A Blended Family: Her Mother Was Neanderthal, Her Father Something Else Entirely

In a limestone cave nestled high above the Anuy River in Siberia, scientists have discovered the fossil of an extraordinary human hybrid.

The 90,000-year-old bone fragment came from a female whose mother was Neanderthal, according to an analysis of DNA discovered inside it. But her father was not: He belonged to another branch of ancient humanity known as the Denisovans.

Scientists have been recovering genomes from ancient human fossils for just over a decade. Now, with the discovery of a Neanderthal-Denisovan hybrid, the world as it was tens of thousands of years ago is coming into remarkable new focus: home to a marvelous range of human diversity.

In 2010, researchers working in the Siberian cave, called Denisova, announced they had found DNA from a scrap of bone representing an unknown group of humans. Subsequent discoveries in the cave confirmed that the Denisovans were a lineage distinct from modern humans.

Scientists can’t yet say what Denisovans looked like or how they behaved, but it’s clear they were separated from Neanderthals and modern humans by hundreds of thousands of years of evolution.

Until now, scientists had indirect clues that Neanderthals, Denisovans and modern humans interbred, at least a few times. But the new study, published on Wednesday in the journal Nature, offers clear evidence.

“They managed to catch it in the act — it’s an amazing discovery,” said Sharon Browning, a statistical geneticist at the University of Washington who was not involved in the new study.

What makes the discovery all the more remarkable is that scientists didn’t have to look all that long to find a hybrid. Until today, scientists had discovered only four Denisovans; the fifth turned out to be a first-generation hybrid.

Hybrids may not have been all that uncommon. In 2015, researchers discovered that a modern human who lived in what is now Romania 40,000 years ago had a great-great-grandparent who was Neanderthal.

“It seems that this world at this time was a place full of near-hybrids,” said David Reich, a geneticist at Harvard University who was not involved in the new study. “It must have been a very interesting place.”

A view of a valley beyond the Denisova Cave archaeological site, Russia.CreditBence Viola, Max Planck Institute for Evolutionary Anthropology

The discovery in 2010 of the first Denisovan fossil (called Denisova 3) spurred Russian researchers to carry out a more systematic exploration of the cave floor. It is littered with bone fragments, deposited in sedimentary layers.

Many of those mysterious fragments were sent to Svante Paabo, a renowned geneticist and the director of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany.

The cave, it turned out, had a long history of occupation. The researchers found the genome of a Neanderthal in a toe bone dating back 120,000 years.

Denisovans appeared later, and from the fossils alone it was hard for scientists to know if Denisovans and Neanderthals had ever come into contact. But their DNA hinted at one union, at least: Denisova 3’s genome, researchers discovered, contained traces of Neanderthal DNA.

The newly discovered hybrid came to the attention of Dr. Paabo’s team in 2014, when Russian collaborators sent his team 2,000 badly damaged bone fragments from the cave.

“You can’t even tell if they’re human or animal,” Dr. Paabo said in an interview.

He and his colleagues extracted collagen from the bones and compared the protein to that of living species. Only one fragment had collagen that resembled our own.

That fragment came from an arm or leg bone — it’s impossible to say which. The bone is thick, which means that it belonged to someone at least 13 years old.

Viviane Slon, then a graduate student at the institute, led a search for DNA in the fragment. She began by hunting for a special set of genes found in the fuel-generating factories of the cell, called mitochondria.

Mitochondria carry a set of genes distinct from those of the cell’s nucleus; these genes, unlike those in the nucleus, are inherited solely from the mother.

In 2016, Dr. Slon and her colleagues reported that they had gotten mitochondrial DNA from the mysterious bone fragment, and that it closely matched genetic material from Neanderthals.

The researchers called that individual Denisova 11, and they began searching the bone for nuclear DNA. Fragment by fragment, they began reconstructing the entire genome.

Strangely, only some of the fragments of nuclear DNA matched Neanderthal genes. There was just as much Denisovan DNA in the bone.

“I was wondering, ‘What did I do wrong?’” recalled Dr. Slon, now a postdoctoral researcher at the institute.

In each pair of chromosomes, one came from a Neanderthal, the other from a Denisovan. This individual, she and her colleagues concluded, was a hybrid. “It was a good proof that this was real,” she said.

An examination of the X chromosome showed that Denisova 11 was female. As for which parent was which, the mitochondrial DNA held the answer: Since these genes are only passed down from mothers, Denisova 11’s mother was Neanderthal.

Her Denisovan father’s kin were local, it turned out. His DNA most closely resembles the genetic material from Denisova 3’s pinky, discovered at the cave in 2010. She lived in the cave a few thousand years after Denisova 11, the hybrid human.

Her Neanderthal mother, however, was closely related to Neanderthals who lived thousands of miles to the west in what is now Croatia, 20,000 years after Denisova 11 died. She was only distantly related to the Neanderthals who lived in the cave 120,000 years ago.

“It seems like Neanderthals were moving around quite a bit,” said Dr. Browning.

Dr. Paabo said it’s not possible to figure out why the Neanderthals traveled, or when, until more genomes are discovered.

Despite interbreeding, Neanderthals and Denisovans never merged into a single genetic population. For hundreds of thousands of years, they remained distinct.

