Part the First: If You Stretch Biomedical Science Too Far It Breaks, Every Time. Gene editing using CRISPR technology has made possible great leaps in biomedical science, and Emanuelle Charpentier and Jennifer Doudna were rightly awarded a Nobel Prize in Chemistry for it in 2020. The prospects for CRISPR in therapy for tractable genetic diseases are unlimited. But it must be used with great care and good sense. Then there is this: Once again, a child dies in gene-editing trial in China, rekindling debate on transparency and safety (HuidaGene, under loosened oversight, was testing CRISPR therapy in a boy with muscular dystrophy).
Last year, a little-known Chinese startup took center stage at the American Society for Gene and Cell Therapy annual convention in New Orleans.
Speaking before a sprawling conference hall for the presidential symposium, HuidaGene CEO Alvin Luk presented data from one of the world’s first trials to test if CRISPR gene editing could treat children with Duchenne muscular dystrophy, an intractable, fatal disease. Similar efforts in the U.S. ran aground amid technical challenges, but HuidaGene had surged ahead, using a regulatory pathway that lets Chinese hospitals start studies without oversight from government regulators.
The results, from the first two patients, were not impressive. It wasn’t clear the therapy worked at all. But Luk said the data indicated benefit and the company was about to test a higher dose. Hopefully, that would have far better effects.
Then HuidaGene went dark. For 15 months following that conference, the Shanghai-based company did not issue a single new press release. Luk quietly departed last summer, alongside Chief Technology Officer TJ Cradick, a longtime U.S.-based gene editing executive who had been there less than a year. In February, a listing on a clinical trial registry was updated to announce the study was “complete.”
What happened to the remainder of patients in the study was unclear. But after a monthslong STAT investigation and repeated questions to the company, HuidaGene on Wednesday issued an update.
The study stopped, it said, after a young boy who received the experimental therapy died.
The cause of death was apparently not the therapy itself. Instead, what caused his death was a severe immune response to the dose of the viral vector (AAV, adeno-associated virus) used in the treatment. This has happened before, going all the way back to the death of Jesse Gelsinger in 1999, when gene therapy was in its infancy. Mr. Gelsinger died due to a severe immune response in a proof-of-principle experiment because the dose of the adenovirus vector was too large. This was probably not considered before the experiment. It should have been, though.
This is likely what happened here. But there are other issues to consider in gene therapy. When the first disease genes were being identified, the biomedical community was sure that knowing the gene could and would lead to a cure for the disease. This is true in some cases, where the target tissue can be, well, effectively targeted. Blood stem cells are one concrete target. The liver is another. Both have been successful targets in gene therapy, with the latter providing long-term treatments for Hemophilia A and B (discussed previously here and here). But however it is to be wished for, muscle is a poor target and will remain so for the foreseeable future using current technology. There is simply no efficient mechanism to deliver a functional dystrophin (protein missing in muscular dystrophy) to all skeletal muscle. In the first place, dystrophin is too large for viral vectors, so mini-dystrophin must be used. In the second place, efficient targeting remains a high hurdle.
Thus, gene editing is probably the best chance at an effective intervention (cure is probably impossible). But targeting of skeletal muscle remains a problem until new methods are developed. Should the HuidaGene protocol have been approved? That is for the Chinese to ponder. But spectacular failures like those described here do not reassure the public that scientists have their best interests at heart…something for my distant colleagues at the cutting edge to consider.
