Last fall, the New York-based reproductive endocrinologist John Zhang made headlines when he reported the birth of the world’s first “three-parent” baby — a healthy boy carrying the blended DNA of the birth mother, her husband and an unrelated female donor.

The technique, called mitochondrial replacement therapy, allowed the 36-year-old mother to bypass a defect in her own genome that had led, twice before, to children born with Leigh syndrome, a devastating neurological disorder that typically culminates in death before age 3.

While heralded in many circles as a breakthrough, the news triggered numerous ethical and scientific questions, many of which remained unanswered at the time. Last week, Zhang and his colleagues at the New Hope Fertility Center provided some answers — and raised yet more concerns.

Their new report, published in the journal Reproductive BioMedicine Online, describes both the technique and the participants in greater detail, something that fellow researchers had demanded in order to properly scrutinize Zhang’s methodology.

But in publishing the new material, the journal editors themselves also noted that Zhang’s report still contains “weaknesses and limitations in a number of areas,” including lingering questions about informed consent, the full risks of mitochondrial replacement therapy and the long-term health of the child.

“Although we were able to encourage the authors to include more details of their work in the submission,” journal editor and clinical embryologist Mina Alikani noted in an accompanying editorial co-written with her colleagues, “some uncertainties concerning methodologies and results still remain.”

In a statement provided by the New Hope facility, Zhang conceded that more work needs to be done. “There is always concern about any new procedure and innovation implemented on humans,” Zhang said. “We agree that there are still a lot of unknowns about this technique and will make every effort to monitor the boy’s ongoing progress and test for any adverse outcomes.”

A key weakness in Zhang’s work, according to critics, is that the procedure is not approved in the United States, which forced the team to undertake the procedure in Mexico. “This particular experiment is being done almost entirely outside the normal regulatory structure,” says bioethicist and pediatrician Jeffrey Botkin of the University of Utah, who participated in an Institute of Medicine committee last year that issued a call for more animal research on mitochondrial replacement therapy.

Without proper oversight, Botkin says, vital questions about the technique, as well as the impact of such experiments on resulting embryos, remain difficult to answer.

As it stands, Congress last year prohibited the Food and Drug Administration from considering applications for research in this area, but in December the U.K.’s Human Fertilization and Embryology Authority agreed to let clinics apply to try the procedure on a case-by-case basis. In March, it granted a license to carry out the first procedure to Doug Turnbull, director of the Wellcome Trust Center for Mitochondrial Research at Newcastle University.

“We’re going to look to those in Britain,” Botkin says, “to do careful trials and help us better understand how this technique works.”

In broadest terms, Zhang and his colleagues lifted the nucleus out of the egg of the original mother, leaving behind most — though not all — of her defective mitochondria, which would have led to the almost certain development of Leigh syndrome in the fetus. They then placed that nucleus inside a healthy donor woman’s egg, whose own nucleus had been removed. The result was a hybrid egg with the original mother’s nuclear genes and the donor mother’s cytoplasm and mitochondria. The hybrid egg was fertilized by the father’s sperm and implanted in the birth mother.

The technique could potentially prevent a wide range of mitochondrial diseases, ranging from hereditary blindness to progressive muscle wasting.

A key problem, however, is that not all of the defective mitochondria can be eliminated. The boy, Zhang reports in the new paper, currently carries between 2.36 and 9.23 percent of potentially defective DNA, according to sampling of his urine, hair follicles and circumcised foreskin.

“That’s not surprising,” says Doug Wallace, head of the Center for Mitochondrial and Epigenomic Medicine at the Children’s Hospital of Philadelphia, who was not involved in the study. “As far as I know, very few cases have been found where there is absolutely no carryover of mitochondria from the donor nucleus.”

Even at a 9 percent load of defective DNA, Wallace said, most people with Leigh Syndrome will appear normal. He added that while it is unlikely, levels could be higher in the boy’s other tissues, such as the brain or heart.

Zhang and his team report that physical examination of the boy has included detailed neurological investigation at regular waypoints, including at two weeks, four weeks, two months, three months and four months. All have proved normal, Zhang said, and the boy is still under close monitoring with “a long-term follow-up plan.”