It’s possible they simply didn’t have much opportunity to mate because they lived in small groups spread out across a vast landscape, Dr. Paabo suggested.

“They didn’t meet that often, but when they met they seemed to not have prejudices against each other and mixed freely,” he said.

It’s also possible that hybrids suffered from reproductive disorders, having fewer children than humans without mixed DNA.

Broader interbreeding may have gained momentum when modern humans emerged from Africa roughly 70,000 years ago.

Modern humans lived in bigger, denser groups than Neanderthals or Denisovans, and they moved quickly across Europe and Asia. Recent archaeological digs suggest they reached Australia as early as 65,000 years ago.

Our own DNA provides evidence that those early modern humans interbred with Neanderthals and Denisovans. People with non-African ancestry have fragments of Neanderthal DNA in their genomes, and Denisovan DNA is present in East Asians, Aboriginal Australians and other populations.

Dr. Paabo wonders if it’s a coincidence that these branches of humanity vanished from the fossil record shortly after modern humans showed up in their territories. Neanderthals disappear from the fossil record 40,000 years ago. Evidence from the Siberian cave indicates that Denisovans were gone by then, too.

“Maybe Neanderthals and Denisovans were absorbed into the modern human populations,” said Dr. Paabo. “That could be a big part of the story.”



This article was originally published in The New York Times.  Read the original article.

Clues to Your Health Are Hidden at 6.6 Million Spots in Your DNA

Scientists have created a powerful new tool to calculate a person’s inherited risks for heart disease, breast cancer and three other serious conditions.

By surveying changes in DNA at 6.6 million places in the human genome, investigators at the Broad Institute and Harvard University were able to identify many more people at risk than do the usual genetic tests, which take into account very few genes.

Of 100 heart attack patients, for example, the standard methods will identify two who have a single genetic mutation that place them at increased risk. But the new tool will find 20 of them, the scientists reported on Monday in the journal Nature Genetics.

The researchers are now building a website that will allow anyone to upload genetic data from a company like 23andMe or Ancestry.com. Users will receive risk scores for heart disease, breast cancer, Type 2 diabetes, chronic inflammatory bowel disease and atrial fibrillation.

People will not be charged for their scores.

A risk score, including obtaining the genetic data, should cost less than $100, said Dr. Daniel Rader, a professor of molecular medicine at the University of Pennsylvania.

Dr. Rader, who was not involved with the study, said the university will soon be offering such a test to patients to assess their risk for heart disease. For now, the university will not charge for it.

Dr. Sekar Kathiresan, senior author of the new paper and director of the Center for Genomic Medicine at Massachusetts General Hospital, said his team had validated the heart risk calculation in multiple populations.

But DNA is not destiny, Dr. Kathiresan stressed. A healthy lifestyle and cholesterol-lowering medications can substantially reduce risk of heart attack, even in those who have inherited a genetic predisposition.

The new tool also can find people at the low end of the risk range for the five diseases. This should prove useful to certain patients: for example, a woman who is trying to decide when she should start having regular mammograms, or a 40-year-old man with a slightly high cholesterol level who wants to know if he should take a statin.

Still, there are concerns about how the genetic test will be used. “It carries great hope, but also comes with a lot of questions,” said Dr. David J. Maron, director of preventive cardiology at Stanford University.

“Who should get tested? How should the results be provided? Physicians are not generally well trained to provide genetic test results.”

And, he wondered, will the results actually lead people to make decisions that improve their health?

People may need genetic counseling before and after getting these sorts of risk scores, noted Eric Schadt, dean of precision medicine at the Icahn School of Medicine at Mount Sinai.

Patients may not appreciate the consequences of learning they have a high likelihood of having a heart attack or breast cancer or one of the other diseases the test assesses.

“Do people really understand that once you learn something you cannot unlearn it?” said Dr. Schadt, who is also chief executive of Sema4, a diagnostics company.

But medical experts said this sort of risk assessment is the wave of the future. “I’m not sure we can stop it,” said Dr. John Mandrola, a cardiac electrophysiologist at Baptist Health in Louisville, Ky.

The study began because there was general agreement among researchers that many common diseases are linked not to one mutation, but rather to thousands or millions of mutations, said the first author of the new paper, Dr. Amit V. Khera, a cardiologist at Massachusetts General Hospital and a researcher at the Broad Institute.

In recent years, scientists have cataloged more than 6 million tiny changes in DNA that slightly affect the chances that people will get various diseases.

Each of those genetic alterations has such a small effect — a 1 percent or so increase or decrease in a person’s odds of getting a disease — that it would not be helpful to test for each one in isolation.

But it should be possible, scientists felt, to combine data on all the small DNA changes to construct an individual risk score. To do that, the researchers needed a new algorithm that would weigh the significance of the variations in the genes.

Then they had to test the risk scores they obtained. Dr. Khera and his colleagues turned to the U.K. Biobank, which holds genetic and disease information on half a million people.

The investigators found that their algorithm did predict the odds of being diagnosed with one of the five diseases. But the U.K. Biobank consists mostly of white Europeans.

So the investigators also tested and validated their method in populations of East Asians, South Asians, African Americans and Hispanics.

The researchers also tried their algorithm on 20,000 patients who were seen at Brigham and Women’s Hospital and Massachusetts General Hospital.

