Promising HIV vaccines could stall without coordinated research

Several vaccines and drugs for preventing the spread of HIV are showing signs of success in clinical trials, three decades after scientists began the search. But some researchers fear that progress will stall without a coordinated strategy to ensure that the most promising therapies to prevent infection win support from policymakers and reach the people who need them.

A meeting convened by the World Health Organization (WHO) in Geneva, Switzerland, on 28 February to 1 March aims to address a lack of long-term thinking about the factors — such as cost and ease of use — that can determine whether a vaccine or other preventive therapy succeeds in reducing disease. Some HIV researchers argue that they should study these issues now, while clinical trials of potential vaccines and drugs to block HIV infection are ongoing, to avoid delays in delivering effective therapies to people at risk of infection. Many hope that the WHO meeting will trigger broader discussions about how to support such research given limited resources, and how to prioritize therapies in development.

Waiting to conduct such studies after trials are finished prolongs the time until a preventive therapy reaches people, and in the meantime, the epidemic grows. Worldwide, about 1.8 million people contracted the disease in 2016. “You need to have a good idea about where you want to end up and all of the steps you need to make to get there,” says Mark Feinberg, president of the International AIDS Vaccine Initiative in New York City.

But it is not clear who would make decisions about which projects to prioritize, or when such choices would be made.

Some 25,000 people around the world are participating in clinical trials of treatments to prevent HIV infection. Twelve late-stage trials worldwide are testing experimental vaccines; these include a 2,600-person study in southern Africa of a vaccine designed to block multiple strains of the virus. Others are assessing the potential of proteins called broadly neutralizing antibodies, which might stop HIV from infecting a person’s immune cells. And a pair of phase III trials has enrolled 7,700 people to test whether injections of a drug called cabotegravir can prevent HIV infection for two months at a time.

Delivery concerns

At the meeting, researchers, policymakers and HIV activists will discuss stumbling blocks that have limited the use of potent vaccines and treatments against other diseases, such as high costs and cumbersome delivery requirements. Because no therapy has approached 100% protection against HIV, regulators face tough decisions when considering the cost and effort of delivering treatment to people at risk. In 2009, for example, a phase III study1 of the most promising vaccine identified so far found that it reduced a person’s risk of contracting HIV by only one-third. Health authorities did not recommend it for widespread use.

A modified version of that vaccine is now being tested in 5,400 people in South Africa, and researchers hope that it will reduce a person’s chance of contracting HIV by at least 50%. But even if the trial succeeds, the expense and difficulty of administering the vaccine, which must be given as six shots over 18 months, could make it a hard sell to policymakers and funders. Health-care workers around the world struggle to persuade healthy people to get one-time shots that are highly effective against other deadly diseases.

Similar concerns surround the antibodies in development, because they are given as intravenous infusions, and it is unclear how long treatment must continue to prevent HIV. The antibodies are also relatively expensive to make. Eventually, scientists must be prepared to choose which projects to stall, and which to supplement with studies aimed at developing cheaper, easier ways of administering a given therapy, says Mitchell Warren, executive director of AVAC, an HIV-prevention advocacy organization in New York City.

Money is limited, as is the pool of people available for clinical trials, which becomes larger and more complex as a vaccine or antibody treatment progresses towards the market. “We will need prioritization,” Warren says. “That view needs to be driven by science and financial realities, and the decision process needs to be clear and transparent.”

Another issue facing researchers is how to improve the likelihood that people at risk of HIV infection will take preventive treatments. Success is not guaranteed: Truvada, a daily pill for preventing HIV infection, has not reduced the number of new HIV cases globally since regulators approved it six years ago. In eastern and southern Africa, for instance, young women rarely take the drug, even though they account for 26% of the region’s new infections. Tian Johnson, founder of the African Alliance for HIV Prevention in Johannesburg, South Africa, says that researchers did not adequately consider how poverty, pregnancy, discrimination and abuse might affect whether young women at risk are likely to seek out Truvada. “If you disregard the complexity of a woman’s daily life and reality, you put at risk the millions of dollars you invest in developing a product,” he says.

Despite the challenges ahead, the fact that such discussions are happening is an important step forward, says Feinberg. “You can’t keep your head in the sand,” he says. “You need to work ahead and think of ways that we as a research development community can solve these problems — and they are solvable.”

 

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

Want to repel mosquitoes? Don’t use citronella candles

Citronella candles are great for setting a mood, but they’re not so great for the very thing they’re advertised to do: repel mosquitoes. That’s one conclusion from a new study that tested 11 types of repellents on Aedes aegypti mosquitoes—the vectors of Zika, yellow fever, dengue, and other diseases. To find out which ones worked best, scientists developed a lab test designed to mimic the conditions on someone’s backyard patio. A human sat at one end of a wind tunnel as “bait,” while scientists measured how many mosquitoes moved toward their target, depending on which repellent was used: one of five sprays, five wearable devices, or a citronella candle.

C. Bickel/Science

Most did not live up to the promises on their labels. At a distance of 1 meter, DEET and oil of lemon eucalyptus sprays reduced mosquito attraction by 60%. The only wearable device that worked was an OFF! clip-on fan containing the insecticide metofluthrin. The rest of the products had a weak repellent effect or were no better than no protection at all, the researchers report today in the Journal of Insect Science. Two devices in particular came under harsh criticism from the scientists: bracelets containing herbal extracts and sonic mosquito repellers, which claim to use high-frequency sound to drive away mosquitoes.

 

 

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

Did Pox Virus Research Put Potential Profits Ahead of Public Safety?

Smallpox virus, colorized and magnified in this micrograph 42,000 times, is the real concern for biologists working on a cousin virus — horsepox. They’re hoping to develop a better vaccine against smallpox, should that human scourge ever be used as a bioweapon.

In the brave new world of synthetic biology, scientists can now brew up viruses from scratch using the tools of DNA technology.

The latest such feat, published last month, involves horsepox, a cousin of the feared virus that causes smallpox in people. Critics charge that making horsepox in the lab has endangered the public by basically revealing the recipe for how any lab could manufacture smallpox to use as a bioweapon.