Just what such a long-term plan might look like, however, is uncertain — particularly given that the parents have publicly said that they do not plan to have the boy regularly tested throughout his life to monitor levels of the errant DNA. University of California molecular biologist Patrick O’Farrell, who was not involved in the Zhang study, suggested that this was worrying, given that there could a rising load of mutations as the boy ages.

In this case, a total five eggs underwent the transfer and were fertilized, Zhang and his team reported. The embryo that was ultimately implanted carried about a 5 percent load of the defective DNA, but the researchers did not examine how much defective DNA was carried over in the embryos that were not used.

The remaining fertilized eggs are still available, says Zhang, but he has not tested them to see how much defective DNA each contains. Should the parents decide they’d like to have another baby, Zhang said he would test the others.

Still, without readily accessible data on the transfer of defective DNA in all of the fertilized eggs, O’Farrell argues that important insights are being overlooked. A three-parent baby, he said, offers the rare chance to study the “segregation and transmission of mitochondrial genomes.”

In a telephone interview, Zhang emphasized that analyses are ongoing. “This is new ground, so there are many questions to ask and more studies to come,” Zhang said. “With new tests in new studies, we will continue to learn more.”

For all of the lingering questions, Zhang’s groundbreaking research has sparked a flurry of similar research elsewhere. The editors of the journal carrying his new report credit Zhang with helping to nudge “cautious use” of mitochondrial replacement therapy in the U.K. Meanwhile, the fertility specialist Valery Zukin has used the three-parent technique in the Ukraine to help two infertile women who suffer from a syndrome known as embryo arrest, where their fertilized eggs stop growing before they can be implanted in the uterus.

Both women gave birth to apparently healthy babies this year.

Such news will surely be welcomed by desperate parents looking for new ways to conceive, but experts like O’Farrell continue to worry that the procedure is being deployed too quickly, and with too many question unanswered.

“I feel like extending this work into infertility cases is dangerous,” O’Farrell says. “For every gene that compromises fertility, we need to know whether it also is going to affect later aspects of development.

“If you only rescue fertility,” he adds, “the other defects that gene might cause will still be there.”

Jill Neimark is an award-winning science journalist and an author of adult and children’s books. Her most recent book is The Hugging Tree: A Story About Resilience.

A version of this articleoriginally appeared at Undark, a digital science magazine published by the Knight Science Journalism Fellowship Program at MIT.

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The U.S. Food and Drug Administration approved 23andMe’s personal genetic test for some diseases on Thursday, including Alzheimer’s, Parkinson’s and celiac diseases.

The tests assess genetic risk for the conditions but don’t diagnose them, the FDA says. The agency urges consumers to use their results to “help to make decisions about lifestyle choices or to inform discussions with a health care professional,” according to a press release about the decision.

Jeffrey Shuren, the director of the FDA’s Center for Devices and Radiological Health, wrote, “it is important that people understand that genetic risk is just one piece of the bigger puzzle, it does not mean they will or won’t ultimately develop a disease.” Other known factors that can play into the development of disease include diet, environment and tobacco use.

The FDA has previously scolded the company for marketing the personal genetic testing kits without the agency’s consent. In 2013, the agency told 23andMe to stop selling its personal genome kits in the United States until they gained FDA approval by proving they were accurate.

The company agreed to work with the FDA, as we reported, and a recent FDA review of peer-reviewed studies found more consistent links between certain gene variants and 10 diseases, the FDA says.

As a result, the FDA is now allowing 23andMe to market tests that assess genetic risks for the following 10 diseases or conditions:

• Parkinson’s disease, a nervous system disorder impacting movement

• Late-onset Alzheimer’s disease, a progressive brain disorder that destroys memory and thinking skills

• Celiac disease, a disorder resulting in the inability to digest gluten

• Alpha-1 antitrypsin deficiency, a disorder that raises the risk of lung and liver disease

• Early-onset primary dystonia, a movement disorder involving involuntary muscle contractions and other uncontrolled movements

• Factor XI deficiency, a blood clotting disorder

• Gaucher disease type 1, an organ and tissue disorder

• Glucose-6-phosphate dehydrogenase deficiency, also known as G6PD, a red blood cell condition

• Hereditary hemochromatosis, an iron overload disorder

• Hereditary thrombophilia, a blood clot disorder

The company’s $199 Health and Ancestry test is available directly to consumers, without seeing a physician or genetic counselor. Consumers’ DNA is extracted from a saliva sample. After mailing in their sample, people can see their results online.