They found that those who had a high risk score for a heart attack were indeed four times more likely to have had a heart attack than other patients.

“Unless I do this genetic testing, there is no way I could pick those people out,” Dr. Khera said.

Just as important is finding people at very low risk, he and other researchers said.

At the University of Pennsylvania, doctors will incorporate risk scores on heart attacks into advice to patients on preventive care.

Dr. Rader said he often sees healthy patients in their 30s and 40s with a family history of heart disease. They have borderline levels of LDL cholesterol, the dangerous kind. But many do not want to start taking a statin.

For now, he said, he does his best to assess their risk, then tells some of them “it’s kind of up to you” whether to take a statin. But that advice “is not very satisfying,” he said.

A sophisticated genetic risk score might decide the matter. “If you have a really high score, here’s your prescription,” he said. “If your score is pretty low, you can hold off.”

This sort of sophisticated genetic analysis is still very new, Dr. Mandrola noted. But, he said, in five or 10 years doctors “may look back on the way they predict risk today and ask, ‘What were we thinking?’”


This article was originally published in The New York Times.  Read the original article.

The ‘Zombie Gene’ That May Protect Elephants From Cancer

Elephants ought to get a lot of cancer. They’re huge animals, weighing as much as eight tons. It takes a lot of cells to make up that much elephant.

All of those cells arose from a single fertilized egg, and each time a cell divides, there’s a chance that it will gain a mutation — one that may lead to cancer.

Strangely, however, elephants aren’t more prone to cancer than smaller animals. Some research even suggests they get less cancer than humans do.

On Tuesday, a team of researchers reported what may be a partial solution to that mystery: Elephants protect themselves with a unique gene that aggressively kills off cells whose DNA has been damaged.

Somewhere in the course of evolution, the gene had become dormant. But somehow it was resurrected, a bit of zombie DNA that has proved particularly useful.

Vincent J. Lynch, an evolutionary biologist at the University of Chicago and a co-author of the paper, published in Cell Reports, said that understanding how elephants fight cancer may provide inspiration for developing new drugs.

“It might tell us something fundamental about cancer as a process. And if we’re lucky, it might tell us something about how to treat human disease,” Dr. Lynch said.

Scientists have puzzled over cancer, or the lack thereof, in big animals since the 1970s. In recent years, some researchers have started carrying out detailed studies of the genes and cells of these species, searching for unexpected strategies for fighting the disease.

Some of the first research focused on a well-studied anticancer gene called p53. It makes a protein that can sense when DNA gets damaged. In response, the protein switches on a number of other genes.

A cell may respond by repairing its broken genes, or it may commit suicide, so that its descendants will not have the chance to gain even more mutations.

In 2015, Dr. Lynch and his colleagues discovered that elephants have evolved unusual p53 genes. While we only have one copy of the gene, elephants have 20 copies. Researchers at the University of Utah independently made the same discovery.

Both teams observed that the elephant’s swarm of p53 genes responds aggressively to DNA damage. Their bodies don’t bother with repairing cells — they only orchestrate the damaged cell’s death.

Dr. Lynch and his colleagues continued their search for cancer-fighting genes, and they soon encountered another one, called LIF6, that only elephants seem to possess.

In response to DNA damage, p53 proteins in elephants switch on LIF6. The cell makes LIF6 proteins, which then wreak havoc.

Dr. Lynch’s experiments indicate that LIF6 proteins make their way to the cell’s tiny fuel-generating factories, called mitochondria.

The proteins pry open holes in the mitochondria, allowing molecules to pour out. The molecules from mitochondria are toxic, causing the cell to die.

“This adds an important piece to the puzzle,” said Dr. Joshua D. Schiffman, a pediatric oncologist at the Huntsman Cancer Institute at the University of Utah who has also studied cancer in elephants.

More experiments are needed to confirm that LIF6 works the way Dr. Lynch and his colleagues propose, Dr. Schiffman added. “As a start, I think this is fantastic,” he said.

LIF6 has a bizarre evolutionary history, as it turns out.

All mammals carry a similar gene, simply called LIF. In our own cells, it performs several different jobs, such as sending signals from one cell to another. But almost all mammals — ourselves included — have only one copy.

The only exceptions to that rule are elephants and their close relatives, such as manatees, Dr. Lynch and his colleagues found. These mammals have several copies of LIF; elephants have ten.

These copies arose thanks to sloppy mutations in the ancestors of manatees and elephants more than 80 million years ago.

These newer copies of the original LIF gene lack a stretch of DNA that acts as an on-off switch. As a result, the genes could not make their proteins. (Humans also carry thousands of copies of so-called pseudogenes.)

After the ancestors of elephants evolved ten LIF genes, however, something remarkable happened: One of these dead genes came back to life. That gene is LIF6.

Somewhere in the course of elephant evolution, a cellular mutation inserted a genetic switch next to LIF6, enabling the gene to be activated by p53. The resurrected gene now made a protein that could do something new: attack mitochondria and kill damaged cells.

To find out when the LIF6 gene first came back to life, the researchers took a close looks at DNA retrieved from fossils.

Mastodons and mammoths also carried LIF6. Scientists estimate that they shared a common ancestor with modern elephants that lived 26 million years ago.

