Young Cancer Patients in Poor Countries Get a Boost

When Pascale Yola Gassant went to work as a pediatrician at a children’s hospital in Haiti in 2003, she saw patients with cancer—but could offer no specialists, drugs or radiation therapy to tackle their disease.

Distraught, Dr. Gassant says she warned her manager at St. Damien Pediatric Hospital in Port-au-Prince: “These children were left on their own and they would die without care and without treatment.”

Improving those conditions, which are common in other low-income countries, is the focus of a campaign to treat childhood cancer globally that will be unveiled this week in New York. Led by the World Health Organization in collaboration with St. Jude Children’s Research Hospital in Memphis, Tenn., the effort aims to improve the care of young cancer patients in countries such as Haiti, bringing it more in line with places like the U.S.

The courtyard at St. Damien Pediatric Hospital in Haiti offers patients, staff and visitors a place to stroll.
The courtyard at St. Damien Pediatric Hospital in Haiti offers patients, staff and visitors a place to stroll. PHOTO: GEORGES HARRY ROUZIER FOR THE WALL STREET JOURNAL

That is good news for Dr. Gassant, who in 2004 was desperate for cancer-care expertise at St. Damien Pediatric Hospital. She read oncology books, emailed an American cancer specialist for advice and bought medicine.

In early 2010, a catastrophic earthquake rocked Haiti and the recovery helped Dr. Gassant’s effort. Representatives from St. Jude, which specializes in pediatric cancer, met Dr. Gassant when tending to Haiti’s ravaged medical system. St. Jude funded more staff, including a social worker, for her fledgling cancer unit and sent Dr. Gassant to study pediatric oncology in Guatemala. It began paying for cancer drugs and for sending some patients to the Dominican Republic for radiation. St. Damien still has a ways to go: chemotherapy drugs have to come from El Salvador, more than 1,000 miles away.

In recent years the U.S. and other nations have had breakthroughs treating children with cancer. According to doctors at St. Jude, 50 years ago, in well-off countries, most children with the illness died. Now, 80% or more of them survive. “We have advanced care at supersonic speed,” says Carlos Rodriguez-Galindo, a pediatric oncologist at St. Jude, who sees the progress at his hospital and others in affluent countries.

Well-off countries have made inroads against pediatric cancer ‘at supersonic speed,’ said Dr. Carlos Rodriguez-Galindo of St. Jude Children's Research Hospital.
Well-off countries have made inroads against pediatric cancer ‘at supersonic speed,’ said Dr. Carlos Rodriguez-Galindo of St. Jude Children’s Research Hospital. PHOTO:HOUSTON COFIELD FOR THE WALL STREET JOURNAL

Sadly, he says, the reverse is true in poor countries, where 80% of cancer-stricken children don’t survive. Basic tools to diagnose and fight cancer are lacking, he says: “There is not one single radiation [therapy] center in Haiti—and that is the problem around the world.”

Health organizations and charities have lowered infant mortality and improved child survival around the globe by targeting communicable diseases such as tuberculosis and malaria. But pediatric cancer, which annually afflicts about 300,000 patients world-wide, from newborns through age 19, “has not been a priority in the public health agenda,” except in high-income countries, says André Ilbawi, a cancer surgeon and a WHO technical officer for cancer.

“In the West, we understand cancer,” he says. But in some countries, when a child shows up with a fever or abnormal blood count, doctors don’t recognize leukemia, and “presume they have malaria.” The child will be given malaria drugs that “categorically do not work” against cancer, Dr. Ilbawi says.

Others are on the case. The Hospital for Sick Children in Toronto has paid for doctors from the Caribbean to come to Canada for fellowships in pediatric hematology-oncology. Doctors at the hospital consult with their counterparts in the Caribbean, says Victor Blanchette, co-chairman of the SickKids-Caribbean Initiative.

Dr. Gassant, left, looked in on her patient, 5-year-old John Shivensky Delice, and his mother, Miquerline Ceus, at Saint Damien Pediatric Hospital in Port-au-Prince, Haiti. John, far right, has leukemia, and is receiving chemotherapy.PHOTOS: GEORGES HARRY ROUZIER FOR THE WALL STREET JOURNAL(2)

Texas Children’s Hospital in Houston has focused on sub-Saharan Africa, where every year more than 100,000 children get cancer and 90% of them die, says David Poplack, a professor of pediatric oncology at Baylor College of Medicine. The initiative he started in 2106 targets three countries: Malawi, Botswana and Uganda—a nation of more than 44 million that two years ago didn’t have a single pediatric oncologist, Dr. Poplack says. A priority of the program, called Global HOPE, is training local pediatricians to become pediatric oncologists. These countries are taking so-called Centers of Excellence—clinics created during the AIDS epidemic—and expanding them to diagnose and treat children with cancer.

Before his program, Dr. Poplack says, in Uganda, “70% of the children who came to the hospital died in the first month.” Now, “85% are surviving one month and over 50% are surviving more than a year and a half.”

St. Jude officials say they have been fighting childhood cancer overseas for more than two decades, and recently implemented a five-year, $100 million plan. “I am sure that investment will escalate,” says Dr. James Downing, St. Jude president and chief executive.

St. Jude is joining forces with the WHO to “open the second chapter” of the campaign, says Dr. Rodriguez-Galindo, who is chairman of global pediatric medicine at St. Jude. On Sept. 27, the two organizations will announce a $15 million push against pediatric cancer. They plan to train doctors and nurses to care for young cancer patients and establish global and regional alliances. WHO hopes to coax governments on board while St. Jude and others will contribute cancer know-how. WHO also will work with other partners, Dr. Ilbawi says. WHO seldom has partnered with outside entities, sources say, so this venture with St. Jude is a new model.

