Scientists Are Teaching the Body to Accept New Organs

It was not the most ominous sign of health trouble, just a nosebleed that would not stop. So in February 2017, Michael Schaffer, who is 60 and lives near Pittsburgh, went first to a local emergency room, then to a hospital where a doctor finally succeeded in cauterizing a tiny cut in his nostril.

Then the doctor told Mr. Schaffer something he never expected to hear: “You need a liver transplant.”

Mr. Schaffer had no idea his liver was failing. He had never heard of the diagnosis: Nash, for nonalcoholic steatohepatitis, a fatty liver disease not linked to alcoholism or infections.

The disease may have no obvious symptoms even as it destroys the organ. That nosebleed was a sign that Mr. Schaffer’s liver was not making proteins needed for blood to clot. He was in serious trouble.

The news was soon followed by another eye-opener: Doctors asked Mr. Schaffer to become the first patient in an experiment that would attempt something that transplant surgeons have dreamed of for more than 65 years.

If it worked, he would receive a donated liver without needing to take powerful drugs to prevent the immune system from rejecting it.

Before the discovery of anti-rejection drugs, organ transplants were simply impossible. The only way to get the body to accept a donated organ is to squelch its immune response. But the drugs are themselves hazardous, increasing the risks of infection, cancer, high cholesterol levels, accelerated heart disease, diabetes and kidney failure.

Within five years of a liver transplant, 25 percent of patients on average have died. Within 10 years, 35 to 40 percent have died.

“Even though the liver may be working, patients may die of a heart attack or stroke or kidney failure,” said Dr. Abhinav Humar, a transplant surgeon at the University of Pittsburgh Medical Center who is leading the study Mr. Schaffer joined. “It may not be entirely due to the anti-rejection meds, but the anti-rejection meds contribute.”

Kidneys in particular may be damaged. “It is not uncommon to end up doing a kidney transplant in patients who previously had a lung or liver or heart transplant,” Dr. Humar added.

Patients usually know about the drugs’ risks, but the alternative is worse: death for those needing livers, hearts or lungs; or, for kidney patients, a life on dialysis, which brings an even worse life expectancy and quality of life than does a transplanted kidney.

In 1953, Dr. Peter Medawar and his colleagues in Britain did an experiment with a result so stunning that he shared a Nobel Prize for it. He showed that it was possible to “train” the immune systems of mice so that they would not reject tissue transplanted from other mice.

His method was not exactly practical. It involved injecting newborn or fetal mice with white blood cells from unrelated mice. When the mice were adults, researchers placed skin grafts from the unrelated mice onto the backs of those that had received the blood cells.

The mice accepted the grafts as if they were their own skin, suggesting that the immune system can be modified. The study led to a scientific quest to find a way to train the immune systems of adults who needed new organs.

Dr. Peter Medawar, around 1960, when he won the Nobel Prize for studies of the immune system.CreditBettmann, via Getty Images

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Dr. Peter Medawar, around 1960, when he won the Nobel Prize for studies of the immune system.CreditBettmann, via Getty Images

That turned out to be a difficult task. The immune system is already developed in adults, while in baby mice it is still “learning” what is foreign and what is not.

“You are trying to fool the body’s immune system,” Dr. Humar said. “That is not easy to do.”

Most of the scientific research so far has focused on liver and kidney transplant patients for several reasons, said Dr. James Markmann, chief of the division of transplant surgery at Massachusetts General Hospital.

Those organs can be transplanted from living donors, and so cells from the donor are available to use in an attempt to train the transplant patient’s immune system.

Far more people need kidneys than need any other organ — there are about 19,500 kidney transplants a year, compared with 8,000 transplanted livers. And those transplanted kidneys rarely last a lifetime of battering with immunosuppressive drugs.

“If you are 30 or 40 and get a kidney transplant, that is not the only kidney you will need,” said Dr. Joseph R. Leventhal, who directs the kidney and pancreas transplant programs at Northwestern University.

Another reason to focus on kidneys: “If something goes wrong, it’s not the end of the world,” Dr. Markmann said. If an attempt to wean patients from immunosuppressive drugs fails, they can get dialysis to cleanse their blood. Rejection of other transplanted organs can mean death.

The liver intrigues researchers for different reasons. It is less prone to rejection by the body’s immune system. When rejection does occur, there is less immediate damage to the organ.

And sometimes, after people have lived with a transplanted liver for years, their bodies simply accept the organ. A few patients discovered this by chance when they decided on their own to discard their anti-rejection drugs, generally because of the expense and side effects.

An estimated 15 to 20 percent of liver transplant patients who have tried this risky strategy have succeeded, but only after years of taking the drugs.

In one trial, Dr. Alberto Sanchez-Fueyo, a liver specialist at King’s College London, reported that as many as 80 percent could stop taking anti-rejection drugs. In general, those patients were older — the immune system becomes weaker with age. They had been long-term users of immunosuppressive drugs and had normal liver biopsies.

But the damage caused by immunosuppressive drugs is cumulative and irreversible, and use over a decade or longer can cause significant damage. Yet there is no way to predict who will succeed in withdrawing.

The more researchers learned about the symphony of white blood cells that control responses to infections and cancers — and transplanted organs — the more they began to see hope for modifying the body’s immune system.

Many types of white blood cells work together to create and control immune responses. A number of researchers, including Dr. Markmann and his colleague, Dr. Eva Guinan of the Dana-Farber Cancer Institute, chose to focus on cells called regulatory T lymphocytes.

These are rare white blood cells that help the body identify its own cells as not foreign. If these regulatory cells are missing or impaired, people can develop diseases in which the body’s immune system attacks its own tissues and organs.

The idea is to isolate regulatory T cells from a patient about to have a liver or kidney transplant. Then scientists attempt to grow them in the lab along with cells from the donor.

Then the T cells are infused back to the patient. The process, scientists hope, will teach the immune system to accept the donated organ as part of the patient’s body.

“The new T cells signal the rest of the immune system to leave the organ alone,” said Angus Thomson, director of transplant immunology at the University of Pittsburgh Medical Center.

Dr. Markmann, working with liver transplant patients, and Dr. Leventhal, working with kidney transplant patients, are starting studies using regulatory T cells.

At Pittsburgh, the plan is to modify a different immune system cell, called regulatory dendritic cells. Like regulatory T cells, they are rare and enable the rest of the immune system to distinguish self from non-self.

One advantage of regulatory dendritic cells is that researchers do not have to isolate them and grow them in sufficient quantities. Instead, scientists can prod a more abundant type of cell — immature white blood cells — to turn into dendritic cells in petri dishes.

