The Good, Part the First: Basic Science Has the Answer, Once Again. T cells of the immune system are responsible for the establishment of self-tolerance and adaptive immune function. T cells come from the thymus, which is mammals basically disappears early in life in a process called involution.
Understanding how the thymus might regenerate has been a goal of immunology for a very long time. A paper in Science (paywall) represents a fundamental advance in the basic science of vertebrate thymus development and regeneration:
Editor’s Summary. Although acute damage and age-related decline can lead to a loss of thymic and immune function, the adult mammalian thymus retains some limited regenerative capacity. Czarkwiani et al. found that juvenile axolotls can fully regenerate their thymuses after complete removal. Thymus regeneration was associated with restoration of morphological and transcriptional features. Whereas the key mammalian thymic transcription factor FOXN1 was dispensable for thymus regeneration, single-cell transcriptomics identified the growth factor midkine as a likely driver. Future studies in axolotls could inform new therapeutic approaches for promoting thymus regeneration.
Abstract. The thymus is the primary site of T cell development, central to the establishment of self-tolerance and adaptive immune function. In mammals, the thymus undergoes age-related involution, resulting in a global decline in immune function. The thymus has some regenerative ability that relies on pre-existing thymic remnants but is insufficient to prevent involution. Here, we show that the juvenile axolotl (Ambystoma mexicanum) is able to regenerate its thymus de novo after complete removal, constituting an exception among vertebrates. Using single-cell transcriptomics and genetic and transplantation approaches, we demonstrate that de novo thymus regeneration results in the restoration of morphology, cell-type diversity, and function. FOXN1, although it has a conserved role in thymus organogenesis, is dispensable for the initiation of thymic regeneration. In contrast, we identify midkine signaling as a possible early driver of de novo thymus regeneration. This study demonstrates an instance of organ-level regeneration of the lymphoid system, which could guide future clinical strategies seeking to promote thymus regrowth.
The paper is complex but convincing. The basic developmental pathways in vertebrates are highly conserved, so this research using an amphibian model system is unlikely to be the answer. But it points the way to getting there. Particularly interesting to the old school biologist in me is the experimental model used in this research. The axolotl (images of possibly the cutest animal that is not a small mammal) along with other amphibians and sea urchins, starfish, and flies have been models for developmental biology dating back to when the discipline was called embryology, long before genes were understood.
Like too many other creatures, due to pollution and habitat destruction the axolotl is a critically endangered species and their only natural habitat is a small wetland in Mexico City:
An ancient wetland system of islands and canals that pre-dates the Aztecs endures quietly in Mexico City.
These wetlands, cradled within North America’s most populous city, are the only place on Earth where you can find one of the most recognizable — and endangered — creatures on the planet: the axolotl.
Now, a new survey has confirmed what scientists and locals have feared: The charismatic salamander is nearing extinction in the wild, driven by habitat loss, pollution and the introduction of invasive fish that prey on it.
Led by the Ecological Restoration Laboratory of the National Autonomous University of Mexico (UNAM), with support from Conservation International-Mexico, the survey is the most comprehensive effort of its kind, covering 115 monitoring sites across the 2,500-hectare (6,180-acre) Xochimilco Protected Area, a UNESCO World Heritage Site known for its canals and farm islands, called chinampas.
The University of Kentucky maintains the Ambystoma Genetic Stock Center. But it would be far better to maintain populations in the wild. If this one population in Mexico City disappears, well, extinction is forever.
The Good, Part the Second: Cancer Killer Cells Produced in the Body Cure Multiple Myeloma. CAR-T cell therapy was proved in principle more than twelve years ago. Recent research has shown that these cells can be made in the patient instead of in the laboratory and then infused back into the patient:
Immune cells engineered to home in on cancer cells like guided missiles can be lifesavers—if patients can get them in time. Currently, their T cells must be harvested and given a surface protein, a chimeric antigen receptor (CAR), through genetic manipulation, a slow and expensive lab process. Making the cells directly inside the body should be faster, and early clinical data now suggest the strategy can work. In one of the first trials, the approach induced the so-called in vivo CAR-T cells in four patients with multiple myeloma, a blood cancer, and evicted the malignant cells from their bone marrow.
The results, presented today (December 9) at the American Society of Hematology (ASH) annual meeting, are preliminary but “really impressive,” says cancer biologist Bin He of the Houston Methodist Research Institute, who isn’t connected to the work. Moreover, the trial is the second this year to unveil positive findings from in vivo CAR-T cells for multiple myeloma. Patients in the earlier study suffered significant side effects, likely because of the viruses that ferried the needed genes into the immune cells, although the problems were less severe in the newer trial, despite using the same class of virus. “The question is no longer can you really do this,” says Yvonne Chen, a cancer immunotherapy researcher at the University of California, Los Angeles. “The question now is can you reach the level of efficacy that’s expected and will the safety profile meet the target.”