Dr. Lynch speculated that LIF6 came back to life at the same time that the ancestors of living elephants evolved extra copies of p53. As they developed more powerful defenses against cancer, the animals could begin reaching their enormous sizes.

Elephants likely evolved other new genes that follow p53’s orders, Dr. Lynch predicted. He also suspects that elephants have also evolved ways to fight cancer that are separate from p53 altogether.

“I think it’s all of the above,” he said. “There are lots of stories like LIF6 in the elephant genome, and I want to know them all.”


This article was originally published in The New York Times.  Read the original article.

A targeted approach to treating glioma

Glioma, a type of brain cancer, is normally treated by removing as much of the tumor as possible, followed by radiation or chemotherapy. With this treatment, patients survive an average of about 10 years, but the tumors inevitably grow back.

A team of researchers from MIT, Brigham and Women’s Hospital, and Massachusetts General Hospital hopes to extend patients’ lifespan by delivering directly to the brain a drug that targets a mutation found in 20 to 25 percent of all gliomas. (This mutation is usually seen in gliomas that strike adults under the age of 45.) The researchers have devised a way to rapidly check for the mutation during brain surgery, and if the mutation is present, they can implant microparticles that gradually release the drug over several days or weeks.

“To provide really effective therapy, we need to diagnose very quickly, and ideally have a mutation diagnosis that can help guide genotype-specific treatment,” says Giovanni Traverso, an assistant professor at Brigham and Women’s Hospital, Harvard Medical School, a research affiliate at MIT’s Koch Institute for Integrative Cancer Research, and one of the senior authors of the paper.

The researchers are also working ways to identify and target other mutations found in gliomas and other types of brain tumors.

“This paradigm allows us to modify our current intraoperative resection strategy by applying molecular therapeutics that target residual tumor cells based on their specific vulnerabilities,” says Ganesh Shankar, who is currently completing a spine surgery fellowship at Cleveland Clinic prior to returning as a neurosurgeon at Massachusetts General Hospital, where he performed this study.

Shankar and Koch Institute postdoc Ameya Kirtane are the lead authors of the paper, which appears in the Proceedings of the National Academy of Sciences the week of Aug. 6. Daniel Cahill, a neurosurgeon at MGH and associate professor at Harvard Medical School, is a senior author of the paper, and Robert Langer, the David H. Koch Institute Professor at MIT, is also an author.

Targeting tumors

The tumors that the researchers targeted in this study, historically known as low-grade gliomas, usually occur in patients between the ages of 20 and 40. During surgery, doctors try to remove as much of the tumor as possible, but they can’t be too aggressive if tumors invade the areas of the brain responsible for key functions such as speech or movement. The research team wanted to find a way to locally treat those cancer cells with a targeted drug that could delay tumor regrowth.

To achieve that, the researchers decided to target a mutation called IDH1/2. Cancer cells with this mutation shut off a metabolic pathway that cells normally use to create a molecule called NAD, making them highly dependent on an alternative pathway that requires an enzyme called NAMPT. Researchers have been working to develop NAMPT inhibitors to treat cancer.

So far, these drugs have not been used for glioma, in part because of the difficulty in getting them across the blood-brain barrier, which separates the brain from circulating blood and prevents large molecules from entering the brain. NAMPT inhibitors can also produce serious side effects in the retina, bone marrow, liver, and blood platelets when they are given orally or intravenously.

To deliver the drugs locally, the researchers developed microparticles in which the NAMPT inhibitor is embedded in PLGA, a polymer that has been shown to be safe for use in humans. Another desirable feature of PLGA is that the rate at which the drug is released can be controlled by altering the ratio of the two polymers that make up PLGA — lactic acid and glycolic acid.

To determine which patients would benefit from treatment with the NAMPT inhibitor, the researchers devised a genetic test that can reveal the presence of the IDH mutation in approximately 30 minutes. This allows the procedure to be done on biopsied tissue during the surgery, which takes about four hours. If the test is positive, the microparticles can be placed in the brain, where they gradually release the drug, killing cells left behind during the surgery.

In tests in mice, the researchers found that treatment with the drug-carrying particles extended the survival of mice with IDH mutant-positive gliomas. As they expected, the treatment did not work against tumors without the IDH mutation. In mice treated with the particles, the team also found none of the harmful side effects seen when NAMPT inhibitors are given throughout the body.

“When you dose these drugs locally, none of those side effects are seen,” Traverso says. “So not only can you have a positive impact on the tumor, but you can also address the side effects which sometimes limit the use of a drug that is otherwise effective against tumors.”

The new approach builds on similar work from Langer’s lab that led to the first FDA-approved controlled drug-release system for brain cancer — a tiny wafer that can be implanted in the brain following surgery.

“I am very excited about this new paper, which complements very nicely the earlier work we did with Henry Brem of Johns Hopkins that led to Gliadel, which has now been approved in over 30 countries and has been used clinically for the past 22 years,” Langer says.

An array of options

The researchers are now developing tests for other common mutations found in brain tumors, with the goal of devising an array of potential treatments for surgeons to choose from based on the test results. This approach could also be used for tumors in other parts of the body, the researchers say.

“There’s no reason this has to be restricted to just gliomas,” Shankar says. “It should be able to be used anywhere where there’s a well-defined hotspot mutation.”