“It takes one week to generate dendritic cells,” Dr. Thomson said. In contrast, it can take weeks to grow enough regulatory T cells.

The regulatory T cells also have to remain in the bloodstream to control the immune response, while dendritic cells need not stay around long — they control the immune system during a brief journey through the circulation.

“Each of us is taking advantage of a different approach,” Dr. Markmann said. “It is not clear yet which is best. But the field is at a fascinating point.”

What about patients who already had an organ transplant? Is it too late for them?

“I get asked that question almost every day I am seeing patients,” Dr. Leventhal said.

For now, the answer is that it is too late. These patients are not candidates for these new strategies to modify the immune system. But researchers hope that situation will change as they learn more.

When Michael Schaffer, the Pittsburgh patient, was told that he needed a liver and that he could be the first patient in the group’s clinical trial, he shrugged. “Someone has to be first,” he said.

Mr. Schaffer began a search to find a living donor, a close relative willing to undergo a major operation to remove a lobe of liver — or a stranger whose cells were compatible and who was willing to donate.

The Pittsburgh scientists told him how to proceed. Ask immediate family, then relatives, friends and colleagues. If that failed, he would have to start advertising with fliers and posts on Facebook.

Mr. Schaffer is one of eight brothers. Four were older than 55, too old to safely undergo removal of part of their liver. The three younger brothers were in poor health.

He moved on to nieces and nephews. Three agreed to donate, and one, Deidre Cannon, 34, who was a good match, went forward with the operation.

It took place on Sept. 28, 2017. Afterward, Mr. Schaffer was taking 40 pills a day to prevent infections and to tamp down his immune system while his body learned to accept the new organ.

But now he has tapered down to one pill, a low dose of just one of the three anti-rejection drugs he started with. And doctors hope to wean him even from that.

His case may be intriguing, but he is just one patient. The scientists plan to try the procedure on 12 more patients and, if it succeeds, to expand the study to include many more patients at multiple test sites.

For Mr. Schaffer, it has all been worthwhile. He is active, working with a teenage grandson to replace the tiles on his kitchen floor. He shovels snow and mows lawns as a favor for his neighbors, and helps take care of his grandchildren after school.

“My goal is to live to be 100 and get shot in bed by a jealous husband,” Mr. Schaffer said.

 

 

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

Superbug From India Spread Far and Fast, Study Finds

An antibiotic-resistant gene originally discovered in bacteria from India was found 8,000 miles away in a remote Arctic environment, according to a new study. Researchers believe the gene, found in bacteria in the soil of a Norwegian archipelago, made the trek in less than three years, highlighting the speed with which antibiotic resistance can spread on a global scale.

Antibiotic resistance is a persistent and growing global health concern. At least 700,000 people die globally each year from antibiotic-resistant infections, according to a 2014 report from the British government. As some bacteria have evolved to fight off even last-resort treatments, that number is on track to increase as much as 10-fold in the coming decades, according to the report.

These so-called superbugs have spread through hospitals and health-care facilities due to overuse of antibiotics in medicine and in farming. But they also crop up throughout the environment via water and food, carried in the guts of animals or humans, researchers say. Resistance without human intervention continuously occurs as bacteria evolve genes to compete with each other—a process millions of years older than humans. All of these factors make it difficult for scientist to track exactly how some antibiotic-resistant genes emerge and proliferate.

“We’re trying to understand these other factors that come into play,” said David Graham, an ecosystems engineer at Newcastle University in the U.K. and lead researcher on the study. “If we don’t know the pathways, we can’t come up with the right solutions.”

Dr. Graham and his team collected soil samples from eight locations in Svalbard, a Norwegian island chain in the Arctic Ocean. The team chose an isolated area with minimal human impact to discount human antibiotic use. The team then analyzed the DNA from the bacteria and other organisms in the dirt.

“The arctic is a perfect microcosm for studying pathways,” said Clare McCann, an environmental engineer at Newcastle University in the U.K. and first author on the study. “You can very quickly and easily discount any human use there.”

Researchers found 131 genes linked to antibiotic resistance. That level of genetic diversity isn’t unusual, says Dr. Graham, though two genes and their high abundance specifically caught the team’s attention. The gene called pncA creates resistance to the tuberculosis drug pyrazinamide. The other gene produces the notorious “superbug” protein NDM-1.

The findings were published Sunday in the journal Environment International.

New Delhi metallo-beta-lactamase-1, or NDM-1, makes some certain gut bacteria resistant to the last-resort group of antibiotics known as  carbapenems. Since its discovery in 2008, NDM-1 has spread to over 100 countries, including the U.S. “This is a gene that’s causing havoc in hospitals,” said Gerry Wright, the director of the Institute for Infectious Disease Research at McMaster University in Canada, who wasn’t involved with the study.

The gene was found only in soil samples that had high nutrient levels, reflecting the presence of plants and animal feces, meaning that NDM-1 was most likely transported to the environment via animals or other mechanisms, the researcher said, rather than having developed there on its own.

Superbug From India Spread Far and Fast, Study Finds

Researchers were analyzing samples that had been collected in 2013. NDM-1 emerged in Indian groundwater in 2010, so researchers believe that the gene made the 8,000 mile journey to the Arctic in just three years. “This gene has spread around the world so incredibly fast,” said Dr. Wright. “It’s something that’s not surprising to me, but it should be frightening to everybody.”

It isn’t just the speed that concerns scientists; it is also the location. “What’s terrible is that we’re talking about a really remote place, a place that we don’t think of as a hotbed of antibiotic resistance,” said Martin Blaser,  the chairman of the Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria, who wasn’t involved in the research. “This is really bad news.”

Researchers can’t exactly say how the superbug gene arrived in the Arctic, though it may have been picked up in the guts of migratory seabirds. Although NDM-1 won’t harm humans while it is in the soil, the finding is important for those who track how genes spread.

“This moves us forward in our quest to understand the global distribution of these genes,” said Jill Mikucki, an assistant professor of microbiology at the University of Tennessee, who wasn’t involved in the research.

The gene pncA seemed to have developed in the Arctic on its own, researchers say, because it was found in all of the soil samples regardless of nutrient level. Because the gene is resistant to tuberculosis drugs, researchers believe there is the potential to find a tuberculosis-fighting antibiotic in the soil that may have prompted the resistance to develop. “If there is a gene out there with resistance, there is almost certainly an organism that can counterbalance that,” said Dr. Graham.

