Less-Invasive Liver-Donor Surgery May Shorten Transplant Waiting List

The patient in the operating room was Stanley Kareta, a 29-year-old Army captain who had agreed to donate half of his liver to his wife’s father.

The older man had a liver disease so advanced that his only hope of survival was a transplant. But with about 14,000 people on the nation’s waiting list for donor livers, most of which come from deceased donors, there was little chance he would be approved for one in time.

His only option was to find a living donor willing to give up part of his or her liver for transplant. In this procedure, surgeons cut off part of a healthy person’s liver and transplant it into a patient suffering from end-stage liver disease. With the liver’s extraordinary ability to regenerate, both the donor and the recipient typically enjoy a full recovery.

Rarely done

This type of procedure isn’t without risk, however. And because doctors are often reluctant to subject healthy people to such a major operation, and few living donors step forward, it is rarely performed.

Adding to the challenge in Capt. Kareta’s case, Adel Bozorgzadeh, chief of organ transplantation at UMass Memorial Medical Center in Worcester, Mass., had decided on a surgical approach still in its infancy. Rather than making a large incision in the abdomen, he and his team would use laparoscopy, a minimally invasive—but technically challenging—technique.

Surgeons often use minimally invasive techniques to repair heart defects and knees and to remove gallbladders, ovaries and esophageal cancer, among other procedures. The approach can lead to faster recovery, less pain, and fewer wound infections and incision hernias.

But only a handful of surgeons in the U.S. are doing liver donations with laparoscopy, both because ethical concerns about operating on live donors make them cautious about trying a new approach and because this particular surgery is technically challenging.

In the U.S. last year, just 367 of 8,082 liver transplants came from live donors, says the Department of Health and Human Services’ Organ Procurement and Transplantation Network. Just a fraction of those were done with laparoscopy.

If surgeons performed more live-donor liver transplants using laparoscopy, the procedure’s supporters say, it would encourage more donors to step forward. And that could reduce the thousands of deaths in the U.S. each year of people waiting for a liver to become available from a deceased donor, the more usual method. Each day, about 22 people on the waiting list for a liver transplant in the U.S. receive transplants, while about seven die or are removed from the list because they have become too near death for surgery before a liver becomes available, the organ network says.

A challenging operation

However it is done, liver-donation surgery is considered one of the most challenging operations there is. It is sometimes said to be like trying to cut a big piece of watermelon without disturbing any of the seeds inside. Minuscule blood vessels and bile ducts run throughout the organ. The surgeon has to divide them with precision, and there is no room for error. Any bleeding or bile leakage must be stanched to avoid possibly dangerous complications. Deaths of liver donors are rare, but do occur in an estimated 1 out of 500 cases.

Open liver surgery generally involves an L-shaped incision halfway across the donor’s stomach from hip to belly button and all the way up the chest. The incision can be as much as a foot and a half long and requires cutting through core abdominal muscles.

The laparoscopic approach, by contrast, makes only small incisions and uses a tiny camera. Shorter recovery times mean donors can return to their normal lives faster, including heavy physical work.

Benjamin Samstein, chief of liver transplantation at NewYork-Presbyterian/Weill Cornell Medical Center, has led the way in bringing laparoscopic liver-donor surgery to the U.S. Last year his team did all five of its donor operations for pediatric transplants and seven of its 14 donor operations for adult transplants using a fully laparoscopic approach.

The small incisions for laparoscopic liver-donor surgery (left) vs. the L-shaped incision for traditional surgery (right).
The small incisions for laparoscopic liver-donor surgery (left) vs. the L-shaped incision for traditional surgery (right). PHOTO: NEWYORK-PRESBYTERIAN AND WEILL CORNELL MEDICINE

Dr. Samstein says his aim is to greatly increase access to liver transplants by making it easier to be a donor. He says the number of live kidney donors nearly doubled in 10 years when laparoscopic donor surgery was introduced in 1995, an increase experts believe was due in large part to laparoscopy. Live kidney donors used to be almost always first-degree relatives—parents, children and siblings—but with laparoscopic surgery making recovery easier and shorter, “people felt more comfortable reaching out to people throughout their communities,” Dr. Samstein says.

2015 paper by Dr. Samstein published in Liver Transplantation and based on 42 cases, mostly adults donating livers to children, found significant advantages for laparoscopy over open surgery: Though operating time was longer, blood loss was less, hospital stay was shorter, and return to work was far faster. Open-surgery patients took, on average, 63 days to return to work, while donors who had laparoscopic surgery took 34 days, the study found.

At Mayo Clinic in Rochester, Minn., Julie Heimbach, surgical director of liver transplantation, recruited one of the leading practitioners of laparoscopic liver-donation surgery in South Korea, Choon Hyuck David Kwon, to help Mayo’s doctors develop their skills. Surgeons at the clinic are now using laparoscopy for the first part of the operation, which enables them to make a somewhat smaller incision and avoid cutting muscle. Several other American hospitals have reached out to Dr. Kwon as well.

But even among surgeons who believe it’s crucial to encourage more living donors, some argue that urging doctors to perform laparoscopy isn’t the way to do it.

‘The whole picture’

“We have to concentrate on the whole picture, not on one technique or the other,” says Robert Fisher, chief of transplantation at Beth Israel Deaconess Medical Center in Boston. Dr. Fisher says he isn’t opposed to laparoscopy but feels most comfortable sticking with the techniques he has been using safely. Transplant specialists can do more to “gain society’s trust” in conventional surgery, he says, and advanced pain-control methods can be almost as effective as laparoscopy at reducing recovery times.

To others, though, the potential for increasing the supply of liver donors is a compelling argument for the laparoscopic approach. “The big question in everyone’s mind,” says Dr. Bozorgzadeh of UMass Memorial Medical Center, “should be, ‘Is it OK to let thousands of people die a year waiting for a liver transplant while we say there are no organs?’ ” No, it is not, he says, “because there are organs. They’re in living donors, and if you learn to do this safely the shortage is partially addressed.”

Dr. Bozorgzadeh’s surgery on Capt. Kareta last summer was only his sixth laparoscopic liver donation. Dr. Bozorgzadeh and his team, including Demetrius Litwin, an expert in minimally invasive surgery, inserted a small needle below Capt. Kareta’s rib cage to inflate his abdominal cavity with carbon-dioxide gas.

They then made four slits of less than a half-inch each, through which they inserted surgical tools and a camera, and a 4-inch incision, called a hand port, through which Dr. Bozorgzadeh slipped a hand that eventually brought out the portion of liver going to the captain’s father-in-law in the operating room next door.

Capt. Kareta’s surgery was successfully completed July 11. He left the hospital after six days, taking only ibuprofen for the pain, and returned to work on Aug. 17, about five weeks after the surgery. The median time for patients to return to light work after open liver-donation surgery is nine to 12 weeks, according to a 2017 paper in Nature Reviews Gastroenterology & Hepatology. By October, Capt. Kareta was wearing his usual equipment for field exercises, including body armor and a rucksack, which together weighed about 65 pounds.

Asked whether his relationship with his father-in-law has changed, he says no, but then chuckles. “He did send me a birthday card on his birthday, saying thank you inside. I think he plans on sending me one for the rest of his life.”

 

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

Good News on Early Breast Cancer: Herceptin Treatment Can Be Shortened

Over the past 20 years, hundreds of thousands of women with breast cancer have taken the drug Herceptin, typically for a year or more. The medicine, used to treat an aggressive form of the disease, is credited with saving many lives, but it also has some tough side effects, particularly damage to the heart.

A large new study that followed thousands of women with early-stage breast cancer for a median of more than five years has found that those treated with Herceptin for only six months did just as well as those who got it for a year — and they suffered fewer side effects.