In Haiti, Dr. Gassant says, cancer care remains a struggle. One patient, 5-year-old John Shivensky Delice, has been hospitalized since April with leukemia. He and his mom, a street vendor, came from a city almost 40 miles from Port-au-Prince, and she hasn’t left his side. She believes her son will be cured.

John has put on weight, but Dr. Gassant isn’t very hopeful. Since 2010, she has cared for 27 children with his form of aggressive leukemia. One is considered to have survived the illness; a handful of others are in treatment or remission.

“In America, he would have every chance to survive,” Dr. Gassant says. “He would get a bone-marrow transplant, but there are none in Haiti.”

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

Chemists find a recipe that may have jump-started life on Earth

In the molecular dance that gave birth to life on Earth, RNA appears to be a central player. But the origins of the molecule, which can store genetic information as DNA does and speed chemical reactions as proteins do, remain a mystery. Now, a team of researchers has shown for the first time that a set of simple starting materials, which were likely present on early Earth, can produce all four of RNA’s chemical building blocks.

Those building blocks—cytosine, uracil, adenine, and guanine—have previously been re-created in the lab from other starting materials. In 2009, chemists led by John Sutherland at the University of Cambridge in the United Kingdom devised a set of five compounds likely present on early Earth that could give rise to cytosine and uracil, collectively known as pyrimidines. Then, 2 years ago, researchers led by Thomas Carell, a chemist at Ludwig Maximilian University in Munich, Germany, reported that his team had an equally easy way to form adenine and guanine, the building blocks known as purines. But the two sets of chemical reactions were different. No one knew how the conditions for making both pairs of building blocks could have occurred in the same place at the same time.

Now, Carell says he may have the answer. On Tuesday, at the Origins of Life Workshop here, he reported that he and his colleagues have come up with a simple set of reactions that could have given rise to all four RNA bases.

Carell’s story starts with only six molecular building blocks—oxygen, nitrogen, methane, ammonia, water, and hydrogen cyanide, all of which would have been present on early Earth. Other research groups had shown that these molecules could react to form somewhat more complex compounds than the ones Carell used.

To make the pyrimidines, Carell started with compounds called cyanoacetylene and hydroxylamine, which react to form compounds called amino-isoxazoles. These, in turn, react with another simple molecule, urea, to form compounds that then react with a sugar called ribose to make one last set of intermediate compounds.

Finally, in the presence of sulfur-containing compounds called thiols and trace amounts of iron or nickel salts, these intermediates transform into the pyrimidines cytosine and uracil. As a bonus, this last reaction is triggered when the metals in the salts harbor extra positive charges, which is precisely what occurs in the final step in a similar molecular cascade that produces the purines, adenine and guanine. Even better, the step that leads to all four nucleotides works in one pot, Carell says, offering for the first time a plausible explanation of how all of RNA’s building blocks could have arisen side by side.

“It looks pretty good to me,” says Steven Benner, a chemist with the Foundation for Applied Molecular Evolution in Alachua, Florida. The process provides a simple way to produce all four bases under conditions consistent with those believed present on early Earth, he says.

The process doesn’t solve all of RNA’s mysteries. For example, another chemical step still needs to “activate” each of RNA’s four building blocks to link them into the long chains that form genetic material and carry out chemical reactions. But making RNA under conditions like those present on early Earth now appears within reach.

 

 

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

Taming the Groundcherry: With Crispr, a Fussy Fruit Inches Toward the Supermarket

The groundcherry might look at first like a purely ornamental plant. A member of the genus Physalis, it bears papery, heart-shaped husks that resemble Chinese lanterns. (The plant popularly known as the Chinese lantern is a close cousin.) Within each groundcherry casing is a small, tart, edible fruit, similar in appearance to a cherry tomato, that is sometimes sold at farmer’s markets.

The fruit might be more common in supermarkets were it not so difficult to grow in large quantities. Groundcherry bushes sprawl untidily and can drop their fruits early, and the plants possess other undesirable traits. Diminishing these traits through selective breeding would take years.

On Monday, however, a team of researchers reported that, by removing certain portions of the plant’s DNA using common gene-editing techniques, they’ve produced a groundcherry with a larger fruit and a more ordered bush, greatly speeding the process of domestication. Their work, which appeared in the journal Nature Plants, is part of a scientific initiative called the Physalis Improvement Project.

Groundcherries are related to tomatoes, which have a well-studied genome. Joyce Van Eck, a plant geneticist at Cornell University and the Boyce Thompson Institute and an author of the paper, and her colleagues had already discovered that, using Crispr, a gene-editing technique that can snip out portions of the genome, they could alter a specific tomato gene and produce plants that produced flowers more quickly.

The scientists wondered whether the groundcherry could be similarly altered, to help fast-track the domestication process. They examined the groundcherry genome for analogues of known tomato genes, and found one: an analogue of a gene called “SELF-PRUNING” or SP, that in tomatoes controls the shape of the plant.

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Stages of a groundcherry fruit’s growth at left, with the plant at right.CreditZachary Lippman/Cold Spring Harbor Laboratory/Howard Hughes Medical Institute

Using Crispr, the team removed a small portion of SP from the groundcherry genome. The resulting plants, when they grew, arranged themselves into more compact bushes. The team performed similar experiments with genes that influence flower number and fruit size.

“Sure enough, when we got those fruit off, they were larger than the parent groundcherry,” Dr. Van Eck said. “Close to 25 percent more weight in the fruit.”