Finding undiscovered antibiotics in soil is a possibility–that is how the first antibiotics were discovered, and researchers are currently working to pull undiscovered antibiotics from dirt. But as of right now, the evolutionary struggle with antibiotic resistance is one that modern medicine is losing. “We really rely on antibiotics, and this resistance thing is only going in one direction. It’s getting worse,” said Dr. Wright. “You can run, but you can’t hide.”

 

 

 

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

How a shampoo bottle is saving young lives

ON HIS first night as a trainee paediatrician in Sylhet, Bangladesh, Mohamad Chisti (pictured above) watched three children die of pneumonia. Oxygen was being delivered to them, through a face mask or via tubes placed near their nostrils, using what is called a basic “low-flow” technique which followed World Health Organisation (WHO) guidelines for low-income countries. But it was clearly failing. He decided to find a better way.

Last year 920,000 children under the age of five died of pneumonia, making it the leading killer of people in that age group. This figure is falling (in 2011 it was 1.2m), but it still represents 16% of all infant deaths. Such deaths are not, however, evenly distributed. In Bangladesh pneumonia causes 28% of infant mortality.

Pneumonia is a result of bacterial, viral or fungal infection of the lungs. Its symptoms of breathlessness result from a build-up of pus in the alveoli. These are tiny sacs, found at the ends of the branching airways within the lungs, that are richly infused with capillary blood vessels. They are the places where oxygen enters the bloodstream and carbon dioxide leaves it. Stop the alveoli doing their job and a patient will suffocate.

Pneumonia is particularly threatening to malnourished children—which many in Bangladesh are. First, malnourishment debilitates the immune system, making infection more likely. Second, to keep its oxygen levels up and its CO2 levels down, a child with pneumonia breathes faster and faster. But this takes a lot of energy, so undernourished infants do not have the ability to keep such an effort up for long. Dr Chisti’s device is designed to reduce the effort required to breathe, and to do so cheaply. (The reason for the WHO’s recommended approach in poor countries is that the sort of ventilator routinely available in the rich world costs around $15,000. But low-flow oxygen delivery does not reduce the effort required to breathe.)

His invention was inspired by something he saw while visiting Australia. On this trip he was introduced to a type of ventilator called a bubble-CPAP (continuous positive airway pressure), which is employed to help premature babies breathe. It channels the infant’s exhaled breath through a tube that has its far end immersed in water. The exhaled breath emerges from the tube as bubbles, and the process of bubble formation causes oscillations of pressure in the air in the tube. These feed back into the child’s lungs. That improves the exchange of gases in the alveoli and also increases the lungs’ volume. Both make breathing easier.

At about $6,000, standard bubble-CPAPs are cheaper than conventional ventilators. But that is still too much for many poor-country hospitals. However, after a second piece of serendipitous inspiration, when he picked up a discarded shampoo bottle that contained leftover bubbles, Dr Chisti realised he could probably lash together something that did the same job. Which he did, using an oxygen supply (which is, in any case, needed for the low-flow oxygen delivery method), some tubing and a plastic bottle filled with water. And it worked.

In 2015 he and his colleagues published the results of a trial that they had conducted in the institution where he practises, the Dhaka Hospital of the International Centre for Diarrhoeal Disease Research. This showed that the method had potential. The hospital now deploys it routinely and the number of children who die there from pneumonia has fallen by three-quarters. That means the survival rate in the Dhaka Hospital is today almost on a par with that of children treated in rich-world facilities, using conventional ventilators.

Dr Chisti says that, as well as saving lives, his device has cut the hospital’s spending on pneumonia treatment by nearly 90%. The materials needed to make his version of a bubble-CPAP ventilator cost a mere $1.25. The device also consumes much less oxygen than a conventional ventilator. In 2013 the hospital spent $30,000 on supplies of the gas. In 2017 it spent $6,000.

The idea is spreading. Dr Chisti and his team are about to start trials of the new ventilator in a group of hospitals in Ethiopia. If it works as well there as it does in Dhaka, it will surely be taken up elsewhere. All in all, the Chisti bottle-based ventilator shows what can be achieved by stripping an idea down to its basic principles. Effectiveness, it neatly demonstrates, need not always go hand in hand with high tech.

 

 

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

The Placenta, an Afterthought No Longer

The placenta may be dismissed as “afterbirth,” deemed an afterthought in discussions about pregnancy and even relegated, literally, to the trash bin. But at long last it is beginning to get its due.

In the past three weeks, scientists have published three significant studies of this ephemeral organ. One gave a detailed analysis of all the genes expressed, or converted into functioning proteins, in the placenta; another experimented with a way to silence that expressionwhen it causes trouble. In the third, researchers created mini-placentas, three-dimensional clusters of cells, or organoids, that mimic the real thing in the lab, and can be used as models for studying it.

In addition, at a recent meeting in Bethesda, Md., of the Human Placenta Project, several teams of researchers showed off sophisticated new techniques that enable the placenta to be studied in real time. That work could help doctors diagnose dangerous complications in pregnancy — including pre-eclampsia (a form of high blood pressure), preterm birth and fetal growth restriction — early enough to intervene. It might also help to reveal why boys are much more vulnerable than girls to disorders of brain development, including schizophrenia, A.D.H.D., autism, dyslexia and Tourette syndrome.

“The missing link between complications during pregnancy and development of the fetal brain has been hiding in plain sight for a long time,” said Dr. Daniel R. Weinberger, director of the Lieber Institute for Brain Development in Baltimore, Md. “It’s the placenta.”

During the course of human pregnancy, the placenta grows from a few cells into an organ weighing more than a pound. It often is compared to an aggressive cancer. But a more apt metaphor might be a military invasion, as 90 percent of the placenta is made up of cells not from the mother but from the fetus.

Early in gestation, the fertilized egg implants itself in the mother’s uterine lining and sends out a few cells to breach it. These foot soldiers produce proteins that disarm the mother’s defenses, destroy the smooth muscles that line her blood vessels and dilate and redirect the vessels to feed the embryo. As the placental beachhead grows, its cells specialize to do the work of heart, lungs, liver and kidneys until the fetus can fend for itself. Groups of cells exchange oxygen for carbon dioxide; provide nutrients and hormones; protect the fetus from harmful stress, germs and chemicals; and remove waste.

This incursion fails as often as 20 percent of the time, and when it does, it can cause severe complications for the fetus, at birth and afterward. It may also forecast trouble for the mother’s health later in life: pre-eclampsia can portend heart disease and stroke, and gestational diabetes can signal later obesity and metabolic disease.

“There is nothing in medicine that can return so much on an investment as a healthy pregnancy and delivery, because that has years and years of impact later,” said Dr. George R. Saade, chief of obstetrics at the University of Texas Medical Branch. “And placental health is critical to the health of a pregnancy.”