They also plan to do some tests of the IDH-targeted treatment in larger animals, to help determine the right dosages, before planning for clinical trials in patients.

“We feel its best use would be in the early stages, to improve local control and prevent regrowth at the site,” Cahill says. “Ideally it would be integrated early in the standard-of-care treatment for patients, and we would try to put off the recurrence of the disease for many years or decades. That’s what we’re hoping.”




This article was originally published in MIT News. Read the original article.

Sensor could help doctors select effective cancer therapy

MIT chemical engineers have developed a new sensor that lets them see inside cancer cells and determine whether the cells are responding to a particular type of chemotherapy drug.

The sensors, which detect hydrogen peroxide inside human cells, could help researchers identify new cancer drugs that boost levels of hydrogen peroxide, which induces programmed cell death. The sensors could also be adapted to screen individual patients’ tumors to predict whether such drugs would be effective against them.

“The same therapy isn’t going to work against all tumors,” says Hadley Sikes, an associate professor of chemical engineering at MIT. “Currently there’s a real dearth of quantitative, chemically specific tools to be able to measure the changes that occur in tumor cells versus normal cells in response to drug treatment.”

Sikes is the senior author of the study, which appears in the Aug. 7 issue of Nature Communications. The paper’s first author is graduate student Troy Langford; other authors are former graduate students Beijing Huang and Joseph Lim and graduate student Sun Jin Moon.

Tracking hydrogen peroxide

Cancer cells often have mutations that cause their metabolism to go awry and produce abnormally high fluxes of hydrogen peroxide. When too much of the molecule is produced, it can damage cells, so cancer cells become highly dependent on antioxidant systems that remove hydrogen peroxide from cells.

Drugs that target this vulnerability, which are known as “redox drugs,” can work by either disabling the antioxidant systems or further boosting production of hydrogen peroxide. Many such drugs have entered clinical trials, with mixed results.

“One of the problems is that the clinical trials usually find that they work for some patients and they don’t work for other patients,” Sikes says. “We really need tools to be able to do more well-designed trials where we figure out which patients are going to respond to this approach and which aren’t, so more of these drugs can be approved.”

To help move toward that goal, Sikes set out to design a sensor that could sensitively detect hydrogen peroxide inside human cells, allowing scientists to measure a cell’s response to such drugs.

Existing hydrogen peroxide sensors are based on proteins called transcription factors, taken from microbes and engineered to fluoresce when they react with hydrogen peroxide. Sikes and her colleagues tried to use these in human cells but found that they were not sensitive in the range of hydrogen peroxide they were trying to detect, which led them to seek human proteins that could perform the task.

Through studies of the network of human proteins that become oxidized with increasing hydrogen peroxide, the researchers identified an enzyme called peroxiredoxin that dominates most human cells’ reactions with the molecule. One of this enzyme’s many functions is sensing changes in hydrogen peroxide levels.

Langford then modified the protein by adding two fluorescent molecules to it — a green fluorescent protein at one end and a red fluorescent protein at the other end. When the sensor reacts with hydrogen peroxide, its shape changes, bringing the two fluorescent proteins closer together. The researchers can detect whether this shift has occurred by shining green light onto the cells: If no hydrogen peroxide has been detected, the glow remains green; if hydrogen peroxide is present, the sensor glows red instead.

Predicting success

The researchers tested their new sensor in two types of human cancer cells: one set that they knew was susceptible to a redox drug called piperlongumine, and another that they knew was not susceptible. The sensor revealed that hydrogen peroxide levels were unchanged in the resistant cells but went up in the susceptible cells, as the researchers expected.

Sikes envisions two major uses for this sensor. One is to screen libraries of existing drugs, or compounds that could potentially be used as drugs, to determine if they have the desired effect of increasing hydrogen peroxide concentration in cancer cells. Another potential use is to screen patients before they receive such drugs, to see if the drugs will be successful against each patient’s tumor. Sikes is now pursuing both of these approaches.

“You have to know which cancer drugs work in this way, and then which tumors are going to respond,” she says. “Those are two separate but related problems that both need to be solved for this approach to have practical impact in the clinic.”




This article was originally published in MIT News. Read the original article.

Genetic Tests Can Hurt Your Chances Of Getting Some Types Of Insurance

Taking a genetic test in your 20s or 30s could, indeed, affect your ability to get long-term-care insurance later — or at least the price you’ll pay. And people who are considering enrolling in Medicare after age 65 would do well to read the fine print of the sign-up rules. Readers have insurance questions on these topics this month, and we have answers:

Q: Can getting a genetic test interfere with being able to buy long-term-care insurance in the future? If you do get a plan, can the insurer drop you after you find out the results of a genetic test?

In general, long-term-care insurers can indeed use genetic test results when they decide whether to offer you coverage. The federal Genetic Information Nondiscrimination Act does prohibit insurers from asking for or using your genetic information to make decisions about whether to sell you health insurance or how much to charge you. But those privacy protections don’t apply to long-term-care policies, life insurance or disability insurance.

When you apply for a long-term-care policy, the insurer is permitted to review your medical records and ask you questions about your health history and that of your family. It’s all part of the underwriting process to determine whether to offer you a policy and how much to charge.