Heartened by these successes, the researchers are working to see whether they can control the shape of groundcherry bushes with more precision. They are also keen to find a solution to the problem of fruit dropping off the bush.

“That can really complicate harvesting,” Dr. Van Eck said.

Tomatoes are known to carry a gene that influences the formation of a weak point on the stem of the fruit. Perhaps modulating this gene in the groundcherry will make possible a variety that keeps a firmer grip on its fruits.

It took around two years to complete the experiments. In the future, changes could take less time, or more, depending on how much work is necessary to adjust a given trait.

Still, Dr. Van Eck estimates that with conventional breeding techniques, addressing such traits can often take at least five years. And that’s if the trait breeders want to encourage is already present in some plants. If the trait isn’t readily available, then they face a much more difficult task of trying to track it down, then beginning the breeding process.

Because this application of Crispr involves only the removal of DNA, not the addition of new material, the resulting produce isn’t considered a genetically modified organism in the U.S. or Canada, Dr. Van Eck said.

The researchers suggest that this technique could be helpful in bringing plants that aren’t grown widely into greater circulation. The groundcherry, with its unusual look and enticing taste, could be a good first candidate.

 

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

Deep in Human DNA, a Gift From the Neanderthals

People of Asian and European descent — almost anyone with origins outside of Africa — have inherited a sliver of DNA from some unusual ancestors: the Neanderthals.

These genes are the result of repeated interbreeding long ago between Neanderthals and modern humans. But why are those genes still there 40,000 years after Neanderthals became extinct?

As it turns out, some of them may protect humans against infections. In a study published on Thursday, scientists reported new evidence that modern humans encountered new viruses — including some related to influenza, herpes and H.I.V. — as they expanded out of Africa roughly 70,000 years ago.

Some of those infections may have been picked up directly from Neanderthals. Without immunity to pathogens they had never encountered, modern humans were particularly vulnerable.

“We were actually able to not only say, ‘Yes, modern humans and Neanderthals exchanged viruses,’” said David Enard, an evolutionary biologist at the University of Arizona and co-author of the new paper, published in the journal Cell. “We are able to start saying something about which types of viruses were involved.”

But if Neanderthals made us sick, they also helped keep us well. Some of the genes inherited from them through interbreeding also protected our ancestors from these infections, just as they protected the Neanderthals.

Lluis Quintana-Murci, a geneticist at the Pasteur Institute in Paris who was not involved in the new research, said that until now, scientists had not dreamed of getting such a glimpse at the distant medical history of our species.

“Five years ago, we would never have imagined that,” he said.

Our immune cells kill off viruses with an arsenal of weapons, such as antibodies and signals that cause infected cells to commit suicide. But Dr. Enard began his research by wondering if humans have evolved other ways to avoid getting infected.

Viruses can’t replicate on their own. They appropriate proteins inside our cells to do the heavy lifting, copying viral genes and building new shells to put them in. If those proteins were to change shape, however, it should become harder for viruses to use them to multiply.

“Instead of a strategy where you attack the virus, you run away from it,” said Dr. Enard.

To learn whether this is really a defense the body uses, Dr. Enard needed to find all the human proteins known to interact with at least one virus. But no such list existed. So he plowed through the scientific literature, looking for every example.

Once he had built a catalog of 1,300 proteins — it took four months — he studied their evolutionary history. By comparing these proteins across different species, he discovered that many have changed over the course of evolution.

In the several million years since our ancestors split from other primates, one-third of the adaptive changes in our proteins have occurred among those that interact with viruses. And this remarkable discovery led Dr. Enard and Dr. Dmitri Petrov, an evolutionary biologist at Stanford University, to wonder about Neanderthals.

The common ancestor both of modern humans and Neanderthals lived roughly 600,000 years ago, probably in Africa. Neanderthals left the continent long before modern humans and spread across a huge range, from the coast of Spain to Siberia, before becoming extinct.

From fossils, scientists have been able to reconstruct entire genomes of Neanderthals. And they’ve found that living people with non-African ancestry carry 1 percent or 2 percent Neanderthal DNA.

That remnant DNA got into our gene pool through repeated interbreeding. But after Neanderthals became extinct, their DNA gradually declined in our genomes.

It’s likely that most Neanderthal genes were bad for our health or reduced our fertility, and therefore were lost in modern humans. But certain Neanderthal genes became more common, probably because they provided some kind of evolutionary advantage.

In recent years, researchers have found that some of those genes encode proteins made by immune cells. They speculated that modern humans benefited by borrowing Neanderthal genes to fight infections.

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A human T-cell, green, which helps the immune system fight viruses, under attack by H.I.V., in yellow. Neanderthal genes may have protected modern humans from an ancestor to the virus.CreditScience Source

Dr. Enard and Dr. Petrov had a more specific question: Did modern humans acquire genes that helped cells evade specific viruses by altering the shapes of cellular proteins?

The researchers pored through the genomes of living Asians and Europeans, and discovered a large fraction of those Neanderthal genes make proteins that interact with viruses.

The viruses that infected Neanderthals must have posed a major threat to modern humans as they left Africa. They had no immunity to these infections. But Neanderthals did, and through interbreeding, Neanderthals provided modern humans with genetic defenses.

“It’s like they brought the knife, but they also brought the shield,” Dr. Petrov said.

Dr. Enard and Dr. Petrov also found clues about exactly what kinds of viruses these Neanderthal genes protect against.

In living humans, many of the proteins made by those genes interact only with influenza viruses, for example. Others interact only with H.I.V.

“We are not saying that viruses that infect the human population now come from Neanderthals,” said Dr. Enard. It’s clear, for example, that H.I.V. jumped into humans just a century ago from chimpanzees.