The shorter regimen also saved money. A yearlong course of the drug costs $76,700.

Dr. Bruce E. Johnson, president of the American Society of Clinical Oncology, said the study’s findings should change treatment for women who have early-stage breast cancer treatable by Herceptin. He was not involved in the research, which was done in Britain and will be presented at a meeting of the oncology society next month.

“A lot of people will likely adopt a shorter regimen based on this finding,” Dr. Johnson said.

Cancer specialists say the study offers not only important news for women’s health, but also highlights a type of research that pharmaceutical companies almost never do and that is also critically important for cancer drugs that can often be quite toxic.

The study has not yet been published in a medical journal, and some experts reserved judgment until the data have been peer-reviewed.

Dr. Johnson noted that as the field of cancer research matures, more efforts are being made to fine-tune treatments — lessening doses or duration, or even dropping some forms of therapy entirely for certain patients — to minimize harsh side effects without sacrificing efficacy.

For example, a study last year showed that many patients with colon cancer could safely shorten their course of chemotherapy from six months to three. And a study in 2016 found that many women with early-stage breast cancer, who traditionally would have been given chemo, could safely skip it, based on tests of gene activity in their tumors.

Dr. Otis W. Brawley, chief medical and scientific officer of the American Cancer Society, said there was also an increasing recognition among doctors that it is safe to monitor some early cancers, including certain tumors in the prostate, thyroid gland, kidney and bladder, rather than perform surgery immediately. Some tumors will eventually require removal, but others will not grow, spread or threaten the patient’s life or health.

The Herceptin study was paid for by the British government. Dr. Johnson said that although drug companies finance many studies, they are not eager to pay for research that may decrease use of their products.

Dr. Brawley agreed, saying: “When drug companies do research, they’re interested in gaining knowledge such that they can make money for their shareholders. There is a difference. You will not see drug companies doing this kind of study. They don’t mind that somebody else did it, but they will not get caught doing a study that decreases their bottom line.”

Courtney Aberbach, a spokeswoman for Herceptin’s maker, Genentech, owned by Roche, said in an email that previous studies had not found that a shorter duration worked as well as the longer one.

She said the 12-month course was still the only regimen approved for early-stage disease by the Food and Drug Administration and recommended by several international organizations that issue treatment guidelines.

But Dr. Brawley pointed out that this type of research underlines the importance of government entities in conducting or supporting cancer research, because their goal is to increase understanding of the disease.

The new study is the first to show that women with early-stage disease can safely cut back on Herceptin, Dr. Helena Earl, its first author, at the University of Cambridge in Britain, said in an email.

“Here we are asking the question whether less is more,” she said.

Studies like the new one, aimed at finding out whether one treatment is no worse than another, are more difficult and more expensive — requiring more patients and longer follow-up — than studies trying to prove that one treatment is better than another, Dr. Brawley said.

About 15 percent of women with early breast cancer have tumors that respond to Herceptin, also called trastuzumab. Such tumors are particularly aggressive, because they have high levels of a protein called HER2, which promotes cancer growth. The drug significantly increases survival in those women.

But it has risks as well, particularly heart problems, which are sometimes permanent.

“I have personally seen congestive heart failure caused by Herceptin,” Dr. Brawley said. “The longer you give it, the likelier they are to get it. So it’s a wonderful thing if you can give it for a shorter time.”

In the United States, 266,000 new cases of invasive breast cancer are expected in 2018, and nearly 41,000 deaths. Globally, the most recent statistics come from 2012, when there were 1.7 million new cases.

The women in the study had early-stage breast cancer, meaning it had not spread to bones or organs — stages 1, 2 and 3. The findings do not apply to women with more advanced disease that has spread, Stage 4. Those patients need a longer course of treatment, Dr. Earl said.

She said the findings would undergo “rigorous scientific scrutiny” by other researchers and be published in a peer-reviewed journal.

In addition, the results will be analyzed further to determine whether there are subgroups of patients with specific levels of risk that would signal different advice about Herceptin.

“The final call will be with our colleagues and patients to decide whether these results will change practice,” Dr. Earl said.

“This could be absolutely practice-changing for a lot of patients,” said Dr. Jennifer Litton, an associate professor of breast medical oncology at MD Anderson Cancer Center in Houston.

But she added, “I’d like to see the data, and see it peer-reviewed, before I make a big practice change.”

In the meantime, the results should reassure women who in the past had to quit Herceptin after only six months because of side effects, Dr. Litton said.

She had a patient like that whom she had worried about. “Now I don’t feel bad,” Dr. Litton said.

Dr. Earl’s study, called the Persephone trial, included 4,089 women in Britain who were picked at random to take the drug for six or 12 months, along with standard chemotherapy. The women were 23 to 82 years old, with a median age of 56. They were followed for a median of more than five years.

After four years, the disease-free survival rate was 89.4 percent in those treated for six months, and 89.8 percent in the 12-month group.

Disease-free survival means they had no signs of breast cancer, and the lack of difference between the two groups suggests that their overall survival should be equal as well, Dr. Johnson said, though longer follow-up would be needed to be sure.

Dr. Earl said they would be followed for 10 years.

Toxicity can build up over time, and with the shorter course, half as many women had to quit treatment early because of heart problems: 4 percent in the six-month group, versus 8 percent in the 12-month group.

Earlier studies that proved Herceptin’s effectiveness treated patients for a year, a somewhat arbitrary duration, but one that became the standard of care because there was data to support it.

To change that standard, researchers had to produce evidence that it could be safely done. Dr. Earl’s study is the first step in that direction.

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

New Migraine Drugs Offer Hope to Sufferers

Lisa DeLeonardo set a Google alert so she would know exactly when the first in a new class of migraine drugs was approved.

It happened Thursday, when the U.S. Food and Drug Administration approved Amgen and Novartis ’ application for erenumab, whose brand name is Aimovig. It’s an injectable drug touted as the first treatment designed specifically to prevent migraines, and is expected to be available to patients within a week for an annual price of $6,900. Three other similar treatments are expected to hit the market within the next year.

“I’ve been pretty desperate for this to come out and get approved,” says Dr. DeLeonardo, a 46-year-old psychologist in Delaware. “It feels the closest to kind of a miracle.”

The new treatments provide hope to the estimated 37 million people in the U.S. who suffer from migraines, predominantly women. The neurological disorder is characterized by intense, painful headaches, often accompanied by other symptoms, such as sensitivity to light and noise, and nausea.

Until now migraine patients have largely had to take drugs created to treat other diseases, such as epilepsy and high blood pressure. “What is coming is a complete change in the way we will treat migraine,” says Stewart Tepper, a neurology professor at the Geisel School of Medicine at Dartmouth. He has done consulting work for most of the companies working on the new class of drugs and was the lead investigator on the Amgen/Novartis trial with chronic migraine patients.

The new drugs are injectable antibodies that target a protein called CGRP. It’s in neurons in the brain and the trigeminal nerve, which is responsible for conveying pain messages to the brain. Researchers believe the new treatments interfere with the CGRP within the trigeminal nerve, preventing migraine pain signals from entering the brain. There are also two oral CGRP treatments in development for use when a patient has a migraine or feels one coming on.

Aimovig’s price is much higher than the inexpensive generics currently used to treat migraines, raising questions about how insurers will handle it. Ronny Gal, a senior research analyst at Sanford C. Bernstein & Co., said insurers will likely cover it but may often require patients to have tried a generic drug first. Express Scripts , a drug-benefit manager, agreed not everyone will need the drug. “We see it for people with migraine who have previously failed a preventive therapy,” says Brian Henry, a spokesman.

Amgen and Novartis say they feel confident that most insurance plans will provide coverage for adults with four or more migraines a month without requiring them to prove that they’ve unsuccessfully tried multiple other migraine medications.