If the insurer asks you whether you’ve undergone genetic testing, you generally must disclose it, even if the testing was performed through a direct-to-consumer site like 23andMe, says Catherine Theroux, a spokeswoman for LIMRA, an insurance industry trade group.

You should release any medically relevant information, she says.

Some states provide extra consumer protections related to genetic testing and long-term-care insurance, says Sonia Mateu Suter, a law professor at George Washington University who specializes in genetics and the law. But most follow federal law.

If you get genetic testing after you have a policy, the results can’t affect your coverage.

“Once the policy has been underwritten and issued, the insurer doesn’t revoke the policy if new medical information comes to light,” Theroux says.



This article was originally published in NPR. Read the original article.

Anti-Vaccine Activists Have Taken Vaccine Science Hostage

Americans who don’t want to vaccinate are increasingly getting their way: A June study found that, over the past decade, the number of philosophical vaccine exemptions rose in two-thirds of the states that allow them.

What drives these wrongheaded decisions is fear — fear that vaccines are somehow dangerous, even though research shows the opposite. And these choices have consequences. The 2015 Disneyland measles outbreaksickened at least 125 people, many of them unvaccinated.

As a science journalist, I’ve written several articles to quell vaccine angst and encourage immunization. But lately, I’ve noticed that the cloud of fear surrounding vaccines is having another nefarious effect: It is eroding the integrity of vaccine science.

In February I was awarded a fellowship by the nonpartisan Alicia Patterson Foundation to report on vaccines. Soon after, I found myself hitting a wall. When I tried to report on unexpected or controversial aspects of vaccine efficacy or safety, scientists often didn’t want to talk with me. When I did get them on the phone, a worrying theme emerged: Scientists are so terrified of the public’s vaccine hesitancy that they are censoring themselves, playing down undesirable findings and perhaps even avoiding undertaking studies that could show unwanted effects. Those who break these unwritten rules are criticized.

The goal is to protect the public — to ensure that more people embrace vaccines — but in the long-term, the approach will backfire. Our arsenal of vaccines is exceptional, but it could always be better. Progress requires scientific candor and a willingness to ask inconvenient questions.

Here’s a case that typifies this problem and illustrates how beneficial it can be when critical findings get published. In 2005, Lone Simonsen, who was then with the National Institute of Allergy and Infectious Diseases, and her colleagues published a study in JAMA Internal Medicine showing that the flu vaccine prevented fewer deaths than expected in people over 65.

“I had interesting conversations with vaccine people. They said, ‘What are you doing, Lone? You are ruining everything,’” recalls Dr. Simonsen, who is now a global public health researcher at George Washington University. Her work helped lead to the development of a more effective flu vaccine for older people, yet she felt ostracized. “I felt it personally, because I wasn’t really invited to meetings,” she says. “It took a good decade before it was no longer controversial.”

It’s understandable for scientists to be nervous. The internet has made it easy for anti-vaccine activists to mislead. Dr. Simonsen’s study, for instance, inspired a story with the ridiculous headline “Flu Vaccines Are Killing Senior Citizens, Study Warns.”

But concerns over what these groups might do are starting to take precedence over scientific progress.

“Scientists’ perception of public irrationality is having an impact on our ability to rationally discuss things that deserve discussion,” says Andrew Read, the director of the Center for Infectious Disease Dynamics at Pennsylvania State University. Dr. Read studies how pathogens evolve in response to vaccines, and he is fiercely pro-vaccine — his goal is to keep the shots effective. He says he has had unpleasant encounters at scientific conferences; colleagues have warned him, for instance, not to talk too openly about his work. “I have felt the pressure — and for that matter the responsibility — acutely,” he says.

In 2009, Danuta Skowronski, the lead epidemiologist in the division of Influenza and Emerging Respiratory Pathogens at the British Columbia Center for Disease Control, and her colleagues stumbled across unexpected data that suggested a link between seasonal flu shots and an increased risk for pandemic flu. The findings could not prove a causal link — perhaps people who get seasonal flu shots differ from those who don’t in ways that make them more susceptible to pandemic strains. But one possible interpretation is that seasonal flu shots inhibit immunity to those strains. Dr. Skowronski’s team replicated the findings in five different studies and then shared the data with trusted colleagues. “There was tremendous pushback,” Dr. Skowronski recalls, and some questioned whether “the findings were appropriate for publication.”

“I believed I had no right to not publish those findings,” Dr. Skowronski says. “They were too important.” The findings were submitted to three journals and underwent at least eight lengthy reviews before the final study was published in PloS Medicine.

Last September, researchers with the Vaccine Safety Datalink, a collaborative project between the Centers for Disease Control and Prevention and various health care organizations, published a study in the journal Vaccine that found an association — not a causal link, the authors were careful to note — between a flu vaccine and miscarriage. Soon after, Paul Offit, the director of the Vaccine Education Center at the Children’s Hospital of Philadelphia and co-inventor of a lifesaving rotavirus vaccine, said in The Daily Beast that the paper shouldn’t have been published, in part because the study was small and conflicted with earlier research. He also suggested that the authors had cherry-picked their data — a charge they vehemently deny. One physician questioned in the popular blog Science-Based Medicine why the research had been funded in the first place.

Dr. Offit says that researchers should handle findings differently when there’s a chance they might frighten the public. He thinks that small, inconclusive, worrying studies should not be published because they could do more harm than good. “Knowing that you’re going to scare people, I think you have to have far more data,” he explains.

