genetics

RECENT POSTS

‘Genetic Superheroes’: Rare Exceptions Resist Mutations Thought To Be Disease Destiny

(Photo by Dan Steinberg/Invision for Warner Bros. Consumer Products/AP Images)

(Photo by Dan Steinberg/Invision for Warner Bros. Consumer Products/AP Images)

They had me at the phrase “genetic superheroes.”

The phrase isn’t in the Nature Biotechnology study itself, which has a long, journal-ish title involving “analysis of 589,306 genomes” and “severe Mendelian childhood diseases.”

But the accompanying commentary by Daniel MacArthur of Massachusetts General Hospital and Cambridge’s Broad Institute is headlined “Superheroes of disease resistance.” It describes “genetic superheroes, people who remain healthy even though they carry genetic variants known to cause severe Mendelian diseases,” such as cystic fibrosis or sickle-cell anemia.

Calling Marvel and Universal Studios: There’s a new breed in town. The journal paper describes an epic search among more than a half-million genomes that turned up a tiny population of 13 people whose genes dictated that they should have been very sick or dead — but weren’t.

There’s more on the study in Wired and The Atlantic.

I turned to Dr. Isaac Kohane, chair of Harvard Medical School’s Department of Biomedical Informatics, for insight. His thoughts are transcribed below:

What does it mean that [Dr. Rong] Chen and colleagues studied a half-million individuals and found that 13 of them appeared to be quite resistant to a set of mutations that, in the textbook, are said to be absolutely disease-causing? Is this the new fountain of youth? The new disease barrier? Who are these superheroes? And what does it tell us about our medicine, as practiced today, and about our biology?

One optimistic perspective is that, just like the 80-year-old morbidly obese individual, or the 110-year-old happy smoker, we can learn by looking at the genomes of these individuals — or perhaps their lifestyle — what’s protected them from what is commonly thought of as a disease-causing insult, whether genetic or otherwise?

And indeed, there are some examples where we have found natural accidents: mutations in individuals that, for example, seem to protect them from cardiovascular disease and are now resulting in possibly useful cholesterol-lowering drugs.

From this perspective, finding these individuals — and more like them — is the tip of the spear of the new genomic medicine.

Nonetheless, I would argue that there is a less black-and-white perspective on these superheroes. And that is that they constitute a few points on a continuum of what we call the penetrance of genetic variants. By that I mean, the likelihood that a genetic variant, a mutation, will cause disease based on everything else that maintains your health. Let me get concrete: Continue reading

Opinion: What A Cancer Cure ‘Moon Shot’ Might Look Like

During his final State of the Union address, President Obama announced a new national effort to cure cancer. He said Vice President Joe Biden, who lost his 46-year-old son to cancer last year, would lead the effort. (Evan Vucci/AP)

During his final State of the Union address, President Obama announced a new national effort to cure cancer. He said Vice President Joe Biden, who lost his 46-year-old son to cancer last year, would lead the initiative. (Evan Vucci/AP)

In his final State of the Union address Tuesday night, President Obama called for a historic new effort to find a cure for cancer, a “moon shot.”  

“For the loved ones we’ve all lost, for the family we can still save, let’s make America the country that cures cancer once and for all,” Obama said in naming Vice President Joe Biden to lead the effort. 

So what might such a massive endeavor look like? Here, Barrett Rollins, M.D., Ph.D., chief scientific officer at the Dana-Farber Cancer Institute, offers his vision:

President Obama’s call for a new national effort against cancer — a “moon shot” — comes at a most opportune time. Cancer research has advanced significantly and now genomic analysis of tumors can reveal the specific DNA changes that drive cancer growth.

Our patients at Dana-Farber/Brigham and Women’s Cancer Center and Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, through the Profile research project, are benefiting from this — using the powerful technique of next-generation sequencing, scanning more than 300 cancer-related genes in every patient’s tumor to look for abnormalities. In a growing number of cases, the DNA changes can be targeted by precision therapies such as designer drugs that block overactive growth pathways. Often it will take combinations of targeted drugs to halt cancer progression, and many studies of these combinations are underway.