Some doctors say the new treatments are over-hyped. “The treatments are only about as effective as existing treatments,” says Elizabeth Loder, a professor of neurology at Harvard Medical School and chief of the division of headache at Brigham and Women’s Hospital in Boston who wasn’t involved in any of the CGRP trials. Dr. Loder also says the long-term safety and effects of the drugs are unclear, concerns she raised in a recent JAMA editorial. Amgen and Novartis say Aimovig has been safely tested in more than 3,000 patients, with the most common reported side effects injection site reactions and constipation. Some patients are in an extended five-year trial.

‘I’ve been pretty desperate for this to come out and get approved,’ says Lisa DeLeonardo, who suffers from migraines.
‘I’ve been pretty desperate for this to come out and get approved,’ says Lisa DeLeonardo, who suffers from migraines. PHOTO: ROBERTA MOLOFF

The drugs’ proponents say they are a significant improvement over existing options, with very low side effects. Most studies have found that patients have a one in two chance of reducing migraine attacks by more than 50% and a one in three chance of having a 75% or more reduction, says David Dodick, a professor of neurology at Mayo Clinic in Phoenix and chair of the American Migraine Foundation, who has consulted with companies developing new migraine treatments.

The new drugs are for patients with episodic or chronic migraines. Patients with episodic migraines have four to 14 days with migraine headaches a month, while chronic patients have 15 days or more a month. The studies on Aimovig showed episodic migraine patients had on average three to four fewer migraine days a month, while chronic migraine patients had about six fewer migraine days a month.

Dr. Dodick notes that more than 80% of chronic migraine patients discontinue medications by a year. “Side effects are a big deal with the currently available treatments,” he says.

Such was the case for Dr. DeLeonardo, the Delaware psychologist and migraine sufferer. She had tried an anti-seizure medication commonly used with migraine patients and it helped for a few months, but side effects such as memory problems made her stop taking it. She also tried a beta-blocker, a class of drugs commonly used for high blood pressure, but it slowed her heart rate down and made it hard to exercise.

Ms. DeLeonardo enrolled in the Amgen/Novartis trial in 2015. “It was phenomenal,” she says, “and really life-changing.” She had some months with three to four migraines—compared with a dozen or more previously—and the migraines she did have were less intense.

She is concerned about the cost for the new treatments, but hopeful. “I am definitely hoping that insurance will cover much of the cost. I would not be able to afford paying thousands of dollars a year for it,” she says.

 

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

Scientists See Promise in Resurrecting These Rhinos That Are Nearly Extinct

When the last male northern white rhinoceros died in March, people mourned the beloved mammal’s step toward extinction.

With no members of the subspecies left in the wild and just two females remaining in captivity, it felt like the last bit of sand was draining through the rhino’s hourglass.

But several teams of scientists are working to flip the hourglass back over.

One group, led by researchers at the San Diego Zoo Institute for Conservation Research, hopes to revive the northern white rhino using preserved cells. In a study published Thursday in Genome Research, the scientists sequenced the DNA of these cells and concluded that they hold a promising amount of genetic diversity for re-establishing a viable population of northern whites.

With the right advances in assisted reproduction or cloning, there could be a second chance for this “unique form of rhinoceros,” said Oliver Ryder, director of conservation genetics at San Diego Zoo Global.

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Dr. Oliver Ryder, of the San Diego Zoo Global’s Frozen Zoo, inspecting cell cultures from a store of tissue and genetic material.CreditSan Diego Zoo Global

Not everyone agrees that having the capacity to bring back the northern white rhino means it should be done. Critics question whether the buzz around resurrecting a functionally extinct creature takes attention and resources away from other animals with greater chances of survival.

They also point out that any resurrected northern white rhinos would likely remain in captivity, rather than roaming free in their former habitat in central and eastern Africa, where poaching for horns remains a serious threat.

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Nola, a northern white rhino at the San Diego Zoo, died in 2015.CreditSan Diego Zoo Global

In their study, Dr. Ryder and his colleagues focused on the feasibility of recovering the northern white rhino using cells stored in the Frozen Zoo, a large collection of cryopreserved samples at the San Diego Zoo. These cell lines represent eight presumably unrelated northern whites, Dr. Ryder said.

The researchers sequenced these genomes and compared them to genomes from southern white rhinos, the northern white rhino’s closest kin, which underwent a spectacular recovery under protection over the last century, although it remains near-threatened.

They confirmed scientists’ long-held hypothesis that the two rhinos are subspecies, rather than distinct species. This close relationship might bode well for someday using southern white rhinos as surrogates for northern white embryos.

The scientists also discovered sufficient genetic diversity in their northern white rhino samples when compared with the southern white rhinos, Dr. Ryder said. “If it came down to the materials in the Frozen Zoo, we could turn those cells into animals.”

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A sample from the Frozen Zoo at San Diego, which holds thousands of specimens from many species.CreditSan Diego Zoo Global

But Marty Kardos, an evolutionary biology researcher at the University of Montana, cautioned that the southern white rhino comparison is “not necessarily worth banking on.” Purely by chance, harmful mutations could exist at high frequency among the northern white rhinos, and have a detrimental effect, he said.

Jason Gilchrist, an ecologist at Edinburgh Napier University in Scotland, questioned the point of reviving an animal that can’t return to its native way of life. “As an ecologist, what I want is to see wild ecosystems functioning as close to naturally as they can,” he said.

Joseph Bennett, a conservation researcher at Carleton University in Ontario, feels the northern white rhino is a good candidate for resurrection because there’s a relatively high chance of success compared to more ambitious projects like the de-extinction of the woolly mammoth or passenger pigeon.

It could be a “really nice ‘good news story’ for people,” he said.

Cathy Dean, chief executive of the charity Save the Rhino, said that efforts to revive the northern white rhino likely attract different sources of funding than conserving remaining wild rhinos. Still, she wishes other rhinos, like the critically endangered SumatranJavan and black rhinos, received nearly as much airtime as the northern white, she said.

Dr. Ryder said his team’s efforts are not in lieu of, but in addition to, efforts to conserve wild animals, adding that “we are seeing species go extinct in spite of a global commitment” to protect them.

In light of that, he said, providing “more options for the existence of species into the future is an appropriate quest.”

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

The Thing Inside Your Cells That Might Determine How Long You Live

Once there was a mutant worm in an experiment. It lived for 46 days. This was much longer than the oldest normal worm, which lived just 22.

Researchers identified the mutated gene that had lengthened the worm’s life, which led to a breakthrough in the study of aging — it seemed to be controlled by metabolic processes. Later, as researchers studied these processes, all signs seemed to point to the nucleolus.

Under a microscope, it’s hard to miss. Take just about any cell, find the nucleus, then look inside it for a dark, little blob. That’s the nucleolus. If the cell were an eyeball, you’d be looking at its pupil.

You’ve got one in every nucleus of every cell in your body, too. All animals do. So do plants, and yeast — and anything with a cell with a nucleus. And they’ve become much more important in our understanding of how cells work.

“We think the nucleolus plays an important role in regulating the life span of animals,” said Adam Antebi, a cellular biologist at the Max Planck Institute for Biology of Ageing in Germany. He’s an author of a new review published last week in Trends in Cell Biology that examines all the new ways that researchers have fallen in love with the nucleolus — especially its role in aging.

You may have forgotten this from biology class, but the nucleolus is the cell’s ribosome factory. Ribosomes are like micro-machines that make proteins that cells then use for purposes like building walls, forming hairs, making memories, communicating and starting, stopping and slowing down reactions that help a cell stay functioning. It uses about 80 percent of a cell’s energy for this work.

But there’s more to the nucleolus than just making ribosomes.