CAR-T cells, which Science named as part of its 2013 Breakthrough of the Year, were first approved by U.S. regulators in 2017 and are now standard treatments for several types of blood cancers, including multiple myeloma. Specialized facilities turn a patient’s T cells into cancer fighters by exposing them to viruses that infect them and deliver the CAR gene. Researchers are now looking to broaden the cells’ repertoire, testing them against solid tumors, autoimmune diseases, and other illnesses.
But some patients die of their cancers during the month it typically takes to make CAR-T cells. And the high cost, usually in the hundreds of thousands of dollars, puts the treatment out of reach for many people. Before patients can receive their upgraded T cells, they also need risky chemotherapy to wipe out their natural T cells.
These drawbacks explain why researchers are so enthusiastic about the potential of making the cells in the body. “The field is gradually switching from ex vivo to in vivo CAR-T cells,” says immunobioengineer Matthias Stephan of the Fred Hutchinson Cancer Center.
Gene therapy has been on the table for more than thirty years. The problems with gene therapy are not theoretical. They are technical. In the case of CAR-T therapy using lab-made cells, infusion sometimes causes a surge in the immune response that makes the patient sick. Sometimes the patient dies. This is much less likely to happen with CAR-T cells made inside the patient.
While this research has not solved all the problems with CAR-T therapy, the simple fact that CAR-T cells do not have to be harvested from the patient, modified, cultured, and then put back in the patient makes the procedure much less complicated and expensive, not to mention faster and probably safer.
When the War on Cancer was declared in 1971 by President Nixon at the insistence of the indomitable Mary Lasker, this kind of therapy was to be wished for, but no one had any idea how to get here. But here we are in the year 2025, and only because of support for incremental research funded by the National Institutes of Health, the American Cancer Society, and other similar agencies. This is the kind of research that does not fit the MAGA/MAHA world. It never will. But it is the only way to proceed. For every project that “works as hoped,” probably twenty fall short. But what is learned in those leads to advances that do things like cure multiple myeloma.
Conventional CAR-T cells have enabled some multiple myeloma patients to stave off the return of their cancer for more than 5 years. Whether any of the in vivo approaches will provide such lasting benefits remains to be seen. Still… the field is progressing fast. “Patients should be optimistic.”
Yes, they should.
The Good, Part the Third: Personalized mRNA Vaccines and Cancer Treatment. There is that word, again, mRNA, in this article from Scientific American: Personalized mRNA Vaccines Will Revolutionize Cancer Treatment—If Funding Cuts Don’t Doom Them. For the next few years, bet on doom. But there will be a dawn, provided society doesn’t collapse completely. Similar research on pancreatic cancer has been covered here before. It works!
As soon as Barbara Brigham’s cancerous pancreatic tumor was removed from her body in the fall of 2020, the buzz of a pager summoned a researcher to the pathology department in Memorial Sloan Kettering’s main hospital in New York City, one floor below. Brigham, now 79, was recovering there until she felt well enough to go home to Shelter Island, near the eastern tip of Long Island. Her tumor and parts of her pancreas, meanwhile, were sent on an elaborate 24-hour course through the laboratory. Hospital staff assigned the organ sample a number and a unique bar code, then extracted a nickel-size piece of tissue to be frozen at –80 degrees Celsius. They soaked it in formalin to prevent degradation, then set it in a machine that gradually replaced the water in each cell with alcohol.
Next, lab staff pinned the pancreas to a foam block, took high-resolution images with a camera fixed overhead and used a scalpel to remove a series of sections of tumor tissue. These sections were embedded in hot paraffin and cut into slices a fraction of the thickness of a human hair, which were prepped, stained and mounted on glass slides to be photographed again. By the time a pathologist looked at Brigham’s tumor under a microscope the next day, more than 50 people had helped steer it through the lab. Still, this work was all a prelude.
The real action came some two months later, when Brigham returned to the hospital to receive a vaccine tailored to the mutations that differentiated her tumor from the rest of her pancreas. Made of messenger RNA (mRNA) suspended in tiny fat particles, the vaccine was essentially a set of genetic instructions to help Brigham’s immune system go after the mutant proteins unique to her tumor cells. It was, in other words, her very own shot.
