Scientists at Columbia University have used a precise gene-editing tool, base editing, to make changes in three disease-linked genes in early-stage human embryos. The goal wasn’t to create pregnancies, but to test the safety and limits of rewriting DNA at the very early stages of life.

The paper, not yet peer reviewed, sparked immediate controversy. Some researchers hailed it as a technical milestone that could one day prevent devastating inherited diseases before birth. Others warned it edges society closer to the prospect of “designer babies”—an idea bioethicists have argued is akin to modern eugenics.

The debate is hardly hypothetical. The work has already attracted commercial interest. New York-based Nucleus Genomics, which screens in vitro fertilization (IVF) embryos for serious genetic disorders, has also developed predictive models for complex traits such as intelligence. The company plans to sponsor future research by study leader Dieter Egli and team.

Critics worry that even experimental advances could fuel demand from wealthy patients while encouraging companies to develop and market embryo-editing technologies, despite unresolved ethical and safety concerns.

Egli argues the findings should be public precisely because these debates are no longer academic curiosity. He has repeatedly called for scientists, regulators, and the public to weigh the pros and cons of editing human embryos. As for clinical use today, his position is unequivocal: “You can’t use it. It’s as clear as day and night,” he told Nature.

Conceptual Shift

Why edit embryos at all?

Cells in an early embryo eventually give rise to every tissue in the body. Correct a harmful mutation at the start of development, and the fix could, in theory, propagate throughout a child’s entire body—and even be passed on to future generations.

The strategy could help in genetic disorders that hamper fetal development or trigger diseases in newborns. For some developmental and metabolic conditions, intervention after birth may already be too late. Even when treatment is possible, gene editors must be able to target various organs, which is an ongoing challenge.

In various efforts, scientists have already repaired disease-causing mutations in mouse embryos and fetuses, including those linked to blood disorders. But mice aren’t humans. Early embryos from the two species repair DNA damage in fundamentally different ways, making it tough to gauge whether a strategy that works in mice will succeed, or prove safe, in people. That uncertainty has fueled interest in testing gene-editing tools directly in human embryos.

Not everyone is on board. International scientific groups have repeatedly called for a temporary ban on editing human embryos, and the practice is illegal in several countries.

That didn’t stop Chinese scientist He Jiankui. In 2018, he announced the birth of gene-edited babies after using a tool called CRISPR-Cas9, claiming the changes would protect them against HIV infection. Global outrage ensued.

By then, years of research had already highlighted CRISPR’s risk. The tool cuts both strands of DNA and relies on the body’s repair machinery to stitch them back together. But the process can go awry, introducing unintended mutations, deleting large chunks of DNA, or altering the wrong locations on the DNA strands altogether. He’s reckless experiment resulted in three years of imprisonment, although he still defends the work.

Subsequent studies only deepened concerns. In some cases, CRISPR editing in human embryos caused extensive genetic damage. In one study,  it completely destroyed the chromosome that housed the target gene.

An Imperfect Upgrade

The new study tested a next-generation gene editor designed to overcome some of CRISPR’s biggest shortcomings.

Egli and team used an approach called base editing, which rewrites individual DNA letters. Unlike CRISPR, base editing only nicks the DNA strands and is generally thought to be more precise. The technology hit a major milestone last year when it helped cure a baby with a potentially fatal genetic disorder, and earlier lab studies hinted it could also succeed in human embryos.

Working with early-stage embryos, the team edited three genes with the potential to cause illness. In each case, they converted the genetic letter A to G at precise locations. One of the genes, PCSK9, regulates “bad” cholesterol levels. Mutations are associated with a high risk of heart problems. The team’s edit was designed to switch off the gene, mirroring strategies already being explored in adults.

The other two targets, HBG1 and HBG2, control production of fetal hemoglobin, an oxygen-carrying protein. The edits made here reflected a natural protective variant that could lessen symptoms in blood disorders, such as sickle cell disease and beta thalassemia.

The team found no signs of widespread DNA damage, suggesting the tool is more precise than CRISPR. But it wasn’t perfect. Many embryos emerged as so-called genetic mosaics, with some cells carrying the intended edit and others retaining their original genetic blueprint.

That’s a huge problem. As an embryo develops, unedited cells could outcompete edited ones, leaving the disease-causing mutation largely intact. In some embryos, edited cells stopped dividing altogether.

And a lack of obvious chromosome damage doesn’t guarantee safety. The edits could still trigger harmful effects that aren’t noticeable until after birth—when it’s already too late to reverse them.

Calls for Scrutiny

Egli stresses that embryo editing is still far from being ready for the clinic. “These base editors—they can have damaging effects on the embryo. So why would you use it if you don’t fully understand that?” he told Nature.

