genomics

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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

For $9,000, Your Personal Genome Sequenced

Updated at 10:52 AM, August 28th, 2013

If you’ve got $9,000 handy and a hankering to learn more about your genetic roadmap, here’s your chance.

Partners Healthcare, the largest hospital system in Massachusetts, announced yesterday that complete genomic sequencing is now available to patients. The full test would take 16 weeks, said spokesman Rich Copp, and insurance coverage would be determined on a case by case basis.

greyloch/flickr

greyloch/flickr

Formerly a technique limited to the laboratory, complete genome sequencing maps the 3 billion pairs of DNA in a human’s genome. In recent years, scientific and technical advances have made genetic sequencing available for clinical use.

That’s a far cry from 2006, when scientists were still diagnosing a “market failure” in providing “rapid, low-cost medical grade genomes.” It was enough to spur the creation of the Archon Genomics X-Prize, which promised a $10 million prize to a team that could sequence 100 genomes in 30 days for less than $10,000 per genome. The X-Prize team ultimately called off the competition, citing commercial interests making the prize incentive superfluous:

What we realized is that genome sequencing technology is plummeting in cost and increasing in speed independent of our competition. Today, companies can do this for less than $5,000 per genome, in a few days or less – and are moving quickly towards the goals we set for the prize. – Peter Diamandis, chairman of X-Prize Committee

But where, exactly, will your new $9,000 map lead you? Shortly after he was diagnosed with cancer, Steve Jobs spent $100,000 on getting his genome completely sequenced. Continue reading

Say ‘Om': Researchers Find Gene Action Altered After Relaxation Practice

(Synergy by Jasmine/flickr)

It’s widely accepted that yoga, meditation and other practices that involve conscious relaxation can reduce stress and enhance a person’s general well-being. But for many, notions of “mindfulness” and “wellness” still come off as a tad New Age-y and amorphous.

So here, for skeptics, is a molecular-level reality check: Researchers at Massachusetts General Hospital and Beth Israel Deaconess Medical Center report that the relaxation response – a state of deep rest attained through breathing, meditation, yoga and other practices — triggers changes in gene expression that can affect the body’s immune function, energy metabolism and insulin secretion. The new research — the first to look at rapid, gene-level changes following the relaxation practice — is published in the journal PLOS ONE.

Herbert Benson, a senior author of the new study, first described the “relaxation response” — what he calls the physiologic opposite of fight-or-flight — nearly 40 years ago. He’s now the director emeritus of the Benson-Henry Insitute for Mind-Body Medicine at MGH, where the technique is used to help patients manage a wide variety of medical conditions from anxiety and chronic pain to cancer.

Benson says the new research should give a credibility boost to his endeavors (which, by the way, non-Westerners have been practicing in various forms for thousands of years). “There’s now a scientific basis for these mind-body approaches that work,” Benson said. “For the mainstream, every little bit of evidence helps.”

Benson’s collaborator, Towia Libermann, PhD, director of the Beth Israel Deaconess Medical Center (BIDMC) Genomics, Proteomics, Bioinformatics and Systems Biology Center and co-senior author of the study, says the evidence clearly links the relaxation response to rapid changes in gene expression. “There is a relatively small subset of biological pathways affected by relaxation response,” he said. For instance, a pathway involved in immune disturbances and inflammation was repressed after the relaxation technique while another set of pathways involved in mitochondrial function and energy production were enhanced. Continue reading

An Immune Element In Autism? Gene Screen Finds More Evidence

DNA double helix (National Human Genome Research Institute)

DNA double helix (National Human Genome Research Institute)

A better early blood test for autism.” That’s how the headlines tended to read in last week’s coverage of new findings by Harvard-led researchers published in the journal PLOS ONE.

But there was another aspect of the new research worthy of at least a grabby sub-headline: the analysis of gene activity in children with autism found a strikingly strong role played by genes connected to immune function.

‘The main point is: This is not a monolithic disease.’

That robust immune element surprised the work’s senior investigator, Dr. Isaac Kohane of Harvard Medical School and Boston Children’s Hospital. And it may have practical implications, says Dr. Martha Herbert, a Harvard neurologist and author of “The Autism Revolution.” The study looked at genes getting switched off and on, and “diet and environment could contribute to at least some of these genetic changes,” she said.