Part the Second: The Revenge of Kingdom Plantae. I once read somewhere that a Texan, asked if he wanted a salad to go with his 32-ounce porterhouse steak, replied to his server, “Salad? Are you serious? Salad is what food eats!” While browsing my recent Nature, I found this article interesting, primarily because biology for the simple sake of learning something new about natural history is my favorite kind. Turns out that might not have been the best motivation for a career in science way back when (and it certainly is not now). But some of us persist, and Identification of carnivory in the flowering plant Saxifraga via multidisciplinary evidence (open access) is one of those rabbit hole papers we enjoy. For our purposes, the Abstract will suffice:
The transformation from prey to predator is a striking adaptive innovation shared by all carnivorous plants, which capture and digest diverse animal prey for nutrients (nitrogen, N). Here, we report carnivory in the alpine flowering plant Saxifraga candelabrum (Saxifragaceae; Saxifragales). Field experiments and herbarium surveys reveal that this plant actively attracts and captures insect prey via glandular hairs. Enzymatic analyses further confirm the ability of plants to digest prey, and isotope labelling experiments using ¹⁵N-labelled insects demonstrate the transfer of nitrogen from prey to plant tissues, thus verifying the presence of carnivory. Genomic comparisons reveal a significant genome-wide convergence in genes related to carnivory (e.g., leaf morphogenesis, digestion and nutrition) across six independent origins of carnivory in diverse flowering plant lineages. Our findings provide definitive evidence of carnivory in Saxifraga, addressing Charles Darwin’s long-standing hypothesis that some Saxifraga species may be capable of carnivory, and further suggest that carnivory may be more widespread among angiosperms than previously recognized.
Any current paper that mentions Charles Darwin in the abstract is worth a look. This one is “out there” but interesting nevertheless, to the biology nerd:
Carnivorous plants can obtain nutrients (mainly nitrogen) by actively attracting, capturing, and ultimately digesting a diverse array of small animals, altering to some extent the predator-prey relationship between animals and plants. Understanding how carnivory has independently arisen under physiological and ecological constraints has long fascinated biologists. Carnivory has evolved multiple times in angiosperms, including members of 14 families. Carnivorous plants are mainly placed into five major categories based on their trap type, including the widely recognized pitfall trap in pitcher plants , snap trap in Venus flytraps, sticky flypaper trap in sundews, suction trap in bladderworts, and the eel-trap or lobster-trap in corkscrew plants. Despite their diverse mechanisms for trapping prey, most carnivorous plants share a common functional sequence during prey utilization, encompassing prey attraction, capture, digestion, and subsequent nutrient absorption.
Is there any “use” for science such as this? No one can know and that is the point. Research on limpets will lead to the development of strong adhesives that work underwater. The evolution of carnivory in plants has been “accidental,” with different groups using different methods. Could some of the basic chemistry be useful? Who knows? When I began my career working on sea creatures that glow in the dark, some members of my department laughed at us. Well, they laughed at me but kept their counsel in departmental meetings that included faculty, staff, and students. But as it turned out in the end that we were the only group in that place at that time who did fundamental research on a biochemical process that revolutionized cell biology and resulted in the Nobel Prize in Chemistry in 2008.
So, when we hear that only research that meets the priorities of the current administration will be funded going forward, imagine what will be left unknown using that strategy irritable mental gesture. Actually, that is also the point. These things cannot be imagined, even by the smartest politicians and their minions in the world. Or the smartest scientists, for that matter.
Part the Third: The Neanderthal Muscle Head Gene. This one was also too good to pass up and is perhaps more interesting than plants that get their revenge on animals: Neanderthal growth gene turns modern humans into muscle heads:
Do your biceps turn heads? Do your pecs impress? If so, brawny reader, you may have your Neanderthal ancestry to thank for it. In a study out today in Current Biology, scientists identify a gene variant associated with human growth hormone that probably made our close evolutionary cousins stockier and burlier than modern humans. What’s more, some people today have inherited that variant from a long-ago mixing between the two groups—and they tend to carry more lean muscle mass than those with the standard version of the gene.
The work provides compelling evidence that the gene variant “is pushing human physiology a notch in the direction of the Neanderthal,” says Michael Dannemann, a population geneticist at the University of Tartu who wasn’t involved with the study. Even so, he cautions against reading too much into the results: “It’s not like we are now becoming Neanderthals from one variant.”