His team is now working to reduce mosaicism and plans to test the technology in embryos that have developed to roughly 100 cells. This is when fertility clinics typically evaluate and freeze embryos.

Speaking to The New York Times, fertility expert Paula Amato at Oregon Health & Science University, who was not involved in the work, called the strategy “promising.” Genomics researcher Greg Neely at the University of Sydney in Australia also praised the work: “This will go down in history in a positive way—less reckless, more careful and ethical than previous attempts.”

Others remain deeply skeptical. Critics argue that embryo editing permanently alters the genetic inheritance of future generations, who have no say in the decision. The study’s ties to Nucleus Genomics also raised eyebrows. The company previously drew controversy for developing genetic predictions for traits such as intelligence and height and for its slogan “have your best baby.”

To Kian Sadeghi, CEO and cofounder of Nucleus, embryo editing extends that vision. The technology could help couples carrying mutations who struggle to produce enough unaffected embryos for selection during IVF.

Fyodor Urnov at the University of California, Berkeley, who was not involved in the study, isn’t convinced. IVF clinics already screen embryos for many inherited disorders without altering their DNA. Given the risks, selecting an unaffected embryo is often a safer option than rewriting its genome.

“In practical terms, therefore, this preprint will solely impact the rapidly growing movement of embryo editors for purposes of ‘baby improvement’,” he said.

That movement, once taboo, is gaining steam. Yet the traits most often cited by proponents—height, intelligence, emotional regulation—are shaped by hundreds or even thousands of genes, which scientists still don’t fully understand. Such enhancements are far beyond the reach of today’s technology. Every additional edit also increases the chance of unintended consequences.

For Egli, that’s precisely why the research should be discussed openly. “Research is necessary to provide information to discourage the wrong use of a technology,” he said.

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For decades, a handful of molecular switches has haunted the nightmares of cancer researchers. The switches trigger runaway tumor growth and cause the disease to spread across the body in multiple cancers. In theory, this makes them perfect treatment targets. Blocking even one could lead to drugs that are effective against a variety of cancers.

But despite considerable efforts, these switches—all of which are proteins—have escaped our most advanced cancer treatments, earning them the term “undruggable.” This is largely due to a shared trait: They all have smooth surfaces, making it difficult for drugs to interact with them.

But maybe not for much longer.

Researchers recently reported promising results for a new medication targeting a family of undruggable proteins in a clinical trial for advanced pancreatic cancer. The drug, daraxonrasib, nearly doubled survival time compared to chemotherapy, with fewer side effects. It’s not a total cure. But the treatment gives patients precious time, adding roughly 13 months after diagnosis. Patients also reported less pain and better quality of life.

Daraxonrasib is the latest in a new generation of drugs aimed at undruggable proteins. And AI-based tools are now poised to further accelerate progress in the field.

RAS Attack

The RAS family was the first group of oncogenes—or genes that drive cancer—ever discovered. The genes became a major focus in 1982 when several teams independently showed the mutation of a single DNA letter could transform RAS genes into a potent cancer trigger.

The proteins RAS genes encode are like spring-loaded molecular switches that relay signals from a cell’s surroundings. When proteins called growth factors latch onto a cell, RAS switches flip on to promote cell growth and survival, while built-in safeguards quickly turn them off again.

Cancerous mutations break this cycle. The switches get stuck in the “on” position, continuously instructing cells to grow and divide. This is, of course, a hallmark of cancer.

An ideal drug would simply switch RAS off. But most drugs are like rock climbers. They need grooves, pockets, or bumps on a protein to grab onto. Similar to a smooth rock face, RAS offers few such features. Making matters worse, different mutations subtly reshape the protein, so it’s tough to build a one-size-fits-all inhibitor.

The first RAS drug wasn’t approved in the US until 2021, nearly four decades after discovering the genes’ role in cancer. Even then, the drug targeted just one family member of three, limiting its reach to a relatively small group of patients. Many eventually developed resistance.

That’s why daraxonrasib turned heads. Developed by Revolution Medicines in Redwood City, California, the drugs switches off all three RAS family members. Rather than trying to grip the slippery proteins directly, it binds to a partner molecule that helps RAS proteins fold into their final 3D shapes. In this way, the drug hitches a ride on active RAS and shuts the proteins down.

The workaround paid off. The new study enrolled 500 people worldwide with advanced pancreatic cancer. All participants had already tried cancer therapies with limited success. On average, patients receiving daraxonrasib lived 13.2 months and spent most of that time with limited pain. The most common discomfort was a rash. Those receiving chemotherapy fared worse, living roughly 6.6 months and experienced more severe side effects.