If this sounds a bit like the story about CAR-T therapy, that’s because it is. In this case the patient’s pancreatic tumor, which would have probably killed her by now – five years after diagnosis – was used to make the antigens that were expressed in her body using an “mRNA vaccine” against these proteins, which the body did not recognize as “self” and attacked her cancer. Brilliant! And it works, sometimes. The key now is to make the procedure work most of the time. And a bit later, virtually all the time. But, unless mRNA is de-demonized this cannot not happen.
That we have come to this is both tragedy and a farce. mRNA vaccines against COVID-19 were pushed until they met their limit, which was foreseeable. Yes, millions of lives were saved by the vaccines because they lessened severity of disease in those patients. But that is not what the people were told. First, the tragedy:
Had the scientific and political establishments been truthful, as in: We can make these vaccines rapidly and on demand but we are not sure they will stop the pandemic because coronaviruses are known for more than sixty years to evade the immune response in vertebrates. Nevertheless, along with non-pharmaceutical interventions such as masks, social distancing, and a crash program to improve ventilation in workplaces and schools, plus an accelerated research program directed at antiviral drugs against SARS-CoV-2, we can lessen the severity of the pandemic while at the same time developing a long-term solution.
Now the farce, in which our current scientific and political leadership, which are one and the same, have cast mRNA into the scientific outer darkness because reasons. This, even though the theoretical basis of mRNA therapeutics has been strong since the late-1980s. This is madness but to be expected in the current world:
The results of Brigham’s trial were also an early sign that mRNA vaccines may be effective for a wide variety of cancers: whereas pancreatic cancer is known for its low rate of mutations, the earliest data on personalized mRNA vaccines came from studies of melanoma, which researchers had targeted specifically because it tends to mutate so frequently. An earlier phase 2 trial in patients with advanced melanoma found that for those who received both a personalized mRNA vaccine and so-called immune checkpoint inhibitors, the risk of death or recurrence decreased by almost half compared with those who got only checkpoint inhibitors. Ongoing companion trials are targeting kidney and bladder carcinomas and lung cancer. In each case, the vaccine is additive: administered after surgery and with standard drugs. The shot’s job is to prime the immune system to recognize abnormal proteins arising from mutations and attack any lingering malignancy that escaped conventional treatments—or stamp out future recurrence.
There will also be a deeper darkness before the dawn here. The dawn will come, but how many will die unnecessarily because of our dithering? Pull-up bars in airports are coming, though. So, we’ve got that going for us. Which is nice?
The Good, Part the Fourth: Spider Girl Power. The strongest spiderweb on Earth is spun only by females. Or as the tagline puts it, “Bark spider silk is stronger than steel, but males make a weaker version.” File this tidbit under “Mother Nature Knows Best.”
Bark spiders are some of nature’s best engineers. They spin webs that stretch across entire rivers in Madagascar; their silk is stronger than steel—and the toughest on Earth. But only females craft the mightiest webs (Open Access, with pictures), according to a new study in Integrative Zoology.
Researchers tested the silk strength of two bark spider species (Caerostris darwini—pictured—and C. kuntneri). They used a microscope to measure the diameter of the silk strands, and then carefully stretched them until they snapped. In some cases, the female spiders’ silk was more than twice as strong as that of their male counterparts, the team found.
The biochemistry majors in the NC community will remember why spider silk is so strong. Studying the silk produced by bark spiders is likely to improve materials used when skin regeneration is required after accident or disease. Basic science never fails to teach us things that are good to know, even if we cannot predict which research will “pay off.” However, in this case my engram about spiders still creeps me out. Snakes? No problem. Spiders, I give them a wide berth. The caver shown here is very brave.
The Bad, Part the Fifth. Plastic, Now and Always. Help me. Plastic pollution is a scourge visited upon planet Earth by humans. We know this. But, never mind: “To keep profits rolling in, oil and gas companies want to turn fossil fuels into a mounting pile of packaging and other plastic products.”
In 2018, at a Dubai resort next to the blue-green waters of the Persian Gulf, Amin Nasser, CEO of Saudi Aramco, stood before an audience of hundreds of petrochemical executives to set out his vision for the future of the world’s largest oil company. The goals he described weren’t primarily about energy. Instead he announced plans to pour $100 billion into expanding production of plastic and other petrochemicals.
Nasser predicted that with a growing global population wielding more purchasing power every year, petrochemicals—compounds derived from petroleum and other fossil fuels and of which plastics and their ingredients constitute as much as 80 percent—would drive nearly half of oil-demand growth by mid-century. About 98 percent of virgin plastics are made from fossil fuels. In sectors that include packaging, cars and construction, he said, “the tremendous growth in chemicals demand provides us with a fantastic window of opportunity.”