The scientist who did the work, David Evans of the University of Alberta in Canada, has said his team had to synthesize horsepox because they wanted to study the virus and there was no other way to get it.

There was another possibility, NPR has learned. Evans could have done research on a specimen of horsepox collected from the wild, but he didn’t pursue that alternative.

He says using the natural virus might have prevented the pharmaceutical company he is working with from commercializing horsepox as a new vaccine for smallpox. But the head of the company told NPR that he had not been aware that this stored sample of horsepox was potentially available — and would not have wanted to synthesize the virus from scratch if he had known.

“There was some confusion,” Evans told NPR, “probably my fault although I’d thought we’d discussed it back around 2014.”

If he didn’t talk about it with the company, Evans says, it’s because his own inquiries had convinced him that the stored virus “wasn’t suitable for our goals.”

Evans says the virus-making techniques his team has developed will advance the field of pox viruses and help turn them into new vaccines or therapies for diseases like cancer.

“To say that somehow we shouldn’t take advantage of the technology that’s out there — and which is being used in all sorts of different ways in all areas of biology — and put off limits, somehow, one virus doesn’t make a whole lot of sense to me,” he says.

University of Alberta microbiologist David Evans (right) and his research associate Ryan Noyce, created the synthetic horsepox virus.

Melissa Fabrizio/Courtesy of University of Alberta

“I mean, someone had to bite the bullet and do this,” Evans adds. “But now that I’ve done it, my colleagues in this field can go forward and do their experiments. I’m a big boy. I’m used to the occasional bit of abuse rolled at me. And it doesn’t particularly bother me that much.”

For more than a decade, policymakers and biologists have been debating how to oversee new advances that might be misused to create germs that could — by accident or on purpose — start a global outbreak.

Despite lots of expert committees, new rules and heated debates, the horsepox experiment was done by a privately funded group that simply presented its lab-created virus to the world as a fait accompli.

Does the world need a “safer” smallpox vaccine?

While the company that funded the work says its synthetic horsepox has potential as a safer smallpox vaccine, some biosecurity experts question whether there is any need for one. Despite that, the government offers financial incentives that would allow a company to make huge profits from developing a new smallpox vaccine.

“This is a little bit crazy. We have a very problematic, difficult decision to make about the reasonableness and appropriateness of this work, and it’s being pushed forward by those that have obvious conflicts of interest in a for-profit motive,” says Dr. David Relman, a microbiologist at Stanford University who tried, without success, to stop a scientific journal from publishing the details.

Smallpox is an often deadly, contagious disease that holds a unique place in medical history. Back in the 18th century, biologist Edward Jenner invented vaccination by giving people a less-virulent, related pox virus to generate an immune response that protected them from smallpox.

An unprecedented global vaccination campaign wiped out smallpox by 1980, making it the first disease ever eradicated. The virus that causes smallpox now is supposed to reside only in two locations: secure labs in the U.S. and in Russia. The U. S. government also stockpiles smallpox vaccine, in case the virus ever gets used as a weapon.

The possibility of creating a new, safer vaccine is why a pharmaceutical company executive named Dr. Seth Lederman wanted to get his hands on horsepox. He says historical writings suggest that Jenner’s vaccine against smallpox, which was derived from cowpox, actually originated in a pox disease that infected horses.

Trouble was, Lederman had no way of getting horsepox, which is believed to be extinct in nature. At one time, the U.S. Department of Agriculture held a sample. But when Lederman asked, the agency said it no longer had the virus.

Lederman knew Evans, an expert in pox viruses, and the two discussed the possibility of synthesizing horsepox from pieces of made-to-order DNA. Lederman and his company in New York, Tonix Pharmaceuticals, decided to give it a go and fund the effort.

“It was so unlikely that it would work, that maybe we didn’t spend as much time as you might think on the implications of it,” says Lederman, “although we were certainly mindful of the implications of it, and we followed all the applicable regulations in Canada,” where the work was done.

The team ordered bits of DNA from a commercial firm for about $100,000. Evans and colleague Ryan Noyce figured out how to stitch the pieces together, using tricks like helper viruses, to generate infectious horsepox by the summer of 2016.

Asked whether he would have been interested in synthesizing horsepox if he had known it was possible to obtain a sample of the natural virus, Lederman told NPR: “No. A primary rationale for the need for the synthesis is that a natural isolate of horsepox was not thought to be available for vaccine research.”

Unbeknownst to him, however, there was one available.

CDC had a sample of “natural” horsepox virus

In 2014, Evans had tracked down the old USDA sample, which had moved to the Centers for Disease Control and Prevention. He contacted the CDC and was told the process of getting the natural virus would start with something known as a material transfer agreement.

“Dr. Evans indicated that he was working with a New York-based company and they would likely be the ones to request an MTA,” says Dr. Inger Damon, director of the Division of High-Consequence Pathogens and Pathology at the CDC.

But that didn’t happen. “No further request was received,” says Damon, who notes that the CDC often works with commercial companies that are developing new tests, treatments and vaccines.

A natural virus might be harder to “commercialize”

Evans told NPR that the CDC would have supplied him with its horsepox virus for research, but he saw a potential problem. The virus sample was collected back in 1976 from sick Mongolian horses, and Evans worried that some forgotten restriction on sharing or using the virus might crop up later on and become a problem for Tonix’s effort to sell horsepox as a new smallpox vaccine.

“It’s a major problem if one hopes to have any future commercial ‘freedom to operate,’ ” says Evans. “That’s why it would not be suitable for vaccine research if one hoped eventually to commercialize the virus.”

That wasn’t the explanation he has given in the past for why he had to synthesize the virus.

In a report last month describing the work, he and his colleagues stated that natural horsepox may be extinct and that the only known specimen was “unavailable for investigation.”

And he recently told a group of scientists that making the virus was the “solution” to the “problem” of not being able to get access to the one known strain of horsepox.

