Dear Aventine Readers, 

This week we look at some astonishing news that likely flew under the radar: A new fertility technique can correct certain genetic disorders by replacing a mother’s mitochondria with a donor’s, resulting — for the first time —  in children with DNA from three parents.  It’s a new, rare and controversial procedure. Could it pave the way for further fertility interventions, à la designer babies?  Would donor eggs be a better option?  

US researchers paved the way for the first child born with this technique — in Mexico — but the practice is now effectively banned on US soil.  We speak to five researchers about the promises and challenges of a procedure that could prevent disorders that affect about 1 in 5,000 people globally. 

Also in this issue: 

Sincerely, 

Danielle Mattoon 
Executive Director, Aventine

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Eight children born over the last three years in the UK appear headed for healthy lives, despite having been at risk of inheriting severe genetic disorders. They owe it to a groundbreaking but controversial reproductive technique known as mitochondrial donation, also referred to as three-parent IVF because the child inherits DNA from three people. 

The intervention has primarily been developed to enable mothers who carry mutations in the DNA of their mitochondria — the tiny powerhouses that provide cells with energy — to have children who are genetically related to them but not at risk of developing mitochondrial disease. The disorders — which include Leigh syndrome, a severe neurological disease, and Kearns–Sayre syndrome, which affects eyesight and muscle function — are inherited maternally, because mitochondria come almost exclusively from the egg cell. It is estimated that 1 in 5,000 people globally has a mitochondrial disease, though the range and severity of symptoms can vary, making it difficult to get precise numbers. The mothers seeking treatment all have known mitochondrial diseases.  

The technique preserves the DNA of the mother and father in the nucleus of the embryo while replacing faulty mitochondria with those from a donor. Mitochondria, found in the cytoplasm of cells, contain only 37 genes compared to over 20,000 that are found in the nucleus, so while it’s certainly groundbreaking for a baby to be born with DNA from three people, only about 0.1 percent of the DNA comes from the donor.

Those affected by mitochondrial disorders have, understandably, embraced the approach. But the procedure also has its critics, who argue that it could put us on a slippery slope toward designer babies. Some people contend that mothers at risk of passing on faulty mitochondrial DNA could avoid such a fate by using donor eggs as part of regular IVF.

The pioneering technique has its roots in basic science conducted in 1983 which used experiments on mice to try to determine the role maternal and paternal genomes play in the development of early-stage embryos. The transition to humans — with the hope of tackling mitochondrial disease — started in the mid-2000s, led by research teams at Newcastle University in the UK, Oregon Health & Science University and New Hope Fertility Center in New York.

There are currently two approaches being used. One, practiced by the team in Newcastle, is known as pronuclear transfer. The just-fertilized core of an egg, containing genetic information from both parents, is extracted from the cell with the intent of  leaving behind as much of the mother's defective mitochondria as possible. It is then placed into a donor egg cell, which contains healthy mitochondria. Another approach, used by both American teams, is known as spindle transfer. The nuclear chromosomes, known as a spindle, are removed from a mother’s egg — again with the intention of leaving behind the faulty mitochondria — and transplanted into a donor egg whose own spindle has been removed. The hybrid egg is then fertilized with the father’s sperm. Experts told Aventine that there is no clear best approach, in part because there is not yet enough data about how successful either method is. Experts told Aventine that neither approach would represent a dramatic cost increase compared to regular IVF.

Access to the procedure is limited and varies by country. Though the first child born using the technique was under the care of US researchers from New Hope Fertility Center who carried out the procedure in Mexico in 2016, the approach is effectively banned in the US now, thanks to a rider included in the 2016 Congressional Appropriations Act. The UK was the first country to regulate mitochondrial donation in 2015 and since then a single UK clinic, the Newcastle Fertility Centre has been licensed to perform the procedure. In other countries where the procedure is carried out, such as Mexico and Greece, there is no specific legal framework regulating the practice. Mitochondrial donation has also been used in Greece as a means of addressing infertility, but experts told Aventine that there is limited evidence to suggest such an approach is effective. 

The story and science behind the eight healthy children born in the UK, described recently in The New England Journal of Medicine, reveals potential for the procedure and highlights the challenges that remain.  A total of 22 women underwent mitochondrial replacement IVF at the Newcastle facility, which led to the eight births and one ongoing pregnancy. (The chances of success are roughly in line with regular IVF success rates.) All the children are developing normally, though three had minor early health problems that have since cleared. The procedure doesn’t yet guarantee that children born using the approach will be free of mitochondrial disease, but rather promises greatly reduced probability of it being passed on.

Getting this far has been challenging, according to Mary Herbert, professor of reproductive biology at both Newcastle University, UK, and Monash University, Australia, and a co-author of the recent New England Journal of Medicine studies. Securing regulatory approval and sourcing eggs that had to be donated specifically for research in the early years of the research was difficult, as was the development of the technical procedures required to do the work.