Not all placentas develop equally. In the last few years Tracy Bale, director of the University of Maryland’s Center for Epigenetic Research in Child Health and Brain Development, has found that the placenta of a male fetus is more vulnerable to external stress than the placenta of a female fetus. This vulnerability, in turn, may transfer to the embryo, Dr. Bale said. Male fetuses typically are larger than females throughout gestation, but they also have higher rates of spontaneous abortions, stillbirth, premature birth and neurodevelopmental conditions.

It’s not yet clear what makes female fetuses more resilient. But during the first trimester, 58 genes are expressed differently in male fetuses than in females, according to an analysis published in January, in the journal Biology of Sex Differences.

Several of these genes are on the X chromosome. A female fetus has two X chromosomes and two copies of these genes, with one copy typically staying silent. But the analysis showed that many of these gene copies are activated regardless, and so they become a larger factor in female placentas than in males. (The more detailed analysis of gene expression published three weeks ago did not look at sex differences, but provides a framework for similar analyses.)

In May, Dr. Weinberger’s team at the Lieber Institute looked specifically at genes implicated in schizophrenia. They found that many of these genes are abundantly expressed in the fetal placenta, and are activated at even higher levels when the pregnancy is under stress; the effect is more dramatic in male fetuses than in females.

“We suggested that placentas of male fetuses seem to be more susceptible at a genetic level,” Dr. Weinberger said. “I’m very confident the same story is going to be there for autism, A.D.H.D. and other developmental behavioral problems.”

Technological limitations have obscured the central role that the placenta plays in the health of both baby and mother. The placenta is a dynamic organ, but it usually has been studied by dissecting it after delivery.

“That’s too late,” said Dr. Saade of the University of Texas. “It’s like studying cardiac disease or any other medical condition just by doing an autopsy.”

Problems with the placenta often begin in the spiral arteries of the mother — the arteries that the fetus commandeers to feed itself. If they are blocked or too narrow, the fetus may not get enough oxygen and nutrients, and the mother’s blood pressure may spike toward pre-eclampsia. This can begin as early as the first trimester, but few tools are available to diagnose it at that stage.

 

“The tests that are available today are all designed for the third trimester, and that’s way too late,” said Dr. Alfred Z. Abuhamad, chair of the department of obstetrics and gynecology at Eastern Virginia Medical School in Norfolk, Va.

In 2014, the child-health division of the National Institutes of Health set out to find noninvasive methods to identify complications earlier. An infusion of $80 million into placenta research prompted Dr. Abuhamad and others to adapt technologies used in other fields, and has already provided valuable insights into early pregnancy.

Some scientists are betting on magnetic resonance imaging scans, or M.R.I.s, as the most sensitive detectors of placental problems. They are using a method that measures oxygen levels in the blood; it is quick and, so far, seems to catch problems as early as the second trimester. Several teams worldwide are evaluating the technique, each in hundreds of women.

But M.R.I. is not widely in use in obstetricians’ offices, Dr. Abuhamad said, in contrast with ultrasound machines, which would be a more practical option. Traditional ultrasounds can show the structure and location of the placenta, not how well the organ is functioning. But advances over the past five years have sharpened the machine’s focus. One enables the device to detect tiny blood vessels; another, called elastography, was developed to examine the liver, and can help measure the density of placental tissue.

Dr. Abuhamad’s team is using these advances in ultrasound to chart placental health in about 500 pregnant women, including 300 at high risk of complications. They are collecting ultrasound data and blood samples from the women at eight time points during pregnancy to see which early features track with problems later on.

Other teams are trying to identify particles the placenta may release into the bloodstream because that could lead to a simple blood test for diagnosing problems. And one group of researchers is developing an oximeter, a device that quantifies the light reflected back through layers of fat as a measure of blood oxygen.

It will be at least five years before any of these tests makes their way to doctors’ offices. But when they are ready, they are likely to have a huge impact on obstetric practice, said Dr. Diana W. Bianchi, director of the National Institute of Child Health and Human Development.

“The way that prenatal care is currently structured, you hardly see your obstetrician in the first trimester,” she said. “And by the time you get to the third trimester, you’re seeing the obstetrician weekly.”

Instead, when placental screening identified a problem, women might be encouraged to see their doctors frequently through the first trimester. “Knowing that this starts early in the first trimester,” said Dr. Abuhamad, “could we then intervene in the first trimester — identify early, intervene early and prevent the complications?”

 

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

Project Baseline Aims to Ward Off Illness Before We Get Sick

One of the sobering facts about cancer treatment is that it often begins when it is already too late: Studies show that an alarming number of treatable cancers are diagnosed in the advanced stages of disease.

That has long bothered Dr. Sam Gambhir, a top cancer researcher at Stanford University who lost his teenage son to brain cancer in 2015. Dr. Gambhir wondered if there were some surefire way to detect cancer long before people got sick.

“In the cancer field we often find problems long after people have symptoms,” he said. “We rarely find things early.”

Now Dr. Gambhir is leading a large study that seeks to better understand the transition from normal health to disease. The study, called Project Baseline, could lead to the identification of new markers in the blood, stool or urine of healthy people that help predict cancer, cardiovascular disease and other leading killers of Americans. It is a joint effort between Stanford and Duke Universities and Verily, a life sciences company owned by Alphabet, the parent company of Google. Researchers are recruiting 10,000 adults across the United States who will be examined in extreme detail and followed intensively for at least four years.

Many of the people joining the study are healthy adults, which differs from traditional medical trials that focus largely on people who are already ill. Another key difference is that the researchers are collecting a staggering amount of medical data on their subjects: analyzing their microbiomes, sequencing their genomes, subjecting them to a variety of scans and assessing their cognitive health. They are also equipping volunteers with new wearable technology from Verily that records their nightly sleep patterns and tracks their heart rhythms and physical activity.

In another unusual move, the Project Baseline investigators are sharing the research results with their subjects, everything from how much plaque or calcium they find in their arteries to which bacterial strains inhabit their guts.

Some experts worry, however, that providing such detailed medical data to healthy adults could lead to new problems. Dr. Eric Topol, a professor of genomics at the Scripps Research Institute in California, cautioned that the sheer amount of testing, scans and other “deep interrogations” could produce incidental findings that cause unnecessary anxiety. “Sometimes it leads to unwarranted further testing that could even be harmful,” he said.

Dr. Topol is involved in a similar study, called All of Us and financed by the National Institutes of Health, which is building a “biobank” of health information collected from a million Americans. The researchers intend to return genetic data and some other results to participants but are figuring out the best way to do that.

