the genome and its impacts on human health, including information about what the genome is, what genes are and how they can affect both health and medical care, 82.7 percent of parents reported being somewhat (36 percent), very, (28 percent) or extremely (18 percent) interested in newborn genomic testing. Results were similar regardless of parents’ age, gender, race, ethnicity, level of education, family history of genetic disease, or whether or not the infant was a first-born child. Parents who had experienced concerns about the health of their newborn, however, were less likely to be interested in genomic testing. Continue reading

Rethinking Cancer Research Through ‘Exceptional Responder’ Patients

Grace Silva and her oncologist, Jochen Lorch (Photo: Sam Ogden, Dana-Farber Cancer Institute.)

Grace Silva and her oncologist, Jochen Lorch (Photo: Sam Ogden, Dana-Farber Cancer Institute.)

By Richard Knox

By all odds, Grace Silva should have died more than three years ago. Instead, this 58-year-old grandmother is helping scientists rethink cancer treatment and research.

Silva’s case, detailed in this week’s New England Journal of Medicine, is one of only three recently published accounts of what cancer doctors call “exceptional responses” to a drug called everolimus (brand name Afinitor).

It was approved two years ago to treat certain breast cancers and is also used against some kidney and pancreas tumors. A couple of months after Silva started taking the drug, her thyroid tumors, which had spread to her lungs, melted away to nearly nothing. That basically never happens with this aggressive tumor, known as anaplastic thyroid cancer. “It was a near-complete response,” says her oncologist at Dana-Farber Cancer Institute, Dr. Jochen Lorch. “That in itself is exceptional. When we saw it, it was one of the better days around here.”

Studying The Exceptions

More remarkable still, Silva’s tumor stopped growing for 18 months. We’ll come back to what happened after that. But first, you should understand this story isn’t about everolimus or any particular cancer drug. It’s about how cancer specialists are learning how cancer works at the most basic level — by studying exceptional responders like Grace Silva.

And to appreciate why her case is important, you need to know how researchers figured out why she was an exceptional responder. It’s partly due to a five-year-old technology called next generation sequencing. It’s a cheap and rapid way of spelling out the genetic code of, in this case, individual patients’ tumors. Researchers can then look for gene mutations that are driving the uncontrolled growth that is cancer.

Continue reading

Study: Microbe Imbalance Found In New Crohn’s Disease Patients

High magnification micrograph of Crohn's disease in the colon. (Wikimedia Commons)

High magnification micrograph of Crohn’s disease in the colon. (Wikimedia Commons)

Our recent piece on the nation’s first stool bank touched upon the burgeoning field of microbiomics — exploring the “rain forest” of varied species among the trillions of bacteria that inhabit our bodies.

Today brings some related news, just in from Massachusetts General Hospital: Bacterial populations in our guts appear to be involved in the onset of Crohn’s disease, an inflammatory condition that affects up to 700,000 Americans. Crohn’s has been linked to an immune reaction gone awry, possibly related to an imbalance in the bacterial population, but that connection was not clear. A new study looked at 447 patients with Crohn’s disease and 221 without. From the press release:

Advanced sequencing of the microbiome – the genome of the entire microbial population – in tissue samples taken from sites at the beginning and the end of the large intestine revealed a significant decrease in  diversity in the microbial population of the Crohn’s patients, who had yet to receive any treatment for their disease. The samples revealed an abnormal increase in the proportion of inflammatory organisms in Crohn’s patients and a drop in noninflammatory and beneficial species, compared with the control participants. The imbalance was even greater in patients whose symptoms were more severe and those who had markers of inflammatory activity in tissue samples.

“These results identifying the association of specific bacterial groups with Crohn’s disease provide opportunities to mine the Crohn’s-disease-associated microbiome to develop diagnostics and therapeutic leads,” said senior author Ramnik Xavier, MD, PhD, chief of the MGH Gastrointestinal Unit and director of the MGH Center for the Study of Inflammatory Bowel Disease.

NPR has more coverage here: Mix Of Gut Microbes May Play Role In Crohn’s Disease. And an important note: antibiotics early on may make things worse:

Antibiotics are often prescribed for symptoms suggestive of Crohn’s before a diagnosis is made, but in participants who happened to be taking antibiotics at the time samples were taken, the microbial imbalance was even more pronounced, suggesting that the antibiotic use could actually exacerbate symptoms rather than relieve them, the authors note. Next steps will be to uncover the function of these microbes and their products and to learn how the microbiome and microbial products interact with the patient’s immune system, with the possibility that these interactions could represent the molecular basis for the disease.

Growing Up Genomic: What Happens When You Know All A Baby’s Genes?

DNA

How would it change your life if you knew all your genes from the get-go? I mean, not just a little foray onto 23andMe when you’re 23 and curious, but a full sequencing of all your significant DNA at birth? Would you grow up with some deeply different ideas about yourself and your future than you would have otherwise? If, say, you knew you were at high risk for cancer or Alzheimer’s?

This is not just a thought experiment. Boston-based researchers have just announced that they will be seeking subjects for a $6-million study called BabySeq that involves sequencing more than 200 babies’ full sets of genes at birth, then following them to see how that genetic knowledge affects their lives and medical care. To which I say: Darn. This genomic future keeps arriving even faster than I expect.

The press release is below — Boston parents-to-be, take note: Recruitment is expected to begin early next year.  I spoke with Dr. Robert C. Green, one of the lead researchers; our conversation, lightly edited:

So what is the question that this research project seeks to answer?

RCG: This is a research project at Brigham and Women’s Hospital and Boston Children’s Hospital, led by myself and Alan Beggs, that asks the question: What happens when you sequence newborn babies? What happens when you sequence healthy newborn babies and what happens when you sequence ill newborn babies?

The philopsophy with which we’ve started this project is that sequencing is here,  it’s getting cheaper and cheaper, and more accessible. And everyone thinks that this is going to be a great boon to your health; it’s going to tell you about diseases and conditions that are going on, and it’s going to warn you about diseases and conditions to come. And we’d like to find out how this really plays out in these two very different situations.

If you have access to the reference book of life, and you  can open it to any page you want, what do you get to read there, and how does it influence you?

In other words, if you have access to the reference book of life, and you  can open it to any page you want, what do you get to read there, and how does it influence what your doctor does with you, what your doctor says to you, what your parent-and-child bonding is like? These are tremendously controversial issues, they’re issue we simply don’t know the answers to because the technology is so new, but it’s hurtling down the track at such speed that we must ask these questions as soon as we can, and as scientifically as we can, so that we understand the answers as the technology is being rolled out, not after it’s rolled out.

How many babies will be sequenced in this ‘BabySeq’ project?

There will be 480 babies enrolled, of whom half — or 240 — would be sequenced. It’s designed as a randomized, controlled trial. Continue reading