So “anti-inflammatory approaches to diet modification — such as a high nutrient plant- based diet, solidly adequate Vitamin D levels and plenty of antioxidants and essential fatty acids — could help to downregulate the more troublesome of the gene expression changes. Since these are low-risk interventions, they could be pursued even while we wait for this kind of blood test for autism to become more accurate.”

Dr. Kohane, a bio-informatics specialist, was a relative newcomer to autism research when he began the gene expression work, and any preconceptions stemmed from the dominant thinking in the field: that autism was all about synapses, the connections between neurons. He went into the gene analysis unbiased, he says, open to whatever signals the genes themselves would produce. As he tells it:

Remember, gene expression is not DNA, it’s genes getting switched on and off — it’s RNA. You’re looking at real-time physiology: genetic potential plus environmental influences. What I was expecting to see was either nothing, or a lot of synaptic genes. So I was really pleased when I looked at the gene expression signature — the sets of genes switched on and off in these children we studied — and sure enough, there was a good group of 55 genes that predicted with some accuracy who had autism and who did not.

We saw a group of genes that were characteristic of the synapse, so that was very reassuring, that in the blood you could see something developing in the brain. But then I saw there were a number of other genes that were involved in inflammation.

I wondered whether I was seeing this because I was looking at white blood cells. But why would it be that I saw it in one group of kids, the ones with autism, and not in the control group? And so then I started looking through the literature and there was this whole other parallel set of literature about the immune gene signatures in autism. Continue reading

You Too Can Feel Like A Longwood M.D.-PhD, Or At Least Vote Like One

vote

I just voted.

No, not in that election. I just voted in a Brigham And Women’s Hospital research contest for a $100,000 prize to be announced Nov. 15. The voting deadline is tonight at midnight, and you, too, are welcome to weigh in here.

One of the contestants, Dr. Robert C. Green, contacted us to spread word of the contest and request support for his entry. Needless to say, my vote is secret but I can disclose that we’ve covered his work repeatedly, including a major first-of-its kind project to study how sequencing patients’ DNA can best be used in clinical practice. His proposal for the vote involves sequencing DNA in newborns: The day will soon be upon us when a baby’s full DNA can be analyzed at birth to determine future health risks. How do parents and pediatricians handle this information?

The competitors:”Using Electronic Health Records and Genetics to Personalize the Treatment of Multiple Sclerosis” and “Using Cutting-Edge Technology to Unravel the Mysteries of the Immune System.” You can watch videos of the contestants explaining their projects here.

Of course I feel very important helping to decide which august researchers get the prize money. But I also sent an email to a researcher friend headlined: “Is it me or is this kind of an odd way to decide who gets a prize??

“Odd,” he replied.

I mean, it’s one thing if it’s an online survey seeking votes on which celebrities are most popular. But isn’t research supposed to be “peer reviewed”? (Note: the projects were in fact peer-reviewed in advance by a Brigham senior-scientist committee before being put out to this public vote.) I hate to run myself down, but I strongly suspect I’m not a peer. Though it’s certainly fun to feel for a moment like a Longwood MD-PhD — all I need to really measure up is, er, a medical degree and a doctorate…

(Voted and feel like you still want more input? Info on the Brigham’s first annual open-to-the-public Research Day on Nov. 15 here.)

Questioning Last Week’s Big DNA News

DNA double helix (National Human Genome Research Institute)

DNA double helix (National Human Genome Research Institute)

The New York Times led with it. The Wall Street Journal splashed it, and NPR aired it, and we piggybacked with a local angle. The media herd was stampeding.

But I have to confess, it was hard to decipher from the press releases and papers exactly what the fuss was about. Bulletin: What had been known as “junk DNA” was in fact full of important gene switches. But I thought we already knew that. There was a vivid verbal image of a “Google Maps” for the genome. But what would that mean, exactly?

So I was immediately drawn to today’s blog post by evolutionary biologist Michael Eisen: Blinded by Big Science: The lesson I learned from ENCODE is that projects like ENCODE are not a good idea. An authoritative contrarian voice was calling into question the value of the huge, expensive ENCODE project that garnered all those headlines, and of such projects in general, given the grant funding they take away from the individual scientists who have traditionally produced most discoveries. Read the full post to get the impact of the argument, but here’s a preview:

I believed then, and still believe now, that looking at biology on a big scale is often very helpful, and that it can make sense to let people who are good at doing big projects, and who can take advantage of economies of scale, generate data for the community.