“This is an important moment for people who want to know their genetic health risks and be more proactive about their health,” said Anne Wojcicki, the CEO and co-founder of 23andMe, in a company press release.

Sharon Terry, the CEO of the Genetic Alliance, a nonprofit organization that advocates for health care for people with genetic disorders, likens it to another consumer test. “Women learn they are pregnant using a test directly marketed to them and buy it off the shelf in a drugstore,” she told NPR. “In 10 years we will marvel that this is an ‘advance’ at all. Imagine pregnancy tests being only available through a doctor!”

Robert Green, a professor of medicine at Harvard Medical School, says people should be able to access genetic information in whatever way is best for them. “Some people really want this [genetic] information on their own, and others want it through their physician,” he said. “Both those channels are legitimate. People should just be aware that this information is complicated.”

But some are stillconcerned about whether the genes in question actually correspond to a higher risk of disease reliably enough to warrant direct-to-consumer marketing and testing, as opposed to genetic testing with the guidance of a professional.

Somehealth professionals worry that consumers will “take the results and run,” as Mary Freivogel put it. Freivogel, a certified genetic counselor and the president of the National Society of Genetic Counselors, added that genetics are just “one piece to the story when it comes to developing a disease.”

Freivogel said speaking with a genetic counselor before getting tested for disease is important. “Direct-to-consumer testing takes away a pre-test conversation,” she said, where counselors can help patients think about questions like: “What do you want to know? What are you going to do with this information? Is it something you’re prepared to know, or is it going to just make you anxious?”

And it isn’t clear what consumers should do with their newly calculated disease risk, especially for conditions like Alzheimer’s for which there isn’t a cure or even a course of action to prevent the disease.

What’s more, having the genes is not the same as having the diseases the genes are associated with. A person may have genes that are associated with Alzheimer’s, for example, but that doesn’t mean he or she will ever get the disease. Conversely, some people develop Alzheimer’s without the identified risk genes.

The Alzheimer’s Association does not recommend routine genetic testing for the disease in the general population because it can’t “productively guide medical treatment.”

A genetic test result for Alzheimer’s is “not going to provide useful information even if you’re at an increased risk,” said Keith Fargo, director of scientific programs at the Alzheimer’s Association. “It’s not like there’s a drug you can take right now [to prevent the disease] or a lifestyle change you can make that you shouldn’t make anyway,” such as exercising and eating right to keep your brain healthy.

John Lehr, the CEO of the Parkinson’s Foundation, says personal genetic tests can help identify risk for Parkinson’s disease. But, he wrote in a statement following the FDA’s announcement, the foundation recommends “that people who are interested in testing first seek guidance from their doctors and from genetic counselors to understand what the process may mean for them and their families.”

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There’s a clear culprit in the rising drug overdose death count in Massachusetts, but it’s not heroin. It’s the synthetic opioid fentanyl.

Seventy-five percent of the state’s men and women who died after an unintentional overdose last year had fentanyl in their system, up from 57 percent in 2015. It’s a pattern cities and towns are seeing across the state and across the country, particularly in New England and the Rust Belt states.

Fentanyl may be especially lethal because it’s strong, it’s mixed with other drugs in varying amounts unknown to the user, and it can trigger an overdose within seconds. “It happens so fast, like instantly, as soon as you do the shot,” says Allyson, a 37-year-old woman who started using heroin in her late teens.

“In the past, it [an overdose] was something that you saw happening, like, you could see the person start to slow down, their color would start to turn blue, and then they would go out, within 10 minutes or so,” Allyson says. With fentanyl, there’s no progression. “Now it’s instant,” she says.

Allyson leans back in a chair at the AAC Needle Exchange in Cambridge, Mass., and tugs the hood of her gray sweatshirt down to her eyes. We’ve agreed not to use her full name or the full names of any people in this story who buy illegal drugs, so as not to harm their future job prospects.