“We were wondering if we could find out more about this virus, but the challenge is that there was one stock of it which was unobtainable,” Evans said at a meeting in Singapore in 2017. “And so we thought, ‘Well, could we have a stab at trying to make that?’ ”

After having dropped the conversation with the CDC about horsepox in 2014, Evans contacted the CDC again in March 2016 to once again request access to its stored virus.

“He reached out to see if he could obtain the virus from CDC to compare with a virus he was working on,” says Damon. “It is our understanding that his work to re-create the horsepox virus had begun.”

The company that funded that work didn’t find out that the CDC’s sample of natural virus existed until February 2017. That is when, Lederman says, it saw a reference to it in a scientific article that had been published a few months before. At that point, the horsepox synthesis was a done deal, and Lederman now sees its advantages.

“While the CDC virus would be experimentally interesting (and we’d still like to get some), from what I understand now, concerns over its origins might create challenges from a product development perspective,” Lederman told NPR in an email.

Something that investors understand”

If Tonix’s horsepox virus gets approved by the Food and Drug Administration as a smallpox vaccine, the company could get a lucrative reward: a special voucher that the government gives to companies that have developed medical countermeasures against potential security threats.

Such vouchers can be used to speed up the government’s review of any new drug, and they are fully transferable to other pharmaceutical companies. That means they can be sold, potentially for hundreds of millions of dollars.

“It’s certainly something that investors understand,” says Lederman, whose company highlighted this possibility in a press release about its horsepox work.

Some biodefense experts are questioning whether it makes sense for the government to incentivize this kind of research, especially given the biosecurity concerns.

“We believe that the creation of horsepox demonstrates the need for dialogue in the biodefense arena about the need for another smallpox vaccine,” they recently wrote in the journal Health Security.

Not even Evans seems sure that horsepox will end up being useful as a better smallpox vaccine. “I don’t know. Depending on the day of the week, I could argue either side of the equation,” says Evans.

Surprise at WHO meeting: Synthetic pox virus a fait accompli

Since 2001, according to the World Health Organization, Evans served on a special committee that provides global oversight of research with the remaining, closely-held stocks of smallpox. Research on no other pathogen gets this kind of international scrutiny.

A debate over whether the last stocks of smallpox should be destroyed has gone on for years. But advances in DNA technology seemed to be quickly making that question moot. After all, it was becoming increasingly feasible that someone could re-create a smallpox virus in the lab.

In November 2016, in a last-minute addition to the agenda of the committee’s annual meeting, Evans made an unscheduled presentation to reveal that he had made horsepox, a large pox virus like smallpox, from scratch.

Synthetic biologist Drew Endy, of Stanford University, had just been brought onto the WHO’s smallpox committee to help it consider the implications of new technologies for virus creation. He was stunned to hear this news at the first meeting he ever attended.

“It was a unilateral act,” says Endy. “And so I found it to be, from a personal perspective, shocking in a way.”

Some members of the WHO committee have devoted their entire professional lives to wiping smallpox from the face of the Earth, he notes, and suddenly Evans had forced them to confront the fact that reality had changed.

At the meeting, Evans stated that his rationale for the work was to show that the re-creation of a pox virus was not just a theoretical possibility, according to Asheena Khalakdina, a technical officer at the WHO.

She said that in 2017, when Evans declared his relationship with Tonix and his work on the development of a smallpox vaccine, the WHO rescinded his membership on the smallpox committee.

“I don’t get any personal financial gain from Tonix commercializing a smallpox vaccine,” Evans told NPR, though he does work as a consultant for the company. “The work was done on contract, and they own the virus.”

In 2015, Evans served on another WHO working group to look at how emerging DNA technology would affect the ability to re-create smallpox. His conflict of interest disclosure for that noted that he was discussing a possible research contract with a company interested in synthesizing a pox virus. “They knew I was doing this,” Evans says.

Journal editors debated risks of publishing the work

With the horsepox virus re-created, and the WHO committee informed, the researchers pursued publication of the work in a scientific journal. That is routine practice for biologists, to ensure that others can reproduce and validate the science.

But biologists have argued in recent years over whether it’s wise to openly publish details of research that might be misused to produce a bioweapon.

Evans says his university’s lawyers reviewed his manuscript to make sure that publishing it wouldn’t break any laws and consulted with Canada’s foreign affairs and public health agencies.

“Without publishing the work, there’s really no way for us to communicate with investors and partners,” says Lederman, at Tonix. What’s more, a patent application would make it all public anyway.

A couple of science journals didn’t want the manuscript — and at least one of them noted that it would raise biosecurity concerns.

But a journal called PLOS One took the paper and put it through a small review panel that is supposed to screen research that might pose risks to the public if it were published.

The chair of that committee is Grant McFadden, an expert on poxviruses at Arizona State University. He also serves on the WHO’s smallpox committee and says he knows Evans well. “Everyone in the pox virus community pretty much knows everyone else,” says McFadden.

He saw no problem with publishing because, in his view, the advance just built on virus-making technologies that were already described in the open scientific literature. He and the other half-dozen members of the journal’s special review committee spent a couple of weeks discussing the paper by email and did not request any additional input from outside security experts.

“We felt we had enough sufficient internal expertise to make a call,” McFadden tells NPR. “At the end of the day, everyone who weighed in was convinced that the scientific value of the paper outweighed the concerns.”

After all, he says, labs like his are already using more traditional DNA technologies to generate modified pox viruses. Going the fully-synthetic, made-to-order route could more efficiently generate pox viruses with multiple genetic alterations in the future. And if the FDA ever had to consider a modified pox virus as a therapy, creating it from scratch could make the review process more straightforward.

“There are going to be multiple scientific issues in the future where making a synthetic virus from scratch might be the best strategy to get at the question,” says McFadden.

But just because a journal editor has expertise in the science doesn’t mean they understand how to assess a biosecurity threat, says Arturo Casadevall, a microbiologist at Johns Hopkins University who is editor-in-chief of a journal called mBio.

“They cannot evaluate the degree to which that information may be misapplied by others,” says Casadevall, who wants to see a national security board set up so that journal editors have somewhere to go for guidance.

“Perhaps this paper,” he says, “will lead to some additional soul-searching and some action.”