But the lesson I learned from ENCODE is that projects like ENCODE are not a good idea.

American biology research achieved greatness because we encouraged individual scientists to pursue the questions that intrigued them and the NIH, NSF and other agencies gave them the resources to do so. And ENCODE and projects like it are, ostensibly at least, meant to continue this tradition, empowering individual scientists by producing datasets of “higher quality and greater comprehensiveness than would otherwise emerge from the combined output of individual research projects”.

But I think it is now clear that big biology is not a boon for individual discovery-driven science. Ironically, and tragically, it is emerging as the greatest threat to its continued existence. Continue reading

Major Findings: Your Genes As A Panel With A Million Switches

Actually a routing switcher, but a bit of a metaphor for our gene switches (Wikimedia Commons)

There’s now a genetic version of “It’s not just the heat, it’s the humidity.” The journal Nature reports today in a blast of big data that our genome — our full set of genes — is even more complex than we’d suspected.

And — here’s the weather metaphor now — it’s not just the genes, it’s their switches. Here’s the back-story from The Wall Street Journal, which leads with the news that the deepest look yet into the genome finds it “a richer, messier and more intriguing place” than we’d known.

The findings are the product of Encode, or Encyclopedia of DNA Elements, a vast, multiyear project that is trying to pin down the workings of the human genome in unprecedented detail.

Encode succeeded the Human Genome Project, which identified the 20,000 genes that underpin the blueprint of human biology. But scientists discovered that those 20,000 constituted less than 2% of the human genome. The task of Encode was to explore the remaining 98% of biological “desert”—so-called junk DNA—that lies between those genes.

That desert, it turns out, is teeming with action. Almost 80% of the genome is biochemically active, a finding that surprised scientists. In addition, large stretches of DNA that appeared to serve no functional purpose in fact contain about 400,000 regulators, known as enhancers, that help activate or silence genes, even though they sit far from the gene itself.

Now here’s the part about the panel of switches. UMass Medical School sent over a press release about the contributions by its professors Job Dekker — who works on 3-D models of folded chromosomes — and Zhiping Weng to these latest Encode findings,

“The genome is like a panel of light switches in a room full of lights,” said Dekker, “except there are thousands of lights and almost a million switches. We don’t know what switches turn on which lights. And some switches turn on the same lights or turn on multiple lights.” Continue reading

Incidentalome: Accidental Gene Findings You May Not Want To Know

DNA double helix (National Human Genome Research Institute)

DNA double helix (National Human Genome Research Institute)


You’ve heard of the genome — a full collection of DNA — and perhaps the proteome, a full complement of proteins. Now, I’d like to introduce a delicious new word that may soon be relevant in many a doctor’s office: The incidentalome.

What is it? Dr. Robert Green , a medical geneticist at Brigham and Women’s Hospital and Harvard Medical School, offers this helpful analogy: Say you get an X-ray because you think you might have cracked a rib and the radiologist notices a shadow on your lung that appears to be a tumor. That finding is “incidental,” because it turned up even though you weren’t looking for it.

Translate that to the dawning era of genomics in medicine. As DNA analysis gets exponentially cheaper and eventually becomes routine in our care, the labs that sequence our full genomes will be turning up all sorts of extraneous information. A scan ordered for, say, a heart problem could turn up a genetic variant that means you’re predisposed to cancer. Or that you’re at heightened risk for diabetes or Alzheimer’s disease.

What to do? The gene finding only suggests an increased or decreased risk, mind you, not a certainty. Should the lab that finds it tell the doctor who’s treating you? And should your doctor tell you?

‘What is the value of telling people something you’re pretty damned sure they’re going to jump to the wrong conclusion about?’

These incidentalome questions arose first in the context of large-scale genome research, Dr. Green notes, among scientists who wondered what their obligation was to tell subjects about genetic findings that they had stumbled upon. (What if, for example, a subject who has grown up male turns out to have the genes of a female?)

But it is poised to become a question for the clinic: The Laboratory for Molecular Medicine at Partners Center for Personalized Genetics Medicine expects to begin offering whole-genome sequencing as a clinical service as early as this July, he said, and nationally, a few other institutions — Baylor, Wisconsin — are already offering clinical sequencing.

So now might be a time for us all to start thinking: What would you want to know? You may not have been curious enough to pay for one of the direct-to-consumer services that analyze people’s genes, but what if your doctor in the not-too-distant future has the information anyway? Continue reading