Currently the most significant technical challenge facing the procedure is that, regardless of which method is used, it’s almost impossible to avoid carrying some of the mother’s defective mitochondria into the donor egg. Among the eight children in the Newcastle research, five had no or very low carryover of the mother’s mitochondria. But in the remaining three cases, between 5 percent and 16 percent of the mitochondrial DNA was from the mother. This is further complicated because the percentage can diminish or grow over time and vary across different parts of the body. In some preclinical studies a mother’s mitochondrial DNA was observed to become dominant — a process called reversion that is currently poorly understood. Given that the amount of defective mitochondria can change over time, careful long-term monitoring of the eight children is critical, said Paula Amato, professor of obstetrics and gynecology at Oregon Health & Science University.

As with any new approach, it is unproven, and therefore carries a degree of risk. There are also questions about when exactly the technique should be used. In some mitochondrial disorders, called homoplasmic disorders, mothers are guaranteed to pass their faulty mitochondrial DNA on to a child. But in the majority of conditions, known as heteroplasmic disorders, there is only a chance that the faulty DNA will be transferred. In the second scenario, pre-implantation genetic testing (PGT) — in which the DNA of a fertilized embryo from a mother and father is sequenced to detect abnormalities — could be used to determine which embryos have healthy mitochondria and can be safely implanted. 

To understand where mitochondrial donation stands today, and where it might go next, Aventine spoke with five leading researchers whose perspectives describe a nuanced future for this new frontier in reproductive medicine.

A pig lung has been transplanted into a human for the first time. Surgeons in China replaced the left lung of a brain-dead patient with one taken from a genetically engineered pig, according to research published in Nature Medicine. In the experiment, the donor pig had been modified to block the production of immune-triggering sugars and to produce human proteins that regulate inflammation. Doctors replaced the left lung of the patient with a trimmed-down counterpart taken from the animal, and also administered powerful immunosuppressive drugs. The lung functioned as hoped initially, but swelling began after 24 hours and after three days the patient’s antibodies began attacking the new organ. The family of the patient requested removal of the pig lung on day nine. Lungs are among the hardest organs to transplant, even between humans: They are delicate, saturated with blood and vulnerable to infection from the air they contain. That makes the survival of a pig lung inside a human chest — even temporarily — a milestone. The procedure underscores how quickly animal-to-human organ transplants, or xenotransplantation, are moving toward medical reality. Kidneys, hearts, livers and now lungs from engineered pigs have been shown to function in people. One patient has been living with a kidney transplanted from a pig for more than six months, a xenotransplantation record. The question for researchers is increasingly not whether such transplants are possible, but how long it will be until they are able to reliably save lives.

Nuclear batteries are making a comeback. It seems implausible now, but in the 1970s and ’80s, some pacemakers were nuclear powered, sustained by the energy created from the decay of radioactive isotopes. The devices themselves were safe, but their disposal wasn’t: When removed, the devices were supposed to be returned to the government so that the radioactive material could be safely recovered, but hospitals couldn’t reliably track where old units went. Outside of esoteric applications such as deep-space probes and Siberian lighthouses, the technology faded into obscurity. That may now be changing. As IEEE Spectrum reports, a wave of startups and government labs are revisiting the idea of nuclear batteries. Unlike nuclear reactors, these devices don’t split atoms; they harvest energy released as radioactive decay and convert that into electricity. The result is batteries that provide modest quantities of power but last for decades without the need for recharging. China’s Beijing Betavolt New Energy Technology says it will soon introduce a 1-watt device. In the UK, the Atomic Energy Authority and the University of Bristol have demonstrated a carbon-14 battery that could, in theory, run for millennia. Research groups in South Korea and across the US, from Miami to San Diego,  are pursuing similar designs. The catch is much the same as the one that tripped up the technology the first time: stewardship. Nuclear batteries must be tracked, accounted for and disposed of properly, a logistical burden few consumers or companies want to take on. Still, startups imagine their batteries being used in medical implants, wearables, drones, deep-sea sensors, spacecraft and even luxury watches. The question is whether this generation will embrace what the 1980s rejected: a battery that can outlive its owner, and the logistical headaches that come with it.

We may be on the verge of solving peanut allergies. In the US, the prevalence of peanut allergies among children has almost quadrupled in recent decades, from 0.6 percent in 1997 to 2.2 percent in 2016. The causes aren’t fully understood — it may result from cleaner modern environments, earlier antibiotic use, or microbiome disruption from cleaning products — but researchers are making progress on treatment and prevention, according to Scientific American. One approach, oral or patch-based immunotherapy, exposes children to tiny, controlled doses of peanut protein. Clinical trials show this can desensitize patients enough to safely tolerate one or two peanuts, enough to prevent emergencies. Drugs that block or destroy allergy-triggering antibodies offer another path, as do more experimental ideas, including mRNA-based “vaccines ” that aim to reprogram the immune system altogether. For children with mild reactions, gradual exposure over time has also been shown to raise the threshold for allergic responses. But perhaps the most powerful breakthrough lies in prevention. A landmark study published in 2015 showed that only 1.9 percent of children who were introduced to peanuts early developed an allergy, compared with 13.7 percent of those told to avoid them until age five. A follow-up study published last year showed that the protective effect persists for years. Turning that finding into clinical practice, however, will take time. While allergists increasingly recognize early exposure as best practice, widespread adoption is yet to follow. If it does become standard, peanut allergy — a condition that has terrified parents for decades — could become far less common within a generation.