Allyson is a regular client at the needle exchange, where manager Meghan Hynes urges everyone to carry naloxone, the drug that reverses an overdose. Hynes uses her own kit every few weeks.

“Recently we had a guy leave the bathroom and all the color just drained from his face, like immediately, and he just turned blue,” Hynes says, describing what’s become a typical fentanyl overdose. “I’ve never seen anyone turn blue that fast. He was completely blue and he just fell down and was out — not breathing.”

Hynes bent over the man turning blue to pump his heart, but she couldn’t. He was hit with “wooden chest,” a side effect of fentanyl that may be increasing the death toll.

“Your chest seizes up. You literally have paralysis and that’s obviously really dangerous, because if someone needs CPR, you can’t do it,” Hynes says. “And in this situation it spread, so he had lockjaw and his mouth was only open a tiny, tiny bit. And so I could hardly even do rescue breathing for him.”

Breathing for overdose patients is critical because brain cells can die after just five minutes without oxygen. Hynes revived the man on the floor. Because of the increasing overdoses she sees with fentanyl in the mix, she urges clients to stick to a dealer they know, and use with a buddy.

Many drug users also inject a small amount before they give themselves the full shot.

“But it’s really hard to tell these days, even if you do a tester shot,” Allyson says, because the grains of fentanyl that could kill you aren’t mixed uniformly in a bag. That’s a lesson she learned one death-defying night a few months ago.

Allyson, who is homeless, spent the night in a tent with a friend. She woke up and used the last of a bag from the day before to get herself going.

“And I actually said to my friend, I said, ‘Wow, I can’t believe I only saved myself this much.’ It was a very small amount, like a third of what I did the night before,” Allyson says, shaking her head. “I overdosed on it.”

The friend had enough naloxone in the tent, which was far from a road or hospital, to bring Allyson back from the dead.

Fentanyl is an opioid 50 times more powerful than heroin. There’s a legal, Food and Drug Administration-approved version. But labs in China are churning out cheap versions of fentanyl that dealers are selling on the streets mixed with fillers, heroin or other drugs.

Buyers have no idea how much fentanyl they are getting or how much risk they are taking with every injection. So, these days, drug users who frequent this needle exchange assume there’s fentanyl in every bag they buy.

“Most of us know that that’s what we’re getting,” says Sean, who started using heroin more than 20 years ago. “And if you don’t believe it, you’re living in a fairy tale world.”

There’s no reliable way for drug users to test the contents of bags bought on the street. Eddie relies on taste.

“It’s slightly bitter, but it’s mainly sweet if it’s fentanyl. If it’s heroin, you can tell right away because it’s got a bitter taste and it’s a long-lasting aftertaste,” Eddie says. “I will not put anything in my arm before I taste it.”

Eddie and Allyson say they try to avoid fentanyl. But when their last dose of drugs starts to wear off, they’ll take anything to avoid withdrawal, which they describe as the flu on steroids with fever, vomiting, diarrhea and high anxiety.

“It literally feels like your skin is crawling off. You’re sweating profusely,” Allyson says. “Your nose is running, your eyes are running. And that’s all you can focus on. You can’t think.”

Some drug users seek fentanyl because it’s a more immediate rush and intense high. But Allyson doesn’t like it. She says a fentanyl high fades much more quickly than heroin’s, which means she has to find more money to buy more drugs and inject more often, which leads to more risk.

When fentanyl fades, she and Eddie say, they are more likely to take other drugs. “You’re getting a fast rush but it doesn’t last, so people are mixing,” Allyson says.

At 37, Allyson is having experiences most Americans don’t face until much later in life. “As of two days ago, 30 people that I know have passed away. Basically my entire generation is gone in one year,” Allyson says. “It’s the fentanyl, definitely the fentanyl.”

Older drug users who have been through other epidemics say this moment with fentanyl is the worst they’ve seen. A man named Shug twists a towel in his hands.

“Addicts are dying, like, every day. It’s crazy, man,” Shug says, his eyes filling with tears. “Nobody seems to give a damn.”

Shug is grateful for the needle exchange, which hasn’t lost anyone to an overdose. But on the streets outside, the death toll keeps rising.

This story is part of a reporting partnership with NPR, WBUR and Kaiser Health News.

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