Concerned onlookers lobbied to block publication

As word got out that the synthetic pox virus paper was about to be published, worried outsiders began to contact the journal, urging its editors to reconsider.

“I did not see, until a few days before publication, letters that had been sent to the journal expressing great concern,” says Ron Atlas, a microbiologist and emeritus professor at the University of Louisville who serves on the review committee that gave the OK to publish the work. “I don’t think that those letters would have changed my opinion of the research, but there were several very strong letters that said, ‘Do not publish this.’ ”

One of the letter writers was Tom Inglesby, director of the Center for Health Security of the Johns Hopkins Bloomberg School of Public Health. “Anything that lowers the bar for creating smallpox in the world,” says Inglesby, “is a dangerous path.”

Another letter asked why some details couldn’t be held back to at least allow time for a broader discussion. “I thought that that was a very reasonable question to be asking,” says Relman, “prior to publication of the details of how one essentially remakes smallpox.”

McFadden disputes claims that publishing the manuscript would give some terrorist or rogue nation helpful tips.

“If you talk to people in synthetic biology that are professional constructors of novel genomes,” says McFadden, “they would tell you that the technical advance was fairly minor in this case.”

At least one synthetic biologist disagrees with that assessment.

“I think it’s incorrect to assert that it’s a nothing-burger,” says Endy, who adds that he honestly doesn’t want to get specific and draw attention to the most new and potentially useful virus-making tricks. “There are things in this paper that I wouldn’t know how to do and had never been done before.”

 

 

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

Could a protein called klotho block dementia and aging?

Over time, something happens to our cells and organs, and in the past three decades scientists have begun to unravel exactly what that something is – and the cellular mechanisms our bodies use to fight it.

Dubal, an associate professor of neurology at UC San Francisco, thinks we can use the science of aging to help stave off these neurodegenerative diseases.

“Aging is the biggest risk factor for cognitive problems, and cognitive problems are one of the biggest biomedical challenges that we face,” she said. “Why don’t we just block aging?”

The key: klotho?

Blocking aging is easier said than done, but Dubal jumped head first into the problem by studying a protein called klotho.

Klotho was named after the Greek fate Clotho, a mythological figure who spun the thread of life and had say over when gods and mortals lived and died. The Japanese researchers who named the protein found that the amount of klotho produced by mice could affect how long the rodents lived. Other researchers later discovered that humans who naturally have more klotho tend to live longer.

Living longer is one thing, but Dubal, a member of the UCSF Weill Institute for Neurosciences, wanted to know if klotho could help our brains stay healthier and more resilient to cognitive problems. Could klotho levels predict how quickly subjects solved a variety of puzzles that test cognition? In both humans and mice, she found the same result: more klotho meant better cognitive function.

To bring this boost in brain health to everyone, and not just the 20 percent of people who happen to have naturally high klotho, Dubal is testing the protein’s potential as a therapeutic. The protein can exist in two forms: the first is anchored to the cell membranes of your organs, mostly your brain and kidneys; and the second occurs when the protein is cut loose from its anchor and freed to float around the bloodstream. Dubal found that by simply injecting this floating form into mice, she could re-create the cognitive boost she found by genetically increasing klotho.

“We found that those mice that had been treated, within four hours had better brain function,” she said. This worked in young mice, old mice, and mice that had a condition similar to Alzheimer’s.

Next, Dubal’s lab will try to understand how klotho acts on the brain without crossing the blood-brain barrier. And ultimately, could klotho become a therapy for humans to improve brain health and protect against aging and disease?

“For humans, the end game really is: how can we increase our ‘healthspan?’” said Dubal. “And that may go hand in hand with an increase in life span, because the things that help us to live longer are also the things that help us to live better.”

 

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

Doctors Said Immunotherapy Would Not Cure Her Cancer. They Were Wrong.

No one expected the four young women to live much longer. They had an extremely rare, aggressive and fatal form of ovarian cancer. There was no standard treatment.

The women, strangers to one another living in different countries, asked their doctors to try new immunotherapy drugs that had revolutionized treatment of cancer. At first, they were told the drugs were out of the question — they would not work against ovarian cancer.

Now it looks as if the doctors were wrong. The women managed to get immunotherapy, and their cancers went into remission. They returned to work; their lives returned to normalcy.

The tale has befuddled scientists, who are struggling to understand why the drugs worked when they should not have. If researchers can figure out what happened here, they may open the door to new treatments for a wide variety of other cancers thought not to respond to immunotherapy.

“What we are seeing here is that we have not yet learned the whole story of what it takes for tumors to be recognized by the immune system,” said Dr. Jedd Wolchok, chief of the melanoma and immunotherapeutics service at Memorial Sloan Kettering Cancer Center in New York.

“We need to study the people who have a biology that goes against the conventional generalizations.”

Four women hardly constitutes a clinical trial. Still, “it is the exceptions that give you the best insights,” said Dr. Drew Pardoll, who directs the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins Medicine in Baltimore.

The cancer that struck the young women was hypercalcemic small cell ovarian cancer, which typically occurs in a woman’s teens or 20s. It is so rare that most oncologists never see a single patient with it.

But Dr. Douglas Levine, director of gynecologic oncology at New York University Langone Medical Center, specialized in this disease. A few years ago, he discovered that the cancer was driven by a single gene mutation. The finding was of little use to patients — there was no drug on the horizon that could help.

Women with this form of ovarian cancer were sharing news and tips online in a closed Yahoo group. Dr. Levine asked to become part of the group and began joining the discussions. There he discovered patients who had persuaded doctors to give them an immunotherapy drug, even though there was no reason to think it would work.

The women reported that their tumors shrank immediately.

The idea behind immunotherapy is to dismantle a molecular shield that some tumors use to avoid an attack by the body’s white blood cells.

The immune system sees these tumors as foreign — they are fueled by hundreds of genetic mutations, which drive their growth and are recognized by the body. But when white blood cells swarm in to attack the cancer cells, they bounce back, rebuffed.

Immunotherapy drugs pierce that protective shield, allowing the immune system to recognize and demolish tumor cells. But the new drugs do not work against many common cancers.