Instead, it’s likely that modern humans got infected with an ancient relative of H.I.V. Dr. Enard couldn’t say how they were exposed to the new pathogen — perhaps directly through sex with Neanderthals, or by eating animals that both modern humans and Neanderthals hunted.

But it’s clear that, for billions of people alive today, Neanderthal genes likely play an important role in defending against such viruses.

“We are not anything but the result of our past,” said Dr. Quintana-Murci.

 

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

Giving Malaria a Deadline

Malaria is among the world’s worst scourges. In 2016 the disease, which is caused by a parasite and transmitted by mosquitoes, infected 194 million people in Africa and caused 445,000 deaths.

But biologists now have developed a way of manipulating mosquito genetics that forces whole populations of the insect to self-destruct. The technique has proved so successful in laboratory tests that its authors envisage malaria could be eliminated from large regions of Africa within two decades.

A team led by Andrea Crisanti, a biologist at Imperial College, London, altered a gene that disrupts the mosquito’s sexual development; the females become infertile but the males remain able to spread the debilitating gene to an ever-dwindling number of progeny. Dr. Crisanti found that laboratory populations of mosquitoes can be driven to extinction within 11 generations, he and colleagues report in Monday’s issue of Nature Biotechnology. Wild populations could be made to crash in about four years, according to computer models.

The technique involves equipping mosquitoes with a gene drive, a genetic mechanism that forces a gene of choice into all of an organism’s offspring. (Normally, sexual reproduction would pass the gene to only half the progeny.) Genes carried by a gene drive therefore can spread very rapidly through a population, which makes the technique both powerful and potentially dangerous. No gene drive has yet been released in the wild.

Previous efforts to reduce mosquito fertility using gene drives have failed because mutations arise in the stretches of DNA targeted by scientists, nullifying the engineered changes. These mutations are heavily favored by natural selection and permit the mosquitoes to escape the genetic trap.

Dr. Crisanti and his colleagues instead found a way to target a stretch of DNA that does not vary from one mosquito to another, presumably because each DNA unit plays so vital a role that any mutations would kill the organism. This invariant DNA sequence occurs in a gene called doublesex, which determines sexual development in the mosquito species Anopheles gambiae, one of the major carriers of the malaria parasite in Africa.

Dr. Crisanti’s team disrupted the doublesex gene in a way that affects only females. These females develop ambiguous sexual features: they cannot bite because they have male-type mouthparts, and they are infertile. But the males are unaffected and continue spreading the disruptive gene until no more eggs are laid.

In the lab, when males with the doublesex gene drive were placed in cages of wild mosquitoes, the populations were driven to extinction in as few as seven to 11 generations. No mutations could be found in the targeted sequence of DNA.

“We are not saying this is 100 percent resistance-proof,” Dr. Crisanti said. “But it looks very promising.”

Kevin Esvelt, who studies the evolution of gene drives at Massachusetts Institute of Technology, indicated that the biological aspects of mosquito control may now be close to solution. “With this achievement, the major barriers to saving lives are arguably no longer mostly technical, but social and diplomatic,” he said.

Launching a gene drive into the wild is risky. Once released, it can’t be recalled or easily disabled should anything go awry. In 2016, the National Academy of Sciences called for extensive tests and public consultation before any gene drive is released.

The theory of how gene drives could be used to control pest populations was laid out in 2003, in an article by Austin Burt, a biologist at Imperial College, London, and a co-author on the new paper. He hopes that a small-scale field trial can be started in Africa in five years.

Implementing such a program would entail releasing just a few hundred drive-carrying mosquitoes in each village. “We wouldn’t have to hit every village, maybe as few as one percent,” Dr. Burt said. Complete eradication isn’t necessary; the malaria parasite can’t maintain its populations once the number of mosquitoes falls below a certain number.

“If there are no unexpected technical or regulatory delays,” Dr. Burt said, “it’s possible to envisage that gene-drive mosquitoes, in combination with other approaches, could have eliminated malaria in significant parts of Africa in 15 years.”

Achieving such a goal likely will require a continentwide agreement, since a gene drive, once released, probably couldn’t be confined to a single country, and biologists want to avoid any unintended consequences. All insects analyzed so far rely on the doublesex gene to direct their sexual development. It could be disastrous if an altered doublesex gene drive somehow jumped from mosquitoes to another insect species, such as bees.

“That’s not possible,” Dr. Crisanti said. He noted that every insect species has its own version of both the doublesex gene and the gene’s highly conserved region, so a gene drive aimed at one species wouldn’t work in any other. For that same reason, the technique potentially could be aimed at a wide range of noxious insects, each targeted individually.

“These sequences might be an Achilles heel present in many insect pests,” Dr. Crisanti’s team writes in their paper.

Dr. Esvelt acknowledged that the new gene drive could possibly spread to other insects but said that, if it did, the most likely host would be other Anopheles mosquito species. “The known harm of malaria greatly outweighs every possible ecological side-effect that has been posited to date, even if all of them occurred at once,” he said.

 

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

Immune-Based Treatment Helps Fight Aggressive Breast Cancer, Study Finds

Women with an aggressive type of breast cancer lived longer if they received immunotherapy plus chemotherapy, rather than chemo alone, a major study has found.

The results are expected to change the standard of care for women like those in the clinical trial, who had advanced cases of “triple-negative” breast cancer. That form of the disease often resists standard therapies, and survival rates are poor. It is twice as common in African-American women as in white women, and more likely to occur in younger women.

Researchers said the new study was a long-awaited breakthrough for immunotherapy in breast cancer. Until now, most progress had been in other cancers, including lung cancer and melanoma, an aggressive skin cancer.