At the same time, there’s enormous promise in the field of immunotherapy. We’ve learned how to boost the body’s natural defenses against cancer and how to remove the molecular “brakes” that cancer cells exploit to hide from immune soldier cells and hinder their attack on tumors. Drugs that help the immune system fight cancer are coming quickly to the market, and there is promising research on related strategies such as cancer vaccines and genetic manipulation of immune cells to recognize cancer cells in the body. Continue reading

Teasing Out How Anxiety Might Be Linked To Dementia In Older Patients

Researchers report an association between anxiety and dementia in older patients. (sparkle glowplug/Flickr)

Researchers report an association between anxiety and dementia in older patients. (sparkle glowplug/Flickr)

I worry a lot about anxiety. And for good reason. Anxiety disorders are among the most common mental health woes, and they disproportionately afflict women. And increasingly, anxiety is becoming associated with all sorts of negative longer-term consequences, from greater disability among older patients and impaired cognition to higher health care costs.

A recent study of Swedish twins adds to this growing body of research: In analyzing 28 years of data from the Swedish Adoption Twin Study of Aging, researchers from the University of Southern California report that “anxiety symptoms were associated with increased risk of dementia.”

Specifically, the researchers found a “48% increased risk of becoming demented for those who had experienced high anxiety at any time compared with those who had not.”

And when the researchers compared twins, they found that among the pairs in which one twin developed dementia and the other did not: “31.6% of the time, the twin with lower anxiety was the twin who became demented, whereas, 68.4% of the time, the twin with higher anxiety was the twin who became demented. Relatively speaking then, it was about twice as risky to be the twin with the higher anxiety,” said Margaret Gatz, professor of psychology, gerontology and preventive medicine at USC and one of the study authors.

The analysis, published in the journal Alzheimer’s & Dementia, included 1,082 participants who completed questionnaires and in-person tests and underwent screening for dementia beginning in 1984 and throughout the study.

I asked the study’s first author, Andrew J. Petkus, Ph.D., in the psychology department at USC, about the findings. Here, lightly edited, is his email response:

What’s the most surprising finding in this analysis?

Anxiety was found to be associated with higher risk of dementia independent of depression. Although anxiety is the most common mental health problem in later life, it has been given comparatively less research attention than depression. Depression has been well established as a prospective risk factor for dementia. Anxiety and depression typically occur together and most of the work examining depression and dementia does not account for anxiety. Most studies that have found depression to be a risk factor for cognitive decline did not control for anxiety and therefore it is possible that they may be really picking up on anxiety instead of depression.

In addition, our twin analyses — examining cases where one twin developed dementia while the other one doesn’t — higher anxiety was still a significant predictor of dementia. In these analyses the twin who reported more anxiety was almost twice as likely to develop dementia. The twin analyses also suggest that one reason anxiety may be a risk factor in dementia is genetic factors in common to anxiety and dementia. Continue reading

Personalized Medicine Distracts From Public Health, 2 Scholars Argue

Personalized medicine is all the rage. President Obama mentioned it in his State of The Union address this year and launched a multimillion-dollar initiative to push a personalized medicine agenda forward. The head of the National Institutes of Health has made it a priority. And really, what’s not to like about the general concept of medicine that’s personalized (it’s also called “precision medicine”) —  an approach that analyzes an individual’s genetics to make medical decisions about diagnosing and treating disease.

Well, two public health scholars argue in the New England Journal of Medicine that the current high-profile fawning over personalized medicine may be a “mistake” that diverts resources away from other public health efforts that could benefit far more people.