“This is the new challenge in a democratized world of medical research,” Dr. Topol said. “I’m really in favor of it, but it sets up this new issue of dealing with unexpected results that are difficult to interpret.”

The Project Baseline researchers are learning this firsthand. They say they have discovered and promptly alerted participants to potentially lethal conditions that might otherwise have gone unnoticed, like cancer and aortic aneurysms, so they can seek appropriate medical care. But some of the participants have also been frightened by fairly innocuous findings, like chest X-rays that reveal small, usually benign nodules in their lungs that they may look up on the internet and think are cancerous, said Dr. Charlene Wong, a Project Baseline investigator. “For most of our participants, it will not be cancer. But we’re still in the process of working with participants to find out if we can return that data in the right way so that we minimize the anxiety it can cause,” she said.

Dr. Ken Mahaffey, a Project Baseline investigator and cardiologist at Stanford, said that he and his colleagues have “a responsibility, socially, morally and ethically, to get systems in place so we can share the results with participants in ways that they can understand them and then help them engage with their own physicians and clinical providers.”

Despite the anxiety it can cause, many people welcome such data. Studies like Project Baseline are especially appealing to the so-called Quantified Self movement, the growing community of people who track their every biometric with smartphone apps, high-tech gadgets and direct-to-consumer health tests. Some 2,000 people have enrolled in Project Baseline so far, and thousands more have signed up in a registry of potential volunteers who may be called on as the project expands to additional medical centers.

While there have been plenty of longitudinal studies in the past, many of the largest and most important were not very diverse. The landmark Framingham heart study that began in 1948, for example, focused mostly on white adults. Dr. Svati Shah, an associate professor of medicine at Duke, said Project Baseline is recruiting many people who are black, Hispanic, Asian and other ethnicities so the study can shed light on differences in disease risk factors among people of different backgrounds.

That includes people like Rosa Gonzalez, 57, a nurse who lives in Concord, N.C. Ms. Gonzalez, who is Mexican-American, joined the study earlier this year and has encouraged at least a dozen Latino friends and acquaintances to join it as well.

“Other studies present data and talk about Latinos, but they don’t have Latinos in the study,” she said. “I’m trying to set an example so other Latinos see that it’s good to take part so that we can have data that shows how we’re the same or different.”

Dr. Gambhir said the idea for Project Baseline was hatched in 2013, when Google executives approached him and said they wanted to do a landmark study on human health. Dr. Gambhir proposed a study to find early markers of cancer in people who are otherwise healthy.

“We have always thought that if we learn more about what your body is doing before you become ill, then we would have a much better chance of ideally preventing or at least detecting things early,” he said. Google liked the idea but suggested broadening the scope to include other diseases.

Verily declined to say how much it is spending on Project Baseline. But the company is investing in several areas of health care, including the development of contact lenses and miniature sensors that monitor blood sugar levels so patients with diabetes can better manage their disease.

In addition to sharing results with study volunteers, Project Baseline is hosting events and webinars in which study participants can ask the researchers questions and give them suggestions. “This isn’t research that’s happening in a black box,” said Dr. Jessica Mega, Verily’s chief medical officer. “People on the ground are part of this movement.”

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

 

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.

Scientists Are Retooling Bacteria to Cure Disease

In a study carried out over the summer, a group of volunteers drank a white, peppermint-ish concoction laced with billions of bacteria. The microbes had been engineered to break down a naturally occurring toxin in the blood.

The vast majority of us can do this without any help. But for those who cannot, these microbes may someday become a living medicine.

The trial marks an important milestone in a promising scientific field known as synthetic biology. Two decades ago, researchers started to tinker with living things the way engineers tinker with electronics.

They took advantage of the fact that genes typically don’t work in isolation. Instead, many genes work together, activating and deactivating one another. Synthetic biologists manipulated these communications, creating cells that respond to new signals or respond in new ways.

Until now, the biggest impact has been industrial. Companies are using engineered bacteria as miniature factories, assembling complex molecules like antibiotics or compounds used to make clothing.

In recent years, though, a number of research teams have turned their attention inward. They want to use synthetic biology to fashion microbes that enter our bodies and treat us from the inside.

The bacterial concoction that volunteers drank this summer — tested by the company Synlogic — may become the first synthetic biology-based medical treatment to gain approval by the Food and Drug Administration.

The bacteria are designed to treat a rare inherited disease called phenylketonuria, or PKU. People with the condition must avoid dietary protein in foods such as meat and cheese, because their bodies cannot break down a byproduct, an amino acid called phenylalanine.

As phenylalanine builds up in the blood, it can damage neurons in the brain, leading to delayed development, intellectual disability and psychiatric disorders. The traditional treatment for PKU is a strict low-protein diet, accompanied by shakes loaded with nutritional supplements.

But in experiments on mice and monkeys, Synlogic’s bacteria showed promise as an alternative treatment. On Tuesday, company investigators announced positive results in a clinical trial with healthy volunteers.

The researchers are now going forward with a trial on people with PKU and expect to report initial results next year.

Tal Danino, a synthetic biologist at Columbia University, said that a number of other researchers are working on similar projects, but no one has moved forward as fast as Synlogic. “They’re leading the charge,” he said.

One of Synlogic’s co-founders, James J. Collins, a synthetic biologist at M.I.T., published one of synthetic biology’s first proofs of principle in 2000.

He and his colleagues endowed E. coli bacteria with a way to turn a gene on and off when they were exposed to certain chemicals — “like a light switch for genes,” Dr. Collins said in an interview.


Tal Danino


At first, the scientists envisioned using rewired bacteria as environmental sensors — perhaps detecting airborne biological weapons and producing a chemical signal in response.

But then came the microbiome.

In the mid-2000s, microbiologists began charting our inner menagerie of microbes, the vast diversity of organisms that live inside healthy people. The microbiome is continually carrying out complex biochemistry, some of which helps shield us from diseases, scientists found.

Synthetic biologists soon began wondering whether they could add engineered bacteria to the mix — perhaps as internal sensors for signs of disease, or even as gut-based factories that make drugs the body needs.

“You can’t overestimate the impact of the microbiome work,” said Jeff Hasty, a former student of Dr. Collins who now runs his own lab at the University of California, San Diego. “That, in a nutshell, changed everything.”

Dr. Collins and Timothy K. Lu, another synthetic biologist at M.I.T., co-founded Synlogic in 2013, and the company began looking for diseases to take on. One of their picks was PKU, which affects 16,500 people in the United States.