The results don’t rival the dramatic success of CAR T cell therapies in blood cancer. In CAR T, caregivers engineer a patient’s own immune cells to recognize and attack tumors, sometimes producing long-lasting remission after a single infusion.

But the findings have energized the field. If approved, a daily daraxonrasib pill would likely be far more affordable and easier to administer than a personalized cell therapy. And because RAS mutations fuel many solid cancers—which CAR T still struggles to control—the drug could offer a new defense against deadly cancers that are largely beyond cell therapy’s reach. Combining daraxonrasib with earlier-generation RAS inhibitors may further boost its effects.

The Genome Guardian

Daraxonrasib didn’t appear overnight. Scientists used a crystallized snapshot of its target protein as a molecular blueprint. Years of medicinal chemistry followed, with scientists repeatedly tweaking candidate compounds to boost potency, improve selectivity, and minimize toxicity.

AI could dramatically accelerate similar efforts against other undruggable cancer targets. Among the most coveted is p53, often called the “guardian of the genome” for its dizzying array of roles. The protein orchestrates the activity of over 300 genes involved in DNA repair, metabolism, cell death, and inflammation, making it one of the cell’s most important defense systems.

Since its discovery in 1979, p53 has been both a holy grail and a headache for cancer researchers. Mutations in the gene are common in multiple cancers. But like RAS, the protein is flat and smooth. Some mutations destabilize its structure; others turn it into misfolded clumps. A universal p53 drug has remained elusive.

Some researchers are trying to restore the protein. In a small trial earlier this year, they tested a drug that restabilizes a common mutant form of p53. Within 21 days, tumors shrank roughly 20 percent in patients with ovarian, breast, and several other solid cancers.

Other researchers aim to selectively kill cells carrying the mutation. Using AI, a team at Baylor College of Medicine screened nearly 10 million compounds that cause mutated p53 cells to self-destruct, while sparing healthy cells. The search uncovered 83 chemically distinct candidates. One called H3 dramatically suppressed tumor growth in mice.

“These results highlight the potential use of AI-powered drug screening to investigate individual p53 mutants in the future,” they wrote. Although the approach is early-stage and only focused on one mutation, the team is hopeful it can be extended to other cancerous mutations.

Most Wanted

MYC is another formerly undruggable protein that could now be vulnerable. Roughly 70 percent of cancers have abnormal MYC activity. Normally, the protein is a master regulator of growth, directing cells to manufacture proteins, replicate DNA, absorb nutrients, and divide when needed.

Cancer finds many ways to hijack the system and keep cells in a state of runaway growth. MYC gene mutations aren’t just single-letter swaps. Sometimes the gene duplicates or is rearranged across the genome, churning out excessive amounts of the protein it encodes. This genetic diversity makes approaches using gene therapy difficult. And again, like RAS, the MYC protein’s smooth, featureless surface lacks stable anchors for drugs.

An emerging strategy is to disrupt MYC’s interaction with other proteins that it needs to function. A designer protein blocking MYC activity, for example, recently showed promise in a small trial against solid cancers. Other teams are using AI to identify drugs that limit MYC’s ability to fix damaged DNA in tumors, kneecapping their ability to divide. Meanwhile, biotechnology companies are deploying AI to map out MYC’s structure and molecular interactions in search of new ways to shut the protein down.

Daraxonrasib’s success shows that undruggable proteins aren’t untouchable. There’s a lot more work ahead to prove other similar drugs can work too. But scientists are increasingly leaning into AI during all stages of drug development to speed up the process. Maybe, one day, “undruggable” will disappear from our vocabulary altogether.

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There’s truth to the old adage, “Age is just a number.” People of the same age differ vastly in health and mental capabilities. One 80-year-old may be vibe coding with Claude, while another is gradually forgetting familiar faces and memories.

To better gauge this difference, scientists have been developing “clocks” that measure biological age. Rather than the number of candles on a birthday cake, these tools capture health at the cellular level and are remarkably accurate at estimating disease risk and even life expectancy. But how they work is hard to explain.

Now Harvard scientists and collaborators have released a powerful and more interpretable clock. Using the gene activity of thousands of individuals and animals, the clock predicts biological age in rodents, monkeys, and humans, including how many years they have left.

The analysis involved over 11,000 gene activity profiles across four species, highlighted shared mechanisms during aging, and responded to known anti-aging interventions—such as parabiosis, during which aging animals receive blood from a young donor.