Neanderthals and modern humans diverged from a common ancestor some 500,000 years ago. While our lineage continued to evolve in Africa, Neanderthals followed a parallel track in Europe and Asia, eventually going extinct about 40,000 years ago. Their skeletons’ thick, dense bones, large muscle attachment sites, and broad chests and shoulders reveal they were more muscular and robust than humans today. Though researchers have pored over Neanderthals’ ancient DNA for more than 15 years, the genes responsible for this robustness have proved elusive.
Studying the shortlist of genetic differences between modern humans and Neanderthals, evolutionary anthropologist Hugo Zeberg at the Karolinska Institute noticed that one of these variants regulated a key gene in the human growth hormone pathway. The brain’s pituitary gland releases this hormone into the bloodstream, where it binds to receptors on muscle and bone cells and tells them to grow. Too much or too little growth hormone can result in disorders such as gigantism and dwarfism. This particular gene variant makes the receptors more responsive to growth hormones, sending cells a stronger, more urgent signal to proliferate.
…
Zeberg and colleagues, including his former graduate student Philipp Kanis, an evolutionary anthropologist now at the Max Planck Institute for Evolutionary Anthropology (EVA), delved deeper into data banks of ancient and modern genomes to see how common this variant was in different human lineages. They found that 94% of Neanderthal genomes carried it, compared with fewer than 10% of modern humans.
The variant was most common in people of East Asian and South Asian descent (present in 15% and 20% of genomes, respectively) and least common in those of European and Indigenous American descent (present in 0.5% and 2%, respectively). It most likely entered modern human genomes from Neanderthals about 47,000 years ago during a period of mixing between the groups, the authors note.
Next, Zeberg’s and Kanis’s colleagues synthesized cells in a lab that expressed either variant, then flushed them with growth hormones. The cells with the Neanderthal version of the gene grew about 40% larger than those with the more common modern human version.
Next thing you know, a precocious body builder will be asking a lab to do a CRISPR on him…never mind. There is more to this than one single gene difference, but this difference has an effect that is real. And the science of paleogenomics has been essential for understanding a biological fact that is may be very useful. Finally, which one of these scientists who worked on this project has the “Neanderthal” variant? You get only one guess:
Parting Shot: If Health Insurance Is Such a Good Idea, Why Are the Deductibles So High? In this series I have often called health insurance a category mistake that is conflated, on purpose, with health care. My recent experience has brought this home. My much better half and I are the beneficiaries of employer-based health insurance. Since February 2025 we have had to use it. The deductibles have been, in round numbers going from memory: $3400, $3700, $2800, and $2200, plus various and sundry “incidentals.” Tomorrow morning my “co-insurance” for a necessary procedure will be $820. Four years ago the same procedure that diagnosed a tumor that was subsequently cured by chemotherapy and radiation had no “co-insurance” attached. The same procedure in Paris would cost a few hundred dollars, at most, and would be a benefit to the patient.
Insurance is for things that are unlikely to happen, not things that are inevitable. One can debate whether homeowner’s insurance is necessary if the dwelling is owned by the dwellers. But try arguing that your car insurance should be “unnecessary” when you are stopped for speeding or are in an accident. But back to the deductible. While driving down the highway last year, a rock cracked my windshield. The deductible was $250 on a $1500 job (modern cars with sensors in the windshield!). The only time we have made a claim on our homeowner’s insurance was for roof damage due to a hailstorm, $500 deductible. The proverbial family that would have difficulty meeting an unexpected $400 expense could weather the broken windshield or the roof repair.
Suffice it to say that something is out of whack here and getting worse by the year. The solution is not difficult, but it is impossible as long as health insurance instead of health care is what Americans are stuck with. Having said that, we have also found that nurses are still angels who walk the Earth and that doctors and hospitals do a very good job under trying circumstances.
Thank you for reading this abbreviated Coffee Break on this first Friday in August! See you next week. In the meantime, keep pushing for a better world in whatever way you can.