Ronald Bayer, Ph.D., a professor at Columbia University’s Mailman School of Public Health, and Dr. Sandro Galea, dean of the Boston University School of Public Health, write in the journal that the great enthusiasm around personalized medicine “derives from the assumption that precision medicine will contribute to clinical practice and thereby advance the health of the public.” But, they note, that may not be the case:

We suggest, however, that this enthusiasm is premature. “What is needed now” is quite different if one views the world from the perspective of the broad pattern of morbidity and mortality, if one is concerned about why the United States has sunk to the bottom of the list of comparable countries in terms of disease experience and life expectancy, or if one is troubled by the steep social gradient that characterizes who becomes sick and who dies. The burgeoning precision-medicine agenda is largely silent on these issues, focusing instead on detecting and curing disease at the individual level…

Without minimizing the possible gains to clinical care from greater realization of precision medicine’s promise, we worry that an unstinting focus on precision medicine by trusted spokespeople for health is a mistake — and a distraction from the goal of producing a healthier population.

I spoke with Dr. Galea about why he and Bayer targeted personalized medicine, in particular. Here, lightly edited, is what he said:

Personalized medicine has become this rallying cry around resource allocation in the health sciences. The president mentioned in the State of the Union. There is a White House precision medicine initiative, and it has dominated much of the NIH agenda…so it seems important to address it directly…

Nobody is arguing that precision medicine does’t have potential, but the number of people who you could point to who have actually benefited from it are very small. And so we are investing in potential — which is fine — but it’s a matter of calibrating our investment. Instead of investing in a untried, untested approach, we should be investing in things that we know make a difference…

We know that macroeconomic taxation on unhealthy substances, on alcohol, for example, can save thousands of lives, early childhood education can make an enormous difference, efforts to increase and improve vaccination rates, efforts to mitigate cycles of violence, one could go on and on….these could improve the lives of hundreds and thousands of people…

Our commentary was a call for a recalibration…I think there’s a feeling in the scientific community that the precision medicine agenda is becoming the overwhelming direction in which we are headed and that we would benefit from discussion and debate and a more careful calibration of the questions we ask and where we invest our resources.

Continue reading

Practicing Restraint In A No-Empathy Zone: At The Cancer Surgeon’s Office With My Son

Cathy Corman
Guest Contributor

I carry a genetic mutation increasing my risk of developing breast and ovarian cancer. My children have a 50 percent chance of inheriting the mutation. My 22-year-old son recently noticed a breast lump and asked me to join him when he met with a surgical oncologist to be evaluated.

The surgeon performed a skillful physical exam but provided neither effective risk assessment nor empathetic counsel. Afterward, I sent an email to friends briefly explaining what had gone wrong during the appointment. “We want to know how you managed not to hit him,” they asked. I did it by practicing restraint: slowly counting backwards from 10 and taking very deep breaths.

Here’s my countdown:

10. I did not correct the icy-blue-eyed surgeon with steel-grey hair and steady hands — 50? 60? — when he dissuaded my son from pursuing genetic testing. The surgeon had shaken my son’s hand, looked him in the eye, and palpated my son’s slender, muscular chest, identifying the small lump under my son’s left nipple. A positive finding of a mutation, the surgeon said, adjusting the top of his surgical scrubs, could expose my son to discrimination in the workplace and in obtaining health insurance. That is, I did not say, “The scenario you describe is illegal in this country.” As of March 23, 2010, with the passage of the Patient Protection and Affordable Care Act (aka “Obamacare”), if anyone were to attempt to discriminate against this young man in the workplace or in the process of applying for health insurance because of a positive finding for a genetic mutation (a pre-existing condition), this person would be subject to a massive lawsuit.