These findings may lead to the first approval by the Food and Drug Administration for an immunotherapy drug to treat breast cancer. But the approval would likely be limited to a certain type of aggressive cancer.

Although triple-negative tumors occur in only about 15 percent of patients with invasive breast cancer in the United States (or nearly 40,000 each year), they account for a disproportionate share of deaths, as many as 30 percent to 40 percent.

“These women really needed a break,” Dr. Ingrid Mayer, a breast cancer specialist at Vanderbilt University, said in a telephone interview. “Nothing has worked well.”

Dr. Mayer, who was not part of the study, called the findings “very significant.” She said she had received consulting fees from seven drug companies, including Genentech, which is the maker of the immunotherapy drug in the study and paid for the research.

The term triple-negative refers to the tumors’ lack of sensitivity to the hormones estrogen and progesterone, and their lack of a protein called HER2, which is a target of treatment.

The immunotherapy in the study was atezolizumab (brand name Tecentriq), which belongs to a class of drugs called checkpoint inhibitors; the chemotherapy was nab-paclitaxel (Abraxane).

The findings were published on Saturday in The New England Journal of Medicine, and were to be presented at a meeting of the European Society for Medical Oncology, in Munich. The study included 902 patients treated at 246 medical centers in 41 countries. Genentech, which is part of Roche, has already submitted the data to the F.D.A. for approval.

Checkpoint inhibitors like atezolizumab work by helping T-cells — a type of white blood cell that is part of the immune system — recognize cancer and attack it. Research that led to these drugs won this year’s Nobel Prize in medicine.

The drugs generally work for fewer than half of patients but can bring lasting recoveries even to people who were severely ill. Side effects can be dangerous, even life-threatening, and treatment costs more than $100,000 a year.

In other cancers, researchers sometimes describe the tumors as “hot,” meaning they tend to have many mutations — genetic abnormalities that the immune system can recognize as foreign and attack.

But breast cancers tend to be relatively “cold,” with fewer mutations. The immune system is less likely to recognize them as invaders, which may help explain why previous studies of checkpoint inhibitors in breast cancer have been somewhat disappointing, researchers say.

In the new study, the key to success seems to have been giving chemotherapy along with immunotherapy.

“Chemo takes away the invisibility cloak the cancer has managed to put on,” Dr. Mayer said.

The chemo may help to ignite the immune system, in part by killing cancer cells that then spill substances the T-cells detect as foreign and begin to hunt.

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“This is truly a game changer,” said Dr. Sylvia Adams, an author of the study.CreditHilary Swift for The New York Times

The new study “is a big deal and has been the buzz of the breast cancer research world,” said Dr. Larry Norton of Memorial Sloan Kettering Cancer Center in an email. He was not involved in the study, although he said he had done paid consulting work for the past two years for the maker of Abraxane.

Beyond changing treatment practices, he said the research “opens the door to new approaches to harness the immune system to fight breast cancer, and there is every reason to expect major advances there.”

He cautioned that the combined treatment would have to be studied further, to assess side effects.

Dr. Kevin Kalinsky, a breast cancer specialist at NewYork-Presbyterian/Columbia University Irving Medical Center, suggested that patients like those in the study should talk to their doctors “about whether it is possible for them to get access to the medication while we’re waiting for F.D.A. approval.”

He did not take part in this study. He said he has received consulting fees from about 10 drug companies, including Genentech.

The women in the study had triple-negative breast cancer that had been newly diagnosed and had become metastatic, meaning it had begun to spread. Once that occurs, the outlook is grim, with many patients surviving 18 months or less.

Half received chemo alone, and half were given chemo plus immunotherapy.

Among those who received the combination, the median survival was 21.3 months, compared with 17.6 months for those who received chemo alone. The difference was not statistically significant.

But when the researchers looked at women who had a marker called PD-L1 on their cancer cells, the results were striking: The median survival was 25 months in the combination group, versus 15.5 months with just chemo. That finding has not been analyzed statistically, and the patients are still being followed.

Doctors say the survival difference is important.

“This is truly a game changer,” said Dr. Sylvia Adams, an author of the study from NYU Langone Health’s Perlmutter Cancer Center.

Cancer patients with the PD-L1 marker tend to respond better to checkpoint inhibitors than those without it. In this study, 41 percent of patients had the marker. Genentech is seeking approval for treatment in triple-negative patients with the marker.

Dr. Adams said some patients, after initial treatment with both types of drug, have been doing well for two or three years with immunotherapy alone.

The “million-dollar question,” she said, is whether they can safely stop the immunotherapy if they have no sign of cancer. For the time being, they are sticking with the treatment.

She noted that patients in the study had some of the expected side effects of immunotherapy, including lung and pancreas inflammation.

Dr. Adams said she accepted no money from drug companies, but her medical center did receive money from Genentech to pay for the research.

Maribel Ramos, 42, was being treated at another hospital, which recommended chemo for her advanced triple-negative breast cancer.

“I was very worried because I know with that type of cancer, chemo doesn’t work,” Ms. Ramos said. She has three daughters: a 23-year-old and 10-year-old twins.

Her sister, a nurse at New York University, told her about the study there, and she began treatment in February 2016. She didn’t know it at the time, but she had been picked at random to receive the combined treatment. Within a few months, her tumors began to shrink. Nine months ago, for the first time, a scan found no sign of cancer. She is staying on immunotherapy.

“I just feel so happy that you can live longer,” Ms. Ramos said. “I wish that all the ladies that are fighting cancer, especially triple-negative, could get this medicine. I would recommend that all women get a second opinion, and sometimes even a third opinion.” She added, “This can save your life.”