Beyond AlphaFold: how AI is decoding the grammar of the genome, from Nature
2,400 words, or about 9 minutes

Just as AI models can be trained on all the world’s text, they can also be trained on the vast quantities of data stored in DNA. And there’s a lot to go at, because genomes are enormously complex: While we know and understand some short stretches that, say, encode essential proteins, other long strings appear purposeless or reveal their function only under rare conditions. To make things harder to understand, useful DNA strings can overlap or interact with each other across long distances on the DNA chain. Two new kinds of AI are helping make sense of this complexity. Trained on massive amounts of DNA data, they can either predict the function of sequences they’ve never seen before or synthesize missing or corrupted stretches of DNA based on context from the surrounding string. The possibilities could be significant for medicine and synthetic biology: Some researchers imagine a future in which scientists can simply prompt an AI to design a new DNA sequence that performs a desired function inside a cell.

Would You Eat This Bug To Save the World?, from Noema
2,500 words, or about 10 minutes

Eating insects as a climate-friendly alternative to meat isn't a new idea. They’re high in protein, plentiful and have a much smaller carbon footprint than beef or pork. But scaling that idea faces a big hurdle: In much of the West, the thought of eating bugs is objectionable. This story takes a trip to Thailand to explore how entrepreneurs and researchers are experimenting with new ways to overcome that aversion by reimagining insect proteins as part of everyday foods. How about ice cream made out of silkworms? Or soy sauce created from fermented crickets? Given that gummy bears are made from boiled animal carcasses and Worcestershire sauce is made from fermented fish, it shouldn’t be too much of a stretch. The hope is that by incorporating insect proteins into recognizable foods, food manufacturers could reduce the “ick” factor while shrinking their carbon footprints.

Inside the revolutionary idea that we can negotiate with cancer, from New Scientist
2,700 words, or about 11 minutes

Cancer cells grow and spread aggressively, overrunning organs and seeding new tumors. For decades, treatment has focused on a simple, even rudimentary, goal: Kill or remove every last cancer cell. But researchers are exploring an alternative, in which cancer cells are persuaded to reprogram themselves into harmless forms. The idea isn’t entirely new. Since the 1980s, a therapy based on a vitamin A derivative has helped coax certain leukemia cells into becoming normal white blood cells. But attempts to extend this so-called differentiation therapy to other cancers have mostly failed. Now, a growing body of research suggests it may be possible. In mice, molecules designed to push cancer cells toward safer states tripled survival time compared with animals treated with radiation alone. This story traces the progress of this technique from hints in the 1950s that malignant cells could turn benign to newly supercharged research that uses computational biology to help identify molecules capable of rewiring cell behavior. Differentiation therapy is unlikely to become a stand-alone cure, but it could become a powerful additional weapon in neutralizing cancer.

A novel agreement expected to be signed this week between the United States and Britain may do what concerns over climate change failed to do: kickstart the construction of new nuclear power plants in both countries.

The unusual deal, called the Atlantic Partnership for Advanced Nuclear Energy, would allow the countries to cooperate on regulatory approval so that if a reactor design passed safety checks in one country, it would be approved in the other country as well. 

The hope is that cooperation will reduce the regulatory burden, shaving time and significant expense from the construction of new plants. As part of the partnership, several US companies, including X-Energy and TerraPower, will help build a generation of small modular reactors (SMRs) in Britain.

Given nuclear power’s long and controversial history in both countries, our 2024 interview with Richard Rhodes is newly relevant. He is the author of “Energy” and the Pulitzer Prize-winning “The Making of the Atomic Bomb.” He spoke to us for our podcast, “The World as You’ll Know It: The Great Rebuild.”

Rhodes, the greatest living historian of the nuclear age, describes his evolution from a nuclear skeptic to a believer, thanks to his proximity to the scientists building the technology. “I realized that if I believed them about anything, I was going to have to believe them about that,” he says in the interview. He also discusses how haphazard design, massive cost overruns and a robust antinuclear movement doomed a nascent nuclear industry in the US and much of the West: “It was a great time of confusion and mistakes and, and I guess it probably culminated, if one likes to think of it this way, in the accident at Three Mile Island in 1979.” 

If the agreement between the US and UK goes forward, it could mark the beginning of a second wave of nuclear power as countries scramble to meet energy needs.  

You can listen to the episode on our site or wherever you get your podcasts, such as Apple or Spotify. You can read the show notes and transcript here.