In the years since Nasser’s 2018 speech, Saudi Aramco, owned mainly by the government of Saudi Arabia, has acquired a majority stake in the country’s petrochemical conglomerate SABIC. Together the companies have bought into huge Chinese plastic projects and built petrochemical plants from South Korea to the Texas coast. Aramco aims to turn more than a third of its crude into petrochemicals by the 2030s—a near tripling in 15 years.
Although the industry has framed its plans to pivot to plastic as a response to consumer demand for a material central to modern life, another factor is clearly at play: As the looming dangers of climate change are pushing the world away from fossil fuels, the industry is betting on plastic to protect its profitability. Ramping up plastic and petrochemical output, according to Nasser, will “provide a reliable destination for Saudi Aramco’s future oil production.” As one industry analyst observed of the company’s strategy, “the big picture imperative is to avoid being forced to leave barrels in the ground as demand for transportation fuels declines.”
The Market, it just can’t see what happens “the day after tomorrow,” despite what we know about plastics and fear what is probably the truth:
By design, plastic does not readily decompose. Instead it fragments into increasingly minuscule pieces—reaching down to the nanoscale—that have been found just about everywhere scientists have looked. They suffuse the air we breathe, the water we drink and the food we eat. They’ve been detected in blood, semen, breast milk, bone marrow and placentas. Scientists are only beginning to explore what this omnipresence means for the health of humans and the environment, but the signs are worrying. One recent study found microplastics in tissue from human kidneys, livers and brains, and a study of 12 dementia patients’ brains showed greater accumulations than those of people without the disease. Other research found the tiny particles in the neck-artery plaque of nearly 60 percent of patients tested; three years later the rates of heart attacks, strokes and death were 4.5 times higher among people whose samples contained microplastics.
Meanwhile, in my community, single-use plastic bottles continue to proliferate. The most outrageous example is at my regular golf course, which after a complete renovation dispensed with the six water jugs that were used to refill personal water bottles. In the summer in these parts that meant at least six refills in one round. Now we have plastic bottles (complete with the course logo) filled with tap water from somewhere ending up in the landfill here. How nice! My questions about this have been met with incomprehension for the most part.
The Ugly, Part the Sixth: Human Sociality Remains Inscrutable. In A Headless Mystery, “Archaeologists find evidence that a wave of mass brutality accompanied the collapse of the first pan-European culture.”
In 2017, archaeologists digging in the middle of a Slovak wheat field uncovered four headless skeletons. The burials, in a ditch dug on the edge of a settlement more than 7000 years ago, belonged to one of Europe’s first farming communities. Burying people in or near settlements wasn’t unusual at the time—but burying them without heads was.
Year after year, the researchers have returned to find more and more headless skeletons on the outskirts of Vráble, a small village 100 kilometers east of Bratislava. “Everywhere we started to dig, we found bones. Everywhere we were sitting or standing, there were bones,” says Katharina Fuchs, a biological anthropologist at Kiel University (KU) who has excavated in Vráble every summer since 2021. In the summer of 2022, she and colleagues from KU and Constantine the Philosopher University in Nitra recovered the skeletal remains of 34 people, piled on top of each other two or three deep in a space about the size of a parking spot. With the exception of one child, none of them had heads.
Known as the Linear Pottery culture (or LBK, after their German name, Linearbandkeramik), these early agriculturalists were direct descendants of the people who began to domesticate plants and animals in the hills of Anatolia around 9000 B.C.E. By 5500 B.C.E., they had reached today’s Hungary. Then they spread westward, farther into Europe. The LBK farmers flourished for more than 400 years, eventually occupying a 1500-kilometer belt of fertile land stretching as far west as the Paris Basin.
Then something went terribly wrong. Vráble and other mass graves across Europe attest to a wave of brutality around 5000 B.C.E., about the same time as hundreds of LBK settlements across the continent abruptly vanished. In the aftermath, parts of the continent remained empty for centuries. Other settlements transitioned peacefully into something else, with people living in the same place and continuing to farm, but building houses and decorating their ceramics in a different way. “The LBK were the first farmers, the first large pan-European culture, and the first time we see these repeated finds of violence,” says Christian Meyer, an independent osteoarchaeologist who has studied human remains from multiple LBK mass graves.
There is no way to interpret what our fellow human beings of the Linear Pottery Culture were thinking when they filled graves with headless corpses, but brutality seems to be the correct term. Inexplicable, yes. But not all that unusual, even by modern “standards.”
See you next week!
Thank you KLG. Fantastic news on the Multiple Myeloma and Pancreatic cancer fronts.