Drugs have recently become available that can drive down levels of phenylalanine. But they only work in a fraction of patients, and they come with side effects of their own.

“The current tools that we have available are not good enough,” said Christine S. Brown, the executive director of the National PKU Alliance.

For years, researchers have explored treating PKU with gene therapy, hoping to insert working versions of the defective gene, called PAH, into a patient’s own cells. But so far the approach has not moved beyond studies in mice.

Image
A transmission electron microscopy image of Synlogic’s newly engineered bacteria.CreditW.M.Keck Biological Imaging Facility, The Whitehead Institute

To Synlogic, PKU looked like a ripe opportunity to use synthetic biology to create a treatment that might gain government approval.

Company researchers selected a harmless strain of E. coli that’s been studied for more than a century. “Most people have healthy, good E. coli in their intestinal tracts,” said Paul Miller, the chief scientific officer of Synlogic.

The researchers inserted genes into the bacteria’s DNA so that once they arrived in the gut, they could break down phenylalanine like our own cells do.

One of the new genes encodes a pump that the bacteria use to suck up phenylalanine around them. A second gene encodes an enzyme that breaks down the phenylalanine into fragments. The bacteria then release the fragments, which get washed out in urine.

The Synlogic team wanted the microbes to break down phenylalanine only in the right place and at the right time in the human body. So they engineered the bacteria to keep their phenylalanine genes shut down if they sensed high levels of oxygen around them.

Only when they arrived in a place with little oxygen — the gut — did they turn on their engineered genes.

To test the bacteria, the researchers created mice with the mutation that causes PKU. When the mice received a dose of the bacteria, the phenylalanine in their blood dropped by 38 percent, compared with mice without the microbes.

The researchers also tried out the bacteria on healthy monkeys. When monkeys without the microbes ate a high-protein diet, they experienced a spike of phenylalanine in their blood. The monkeys with engineered bacteria in their guts experienced only a gentle bump.

For their human trial, Synlogic recruited healthy people to swallow the bacteria. Some took a single dose, while others drank increasingly large ones over the course of a week. After ingesting the bacteria, the volunteers drank a shake or ate solid food high in protein.

On Tuesday, Synlogic announced that the trial had demonstrated people could safely tolerate the bacteria. In addition, the more bacteria they ingested, the more bits of phenylalanine wound up in their urine — a sign the bacteria were doing their job.

The next step will be to see if the microbes can lower phenylalanine levels in people with PKU.

“I’m amazed at how fast we got to where we are,” said Dr. Collins, who was not involved in Synlogic’s PKU research.

In July, Dr. Danino and his colleagues published a review in the journal Cell Systems, cataloging a number of other disorders that researchers are designing synthetic microbes to treat, including inflammation and infections.

Dr. Danino and Dr. Hasty are currently collaborating on another project: how to use synthetic biology against cancer.

One huge challenge in developing drugs for cancer is that they often fail to penetrate tumors. But microbiome researchers have discovered that natural bacteria regularly infiltrate tumors and grow inside them.

Now scientists are engineering bacteria that can also make their way into tumors. Once there, they will unload molecules that attract immune cells, which the researchers hope will kill the cancer.

“I think anywhere there are bacteria in the body is an opportunity to engineer them to do something else,” said Dr. Danino.

 

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

The Fertility Clinic That Cut IVF Prices in Half

The women in the waiting area come from as far as North Carolina and Michigan. Employees usher them into rooms decorated in earth tones. Elevator music plays and the beds are warmed.

The stirrups are the only sign that this isn’t a spa.

CNY Fertility Center is one of the busiest fertility clinics in the country, with four locations in Upstate New York and another soon to open in Atlanta. It’s also among the most affordable.

Embryologist Maureen Woodward places frozen embryos into storage tanks at the CNY Fertility Center in Syracuse. Instruments for moving embryos in culture dishes sit on desks throughout the embryology lab. Embryo samples are taken from a culture dish so that they can be frozen.PHOTOS: HEATHER AINSWORTH FOR THE WALL STREET JOURNAL

CNY is part of a small number of fertility clinics that charge a fraction of what other clinics do for in vitro fertilization (IVF). Doctors at these clinics argue that a high-volume, low-cost fertility program can make money, help start new families and open the market to people who otherwise couldn’t afford IVF. Insurance usually doesn’t fully cover these types of procedures.

Cost is a huge issue when it comes to who can access fertility treatments. “Fertility patients want options,” says Jake Anderson, a former venture capital partner who co-founded FertilityIQ, a San Francisco-based website that lets patients evaluate IVF clinics. “For years we thought there had to be trade-offs between price, volume and quality, but maybe we’ve been wrong all along.”

Robert Kiltz, the 62-year-old owner and director of the fertility clinic, says CNY charges $3,900 for one cycle of IVF. That’s about a third of the national average cost.

CNY patients must also pay for medications, monitoring and sometimes a frozen embryo transfer, bringing the total average cost to about $8,000 a cycle. That compares with a U.S. average of $20,700, as calculated by FertilityIQ, which has verified patient reviews of more than 400 fertility clinics. Its data come from more than 10,000 patients who have had IVF performed over the past 18 months.

The more than 190 IVF patients at CNY report a household income of $85,000 a year, compared with $182,000 nationally, according to FertilityIQ. Nearly 20% earn less than $50,000 a year, compared with just 4% nationally.

CNY’s birthrates, as reported to the Society for Assisted Reproductive Technology, a national organization of fertility specialists, are in line with national average by most accounts. In some age groups they are below average.

Dr. Kiltz says CNY has been profitable every year since its 1997 opening. Business has grown roughly 20% to 30% a year in recent years. “I believe we are opening up the market and making it more accessible and affordable to more people who don’t have access where they’re at,” Dr. Kiltz says.

Many outside experts say the clinic’s outcomes are respectable.

“He’s got very effective pregnancy rates for basically half the cost,” says David Adamson, a past president of the American Society for Reproductive Medicine and CEO of ARC Fertility, a national network of fertility clinics.

Dr. Kiltz says patients have few barriers at his clinics. Some clinics restrict fertility treatments if women are obese or too old or have a lot of previous failed cycles. He will take most anyone.

“Who deserves to have a baby? I don’t have any restrictions,” he says.

Not everyone agrees with that philosophy.

“Most fertility centers draw lines around people that they think intervention is futile based on age or hormone measures or other tests that make them say you don’t have the biology to become pregnant,” says Arthur Caplan, head of medical ethics at NYU School of Medicine.

Though there are no age cutoff guidelines for fertility clinics, Dr. Caplan has advocated a limit of 60 for single parents. “You want to protect the child’s best interest,” Dr. Caplan says.