If building a cell were like building a building, and the DNA contained the blueprint, the nucleolus would be the construction manager or engineer. “It knows the supply chain, coordinates all the jobs of building, does quality control checks and makes sure things continue to work well,” said Dr. Antebi.

How well it balances these tasks influences a cell’s health and life span. And in certain cells, its size has something to do with it.

The nucleolus can wax and wane in response to a body’s available nutrients and growth signals.

The more growth signals it intercepts, the more machines, or ribosomes, it makes. It gets bigger to contain them, but mysteriously this also shortens a cell’s or organism’s life. When food is restricted, or a metabolic pathway is silenced or slowed down, nucleoli shrink, making fewer ribosomes, and cells live longer.

Dr. Antebi thinks that as the nucleolus gets smaller, it also starts remodeling the things it would create to make the best of available supplies.

This is a highly coordinated process, he said. And life span can be thought of as how well the nucleolus balances the need to grow with the need to repair, correct mistakes and make sure everything works.

A drug called rapamycin, that blocks the signals of one metabolic pathway, extends life in different species from yeast, worms and fruit flies to mice. Centenarians tend to have cells in which there is reduced signaling in another pathway that involves insulin.

Researchers have found that modest dietary restriction and exercise shrank nucleoli in muscle cells of some people over age 60. People with diseases like cancer or progeria, a kind of accelerated aging, tend have enlarged nucleoli.

You can see these kinds of effects in many different species. “It’s amazing — even if genetically identical, some live a short life and some live a long life,” said Dr. Antebi.

“We think that the smaller nucleoli may be a cellular hallmark of longevity” in certain cells under certain conditions, he added.

More research is needed to see if the size of these structures are just markers for longevity or aging or if they actually cause it.

“We’ve spent lots of money on trying to find biomarkers of longevity or aging, and maybe it’s just sitting under the microscope for us to see,” said Dr. Antebi.

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

Every Cell in Your Body Has the Same DNA. Except It Doesn’t.

ames Priest couldn’t make sense of it. He was examining the DNA of a desperately ill baby, searching for a genetic mutation that threatened to stop her heart. But the results looked as if they had come from two different infants.

“I was just flabbergasted,” said Dr. Priest, a pediatric cardiologist at Stanford University.

The baby, it turned out, carried a mixture of genetically distinct cells, a condition known as mosaicism. Some of her cells carried the deadly mutation, but others did not. They could have belonged to a healthy child.

We’re accustomed to thinking of our cells sharing an identical set of genes, faithfully copied ever since we were mere fertilized eggs. When we talk about our genome — all the DNA in our cells — we speak in the singular.

But over the course of decades, it has become clear that the genome doesn’t just vary from person to person. It also varies from cell to cell. The condition is not uncommon: We are all mosaics.

For some people, that can mean developing a serious disorder like a heart condition. But mosaicism also means that even healthy people are more different from one another than scientists had imagined.

Magical Mystery

In medieval Europe, travelers making their way through forests sometimes encountered a terrifying tree.

A growth sprouting from the trunk looked as if it belonged to a different plant altogether. It formed a dense bundle of twigs, the sort that people might fashion into a broom.

Germans call it Hexenbesen: witches’ broom. As legend had it, witches used magic spells to conjure the brooms to fly across the night sky. The witches used some as nests, too, leaving them for hobgoblins to sleep in.

In the 19th century, plant breeders found that if they cut witches’ broom from one tree and grafted it to another, the broom would grow and produce seeds. Those seeds would sprout into witches’ broom as well.

Today you can see examples of witches’ broom on ordinary suburban lawns. Dwarf Alberta spruce is a landscaping favorite, growing up to ten feet high. It comes from northern Canada, where botanists in 1903 discovered the first known dwarf clinging to a white spruce — a species that can grow ten stories tall.

Pink grapefruits arose in much the same way. A Florida farmer noticed an odd branch on a Walters grapefruit tree. These normally bear white fruit, but this branch was weighed down with grapefruits that had pink flesh. Those seeds have produced pink grapefruit trees ever since.

Charles Darwin was fascinated by such oddities. He marveled at reports of “bud sports,” strange, atypical blooms on flowering plants. Darwin thought they held clues to the mysteries of heredity.

The cells of plants and animals, he reasoned, must contain “particles” that determined their color, shape and other traits. When they divided, the new cells must inherit those particles.

Something must scramble that heritable material when bud sports arose, Darwin declared, like “the spark which ignites a mass of combustible matter.”

Only in the 20th century did it become clear that this combustible matter was DNA. After one cell mutates, scientists found, all its descendants inherit that mutation.

Witches’ broom and bud sports eventually came to be known as mosaics, after the artworks made up of tiny tiles. Nature creates its mosaics from cells instead of tiles, in a rainbow of different genetic profiles.

Before DNA sequencing was commonplace, scientists struggled to tell the genetic differences between human cells. Cancer offered the first clear evidence that humans, like plants, could become mosaics.

In the late 1800s, biologists studying cancer cells noticed that many of them had oddly shaped chromosomes. A German researcher, Theodor Boveri, speculated at the turn of the century that gaining abnormal chromosomes could actually make a cell cancerous.

As soon as Boveri floated his theory, he faced intense opposition. “The skepticism with which my ideas were met when I discussed them with investigators who act as judges in this area induced me to abandon the project,” he later said.

Boveri died in 1915, and it took nearly five decades for scientists to discover he was right.

David A. Hungerford and Peter Nowell found that people with a form of cancer called chronic myelogenous leukemia were missing a substantial chunk of chromosome 22. It turned out a mutation had moved that chunk over to chromosome 9. The cells that inherited that mutation became cancerous.

It’s hard to think that a tumor might have anything in common with a pink grapefruit. Yet they are both products of the same process: lineages of cells that gain new mutations not found in the rest of the body.

Some skin diseases proved to be caused by mosaicism, too. Certain genetic mutations cause one side of the body to become entirely dark. Other mutations draw streaks across the skin.

The difference is in the timing. If a cell gains a mutation very early in development, it will produce many daughter cells that will end up spreading across much of the body. Late-arising mutations will have a more limited legacy.

A Brain Biography

Dr. Walsh and his colleagues have found evidence of mosaicism in some very unexpected places.

They investigated a mysterious disorder called hemimegalencephaly, which causes one side of the brain to become overgrown. The researchers examined tissue from patients who had brain surgery to treat the seizures triggered by hemimegalencephaly.

Some of the brain cells in the patients — but not all of the cells — shared the same mutant genes. It’s possible that these mutant neurons multiplied faster than others in the brain, triggering one side to become enlarged.

Preliminary studies suggest that mosaicism underlies many other diseases. Last year, Christopher Walsh, a geneticist at Harvard University, and his colleagues published evidence that mosaic mutations may raise the risk of autism.

But scientists are also finding that mosaicism does not automatically equal disease. In fact, it’s the norm.

When a fertilized egg — known as a zygote — starts dividing in the womb, many of its early descendant cells end up with the wrong number of chromosomes. Some are accidentally duplicated, and others lost.

Most of these unbalanced cells divide only slowly or die off altogether, while the normal cells multiply far faster. But a surprising number of embryos survive with some variety in their chromosomes.

Markus Grompe, a biologist at Oregon Health & Science University, and his colleagues looked at liver cells from children and adults without liver disease. Between a quarter and a half of the cells were aneuploids, typically missing one copy of one chromosome.

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CreditJason Holley

Along with altered chromosomes, human embryos also gain smaller mutations in the genome. Stretches of DNA may be copied or deleted. Single genetic letters may get incorrectly reproduced.

It wasn’t possible to study such molecular changes accurately until DNA-sequencing technology became sophisticated enough.