About 266,120 new cases of invasive breast cancer are expected in women in 2018 in the United States, and 40,920 deaths.

 

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

Researchers Explore a Cancer Paradox

Cancer is a disease of mutations. Tumor cells are riddled with genetic mutations not found in healthy cells. Scientists estimate that it takes five to 10 key mutations for a healthy cell to become cancerous.

Some of these mutations can be caused by assaults from the environment, such as ultraviolet rays and cigarette smoke. Others arise from harmful molecules produced by the cells themselves. In recent years, researchers have begun taking a closer look at these mutations, to try to understand how they arise in healthy cells, and what causes these cells to later erupt into full-blown cancer.

The research has produced some major surprises. For instance, it turns out that a large portion of the cells in healthy people carry far more mutations than expected, including some mutations thought to be the prime drivers of cancer. These mutations make a cell grow faster than others, raising the question of why full-blown cancer isn’t far more common.

“This is quite a fundamental piece of biology that we were unaware of,” said Inigo Martincorena, a geneticist at the Wellcome Sanger Institute in Cambridge, England.

These lurking mutations went unnoticed for so long because the tools for examining DNA were too crude. If scientists wanted to sequence the entire genome of tumor cells, they had to gather millions of cells and analyze all of the DNA. A mutation, to be detectable, had to be very common.

But as DNA sequencing grew more sophisticated, Dr. Martincorena and other researchers developed methods for detecting very rare mutations, and they began to wonder if those mutations might be found in healthy cells, hidden below the radar.

Dr. Martincorena and his colleagues began their search in skin; its cells are battered daily by the sun’s ultraviolet rays, which trigger mutations. “We thought it was the lowest-hanging fruit,” Dr. Martincorena said.

In a study in 2015, he and his colleagues collected bits of skin left over from cosmetic surgeries to lift drooping eyelids. They examined 234 biopsies from four patients, each sample of skin about the size of a pinhead. They gently coaxed the top layers of cells, known as epithelial cells, from the underlying tissue.

Dr. Martincorena’s team then fished the DNA from the healthy epithelial cells, and carefully sequenced 74 genes that are known to play an important role in the development of cancer. Mutations that are common in cancer genes were remarkably common in these healthy skin cells, too, the researchers found. About one of every four epithelial cells carried a mutation on a cancer-linked gene, speeding up the cell’s growth.

It was possible, the scientists knew, that skin was peculiar. Maybe inside the body, away from the onslaught of ultraviolet rays, were healthy cells that didn’t carry these key mutations.

To find out, the researchers decided to study cells of the esophagus. The team gathered tissue samples from nine healthy organ donors who had died, then they sliced the tissue into dozens of tiny squares and examined the same 74 cancer-related genes.

Dr. Martincorena and his colleagues found that new mutations arose more slowly in the esophagus than in skin. But once those mutations emerged, they caused the esophageal cells to multiply faster than normal esophageal cells. Over time, these rogue cells spread out across the esophagus, forming colonies of mutant cells, known as clones. Although these clones aren’t cancer, they do exhibit one of cancer’s hallmarks: rapid growth.

“These mutant clones colonize more than half of your esophagus by middle age,” said Dr. Martincorena. “It was eye-opening for me.” Dr. Martincorena and his colleagues reported their findings on Thursday in the journal Science.

By examining the mutations, the researchers were able to rule out external causes for them, like tobacco smoke or alcohol. Instead, the mutations seem to have arisen through ordinary aging. As the cells divided over and over again, their DNA sometimes was damaged. In other words, the rise of these mutations may just be an intrinsic part of getting older.

“It seems that no matter how well one takes care of oneself by eating well, getting exercise and limiting certain vices, there’s likely only so much one can do against the need of the body to replace its cells,” said Scott Kennedy, a cancer biologist at the University of Washington who was not involved in the study.

The study also raised questions about efforts to detect cancer at its earliest stages, when cancer cells are still rare, Dr. Kennedy said: “Just because someone has mutations associated with cancer doesn’t mean actually they have a malignancy.”

Given the abundance of cancer mutations in healthy people, why isn’t cancer more common? Dr. Martincorena speculated that a healthy body may be like an ecosystem: Perhaps clones with different mutations arise in it, compete for available space and resources, and keep each other in check.

If so, fighting cancer might one day be a matter of helping harmless clones outcompete the ones that can lead to deadly tumors.

“There is no therapy being thought out in these terms now,” said Dr. Martincorena. “But I think it opens up new avenues. I think knowledge is always a weapon.”

 

 

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

The Problem With Probiotics

Even before the microbiome craze — the hope that the bacteria in your gut holds the key to good health — people were ingesting cultures of living micro-organisms to treat a host of conditions. These probiotics have become so popular that they’re being marketed in foods, capsules and even beauty products.

Probiotics have the potential to improve health, including by displacing potentially harmful bugs. The trouble is that the proven benefits involve a very small number of conditions, and probiotics are regulated less tightly than drugs. They don’t need to be proved effective to be marketed, and the quality control can be lax.

In a recent article in JAMA Internal Medicine, Pieter Cohen, an associate professor of medicine at Harvard Medical School, urges us to consider the harms as well as the benefits. Among immune-compromised individuals, for instance, probiotics can lead to infections.

Consumers can’t always count on what they’re getting. From 2016 to 2017, the Food and Drug Administration inspected more than 650 facilities that produce dietary supplements, and determined that more than 50 percent of them had violations. These included issues with the purity, strength and even the identity of the promised product.