Ms. Woodward prepares embryo culture dishes.
Ms. Woodward prepares embryo culture dishes. PHOTO: HEATHER AINSWORTH FOR THE WALL STREET JOURNAL

CNY has had one medical malpractice judgment against it in its 20-year history. A couple sued the clinic, Dr. Kiltz and another doctor there for breach of contract, medical malpractice and negligence.

Donald W. Boyajian, the attorney representing the couple, says the suit revolved around the clinic’s failure to screen an egg donor for genetic diseases. The couple had a daughter born with cystic fibrosis six years ago after using an egg donor for IVF at CNY. A jury issued a verdict in 2016 awarding the couple $8.2 million in damages and interest. CNY’s spokesman declined to discuss the case because the verdict is under appeal.

While CNY is among the longest-established low-cost, high-volume clinics, at least two others have similar models. In Colorado, High Quality Affordable fertility centers charges $5,800 for an IVF cycle, or about $9,000 to $10,000 all-included.

In Arizona, Mark Amols says he started an affordable fertility clinic after experiencing firsthand how unaffordable treatments are. He and his wife spent close to $20,000 on fertility treatments 11 years ago. Dr. Paul Magarelli, medical director and CEO of High Quality Affordable centers, helped Dr. Amols when he started New Direction Fertility Centers in Gilbert, Ariz., three years ago.

When he opened in 2015 he decided to charge patients $4,800 for a cycle of IVF, plus the cost of medications. High-volume clinics have more purchasing power and can negotiate better prices for materials and equipment, he says.

CNY patients gave the clinic a 2.5 out of 5 for how frequently they see a doctor, which is a low score, Mr. Anderson says. Dr. Kiltz acknowledges that he may have fewer reproductive endocrinologists on staff than other clinics. Nurse practitioners consult with and monitor women trying to get pregnant. “Some people might not like that model,” he says.

Norbert Gleicher, medical director and chief scientist at the Center for Human Reproduction in Manhattan, says of Dr. Kiltz, “He’s running a very tight ship. He’s doing a ton of cycles with a few physicians. So he’s delegating a lot of stuff to non-physician staff.” (Dr. Gleicher and Dr. Kiltz have no business relationship.)

At Dr. Gleicher’s clinic, three reproductive endocrinologists oversee about 800 IVF cycles a year. Last year CNY had five REs and oversaw roughly 2,500 cycles.

CNY’s flagship Syracuse clinic takes up 20,000 square feet. Most of the clinics also have a spa, called CNY Healing Arts. The spas offer acupuncture, massage and yoga for fertility patients and the general public.

About three years ago the clinic started offering payment plans and in-house financing. More than half of CNY’s patients end up with a one-to-two-year payment plan, for which they are charged a monthly $40 administrative fee.

Melissa and Paul Randazzo, seen here with 5-year-old Liliana and twins Violet, left, and Izabel, right. The Randazzos had their twins with the help of CNY.
Melissa and Paul Randazzo, seen here with 5-year-old Liliana and twins Violet, left, and Izabel, right. The Randazzos had their twins with the help of CNY.

Dr. Kiltz’s patients give CNY high ratings. It has an average ranking of 9.3 out of 10 with 193 reviews, placing it in the top 5% of clinics nationally, according to FertilityIQ. The average clinic on the site has a 7.4 rating.

Melissa Randazzo, a 32-year-old Michigan resident, paid nearly $25,000 to a local fertility clinic seven years ago to have her now-5-year-old daughter. She knew her family couldn’t afford that again. Through some research she found CNY. After two transfers, she had twin girls, Violet and Izabel, now 8 months old. The Randazzos used a two-year payment plan to pay for the IVF, spending a total of about $7,500, plus $1,000 in travel costs.

Ms. Randazzo, who runs a jewelry business from home, says of Dr. Kiltz, “I know he’s busy and I know he has a million patients, but when he came in the room, it was like we were the only people he was seeing that day.”

 

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

The Genetic Test Some Men Don’t Know They Need

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

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

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

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

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

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

Genetic Gender Gap

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

Men

Women

Any type of cancer risk

27%

73%

Breast/ovarian cancer risk

8%

92%

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

 

 

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

Dying Organs Restored to Life in Novel Experiments

When Georgia Bowen was born by emergency cesarean on May 18, she took a breath, threw her arms in the air, cried twice, and went into cardiac arrest.

The baby had had a heart attack, most likely while she was still in the womb. Her heart was profoundly damaged; a large portion of the muscle was dead, or nearly so, leading to the cardiac arrest.

Doctors kept her alive with a cumbersome machine that did the work of her heart and lungs. The physicians moved her from Massachusetts General Hospital, where she was born, to Boston Children’s Hospital and decided to try an experimental procedure that had never before been attempted in a human being following a heart attack.

They would take a billion mitochondria — the energy factories found in every cell in the body — from a small plug of Georgia’s healthy muscle and infuse them into the injured muscle of her heart.

Mitochondria are tiny organelles that fuel the operation of the cell, and they are among the first parts of the cell to die when it is deprived of oxygen-rich blood. Once they are lost, the cell itself dies.

But a series of experiments has found that fresh mitochondria can revive flagging cells and enable them to quickly recover.

In animal studies at Boston Children’s Hospital and elsewhere, mitochondrial transplants revived heart muscle that was stunned from a heart attack but not yet dead, and revived injured lungs and kidneys.

Infusions of mitochondria also prolonged the time organs could be stored before they were used for transplants, and even ameliorated brain damage that occurred soon after a stroke.

In the only human tests, mitochondrial transplants appear to revive and restore heart muscle in infants that was injured in operations to repair congenital heart defects.

For Georgia, though, the transplant was a long shot — a heart attack is different from a temporary loss of blood during an operation, and the prognosis is stark. There is only a short time between the onset of a heart attack and the development of scar tissue where once there were living muscle cells.

The problem was that no one knew when the baby’s heart attack had occurred. Still, said Dr. Sitaram Emani, a pediatric heart surgeon who administered the transplant, there was little risk to the infant and a chance, though slim, that some cells affected by her heart attack might still be salvageable.

“They gave her a fighting chance,” said the infant’s mother, Kate Bowen, 36, of Duxbury, Mass.