In 2017, researchers at the Wellcome Trust Sanger Institute in England examined 241 women, sequencing batches of white blood cells from each. Every woman had acquired about 160 new mutations, each present in a sizable fraction of her cells.

The women gained these mutations as embryos, the scientists theorized, with two or three new mutations arising each time a cell divided. As those new mutations occurred, the embryonic cells passed them all down to their descendants, a mosaic legacy.

Dr. Walsh and his colleagues have discovered intricate mosaics in the brains of healthy people. In one study, they plucked neurons from the brain of a 17-year-old boy who had died in a car accident. They sequenced the DNA in each neuron and compared it to the DNA in cells from the boy’s liver, heart and lungs.

Every neuron, the researchers found, had hundreds of mutations not found in the other organs. But many of the mutations were shared only by some of the other neurons.

It occurred to Dr. Walsh that he could use the mutations to reconstruct the cell lineages — to learn how they had originated. The researchers used the patterns to draw a sort of genealogy, linking each neuron first to its close cousins and then its more distant relatives.

When they had finished, the scientists found that the cells belonged to five main lineages. The cells in each lineage all inherited the same distinctive mosaic signature.

Even stranger, the scientists found cells in the boy’s heart with the same signature of mutations found in some brain neurons. Other lineages included cells from other organs.

Based on these results, the researchers pieced together a biography of the boy’s brain.

When he was just an embryonic ball in the womb, five lineages of cells had emerged, each with a distinct set of mutations. Cells from those lineages migrated in different directions, eventually helping to produce different organs — including the brain.

The cells that became the brain turned into neurons, but they did not all belong to the same family. Different lineages merged together. In essence, the boy’s brain was made of millions of mosaic clusters, each composed of tiny cellular cousins.

It’s hard to say what these mosaic neurons mean to our lives — what it means for each of us to have witches’ broom growing in our skulls. “We don’t know yet whether they have any effect on shaping our abilities or challenges,” said Dr. Walsh.

What we do know is that mosaicism introduces randomness into the development of our brains. Mutations, which arise at random, will form different patterns in different people. “The same zygote would never develop exactly the same way twice,” said Dr. Walsh.

A Heart in Pieces

As ubiquitous as mosaicism may be, it’s still easy to overlook — and surprisingly hard to document.

Astrea Li, the infant examined by Dr. Priest at Stanford, had gone into cardiac arrest the day she was born. Her doctors put a defibrillator in her heart to shock it back into the proper rhythm.

Dr. Priest sequenced Astrea’s genome to search for the cause of her disorder. He concluded that she had a mutation in one copy of a gene called SCN5A. That mutation could have caused her trouble, because it encodes a protein that helps trigger heartbeats.

But when Dr. Priest ran a different test, he couldn’t find the mutation.

To get to the bottom of this mystery, he teamed up with Steven Quake, a Stanford biologist who had pioneered methods for sequencing the genomes of individual cells. Dr. Priest plucked 36 white blood cells from the child’s blood, and the scientists sequenced the entire genome of each cell.

In 33 of the cells, both copies of a gene called SCN5A were normal. But in the other three cells, the researchers found a mutation on one copy of the gene. Astrea had mosaic blood.

Her saliva and urine also turned out to contain mosaic cells, some of which carried the mutation. These findings demonstrated that Astrea had become a mosaic very early in her development.

The skin cells in her saliva, the bladder cells in her urine and her blood cells each originated from a different layer of cells in two-week-old embryos.

Astrea’s SCN5A mutation must have originated in a cell that existed before that stage. Its daughter cells later ended up in those three layers, and ultimately in tissues scattered throughout her body.

They might very well have ended up in her heart, too. And there the mutation could have theoretically caused Astrea’s problems.

While Dr. Priest was reconstructing Astrea’s mosaic origins, she was recovering from the surgery to implant her defibrillator. Her parents, Edison Li and Sici Tsoi, brought her home. And for a few months, it seemed she was out of the woods.

One day, however, her defibrillator sensed an irregular heartbeat and released a shock — along with a wireless message to Astrea’s doctors.

Back at the hospital, doctors discovered a new problem: her heart had become dangerously enlarged. Researchers have linked mutations in the SCN5A gene to the condition.

Her heart soon stopped. Her doctors attached a mechanical pump, and soon a donated heart became available.

Astrea underwent transplantation surgery and recovered well enough to go home. She went on to enjoy a normal childhood, performing cartwheels with her sister and listening obsessively to the soundtrack of “Frozen.”

The transplant did not just give Astrea a new lease on life. It also gave Dr. Priest a very rare chance to look at a mosaic heart up close.

The transplant surgeons had clipped some pieces of Astrea’s cardiac muscle. Dr. Priest and his colleagues extracted the SCN5A gene from the cells taken from different parts of her heart.

On the right side of the heart, he and his colleagues found that more than 5 percent of the cells had mutant genes. On the left, nearly 12 percent did.

To study the effect of this mosaicism, Dr. Priest and his colleagues built a computer simulation of Astrea’s heart. They programmed it with grains of mutant cells and let it beat.

The simulated heart thumped irregularly, in much the same way Astrea’s had.

The experience left Dr. Priest wondering how many more people might be at risk from a hidden mix of mutations.

Unless he winds up with another patient like Astrea, we may never find out.

 

 

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

New Cancer Treatments Lie Hidden Under Mountains of Paperwork

Dr. Nikhil Wagle thought he had a brilliant idea to advance research and patient care.

Dr. Wagle, an oncologist at the Dana Farber Cancer Institute in Boston, and his colleagues would build a huge database that linked cancer patients’ medical records, treatments and outcomes with their genetic backgrounds and the genetics of their tumors.

The database would also include patients’ own experiences. How ill did they feel with the treatments? What was their quality of life? The database would find patterns that would tell doctors what treatment was best for each patient and what patients might expect.

The holdup, he thought, would be finding patients. Instead, the real impediment turned out to be gathering their medical records.

In the United States, there is no single format used by all providers, and hospitals have no incentive to make it easy to transfer records from one place to another. The medical records mess is hobbling research and impeding attempts to improve patient care.

“Data are trapped,” said Dr. Ned Sharpless, director of the National Cancer Institute. “This is a huge problem. It is phenomenally important.”

The cancer institute has invested millions of dollars into determining the genetic sequences of patients’ tumors, and researchers have found thousands of genes that seem to drive tumor growth.

But until patients’ medical records are linked to the genetic data, life-or-death questions cannot be answered.

“What drug did they get? Did they respond? Did they survive? Were they cured?” Dr. Sharpless asked.

The federal government has mandated uniform standards for electronic health records. “At this point, they are not to a level that helps with the detailed clinical data that we need for the scientific questions we want to ask,” Dr. Wagle said.

A few private companies are trying to tackle the problem. Flatiron Health, just bought by Roche, has obtained about 2.2 million records of cancer patients from medical centers and made them available for research after stripping them of identifiable information.

But Flatiron must employ 900 nurses and certified tumor registrars, people with master’s degrees in coding data, to put it all into a usable form.

“About 50 percent, if not more, of the critical details we need for research are trapped in unstructured documents,” said Dr. Amy Abernethy, the company’s chief medical officer.

“They are in PDFs. Maybe a doctor put in a note by hand, maybe a doctor typed it. That note became a narrative. It is not something that can easily be put into a spreadsheet.”

Dr. Sharpless worries that the data acquired by companies like Flatiron will not be readily available to researchers. But if the companies manage to solve the medical records problem cheaply, he said, “we’d like to work with them to figure out how to liberate the data.”

Dr. Wagle is making data from medical records and patients’ experiences public as he gets them. After 2 1/2 years, though, he is disappointed by how little there is to share.

The patient who inspired his project had a lethal form of thyroid cancer. She was expected to die in a few months. In desperation, doctors gave her a drug that by all accounts should not have helped.