Although the clock isn’t ready for clinical use, it is a boon to scientists working to slow or even reverse the unstoppable progression of time. It “could help researchers to pinpoint which processes are modulated by interventions or diseases,” wrote João Pedro de Magalhães at the University of Birmingham, who was not involved in the work.

Tick, Tock

Biological clocks come in a variety of flavors.

Most rely on AI to make sense of information held in large databases of people. One of these, for example, uses blood proteins related to brain aging to reflect cognition and its decline better than chronological age. Another type, metabolomic age clocks, sorts through protein and fatty acid building blocks to estimate biological age. These clocks correlate well with risk of inflammation, chronic disease, and frailty (where the body struggles to recover from a mild infection or minor fall). More recent multi-omics clocks combine blood measures, metabolism, gene activity, and clinical data for a comprehensive bird’s-eye view of biological age.

But epigenetic clocks remain the field’s defining breakthrough.

As we age, chemical tags accumulate on DNA, switching genes on or off. The pattern of these tags shifts over time and is shaped by everyday life—diet, exercise, stress, sleep quality. Studies have found that the age gaps between biological and lived years measured by the well-known Horvath epigenetic clock, which relies on DNA methylation, were associated with the risk of various types of diseases. Later versions of the Horvath clock could predict maximum lifespan. And other groups have developed “pan-mammalian” epigenetic clocks that work across species.

“One drawback of epigenetic clocks, however, is their limited interpretability,” wrote Magalhães. “The mechanisms that underpin age-related methylation changes are still debated.”

Clocking In

In the new study, the team measured aging by looking at gene activity, or transcriptomics. Transcriptome profiles capture which genes are switched on at any given moment.

Previous studies have linked the aging transcriptome to chronic inflammation, faltering mitochondria, and the gradual breakdown of the extracellular matrix, the molecular scaffolding that supports tissues and organs. With age, these systems go awry.

“Because the signatures reflect changes in the activity of specific genes, transcriptomic biomarkers are more interpretable than are epigenetic ones,” wrote Magalhães. The tradeoff is that gene activity is far more dynamic than DNA methylation, the epigenetic signature used in the Horvath clock. A transcriptome can shift in response to stress, illness, exercise, or even the time of day, making it a less reliable measure of aging.

To make the new clock, the team assembled over 11,000 transcriptomes, heavily relying on data from the Interventions Testing Program, a giant effort to study longevity treatments in mice. The dataset included mice exposed to genetic tweaks, drugs, and dietary therapies known to affect aging and lifespan. The team also added more than 2,600 samples from monkeys, several hundred from rats, and over 4,000 from humans to deliver a cross-species view of aging.

They then built multiple transcriptome clocks that estimated age and mortality risk. To validate the clocks, they turned to an independent dataset that included rodent models of accelerated aging, Alzheimer’s diseases, chronic kidney disease, and other age-related conditions. When applied to individual cells, the clocks yielded older transcriptomic ages in more than 90 percent of the samples, suggesting that aging is deeply rooted at the cellular level.

In humans, the clocks accurately predicted the lifespans of participants enrolled in a large heart health study. They were also sensitive to environmental factors that affect aging, ticking forward after exposure to radiation or chronic diseases and rewinding after treatments such as young-blood transfusion, a strategy shown to rejuvenate elderly rodents.

An analysis of the genes driving the clocks highlighted many of the usual molecular suspects. Aging turned on genes involved in inflammation, cellular energy disfunction, and senescence—where failing cells leak toxic molecules. Many of these signatures appeared across organs and species, suggesting that core aspects of aging have been conserved in mammals.

These findings are especially valuable for longevity researchers, who often work with rodent models. Despite living a fraction of a human lifespan, aging rodents undergo transcriptomic shifts similar to those found in us. The new clock could easily test their biological age after potential anti-aging treatments, capture the immediate effects, and predict lifespan, long before they die. It could, in theory, speed up aging research and the quest for treatments.

But to be clear, like other aging clocks, it isn’t a crystal ball. Scientists don’t know if the transcriptome changes drive aging or merely reflect its aftermath. The signatures could be capturing overall health and resilience, rather than molecular changes associated with aging per se.

That distinction matters. As we grow older, cells activate a variety of protective genes to counter rising stress, inflammation, and damage. Not every age-related transcriptomic change is harmful. Some changes reflect the body’s attempt to fight back. Because transcriptomes capture only a snapshot in time, scientists still need to differentiate genes that contribute to aging from those that help defend against it and learn how those patterns shift over time.

There’s a broader challenge too. Researchers are building more and more biological clocks using different criteria, and they don’t always agree. One may say you’re far older than another. This highlights “the need for any aging biomarker to be validated carefully,” wrote Magalhães.

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