But even an inconclusive paper can be important, others say, as it can spur the larger, more definitive studies that are needed. It should be “put out there for the scientific community, to look at it, see it, know about it, refine study design and go and look again,” says Gregory Poland, a Mayo Clinic vaccinologist and the editor in chief of Vaccine. It is crucial, though, for researchers to carefully explain such results in their papers to prevent misinterpretation.

If a study scares parents away from vaccines, people could die. That’s a big risk to take to protect the sanctity of scientific discourse. I was warned several times that covering this issue could leave me with “blood on my hands,” too. But in the long run, isn’t stifling scientific inquiry even more dangerous?

“If we get to the point where we don’t want to look anymore because we don’t want to know the answer, then we’re in trouble,” says Dr. Edward Belongia, one of the authors of the Vaccine study and director of the Center for Clinical Epidemiology and Population Health at the Marshfield Clinic Research Institute.

This is not to say that anyone is covering up major safety problems, by the way; critical studies generally concern minor issues in specific contexts. But scientists could one day miss more important problems if they embrace a culture that suppresses research. And at the end of the day, by cherry-picking data, public health researchers are doing “exactly what the anti-vaccine people do,” Michael Osterholm, the director of the Center for Infectious Disease Research and Policy at the University of Minnesota, warns.

There’s no question that bad vaccine science does not deserve a forum — and much of the research cited by anti-vaccine activists is very bad indeed. But good science needs to be heard even if some people will twist its meaning. One thing vaccine scientists and vaccine-wary parents have in common is a desire for the safest and most effective vaccines possible — but vaccines can’t be refined if researchers ignore inconvenient data. Moreover, vaccine scientists will earn a lot more public trust, and overcome a lot more unfounded fear, if they choose transparency over censorship.

This article was originally published in The New York Times.  Read the original article.

The Genetic Test Some Men Don’t Know They Need

Mark Meerschaert learned from a posting in a family Facebook group a few years ago that a close male relative tested positive for an inherited mutation in the BRCA2 gene. The gene mutation is widely associated with female breast and ovarian cancer, but increases risk for other cancers, too. The relative suggested that family members consider getting tested.

Dr. Meerschaert, a 62-year-old statistics and probability professor at Michigan State University, ignored the advice at first. He had already been diagnosed with prostate cancer, and as the father of two sons, getting tested didn’t feel urgent or relevant in the same way it might have, he says, if he had daughters. “I was still thinking about it mainly as a problem for the women in the family,” he says.

He isn’t alone. When it comes to genetic testing that may indicate increased cancer risk, a gender gap is worrying researchers.

Mark Meerschaert holds his granddaughter. He urged his children to get tested for an inherited mutation on the BRCA gene.
Mark Meerschaert holds his granddaughter. He urged his children to get tested for an inherited mutation on the BRCA gene. PHOTO: MARK MEERSCHAERT

Women and men who carry inherited BRCA gene mutations associated with increased cancer risk have an even chance of passing them on to their children. But women received genetic testing for hereditary cancer risk three times as often than men in a study published in June in the journal JAMA Oncology. When it came to genetic testing for mutations associated with hereditary breast and ovarian cancer syndrome, such as BRCA1 and BRCA2, the gender gap was even greater: Women were 10 times as likely to get tested than men.

Those inherited gene mutations have health implications for men, too. Men are at higher risk for developing prostate cancer, male breast cancer, pancreatic cancer and melanoma.

Genetic Gender Gap

A study of U.S. adults found most people getting tested for inherited gene mutations were women.



Any type of cancer risk



Breast/ovarian cancer risk



Sources: JAMA Oncology; Christopher Childers, M.D., David Geffen School of Medicine at UCLA

“We were really struck by the massive disparity,” says Christopher Childers, resident physician in the department of surgery at the David Geffen School of Medicine at UCLA and senior author of the JAMA Oncology paper.

Studies about who gets genetic testing in general are evolving. Research like the recent JAMA study confirms what genetic counselors have been seeing: many more women than men coming in for testing.

Doctors and researchers are launching new efforts to address the disparity, starting with men who may already have medical issues or a family history of cancer.

The National Comprehensive Cancer Network, a nonprofit alliance of national cancer centers, recently modified guidelines to include a recommendation that men with metastatic prostate cancer should consider genetic testing. Researchers at Fred Hutchinson Cancer Research Center and the University of Washington launched the Gentlemen study, offering free genetic testing to 2,000 men with advanced prostate cancer to determine if they have inherited mutations linked to increased cancer risk.

Some researchers say genetic testing for men has lagged behind women because scientists still don’t know enough about which mutations increase men’s cancer risk, or by how much. (Previous studies indicate that men are generally less likely than women to go to the doctor.)

Data from recent studies published in the scientific literature helped drive the decision to open the Prostate Cancer Genetics Clinic at the Seattle Cancer Care Alliance, says Heather Cheng, an oncologist, director of the clinic, and a lead investigator of the Gentlemen study. “We want to have a new conversation with men,” she says.