To everyone’s surprise, her tumors shrank to almost nothing, and she survived. She was an “extraordinary responder.”

Why? It turned out that her tumor had an unusual mutation that made it vulnerable to the drug.

And that got Dr. Wagle thinking. What if researchers had a database that would allow them to find these lucky patients, examine their tumors, and discover genetic mutations that predict which drugs will work?

And what about those who were not helped by standard treatments? Could they be identified and spared treatments that will not work?

What researchers needed was a huge database that collected clinical and genetic data, along with patients’ descriptions of their experiences. Those narratives are crucial, Dr. Wagle said, but they are absent from the commercial databases like Flatiron’s. Those comprise anonymous patient data, making it impossible to ask the patients themselves how they fared.

Dr. Wagle decided to build a database, starting with metastatic breast cancer, his specialty. There are about 155,000 metastatic breast cancer patients in the United States. He would use social media, online forums and advocacy groups to reach out to patients for their records.

The Metastatic Breast Cancer Project began in October 2015. Patients have been eager to join, and advocacy groups enthusiastically signed on. So far, the project includes 4,400 women.

Determining the genetic sequences of their tumors and of their healthy cells was straightforward — “the easy part,” Dr. Wagle said.

Gathering their medical records was another story. The data exist in all sorts of formats, and crucial information may be missing altogether.

Simply getting the records delivered, in whatever format, has been a nightmare. Records usually arrive as faxes or via snail mail.

“Even though the patients are saying, ‘I have consented for you to obtain my medical records,’ there is no good way to get them,” Dr. Wagle said.

He hired half a dozen people to work full-time on the project, and corralled doctors and other experts to help part-time. It can take hours to go through a single medical record.

Mary McGillicuddy, who works full-time on the project, explained the system. When patients enroll, they tell the investigators where they were treated, where they had biopsies, where they had scans, and where they had medical procedures.

They give Ms. McGillicuddy and her colleagues permission to request their records. Ms. McGillicuddy faxes requests for records to each medical institution that treated a patient, or diagnosed or sequenced her cancer.

Startlingly, faxing “is the standard,” Ms. McGillicuddy said, for medical records requests.

The process can be frustrating. Fax numbers can be out of date. Some medical centers will not accept electronic patient signatures on the permission forms.

Sometimes, the medical centers just ignore the request — and the second request. In the end, Ms. McGillicuddy said, the project gets fewer than half the records it requests.

Then comes the laborious task of extracting medical information from the records and entering it into the database. A faxed medical record may be 100 or 200 pages long.

So far, the breast cancer project has received 450 records for 375 patients. (Each patient tends to have more than one record, because the women typically are seen at more than one medical center.)

“Patients are incredibly engaged and excited,” Dr. Wagle said. But for the records problem, “right now there isn’t a good solution.”

 

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

Infant Deaths Fall Sharply in Africa With Routine Antibiotics

Two doses a year of an antibiotic can sharply cut death rates among infants in poor countries, perhaps by as much as 25 percent among the very young, researchers reported on Wednesday.

Their large study — of nearly 200,000 children in three African countries — raises the exciting possibility that deploying antibiotics as doctors do vaccines could rapidly reduce deaths among newborns and infants. Death rates in this age group have remained stubbornly high in poor countries even as deaths among all children under age 5 have dropped by half, thanks to vaccines against childhood diseases.

As a result of the study, the World Health Organization is considering whether to recommend routinely giving antibiotics to newborns.

“Our independent expert panel says this holds a lot of promise,” said Dr. Per Ashorn, a W.H.O. expert in maternal and child health. “But we will review it with very rigorous procedures.”

The agency will make a decision “as soon as possible, latest in 2019,” he added.

The Bill and Melinda Gates Foundation, which paid for the study, “is optimistic that this will be a new tool to help prevent childhood mortality,” said Dr. Rasa Izadnegahdar, deputy director of global health at the foundation. “It’s an exciting time.”

But wider use of antibiotics would raise some serious concerns. Would handing out tens of million of doses in poor countries speed the emergence of antibiotic-resistant bacteria? And could it be done without the drugs being stolen or misused?

The study’s authors — from top American, British and African medical schools, and the Atlanta-based Carter Center — argue that those risks are small and much outweighed by the greater good of saving children’s lives.

“At one time, people said you couldn’t give out H.I.V. drugs in Africa because it would create drug resistance,” said Dr. Thomas M. Lietman, an ophthalmologist at the University of California, San Francisco, and the study’s lead author. “That implied that we should just let Africans die so we could keep giving out the drugs in the U.S.”

About 35 million youngsters, Dr. Izadnegahdar said, live in the countries most likely to be targeted — those where a child now has a 1-in-10 chance of dying before age 5.

In the study — known as the Mordor trial and published in the New England Journal of Medicine — 190,238 children under age 5 in 1,500 villages in Malawi, Niger and Tanzania were given one dose of azithromycin or a placebo every six months for two years.

Overall, there were 14 percent fewer deaths among children getting the antibiotic; the reduction was strongest in Niger, where infant mortality is highest.

The protection appeared to be greatest for infants aged 1 month to 5 months; the antibiotic prevented one in four deaths in this group.

The researchers could not say definitively why it worked. Azithromycin, made by Pfizer and sold as Zithromax in the United States, kills many species of bacteria that cause pneumonia and diarrhea, which are major killers of newborns. It also kills malaria parasites.

The new trial grew out of a 2009 study of ways to prevent trachoma, a blinding eye disease, in 18,000 Ethiopian children. The group of children there who got one dose of azithromycin as part of their regimen suffered about half as many deaths as other children.

“That was groundbreaking, just quite amazing,” said Kelly Callahan, who runs the Carter Center’s trachoma program and helped oversee the Ethiopia study. “It was beyond saving sight — it was saving lives.”

Other small studies have shown similar benefits. A 2014 study of Gambian women given one antibiotic dose during labor showed that both they and their babies had fewer overall infections and less often harbored the bacteria responsible for lethal neonatal sepsis.

Some experts argued that distributing antibiotics could hasten the appearance of drug-resistant bacteria. The W.H.O.’s panel would look hard at that, Dr. Ashorn said, “because this would be broadening rather drastically the way we use antibiotics.”

Sabiha Essack, director of antimicrobial research at the University of KwaZulu-Natal in South Africa, said it was “unclear whether the benefits will outweigh the costs” and noted that the study did not look at the effects on the infants’ microbiomes, or bacterial makeup.

But other experts said they considered the risk relatively low, for several reasons.

The drugs would be given only to youngsters, only infrequently and probably only for a few years.

Dr. Charles Knirsch, vice president for clinical research at Pfizer, said his company had donated more than 700 million azithromycin doses to the International Trachoma Initiative, which gives them to people of all ages. No permanent resistance mutations have emerged in any bacteria.

Such mutations “are more of a concern in I.C.U.’s in New York City than in places like Niger, where’s there such low access to antibiotics,” he said.

Each year, when azithromycin is given out, some pneumococcal bacteria resistant to it appear, said Paul Emerson, the trachoma initiative’s director. But those strains fade out within weeks or months, he said.

Also, he noted, the resistance is only to macrolides, the drug class to which azithromycin belongs. Macrolides are not heavily used in Africa, where W.H.O. guidelines still recommend penicillins and even older sulfa drugs because they are cheap and effective.

Pharmaceutical supply chains in some poor countries are plagued by theft, and antibiotics are tempting targets because they cure sexually transmitted diseases and other ills. But less than 1 percent of Pfizer’s donations have been lost to theft or expiration, Dr. Emerson said.

For enhanced security, azithromycin is distributed in special purple packaging saying it is to be used only for trachoma. Also, he noted, pediatric doses are liquids, which adults do not normally take.