Cathy Corman (Courtesy)

Cathy Corman (Courtesy)

9. When this surgeon used the word “anxiety” for the eighth time to a) describe my son and myself and b) provide his vision of a course of action, I did not refer this man to Leslie Jamison’s collection of essays, “The Empathy Exams.”  “Empathy,” writes Jamison, “isn’t just remembering to say that must really be hard — it’s figuring out how to bring difficulty into the light so it can be seen at all. Empathy isn’t just listening, it’s asking the questions whose answers need to be listened to. Empathy requires inquiry as much as imagination. Empathy requires knowing you know nothing. Empathy means acknowledging a horizon of context that extends perpetually beyond what you can see…”

8.  I did not bring up this statistic: Though men make up only 1 percent of breast cancer diagnoses annually in the U.S., they may be up to 25 percent likelier than women to die from the disease, probably because of lack of awareness and late detection. Nor did I mention that generally male breast cancer presents with a detectable lump and is almost always linked to radiation exposure, unusually high levels of estrogen or a genetic mutation. Surely the surgeon knew these statistics? But my son did not. And I did not want to scare him.

7. I said nothing to this surgeon’s response to my son’s question, “But wouldn’t it be relevant to know if I carry the mutation?” His answer: No, you know you have a family history of breast cancer.

6. I said nothing when this surgeon dodged my son’s question: “If my grandfather didn’t have the mutation,” my son wanted to know, “wouldn’t he not have had breast cancer? And wouldn’t it be important for me to know if I carry the mutation, too, to assess my risk?” The surgeon’s reply: The only way you’ll know if you have cancer is to have the lump removed. The surgeon’s answer, while true, sidestepped the elephant in the room: whether my son carries a mutation elevating his risk of breast cancer.

5. When this surgeon ridiculed an actress whose name he could not remember for publicly disclosing her status as a mutation carrier and for undergoing prophylactic mastectomies, I offered him the actress’s name. 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

The Complex Interplay Of Genetics And The Placebo Response

Why do some people respond to placebos while others don’t?

One possible answer: genetics.

A provocative new paper introducing the concept of a “placebome” — that is, the complex interplay between genetics and an individual’s response to placebos — raises questions that might ultimately lead to changes in how clinical studies of drugs are evaluated.

Indeed, researchers from Harvard Medical School suggest that genes, and genetic variation, might play a far bigger role in the placebo response than previously thought.

That the placebo effect is an actual physiological response is well established. But the new report, a research review, looks specifically at the placebo response in the context of drug studies, where some participants get the active medication while others get a placebo, or non-active version of the drug.

The new findings, “call into question whether or not the outcomes in a drug treatment arm of a clinical trial are limited to the effect of the drug on the condition,” says Kathryn Hall, an integrative medicine fellow in the Division of General Medicine and Primary Care at Beth Israel Deaconess Medical Center, and one of the study authors.

Instant Vantage/flickr

Instant Vantage/flickr

Several neurotransmitters, such as dopamine, appear to be involved in the placebo response, Hall said, and variation in the genes in these pathways appears to change our response to placebo. So different people with different genotypes respond differently to placebos.

But Hall takes it one step further. “When you are in a trial you don’t know if you are getting the drug or the placebo, so not just the people in the placebo arm can have placebo responses. We are curious about the drugs’ effect on the placebo response.”

It’s all a bit tough to wrap your brain around, so I asked Hall to give me an example. Here’s what she said:

In the literature we see several studies in which in the placebo arm one group of people with a certain genotype have a strong placebo response and the other group has a weak placebo response. And when we look at the drug treatment arm, we see the outcomes are reversed, the people who had the strong response in the placebo arm now have a low response and the people who didn’t have a response in the placebo arm now have a strong response. The historical interpretation of these results has been that only one group of people responds to the drug and we’re pointing out that it’s more complicated than that. It’s that one group responded to the placebo and that response is eliminated in the drug treatment arm.

What all this means in the real world is still hard to know. But in their paper published this week in the journal, Trends in Molecular Medicine, the researchers offer these three key takeaways in the abstract:

•The predisposition to respond to placebo treatment may be in part a stable heritable trait.

•Candidate placebo response pathways may interact with drugs to modify outcomes in the drug treatment arms of clinical trials.

•Genomic analysis of randomized placebo and no-treatment controlled trials are needed to fully realize the potential of the placebome.

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