Probiotic supplements have also been found to be contaminated with organisms that are not supposed to be there. In 2014, such a supplement’s contamination arguably caused the death of an infant.

Given all of this, what are the benefits? The most obvious use of probiotics would be in the treatment of gastrointestinal disorders, given that they are focused on gut health. There have been many studies in this domain, so many that early this year the journal Nutrition published a systematic review of systematic reviews on the subject.

The takeaway: Certain strains were found useful in preventing diarrhea among children being prescribed antibiotics. A 2013 reviewshowed that after antibiotic use, probiotics help prevent Clostridium difficile-associated diarrhea. A review focused on acute infectious diarrhea found a benefit, again for certain strains of bacteria at controlled doses. There’s also evidence that they may help prevent necrotizing enterocolitis (a serious gastrointestinal condition) and death in preterm infants.

Those somewhat promising results — for very specific uses of very specific strains of bacteria in very specific instances — are just about all the “positive” results you can find.

Many wondered whether probiotics could be therapeutic in other gastrointestinal disorders. Unfortunately, that doesn’t appear to be the case. Probiotics didn’t show a significant benefit for chronic diarrheaThree reviews looked at how probiotics might improve Crohn’s disease, and none could find sufficient evidence to recommend their use. Four more reviews looked at ulcerative colitis, and similarly declared that we don’t have the data to show that they work. The same was true for the treatment of liver disease.

Undaunted, researchers looked into whether probiotics might be beneficial in a host of disorders, even when the connection to gut health and the microbiome was tenuous. Reviews show that there is insufficient evidence to recommend their use to treat or prevent eczemapreterm laborgestational diabetesbacterial vaginosisallergic diseases or urinary tract infections.

Reviews looking at the treatment or prevention of vulvovaginal candidiasis in womenpneumonia in patients hooked up to respirators, and colds in otherwise healthy people show some positive results. But the authors note that the studies are almost all of low quality, small in size, and often funded by companies with significant conflicts of interest.

Individual studies are similarly disappointing for probiotics. One examining obesity found limited effects. Another showed they don’t prevent cavities in teeth. They don’t help prevent infant colic, either.

None of this has prevented probiotics from becoming more popular. In 2012, almost four million Americans used them. In 2014, the global market for probiotics was more than $32 billion.

It’s not clear why. Even in specific diarrhea-focused areas, the case for them isn’t as strong as many think. As with nutrition research, much of this has to do with study design and how proof of efficacy doesn’t translate into real-world applications.

“Sometimes small studies suggest strains work, but when a larger more well-done study is performed, they no longer seem to,” Dr. Cohen said.

When research is done on probiotics, it usually involves a specific organism, defined by genus, species and even strain. When used in studies, they are pure and carefully dosed. But when we buy probiotics off the shelf, especially when they are in food products, we often have no idea what we’re getting.

Further, there’s still a lot we don’t know. A recent study published in Cell compared how the microbiome of the gut reconstituted itself after antibiotic treatment with and without probiotic administration. The researchers found that probiotics (which might have improved diarrhea symptoms) led to a significant delay in microbiome reconstitution, if it occurred at all. And — again — this study was with purified strains of bacteria, which is not what you’re getting in probiotic-containing food.

Of course, people with no immune deficiencies should feel free to eat yogurt and sauerkraut, which can absolutely be part of a healthy diet. Eat them because they’re delicious, and most likely better for you than many other foods, not because of any health claims.

“It’s important that consumers understand that all those nicely labeled containers on store shelves are not vetted by the F.D.A.,” Dr. Cohen said. “They’re not carefully watching over the probiotic space, leaving consumers to be the guinea pigs for these science experiments.”

For too long we’ve assumed that probiotics are doing some good and little harm. That might be true for some, but it’s not assured in the current environment.

 

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

The Results of Your Genetic Test Are Reassuring. But That Can Change.

The results of a genetic test may seem final — after all, a gene mutation is present or it is not. That mutation increases the risk of a disease, or it does not.

In fact, those findings are not as straightforward as they might seem, and the consequences may have grave implications for patients.

While a person’s genome doesn’t change, the research linking particular bits of DNA to disease is very much in flux. Geneticists and testing labs constantly receive new information that leads them to reassess genetic mutations.

As a result, a mutation seen as benign today may be found dangerous tomorrow. And vice versa. But there is no good way to get the new information to doctors and patients.

The result: The gene test you had a few years ago might yield a startlingly different result now.

The problem affects a minority of patients, mostly people with unusual mutations. The more common disease-causing mutations — like those that predispose you to breast or colon cancer — are so well studied that their meaning is not in doubt.

In a recent study, researchers at Myriad Genetics, a diagnostic company, reviewed data on 1.45 million patients who had genetic tests from 2006 to 2016 to see if the results originally reported still held true.

The lab issued new reports for nearly 60,000 of them, meaning the old results had been superseded by new data.

But many patients who carry mutations that have been reclassified remain in the dark. “The system is completely chaotic,” said Dr. Sharon E. Plon, a clinical geneticist at Baylor College of Medicine.

There is no systematic way, she said, to tell patients and doctors that a mutation once thought harmless has been shown to be a health hazard or one thought dangerous is actually benign.

“Some labs report out only one-time results,” said Dr. Theodora Ross, director of the cancer genetics program at the University of Texas Southwestern Medical Center. “They are not going back to reassess test interpretations from ten years ago unless doctors ask.”

But doctors seldom ask, she added.

Normally, a doctor orders genetic testing for a person with a strong family history of, say, heart attacks, strokes or cancer. A sample of a patient’s blood or saliva is sent to a lab, where the patient’s DNA is scanned for unusual alterations.