Those cancers are supported by fewer genetic mutations, and experts believe that the tumor cells just do not look threatening enough to the body to spur a response. So the immune system leaves them alone.

Lung cancer, a genetic type of colorectal cancer and melanoma have huge numbers of mutations, and immunotherapy drugs often are successful in treating them. Cancers of the prostate, pancreas, breast, ovaries — and most other tumors — carry few mutations.

“These are the cancers that rarely respond,” Dr. Pardoll said.

The idea that the drugs might work against something like hypercalcemic ovarian cancer, which is fueled by just one genetic mutation, just made no sense.

“For the vast majority of cancers, there is an amazingly clean correlation between response to therapy and mean mutational load,” Dr. Pardoll said.

Photo

Ms. Sousa returned to work as an organizational psychologist and works out vigorously every day.CreditDaniel Rodrigues for The New York Times

But there were a few oddball exceptions. An unusual skin cancer called Merkel cell carcinoma responded to immunotherapy, scientists found. It is caused by a virus, and researchers suggested the infection itself draws the attention of the immune system.

Mesothelioma also responded, perhaps because the asbestos that caused it also inflames the immune system. And some kidney cancers responded to immunotherapy treatment; no one knows why.

And then came a handful of women with a rare ovarian cancer. Oriana Sousa, 28, a psychologist in Marinha Grande, Portugal, was one of them.

She found out she had cancer in December 2011. She knew something was wrong — for several months she had been feeling tired, constipated and endlessly thirsty. She began vomiting and had abdominal cramps. But her doctors told her she was fine and not to worry.

Finally, her aunt, a nurse, suggested she see a different doctor, who performed a CT scan of her abdomen. It revealed a huge mass. The doctor operated to find out what it was. Two days later, he gave her the bad news: Cancer, and a really terrible form of it.

For the next four years, Ms. Sousa’s doctors tried to control the cancer, giving her rounds of chemotherapy, radiotherapy and surgery. But every time, new tumors emerged.

“I suffered a lot, and I felt I had no life,” she said.

Things are different now. In 2015, she finally persuaded a doctor to give her an immunotherapy drug, nivolumab. Immediately, her tumors shrank and continued shrinking as she continued with the drug — so much that her doctors now say she has no evidence of disease. Life has returned to normal.

“Generally after work, I go to the gym and do classes and work out,” she said. “People who don’t know what I have been through, they can’t imagine I am an oncology patient.”

What saved her? Dr. Eliezer M. Van Allen, a cancer researcher at Dana-Farber Cancer Institute, has come across one clue.

He found that a gene mutated in kidney cancer was sort of a master regulator of other genes, controlling which were turned on and when. But the regulated genes were normal and did not produce proteins that the immune system might recognize as abnormal.

Nonetheless, patients responding to immunotherapy were the ones with the master gene mutation. “We saw this result and weren’t sure what to make of it,” he said.

Dr. Levine and his colleagues found the same phenomenon in patients with hypercalcemic ovarian cancers. One explanation, he and Dr. Van Allen said, is that the immune system may recognize that cells in which genes are erratically turning on and off are dangerous and should be destroyed.

“That is strictly hypothesis,” Dr. Levine cautioned.

One thing is clear, though: When pathologists examine these tumors, they find white blood cells in them — as if the immune system were trying to attack. And that finding has led both Dr. Pardoll and Dr. Padmanee Sharma of M.D. Anderson Cancer Center in Houston to plan new clinical trials.

They know that immunotherapy fails most patients, even those with cancers that are most likely to respond. So they have set out to create a test to determine who might respond to immunotherapy and then treat those patients — regardless of their cancer type.

Dr. Sharma’s study, funded by the Parker Institute, is getting ready to enroll patients. The researchers will look at pathology slides of patients’ tumors to see if white blood cells are worming their way into the cancers. If so, the patients will get an immunotherapy drug to help activate their white blood cells to attack the tumor.

If there are few white blood cells in the tumor tissue, patients will get a combination of two immunotherapy drugs to help move more white blood cells into the tumor and help them attack.

“The trial is written for all comers,” Dr. Sharma said. “If we have learned anything, it is that it is not the tumor type we are treating — it is the immune system.”

At Johns Hopkins, Dr. Pardoll and his colleagues are planning a similar trial. They will be looking for tumors — it does not matter what type — that have a protein, PD-L1, on the surface that repels the immune system. Any patient whose tumor fits that description will get an immunotherapy drug.

It’s a shot in the dark. But sometimes such a shot finds the mark, as Ms. Sousa will tell you.

“Incredible things happen, and against all the odds,” she said.

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

Induced pluripotent stem cells could serve as cancer vaccine

Induced pluripotent stem cells, or iPS cells, are a keystone of regenerative medicine. Outside the body, they can be coaxed to become many different types of cells and tissues that can help repair damage due to trauma or disease. Now, a study in mice from the Stanford University School of Medicine suggests another use for iPS cells: training the immune system to attack or even prevent tumors.

The results suggest it may one day be possible to vaccinate an individual with his or her own iPS cells to protect against the development of many types of cancer.

The iPS cells work as an anti-cancer vaccine because, like many cancer cells, they resemble developmentally immature progenitor cells, which are free from the growth restrictions built into mature cells that make up the body’s tissues. Injecting iPS cells that genetically match the recipient, but that are unable to replicate, can safely expose the immune system to a variety of cancer-specific targets, the researchers found.

“We’ve learned that iPS cells are very similar on their surface to tumor cells,” said Joseph Wu, MD, PhD, director of Stanford’s Cardiovascular Institute and professor of cardiovascular medicine and of radiology. “When we immunized an animal with genetically matching iPS cells, the immune system could be primed to reject the development of tumors in the future. Pending replication in humans, our findings indicate these cells may one day serve as a true patient-specific cancer vaccine.”

Wu is the senior author of the study, which was published online Feb. 15 in Cell Stem Cell. Former postdoctoral scholar Nigel Kooreman, MD, is the lead author.