Dr. Emerson said his initiative would be happy to handle distribution if the W.H.O. approves routinely giving antibiotics to infants.

“How many times do you get an offer to help save tens of thousands of lives?” he said.

Although azithromycin is not approved by the Food and Drug Administration for children under 6 months old, the Centers for Disease Control and Prevention recommends it for infants of any age with whooping cough.

The trial’s gloomy nickname, Mordor, comes from J.R.R. Tolkien’s “Lord of the Rings” trilogy, in which it is the shadowy land of Mount Doom. The initials stand roughly for “Mortality Reduction Through Oral Azithromycin.” (In French, “Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance” — “Oral Macrolides to Reduce Deaths With an Eye on Resistance.”)

The acronym was coined before the initials were chosen, authors said, because the 2009 trial was done in Ethiopia’s Gondar region. In Tolkien’s trilogy, Gondor, the land of men, battles Mordor. (Some readers think Tolkien used Ethiopian place names, Dr. Izadnegahdar said; according to a biographer, he denied consciously doing so.)

“Some team members thought the name was creepy, but the study is about death,” Dr. Lietman said. “It took on a life of its own, and we never looked back.”

The study’s name, Dr. Izadnegahdar said, might be changed to Reach, for “Resilience Through Azithromycin for Children.”

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

Hints of Human Evolution in Chimpanzees That Endure a Savanna’s Heat

Nine years later, Erin Wessling can still remember the first time she visited Fongoli, a savanna in southeast Senegal.

“You feel like you walk into an oven,” she said.

Temperatures at Fongoli can reach 110 degrees Fahrenheit or more. During every dry season, brush fires sweep across the parched landscape, leaving behind leafless trees and baked, orange soil.

“It’s really nuts,” said Ms. Wessling, now a graduate student at the Max Planck Institute for Evolutionary Anthropology.

Yet Ms. Wessling and her colleagues keep coming back to Fongoli, despite the harsh conditions. That’s because it’s home to some remarkable residents: chimpanzees.

To study them, scientists have mostly traveled to African rain forests and woodlands, where the apes live in dense groups. The sparse populations of chimpanzees that live on savannas in western and central Africa are far less understood.

Ms. Wessling and her colleagues think there are important lessons to be learned from chimps like the ones at Fongoli.

Because they are our closest living relatives, they may even tell us something about our own deep history. Millions of years ago, our apelike ancestors gradually moved from woodlands to savannas and began walking upright at some point. The Fongoli chimpanzees demonstrate just how difficult that transition would have been — and how that challenge may have driven some major changes in our evolution, from evolving sweat glands to losing fur and walking upright.

The savanna became the subject of long-term research in 2000, when Ms. Wessling’s undergraduate adviser at Iowa State University, Jill D. Pruetz, first paid a visit.

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The Fongoli chimpanzees offer evidence of how stressful it can be to cope with the intense heat of a savanna, rather than the forest. They don’t roam far from water sources and shift some of their hunts for food to nighttime.CreditFrans Lanting/lanting.com

Surveying Fongoli, Dr. Pruetz decided it would be a good place to observe the differences between chimpanzee life on a savanna compared to forests. In forests, for example, chimpanzees typically thrive on a diet of ripe fruit. That’s a rare treat on a savanna.

But Dr. Pruetz could not simply settle down right away and watch the chimpanzees. At first, the sight of her frightened them off. So Dr. Pruetz and her colleagues let the apes grow accustomed to their company. That alone took four years.

At last, in 2004, Dr. Pruetz and her colleagues could follow the chimpanzees from dawn to dusk. “You just have to drink water all day,” said Dr. Pruetz, now a professor at Texas State University.

The team gradually built up a catalog of strange behaviors — ones rarely if ever seen in others. Forest chimpanzees get enough water from the fruit in their diet so they need less drinking water and can wander in search of food. The Fongoli chimps, by contrast, required daily drinking water and anchored themselves to reliable water sources in the arid landscape.

And while forest chimpanzees are active throughout the day, Dr. Pruetz found that the savanna chimpanzees rest for five to seven hours. Dr. Pruetz could often find them lurking in small caves in the dry season, and when the rainy season arrived, the chimpanzees would slip into newly formed ponds and bob there for hours.

Forest chimpanzees typically spend all night in nests they build in trees. But at Fongoli, the research team noticed that the chimpanzees often made a late-night racket.

Staying up all night to watch them, Dr. Pruetz discovered that they spent hours after sundown searching for food. “It might as well have been a daytime scene,” she said.

All these odd behaviors suggested that the chimps were struggling to cope with Fongoli’s harsh conditions. But all Dr. Pruetz’s observations couldn’t reveal what was happening inside their bodies. “I didn’t know how stressed they were,” she said.

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Erin Wessling with a Fongoli chimp. By gathering chimpanzee urine, she and her colleagues were able to determine how difficult the chimpanzees’ lives were by measuring the levels of cortisol, a stress hormone, and other compounds.CreditErin Wessling

In 2014, Ms. Wessling set out to get an answer — by collecting chimpanzee urine.

Like humans, chimpanzees have molecules in their urine that reflect their physical condition. When they feel stress, for example, they make the hormone cortisol. The pancreas produces a substance called c-peptide in response to food. Its levels can reflect whether chimpanzees are getting enough energy. If a chimpanzee gets dehydrated, the protein creatinine builds up in its urine.

Scientists regularly gather urine from forest chimpanzees, but there, they need only go under a tall tree and hold out a leaf. On the savanna, Ms. Wessling would have to wait until a chimpanzee ambled away from where it had urinated. By the time she reached the spot, the urine might have already seeped into the ground or evaporated. “You basically watch your sample disappear,” Ms. Wessling said.

From 20 chimps, Ms. Wessling gathered 368 urine samples that were taken back to Germany for analysis.

The chimps’ c-peptide levels showed they ate a decent amount of food, and possibly termites to get additional calories.

While that was an indicator of a healthy diet, analyses of the two other compounds told another story. Many of the chimps had produced high levels of cortisol, indicating that life on the savanna could be very stressful. And their creatinine levels were also high, evidence that the heat of the savanna caused them to become dehydrated.

For all the ways that the Fongoli chimps tried to protect themselves from the heat, it still punished them.

“These chimps are sort of right at the edge of what they can do,” Dr. Pruetz said. “This really gives you the biological basis of it.”

The research was published earlier this month in the Journal of Human Evolution.

To scientists who study human evolution, the Fongoli chimpanzees offer some intriguing parallels to our ancestors millions of years ago. Studies of DNA indicate that our two evolutionary branches split roughly seven million years ago.

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Early hominins might have used some of the strategies documented in Fongoli chipmanzees, like staying near water. Humans have skin glands that let us sweat much more than chimpanzees, and the origin of our upright posture might have been an adaptation to stay cooler.CreditFrans Lanting/lanting.com

The earliest members of our branch (known as hominins) may have been chimp-like in some respects, growing fur and walking through forests on their knuckles.

Over millions of years, Africa’s rain forests retreated into patchworks, as savannas expanded. In eastern and southern Arica, hominins moved into open habitats, eventually reaching arid grasslands — places as daunting for survival as Fongoli.

“How and when hominins got better at coping with heat is a fascinating, unsolved problem,” said Daniel E. Lieberman, a paleoanthropologist at Harvard.

The results from Fongoli suggest that a chimpanzee-like ancestor might have eked out an existence on an east African savanna. Food might not pose the biggest challenge. Instead, they would be hard-pressed by the heat.

Early hominins might have used some of the strategies documented in Fongoli, like staying near water and shifting a lot of activity from day to night. But even so, early hominins would have still suffered stress.