Image

Dr. Jesse Esch, right, with Brian Quinn, a cardiology fellow, performing a mitochondrial transplant on Georgia Bowen. Angiograms showing the infant’s coronary arteries and the catheter can be seen on the monitor.CreditKatherine Taylor for The New York Times
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Dr. James McCully prepared to inject mitochondria for Georgia Bowen during her operation. Animal experiments have suggested that the procedure may repair damaged tissue.CreditKatherine Taylor for The New York Times

The idea for mitochondrial transplants was born of serendipity, desperation and the lucky meeting of two researchers at two Harvard teaching hospitals — Dr. Emani at Boston Children’s and James McCully at Beth Israel Deaconess Medical Center.

Dr. Emani is a pediatric surgeon. Dr. McCully is a scientist who studies adult hearts. Both were wrestling with the same problem: how to fix hearts that had been deprived of oxygen during surgery or a heart attack.

“If you cut off oxygen for a long time, the heart barely beats,” Dr. McCully said. The cells may survive, but they may never fully recover.

While preparing to give a talk to surgeons, Dr. McCully created electron micrographs of damaged cells. The images turned out to be revelatory: The mitochondria in the damaged heart cells were abnormally small and translucent, instead of a healthy black.

The mitochondria were damaged — and nothing Dr. McCully tried revived them. One day, he decided simply to pull some mitochondria from healthy cells and inject them into the injured cells.

Working with pigs, he took a plug of abdominal muscle the size of a pencil eraser, whirled it in a blender to break the cells apart, added some enzymes to dissolve cell proteins, and spun the mix in a centrifuge to isolate the mitochondria.

He recovered between 10 billion and 30 billion mitochondria, and injected one billion directly into the injured heart cells. To his surprise, the mitochondria moved like magnets to the proper places in the cells and began supplying energy. The pig hearts recovered.

Image
Dr. Sitaram Emani of Boston Children’s Hospital and his colleagues have treated 11 babies with mitochondrial transplants, most of them successfully.CreditKatherine Taylor for The New York Times

Meanwhile, Dr. Emani was struggling with the same heart injuries in his work with babies.

Many of his patients are newborns who need surgery to fix life-threatening heart defects. Sometimes during or after such an operation, a tiny blood vessel gets kinked or blocked.

The heart still functions, but the cells that were deprived of oxygen beat slowly and feebly.

He can hook the baby up to a machine like the one that kept Georgia Bowen alive, an extracorporeal membrane oxygenator, or Ecmo. But that is a stopgap measure that can work for only two weeks. Half of the babies with coronary artery problems who end up on an Ecmo machine die because their hearts cannot recover.

But one day Dr. Emani was told of Dr. McCully’s work, and the two researchers met. “It was almost an ‘aha’ moment,” Dr. Emani said.

Dr. McCully moved to Boston Children’s, and he and Dr. Emani prepared to see if the new technique might help tiny babies who were the sickest of the sick — those surviving on Ecmo.

It was not long before they had their first patient.

Early one Saturday morning in March 2015, the hospital got a call from a hospital in Maine. Doctors there wanted to transfer to Boston Children’s a newborn baby boy whose heart had been deprived of oxygen during surgery to fix a congenital defect.

The baby was on an Ecmo but his heart had not recovered.

“We turned the intensive care unit into an operating room,” Dr. Emani said.

He snipped a tiny piece of muscle from the baby’s abdomen. Dr. McCully grabbed it and raced down the hall.

Twenty minutes later, he was back with a test tube of the precious mitochondria. Dr. Emani used an echocardiogram to determine where to inject them.

“The spot that is weakest is where we want to go,” he said. “It is important to give as much of a boost as you can.”

Image

Dr. McCully placed mitochondria from Georgia Bowen’s neck muscle into a centrifuge before infusing them into her heart muscle.CreditKatherine Taylor for The New York Times
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Dr. Emani taking tissue samples from Georgia’s neck.CreditKatherine Taylor for The New York Times

He injected a billion mitochondria, in about a quarter of a teaspoon of fluid.

Within two days, the baby had a normal heart, strong and beating quickly. “It was amazing,” Dr. Emani said.

The scientists have now treated 11 babies with mitochondria, and all but one were able to come off Ecmo, Dr. Emani said. Still, three of them ultimately died, which Dr. Emani attributes to a delay in treatment and other causes.

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Dr. Esch prepared the mitochondria to be infused into Georgia’s heart. The fluid amounts to a quarter of a teaspoon.CreditKatherine Taylor for The New York Times

Two died because their hearts were still so damaged, and one died of an infection. All of the more recent patients survived and are doing well.

In comparison, the death rate among a similar group of babies that did not get mitochondrial transplants was 65 percent. And none of the untreated babies recovered any of their heart function — more than a third of the survivors ended up on heart transplant lists.

More recently, Dr. Emani and his colleagues have discovered that they can infuse mitochondria into a blood vessel feeding the heart, instead of directly into the damaged muscle. Somehow the organelles will gravitate almost magically to the injured cells that need them and take up residence.

He and his colleagues are persuaded that these transplants work, but acknowledge that it would take a randomized trial to prove it.

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Photos and get-well wishes in the hospital room where Georgia is recovering.CreditKatherine Taylor for The New York Times
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From left, Kendal, Scarlett, Kate, Ryan and Jack Bowen on a recent visit to Georgia in the I.C.U. She was put on a list for a heart transplant.CreditKatherine Taylor for The New York Times

The main problem is a scarcity of patients. Even if every pediatric center in the United States participated, along with every infant with injured heart muscle, it still would be hard to enroll enough participants in the trial.

But what about adult heart patients? Researchers are hoping that mitochondrial transplants also can repair heart muscle damaged during heart attacks in adults. And finding enough of those patients should not be an issue, said Dr. Peter Smith, chief of cardiothoracic surgery at Duke University.

Already researchers are planning such a trial. The plan is to infuse mitochondria or a placebo solution into the coronary arteries of people having bypass surgery or — an even more dire situation for the heart — having both bypass and valve surgery.

The patients would be those whose hearts are so damaged that it would be difficult to wean them from heart-lung machines after surgery. For these desperate patients, mitochondrial transplants “are a really intriguing option,” Dr. Smith said.

“The likelihood is very high” that the study will begin next year, said Annetine Gelijns, a biostatistician at Mount Sinai Medical Center in New York.

For Georgia Bowen, the procedure came too late: The portion of her heart muscle affected by the heart attack had died. Her doctors implanted a device that takes over the heart’s pumping, and hope her heart will recover enough for them to remove the device.

But, to be safe, they put her on a list for a heart transplant. She seems to be improving, though — she is breathing on her own and can drink breast milk through a tube. Her heart is showing signs of healing.

“Georgia is a miracle who continues to fight daily and persevere through the obstacles she is dealt,” Ms. Bowen said.

“In our hearts, we know she will pull through this and come home.”

 

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