“These cells, as a component of our proposed vaccine, have strong immunogenic properties that provoke a systemwide, cancer-specific immune response,” said Kooreman, who is now a surgery resident in the Netherlands. “We believe this approach has exciting clinical potential.”

Similarities between cancer, iPS cells

To make iPS cells, researchers collect cell samples from an easily accessible source like skin or blood. The cells are then treated with a panel of genes that make them rewind their developmental clock to become pluripotent, allowing them to become nearly any tissue in the body. One key test of pluripotency is the ability of the cells to form a tumor called a teratoma, which is composed of many different cell types, after the cells are injected into animals. (IPS cells used in regenerative-medicine therapies are grown in the presence of other proteins to encourage them to specialize, or differentiate, into specific cell populations before being used clinically.)

Cancer cells also have long been known to echo many features of developmentally immature cells. As part of their cancerous transformation, they often shed the naturally occurring mechanisms that serve to block inappropriate cell division and instead begin proliferating rapidly.

Once activated, the immune system is on alert to target cancers as they develop throughout the body.

Wu and Kooreman wondered exactly how closely iPS and cancer cells resemble one another. They compared the gene expression panels of the two types of cells in mice and humans and found some remarkable similarities, suggesting that these cells share proteins on their surfaces called epitopes that could serve as targets for the immune system.

To test this theory, they used four groups of mice. One was injected with a control solution, one received genetically matching iPS cells that had been irradiated to prevent the formation of teratomas, one received a generic immune-stimulating agent known as an adjuvant, and one received a combination of irradiated iPS cells and adjuvant. All animals in each group were injected once a week for four weeks. Lastly, a mouse breast cancer cell line was transplanted into the animals to observe the potential growth of tumors.

One week after transplantation, all mice were found to have developed tumors of the breast cancer cells at the injection site. Although the tumors grew robustly in the control groups, they shrank in size in 7 out of 10 mice vaccinated with iPS cells plus the adjuvant. Two of these mice were able to completely reject the breast cancer cells and live for more than one year after tumor transplantation. Similar results were obtained when Kooreman and his colleagues transplanted a mouse melanoma and mesothelioma (a type of lung cancer) cell line into mice.

Kooreman and his colleagues further found that immune cells called T cells from vaccinated mice were able to slow the growth of breast cancer cells in unvaccinated mice. Conversely, these T cells also blocked the growth of teratomas in mice injected with nonirradiated iPS cells, showing that the activated T cells were recognizing epitopes that are shared between the breast cancer cells and the iPS cells.

Putting the immune system on alert

“This approach is particularly powerful because it allows us to expose the immune system to many different cancer-specific epitopes simultaneously,” Kooreman said. “Once activated, the immune system is on alert to target cancers as they develop throughout the body.”

The researchers next would like to study whether the approach works in samples of human cancers and immune cells in a laboratory setting. If successful, they envision a future in which people could receive a vaccine comprised of their own irradiated iPS cells as a way to prevent the development of cancers months or years later. Alternatively, the iPS cells could potentially be used as a part of the standard of adjuvant care after primary surgery; chemotherapy or radiation therapy, or both; or immunotherapy as a way to treat established cancers.

“Although much research remains to be done, the concept itself is pretty simple,” Wu said. “We would take your blood, make iPS cells and then inject the cells to prevent future cancers. I’m very excited about the future possibilities.”

 

This article was originally published in Stanford Medicine. Read the original article.

Strong tides may have pushed ancient fish to evolve limbs

PORTLAND, OREGON—The evolution of land animals only happened once, some 400 million years ago. But what pressures pushed sea creatures to evolve limbs for walking? Scientists have proposed several theories, including fish that adapted to living in shallow, plant-choked streams prone to flooding and drought. Now, new research suggests that that strong ocean tides may have played a significant role, stranding animals in tidal pools and giving them an incentive to escape back to the sea. Using computer simulations of ancient Earth, the researchers find that regions of strong ocean tides correspond to locations where fossils have been found of large, bony fishes with limblike fins called sarcopterygians, researchers reported here today at the 2018 Ocean Sciences Meeting.

The hypothesis isn’t mainstream, says Jennifer Clack, a paleontologist at the University of Cambridge in the United Kingdom, who wasn’t involved in the research, “but I don’t think it’s entirely off the wall.”

Nearly a century ago, Alfred Romer, a paleontologist at the University of Chicago in Illinois, proposed that tidal pools might have helped spur the evolution of the earliest four-footed animals, known as tetrapods. In 2014, Steven Balbus, an astrophysicist at the University of Oxford in the United Kingdom, took the idea one step further. He calculated that 400 million years ago, when this evolutionary transition occurred, tides were stronger, because the moon was about 10% closer to Earth. Fish could become easily stranded in tide pools during stronger spring tides, he argued, which occur when Earth, the moon, and the sun are in alignment roughly every 2 weeks. Strandings would be particularly likely in places where the tides were naturally amplified by the local water depth or the shape of the coastline.

And stranded creatures would have been under evolutionary pressure to escape their watery confines, says Mattias Green, an ocean scientist at Bangor University in the United Kingdom. “After a few days in these pools, you become food or you run out of food,” he says. “The fish that had large limbs had an advantage because they could flip themselves back into the water.”

But providing the evidence to support this theory is tough. That’s because plate tectonics have shifted the position of Earth’s continents, and hundreds of millions of years of erosion and other changes have vastly changed the shape of coastlines. But Green, Balbus, and their collaborators have now tried, simulating Earth’s tides millions of years ago to look for coastlines with particularly strong daily tides and pronounced differences between the strong spring tides and their opposites—weaker neap tides. They used a model of Earth’s seafloor and landforms as they existed 400 million years ago, when two supercontinents called Gondwana and Laurussia were coming together, separated by a sea that resembled a wedge. “Having such a big wedge-shaped sea would lead to an enhanced tidal response,” Balbus says. By modeling different local topographies and recording the tides at each location, the researchers identified swaths of coastline along the wedge separating the supercontinents where fish could easily have been stranded.