Some researchers believe social factors contribute to a testing gap. Celebrities like Angelina Jolie have been open about their own experiences with inherited BRCA mutations. Ms. Jolie encouraged women to learn more from medical experts after discovering she had the mutated BRCA1 gene. Women are likelier than men to share genetic testing information with relatives, according to Alicia Zhou, director of research at Color Genomics, a Burlingame, Calif.-based genetic testing company that is studying the issue.

Robin Cole, seated with baseball cap, is a former Pittsburgh Steelers linebacker. He sets up a tent outside the first Steelers home game of each season, including here in 2017, to urge men to talk about prostate cancer.
Robin Cole, seated with baseball cap, is a former Pittsburgh Steelers linebacker. He sets up a tent outside the first Steelers home game of each season, including here in 2017, to urge men to talk about prostate cancer. PHOTO:ROBIN COLE

Robin Cole says he, his father and seven brothers all had or died from prostate cancer. But they avoided the subject when they got together. “It was like it was only going on in our own home,” says Mr. Cole, a 62-year-old former linebacker for the Pittsburgh Steelers. The Robin Cole Foundation sets up a tent outside the first Steelers home game of the season, he says, trying to break the taboo and talk to men about cancer and genetic testing.

Colin C. Pritchard, an associate professor of laboratory medicine at the University of Washington and an author of study about genetic mutations associated with increased prostate cancer risk, attributes some of the gender gap in testing to “a naming problem.” Men with gene mutations associated with hereditary breast and ovarian cancer syndrome are at higher risk of prostate cancer. But they hear the syndrome’s name, he speculates, and don’t think about the risk.

At professional meetings, Dr. Pritchard has suggested calling the syndrome something more inclusive. “We don’t think about what we do in medicine as branding,” Dr. Pritchard says, “but the name impacts the understanding around the genes.”

Kimberly Childers, a genetic counselor at Providence St. Joseph Health in Southern California and lead author of the JAMA gender-gap paper, says she and other researchers are stepping up outreach to men.

Providence St. Joseph Health launched a program to seek out men in urologic oncology and primary care practices—places where men are more likely to go with early concerns about prostate cancer, she says. The experience has led her to believe that the testing gap isn’t due to lack of interest. “Men aren’t being identified,” she says.

Dr. Meerschaert, the Michigan State professor, says he finally decided to seek genetic testing. He learned that, just like his relative, he had a BRCA2 gene mutation. He now screens regularly for skin cancer. He told his sons to get tested, too.

When asked what finally persuaded him to do the genetic testing, he sounds bemused. “My wife insisted,” he says.



This article was originally published in The Wall Street Journal. Read the original article.

Plan to replicate 50 high-impact cancer papers shrinks to just 18

An ambitious project that set out nearly 5 years ago to replicate experiments from 50 high-impact cancer biology papers, but gradually shrank that number, now expects to complete just 18 studies.

“I wish we could have done more,” says biologist Tim Errington, who runs the project from the Center for Open Science in Charlottesville, Virginia. But, he adds, “There is an element of not truly understanding how challenging it is until you do a project like this.”

The Reproducibility Project: Cancer Biology (RP:CP) began in October 2013 as an open effort to test replicability after two drug companies reported they had trouble reproducing many cancer studies. The work was a collaboration with Science Exchange, a company based in Palo Alto, California, that found contract labs to reproduce a few key experiments from each paper. Funding included a $1.3 million grant from the Laura and John Arnold Foundation, enough for about $25,000 per study. Experiments were expected to take 1 year.

The project quickly drew criticism from authors of the original studies and others who worried that the replication studies would inevitably fail because the contract labs lacked the expertise needed to replicate the work.

Costs rose and delays ensued as organizers realized they needed more information and materials from the original authors; a decision to have the proposed replications peer reviewed also added time. Organizers whittled the list of papers to 37 in late 2015, then to 29 by January 2017. In the past few months, they decided to discontinue 38% or 11 of the ongoing replications, Errington says. (Elizabeth Iorns, president of Science Exchange, says total costs for the 18 completed studies averaged about $60,000, including two high-priced “outliers.”)

One reason for cutting off some replications was that it was taking too long to troubleshoot or optimize experiments to get meaningful results, Errington says. For example, deciding what density of cells to plate for an experiment required testing a range of cell densities. Although “these things happen in a lab naturally,” Errington says, this work could have proceeded faster if methodological details had been included in the original papers. The project also spent a lot of time obtaining or remaking reagents such as cell lines and plasmids (DNA that is inserted into cells) that weren’t available from the original labs.

One of the effort’s lessons: Disclosing more protocol details and making materials freely available directly from the original lab or through services like Addgene would speed scientists’ ability to build on the work of others. “Communication and sharing are low-hanging fruit that we can work on to improve,” Errington says. Another problem, Iorns adds, is that academic labs rarely validate their assays, making it difficult to know whether a positive result is real or “just noise.”

The project has already published replication results for 10 of the 18 studies in the journal eLife. The bottom line is mixed: Five were mostly repeatable, three were inconclusive, and two studies were negative, but the original findings have been confirmed by other labs. In fact, many of the initial 50 papers have been confirmed by other groups, as some of the RP:CB’s critics have pointed out.

The RP:CB team is now writing up the remaining eight completed studies and a meta-analysis and summary of the project. The 11 incomplete studies, which will be published in brief form, will still “have a lot of value, but not as much” as the completed replications, Errington says.