That stress might have only been overcome when hominins evolved new physical adaptations. Humans have skin glands that let us sweat much more than chimpanzees, for example. The origin of our upright posture might also be intertwined with our struggle with heat.

Some researchers have proposed that early hominins began standing to aid in reaching fruit hanging from trees. Peter Wheeler, of Liverpool John Moores University, has suggested that an upright posture would have helped hominins stay cool in an arid environment. On the savanna, walking tall might mean walking cool.

Dr. Pruetz suspects Dr. Wheeler may be right, and she hopes to study the Fongoli chimpanzees more to test his idea. The chimpanzees may shift their posture — as far as they can with an ape anatomy — in order to cope with the high temperatures. It’s now possible to get close enough to measure the heat flowing from the chimpanzees with a thermal imaging camera.

“We really haven’t had that opportunity before,” she said. “There’s a lot of fun stuff we can do.”

 

 

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

Bans on paying for human blood distort a vital global market

A WILLING buyer in a market with plenty of willing sellers, Barzin Bahardoust is finding life surprisingly hard. For years he has been trying to pay Canadians for their blood plasma—the viscous straw-coloured liquid in blood that has remarkable therapeutic powers. When his firm, Canadian Plasma Resources (CPR), tried to open clinics in Ontario in 2014, a campaign by local activists led to a ban by the provincial government on paid plasma collection. Undeterred, he tried another province, Alberta—which also banned the practice last year. Then, on April 26th, when CPR announced a planned centre in British Columbia, its government said it too was considering similar legislation. CPR has managed to open two centres, in far-flung Saskatchewan and New Brunswick. Even these have faced opposition.

The global demand for plasma is growing, and cannot be met through altruistic donations alone. Global plasma exports were worth $126bn in 2016—more than exports of aeroplanes. But paid plasma raises ethical, social and medical concerns: that it will lead to health catastrophes, as in the 1980s when tainted blood spread HIV and hepatitis; that it exploits the poor; and that it reduces the supply of “whole” blood, which is almost all donated voluntarily.

None of these worries is well-founded. But Canadian reservations about paid plasma are shared across most of the world. America, China, parts of Canada and some European countries are among the few places that permit it. Those countries are extremely effective in securing supplies: three-quarters are collected in America alone, and another 10% in China, Germany, Hungary and Austria, where payment is also allowed. Of over 1,000 plasma-collection centres worldwide, 700 are in America (see article). Jan Bult, head of a trade association representing companies that manufacture more than half of the world’s plasma products, says none collects plasma in countries that have banned compensation.

Only countries that pay for plasma are self-sufficient in it. (Italy, where donors are given time off work, is close to self-sufficiency.) Half of America’s plasma is shipped to Europe—20m contributions-worth. Canada imports 80% of its plasma products from America. Australia imports 40% of its plasma products, too.

Drug firms from countries that have banned pay-for-plasma do much of their collection in America. Three of the largest collection companies are European: Grifols of Spain, Shire of Ireland and Octapharma of Switzerland. The parent company of another big collector, CSL Behring, is Australian. Together these four firms run nearly eight out of ten plasma-collection centres. Some of their manufacturing capacity is in America, but much is located elsewhere. Switzerland, which collects very little plasma, exported $26bn-worth of plasma products in 2016.

Exported plasma is used to manufacture pharmaceuticals and is distinct from the plasma that, with red and white blood-cells and platelets, is used for transfusion. That saves lives when blood is lost, say, in traumatic accidents or surgery. But whole blood is rarely traded across borders, and very rarely involves payment. The World Health Organisation’s safety guidelines recommend voluntary donations.

Happily, demand for transfusions is declining. Blood-bank management and modern medicine have both grown more efficient. Kevin Wallis, who has managed blood stocks at a holding-centre in south London for nearly 20 years, says that hospitals once used three units of blood for a hip operation, but these days often use none. Despite population growth, the number of red blood-cell units used by hospitals in England has dropped from 2m a year 15 years ago to 1.4m now.

Pharmaceutical plasma is different. It is heat-treated or bathed in chemicals to sterilise it, reducing associated risks. It has all manner of uses. If blood fails to clot properly, as in haemophiliacs, a plasma product helps. A plasma product can restore an immune system weakened, for example, by chemotherapy. A complication known as Rhesus disease, in which the blood type of a fetus is incompatible with the mother’s was responsible for 10% of stillbirths in America as recently as the 1960s. These days plasma products can save the child.

Historically, these products were derived from plasma collected when volunteers donated whole blood. But demand has outpaced donation. So the proportion of plasma products derived from whole blood has declined from 40% in 1990 to 13% in 2015. Plasma today is mostly collected via apheresis, a process where whole blood is extracted, spun in a centrifuge, and the plasma is skimmed off. Red blood-cells are then mixed with an anticoagulant and transfused back into the donor. Blood-donation can take just 10-15 minutes. Apheresis usually takes at least an hour.

Plasma replenishes more quickly than red blood-cells. So donors can give more at one session, and far more frequently. In most countries whole-blood donors can give around 500ml of blood, which yields just 250ml of plasma, at most once every two months. Plasma donors can give up to 800ml of plasma—and in America are allowed to do so twice a week. This quickly adds up. In a year a plasma donor could give over 80 litres of the stuff, compared with just 1.6 litres from a whole-blood donor. Mr Bult says paid repeat donors, who have been intensively screened, help keep plasma products safe.

But a stigma about paying for blood lingers. Sue Lederer, of the University of Wisconsin, dates it to 1970, when Richard Titmuss published “The Gift Relationship”, a book suggesting paid blood was both ethically wrong and less effective than a voluntary system. Often American donors would be compensated not in cash but in chits redeemable at nearby liquor stores, an insalubrious practice nicknamed “ooze for booze”. Prisoners could also trade plasma for days off their sentences.

Then, in the 1980s, half of the world’s tens of thousands of haemophiliacs were infected with HIV or hepatitis by contaminated plasma products. Thousands died from AIDS-related illnesses. Many argued that paying for blood had encouraged donors to lie about dangerous behaviour, such as risky sex or drug use. Official inquiries took place in Canada and Ireland. In France and Japan, health officials and businessmen were jailed. In America, pharmaceutical companies settled class-action lawsuits. The scandal has cast a long shadow. The British government announced an independent inquiry last November.

It remains legal to pay for whole-blood donation in America today. But hospitals refuse to accept it. Today’s plasma, however, is safe from the contamination risks of the past. Modern screening and sanitisation are extremely effective. Graham Sher, chief executive of Canadian Blood Services, a non-profit, says plasma products from paid donors are “as safe as those from our unpaid donors”.

Other prejudices against pay-for-plasma are equally deep-seated. Some data, for example, lend weight to the suspicion that it preys on the poor. American plasma centres are concentrated in less well-off bits of the country. Typically they are in postal districts where 27.4% of the population are poor, according to The Economist’s analysis of census data. This is much higher than the average American poverty rate of 16.5%.

The other worry, shared by Dr Sher, is that paying for plasma may lead to a reduction in whole-blood donation. But, if that were true, the problem would be intensifying, as pay-for-plasma centres have nearly doubled worldwide in the past five years. But Peter Jaworski, of Georgetown University, is sceptical, suggesting that, anecdotes aside, the evidence shows paid plasma donation “does not crowd out voluntary blood-donation”. Americans, for example, continue to donate as much voluntary blood per head as do Canadians.

The aversion to paid-for plasma carries its own risks. According to Grifols, the geographic imbalance puts supplies of plasma products at risk. At the plasma industry’s main annual conference, held this year in Budapest in March, over-reliance on imports from America was a hot topic. Representatives from several countries (including Canada) recognised they must do more to diversify their supplies. Making it legal to pay for plasma is an obvious first step.

 

 

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