The scientists showed that these ancient locations—shifted by plate tectonics to their present-day positions—overlap with many finds of “transitional” fossils of bony fish with limblike fins. For example, large fossil beds and impressions of footprints in modern-day Eastern Europe, Canada, and Ireland match the locations of ancient tidal stranding sites “almost disturbingly well,” Green says. Intriguingly, the simulations also suggest that transitional fossils could be found in other places, like Syria and Afghanistan. But excavating there is challenging because of current political instabilities, says Hannah Byrne, an oceanographer at Uppsala University in Sweden who led the modeling work.

 

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

Concussions Can Be Detected With New Blood Test Approved by F.D.A.

The Food and Drug Administration on Wednesday approved a long-awaited blood test to detect concussions in people and more quickly identify those with possible brain injuries.

The test, called the Banyan Brain Trauma Indicator, is also expected to reduce the number of people exposed to radiation through CT scans, or computed tomography scans, that detect brain tissue damage or intracranial lesions. If the blood test is adopted widely, it could eliminate the need for CT scans in at least a third of those with suspected brain injuries, the agency predicted.

Concussion-related brain damage has become a particularly worrisome public health issue in many sports, especially football, affecting the ranks of professional athletes on down to the young children in Pop Warner leagues. Those concerns have escalated so far that it has led to a decline in children participating in tackle sports.

“This is going to change the testing paradigm for suspected cases of concussion,” said Tara Rabin, a spokeswoman for the F.D.A. She noted that the agency had worked closely on the application with the Defense Department, which has wanted a diagnostic tool to evaluate wounded soldiers in combat zones. The Pentagon financed a 2,000-person clinical trial that led to the test’s approval.

According to the Centers for Disease Control and Prevention, there were about 2.8 million visits to emergency rooms for traumatic brain injury-related conditions in 2013, the most recent year for which the numbers were available. Of these, nearly 50,000 people died. Most patients with suspected traumatic brain injury are evaluated using a neurological exam, followed by a CT scan.

One of the challenges of diagnosing concussions is that symptoms can occur at different times. In some people, they appear instantly, while in others they can show up hours or even days later. Symptoms also vary from person to person. Some experience sensitivity to noise, others lose their balance, and still others become sensitive to bright light.

“A blood test to aid in concussion evaluation is an important tool for the American public and for our service members abroad, who need access to quick and accurate tests,” said Jeffrey Shuren, director of the F.D.A.’s medical device division. The agency, often criticized for the pace of its approvals, noted that it had cleared this diagnostic device in less than six months.

“This is something that has been a long time coming,” said Colonel Dallas Hack, who was director of the Army’s Combat Casualty Care Research Program from 2008 to 2014 and is now retired.

“The concept originally was that we would have something that medical personnel in the field would be able to use to assess whether somebody who had received a head injury needed a higher level of care,” Dr. Hack said.

The test works by measuring the levels of proteins, known as UCH-L1, and GFAP, that are released from the brain into blood and measured within 12 hours of the head injury. Levels of these blood proteins can help predict which patients may have intracranial lesions visible by CT scan, and which won’t. In a statement announcing the approval, the F.D.A. said that the brain trauma indicator was able to predict the presence of intracranial lesions on a CT scan 97.5 percent of the time, and those who did not have such lesions 99.6 percent of the time.

The possibility of testing an athlete on the sidelines could also be used in all sports, but particularly football, which includes high-speed collisions on every play. While professional and collegiate athletes have access to trainers and doctors, players on high school teams and in youth leagues often make do with a volunteer physician or an emergency medical technician, if at all.

Far more athletes play football at younger ages. More than one million boys play football in high school, about the same as those who play baseball and basketball combined. Many more play football in youth leagues, including Pop Warner, one of the most established organizations.

These organizations have seen their insurance costs rise in part because parents of injured players have sued them for not doing enough to protect their children.

Putting an athlete with a concussion back on the field can also have grave consequences. A player who suffers a concussion is susceptible to second-impact syndrome, which occurs when the brain swells after a second concussion, but before the first concussion has been diagnosed.

The F.D.A. approved the test for use in adults, but Henry Nordhoff, chief executive of Banyan Biomarkers, based in San Diego, the company that makes the device, said he thought it might also appeal to physicians evaluating children for concussions. While that would initially be an off-label use, the company plans to soon start a clinical trial evaluating injured children, Mr. Nordhoff said.

There is also a smaller device for the blood test in the works, which Banyan is working on with the French company bioMérieux, and a hand-held one they are developing with Abbott Laboratories. The tests could eventually be used in other countries besides the United States. Worldwide, about 10 million people a year are treated for concussion-related injuries, according to bioMérieux.

While a test to diagnose concussions quickly will be welcomed in the medical and sports worlds, it does not address the growing worries about the cumulative effect of repeated head hits. Head hits absorbed over many years of playing football and other sports have been linked to chronic traumatic encephalopathy, a degenerative brain disease found in autopsies of former football players, other athletes and soldiers.

After spending years discrediting researchers who were establishing a link between head hits and C.T.E., the N.F.L. began pledging tens of millions of dollars to study C.T.E. In some cases, the N.F.L. has also teamed up with the Pentagon.

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

Concussion Blood Test Wins FDA Approval

The Food and Drug Administration has approved the first blood test to evaluate concussions, otherwise known as mild traumatic brain injuries, in patients after accidents, military wounds, sports collisions and other causes.

The blood test from Banyan Biomarkers Inc. could be useful in diagnosing brain injuries that lead to an estimated 2.5 million emergency-room visits each year. The World Health Organization estimates about 10 million people world-wide are affected by mild traumatic brain injuries.

Patients with likely head injury are typically evaluated with cognitive assessments followed by a CT scan of the head to home in on damaged brain tissue, known as intracranial lesions. About 75% of brain injuries occurring each year are diagnosed as mild TBIs, or concussions.

The diagnostic tool measures proteins, known as UCH-L1 and GFAP, released from the brain within 12 hours of a head injury. The FDA said that levels of these blood proteins after a concussion can help predict which patients are likely to have intracranial lesions detectable on a CT image.