Not all of these are harmful. The lab compares the mutations to those shown in scientific studies to cause disease.

Some patients are told they have a mutation that is meaningless. Others learn they have “a variation of unknown significance” in a suspect gene — meaning no one knows quite what to make of it.

Still other patients have a mutation deemed dangerous, meaning there is a very high risk of developing cancer, heart disease or another condition. For those patients, such a result can mean regular monitoring and can alter a number of life decisions, including whether to have children.

Reclassification is a particular problem for members of racial and ethnic minorities —- populations whose genes have not been as well studied as those of white people. It can be difficult to know what a variation in DNA means for these patients.

A federally-supported database, ClinVar, allows laboratories to publicly share data on genetic mutations and what they are thought to mean. But some companies, like Myriad, which host huge databases on genetic mutations, do not contribute to ClinVar.

Even the terminology for DNA variants may not be widely shared. Different labs have different naming schemes.

For example, ClinVar renders one DNA variant this way:

NM_004004.5(GJB2):c.101T>C (p.Met34Thr).

But another lab does it like this:

c.101T>C, p.Met34Thr, GJB2.

Patients searching for information on their own “would not be sure what to type into ClinVar,” said Dr. Heidi Rehm, a clinical geneticist at Massachusetts General Hospital and the Broad Institute.

In addition to the terminology problem, Dr. Ross said, there is a problem of discordance among labs.

When one big lab “reports a reclassification and the other labs do not, and you have family members who get tested at different labs, we have different interpretations of the same patient data,” Dr. Ross said. “How do we deal with that? What do we tell our patients?”

Labs like Myriad often notify a doctor who ordered a genetic test when the results were reclassified. But even when they do, doctors may not be able to reach and inform their patients.

“I’ve changed my practice location over the years, and my patients have moved,” Dr. Plon said. “I have received updated reports for patients who no longer live in Houston, and we have no idea where they live.”

Some geneticists say the burden for getting updated results will fall on patients whose genetic alterations are rare ones. They will have to contact their doctors or genetic counselors annually to ask if there was a reclassification.

A reclassification is not always good news.

Dr. Jason Park, clinical director of the advanced diagnostics laboratory at Children’s Medical Center in Dallas, said he has told parents of children with severe epilepsy that a genetic mutation thought to be the cause of the disease actually is a benign change.

The reclassification may not alter treatment, since there often is no specific treatment for a mutation thought to be causing severe epilepsy. But now parents who thought they had found the cause of their child’s illness learn instead that the cause is unknown.

“For families this can be a major social issue,” Dr. Park said. “There are support groups centered around certain genes. Now they are no longer part of that group.”

But for some, like Ricky Garrison, a 61-year-old firefighter who lives in Denton, Tex., reclassification can be a lifesaver.

He went to a doctor a couple of years ago because a warty growth on his nose, but a pathology lab examining the tissue noticed some unusual changes in proteins linked to Lynch syndrome, a condition that greatly increases the risk for a variety of cancers

He was referred to Dr. Ross and her genetics team, who sent his blood to Invitae to test for mutations in Lynch genes.

Image

Rick Garrison, who lives outside Dallas, went to a doctor because of a growth on his nose. The initial results of genetic testing: “Lynch-like syndrome.”CreditLaura Buckman for The New York Times

The results: Mr. Garrison had a “variant of unknown significance.” And his diagnosis was confusing: “Lynch-like syndrome.” It meant maybe he had Lynch syndrome — and maybe he did not.

Doctors said he should have annual colonoscopies, endoscopies and whole skin exams. But since his was not a mutation definitely linked to Lynch syndrome, his family members — he has five children — were not tested to see if they had inherited it.

“No lab that is reasonable would clinically test a family for a variation of unknown significance,” Dr. Ross said. Instead, family members were told to assume they might have Lynch syndrome and to go ahead with the intense cancer surveillance.

In June, though, the testing lab contacted Dr. Ross with news. Mr. Garrison’s mutation was no longer of “unknown significance.” Research in other patients had shown it to be linked to Lynch syndrome.

Everything changed. His children and direct relatives must be tested for the mutation. He must be monitored constantly for signs of cancer.

He will change his plans to retire next year because he worries about the cost of health insurance for someone with Lynch syndrome. Instead he will keep his firefighter job, which comes with insurance, and wait until he is 65 to retire and get Medicare.

“Cancer will probably get me in the end,” he said. “But because of this, I probably will have a few more good years.”

 

 

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

Switching to plant-based protein could increase America’s food supply by a third

VEGANS are good for the environment. Growing their food requires less land than raising meat does. Animals do not turn all the energy in the crops they eat into calories in their muscles. They need some of that energy to stay alive—and while that overhead is good for the animals, from a food-production standpoint it looks like a waste. This waste means you need more land per calorie of food if you are producing beef than if you are producing broccoli. Admittedly, a lot of grazing is on land that would not necessarily be suitable for arable farming. But the finding from the UN’s Food and Agriculture Organisation that raising livestock takes about 80% of all agricultural land and produces just 18% of the world’s calories is still telling.

Alon Shepon of the Weizmann Institute and colleagues have looked at this in terms of opportunity costs. Choosing to make a gram of protein by feeding an egg-laying hen, rather than getting the equivalent of a gram of egg protein from plants, has an opportunity cost of 40%. Getting the gram of protein from beef represents an opportunity cost of 96%. They argue that if America stopped paying these opportunity costs and got the protein from plants in the first place, it would be equivalent to increasing the food supply by a third—or eliminating all of the losses due to food waste.

 

This article was originally published in The Economist. Read the original article.