The federal agency evaluated data from 1,947 blood samples of adults with suspected concussion. Test results can be made available within three to four hours, according to the FDA.

 

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

Gene-altering treatments are medicine’s best shot yet against Huntington’s disease

For 15 years, Michelle Dardengo watched helplessly as her father lost his memory and became more and more depressed. As his body failed, too, he could no longer take care of himself. He died in 2003 at age 68. Huntington’s disease had robbed him of a longer life.

But for Dardengo, who lives in Vancouver, Canada, the pain was not only in losing him. She knew there was a 50-50 chance that she had inherited the genetic mutation responsible for his death.

She began noticing the warning signs in herself in 2015, when she was 52. At her work, which involved debugging software, she had trouble keeping up. Walking her dogs every day, she saw her balance start to falter. When she went to a doctor about the symptoms, she already knew the grim diagnosis.

As she faces it, however, Dardengo has a sliver of hope. She has joined a study testing an experimental drug meant to stave off the ravages of the disease.

Huntington’s is a genetic disorder that causes nerve cells in the brain to gradually break down, leading to irreversible brain damage. There is no cure—only drugs to help manage the side effects, like depression and involuntary movements. Eventually, people lose their ability to think, walk, and speak.

The drug Dardengo is trying, made by Ionis Pharmaceuticals, is one of a handful of new therapies in development that aim to alter the genetic root of the disease and thus slow or reverse the damage. Scientists have known the cause of Huntington’s for 25 years—an error in a particular gene. But because drugs take so long to develop, only now are genetic treatments beginning to trickle out of the lab to treat the first patients.

A long road

Michelle Dardengo in 2016.

COURTESY OF MICHELLE DARDENGO

Researchers discovered the Huntington’s gene, HTT, in 1993 by studying families affected by the disease. All human beings carry this gene, but people with Huntington’s have a mutated version that contains repeated segments—extra letters of DNA that shouldn’t be there, like a genetic stutter.

Eventually, scientists realized that these repeats cause the gene to make abnormal versions of a protein called huntingtin. In its normal form, this protein is needed for brain development, but aberrant ones clump together in the brain’s nerve cells like balls of spaghetti and cause damage over time.

It proved difficult to treat the disease with conventional “small molecule” drugs, which can be easily made into tablets or capsules. Now scientists are working on treatments that, rather than target the huntingtin protein, try to prevent it from being produced in the first place. These new therapies are meant to stop the disease in its tracks, instead of just treating symptoms as traditional drugs do.

Ionis’s experimental drug uses a technique known as “gene silencing,” or antisense, which involves using strands of chemically modified DNA to essentially gum up the genetic copying mechanism before it can produce harmful huntingtin proteins from the HTT gene.

In a small clinical trial, whose initial results were reported in December, the drug reduced levels of huntingtin in 46 people with early Huntington’s disease—making it the first ever to do so. “The responses we are seeing are as good as we could possibly hope for,” says Blair Leavitt of the University of British Columbia, who headed the trial in Canada. Swiss drug giant Roche has partnered with Ionis to continue development of the drug.

Dardengo was the first patient in that trial to receive the injections, which take about 40 minutes and involve inserting a large needle into the spine so the cerebrospinal fluid can carry the drug to the brain. She still doesn’t know whether she got the drug or a placebo, and in fact, her symptoms haven’t improved yet. But, she says, “the chance of being a placebo didn’t matter to me. Sometimes I feel like I won the lottery.”

The next phase of the trial will last longer and enroll several hundred patients across North America. Dardengo will be one of them.

Frank Bennett, head of research at Ionis, says if the drug works, the goal will be to treat patients as early as possible, maybe even before they start showing any symptoms. “Our hope is that we could stabilize people, and there’s a possibility that some of their symptoms can actually be reversed and they could get better,” he says.

For families like Dardengo’s, that could be life-changing. In the US, about 30,000 people have Huntington’s disease and more than 200,000 people have inherited the genetic mutation from a parent, which gives them a 50 percent chance of getting sick.

Like many parents with Huntington’s, Dardengo has always feared that her children (she has two, both in their 20s) and her future grandchildren will end up with the disease. In addition to her father, her grandfather had Huntington’s, and so did four of his siblings. Now, though, she doesn’t worry as much about the future. She’s optimistic that the Ionis drug will work.

“The biggest difference that a success in the trial would make is a sense of hope for families,” says Leavitt. “There’s never been anything that’s had any effect on this disease.”

Other approaches

Several other gene-based attacks on Huntington’s are in the works. Wave Life Sciences is testing two gene-silencing therapies in clinical trials. Sangamo Therapeutics, Spark Therapeutics, and UniQure are developing gene therapies that use an engineered virus to transport genetic material to brain cells to stop production of the abnormal huntingtin.

Brain surgery would be required to deliver these therapies, but researchers think it would be a one-time procedure, as is the case for other gene therapies. Steven Zelenkofske, chief medical officer at UniQure, says the company is planning to begin a clinical trial by the end of this year or the beginning of 2019.

Some researchers are investigating even newer techniques, like inserting the gene-editing tool CRISPR into human cells, which can then use it as a weapon against the mutated gene.

Even if these approaches work, it could take a year or more for patients to start seeing the effects. And since Huntington’s gets worse over time, it will take even longer to know whether those effects are lasting.

Still, families and researchers are enthusiastic about the new wave of treatments, says George Yohrling, senior director of scientific affairs at the Huntington’s Disease Society of America. The organization’s call center and website for connecting Huntington’s patients to clinical trials saw a four-fold increase in calls and traffic in December after Ionis announced its initial results. “There’s an excitement in the community that I’ve never experienced before,” Yohrling says.

That excitement could still run into some harsh realities. Brain diseases are notoriously difficult to treat. Over the past two decades, drug makers have launched 99 clinical trials investigating 41 different compounds for Huntington’s, but only two drugs have been approved—and those are just to manage symptoms.

Dardengo knows she may not benefit from the drug, but that hasn’t dimmed her optimism. “Even if this doesn’t help me, it’s a chance to help other people with this disease,” she says.

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