In the morning HN digest, an essay popped up about the liver and its strange resilience: half the organ can be given to another person, and after a few months, the mass returns. The author drops a phrase right there that I needed: in a tadpole, a severed spinal cord heals, but in the same frog after metamorphosis, it doesn't. One organism, one spinal cord, two different answers, and between them stands a date.
This breaks the familiar formulation "mammals forgot how to regenerate". It seems they didn't forget, but turned it off — and the turning off has a schedule and a very specific chemical trigger. Next, I went to check who exactly is pulling the switch.
The clawed frog Xenopus tropicalis regrows its tail after amputation up to about stage 59 of development. Then tail resorption begins, and the ability disappears. The test proved direct: in tadpoles with a double knockout of thyroid hormone receptors TRα and TRβ, regeneration is preserved at stages 60/61, exactly where normal animals already cannot. In the knockouts, upon amputation, apoptosis turned on more strongly in the early period, and subsequent cell proliferation proceeded more actively.
The receptors are not needed for regeneration itself: without them, the tail grows back normally. They are needed to stop it. The same hormonal signal is responsible for the tail resorption itself, and in the tail remnant after stage 61, the apoptosis that serves it finishes off the regenerative capacity completely.
Metamorphosis is generally not degradation. It is a change of environment: the tadpole lives in water, the frog comes out onto land. Fins, tail, and cutaneous respiration become unnecessary, but lungs, limbs, and thermoregulation are needed. The organism does not lose regeneration due to oversight — it shuts down a tool that has become dangerous or useless in the new configuration. Humans have a similarly scheduled moment: TSH sharply peaks immediately after birth, and T3 and T4 rise in response to cortisol, umbilical cord clamping, and cold. The hormonal surge on the way out into the world is not frog exoticism.
The window, which in the frog is stretched over the entire metamorphosis, is compressed in the mouse to seven days — and this is already convenient to study. In 2011, the Porrello group showed that in one-day-old mice, the heart regenerates after surgical resection of the apex. By the seventh day, this skill disappears. The restored tissue grew due to the division of already existing cardiomyocytes; fibrosis and hypertrophy were almost absent. After two months, ultrasound showed normal contractility of the restored apex. That is, the window exists literally: a week in a mouse's life separates an organ that repairs itself from an organ that scars forever.
The replication turned out to be noisy. Another group published a paper where they did not see regeneration after apex resection at all. In response, seven laboratories wrote a collective letter: their method works just as stably as in the first publication, and the critics, judging by their own data, removed over 40% of the myocardium in two days — with such a volume of damage, regeneration may simply be impossible. Then methodological dirt begins: to count by the weight of the ventricle or by the ratio of heart mass to body mass, to measure the area immediately or after three weeks, to use resection, cryoinjury, or ligation of the coronary artery. Each choice slightly changes the conclusion.
Honestly: I never found a definitive verdict on this dispute in the sources. It seems that the regeneration of the first days is real, and the disagreements largely grow out of the surgical technique and the method of measurement. But "largely" is not "entirely," and an aftertaste remains.
The key work here is Hirose et al., Science, 2019. They looked at the proportion of diploid cardiomyocytes in 41 species and found that it obeys Kleiber's law — that very ¾-power scaling of metabolism with body mass. The proportion of diploid cells inversely correlated with the standard metabolic rate, body temperature, and serum thyroxine level.
The experiment closed the question of the direction of the relationship in mice. If you turn off thyroid hormone signaling, cardiomyocytes undergo less polyploidization, exit the cell cycle later, and the adult heart retains regenerative potential. The reverse also works: thyroid hormones added from the outside suppress heart regeneration in the zebrafish, which normally can do this all its life.
Hence the conclusion that the authors propose: the loss of heart regeneration is the price for endothermy. Warm-bloodedness requires a high metabolism, a high metabolism requires hormones, and the hormones simultaneously stop the cell cycle where it is dangerous for the cell to divide. The liver, by the way, does not disappear from this scheme — and here begins the most interesting discrepancy.
The liver is removed by 70%, and the mass returns: in a rat in about a week and a half, in a human in months. But it is not the removed piece that is restored. The remaining hepatocytes multiply and simultaneously increase in size, so the debate "hyperplasia or hypertrophy" continues to this day: the functional units of the organ stretch, and the cells themselves divide. At the same time, the liver does not restore its shape — it restores mass and function.
The figures are taken from living donors, not from models. In the A2ALL study on 350 donors and 353 recipients, the gain for the donor over three months was 676 ± 251 grams, that is, about 80% of the donation; for recipients — 549 ± 267 grams and 93%. Nothing magical happens in three days: three months of rapid growth, and still incomplete recovery. Donors with the smallest remnant grew more than expected, but paid for it with elevated bilirubin and INR on days 7 and 30.
Next is the measurement that I consider the most accurate in the whole topic. Olaf Bergmann's group in Dresden dated human hepatocytes by the radiocarbon trace of nuclear tests in DNA. The liver of people from 20 to 84 years old turned out to be on average younger than three years — regardless of the person's age. Renewal does not slow down with age: diploid hepatocytes act as the drivers, not stem cells in the usual sense.
And here is where the scheme starts to creak. The liver is an organ that lives under constant assault: toxins, decay products, viruses. After resection, type 3 deiodinase, which breaks down T3 and T4, turns on in it, and the hormone level transiently falls. In mice without the TRβ receptor, mass recovery is delayed, and at the 48th hour there is a spike in apoptosis that carries away about 30% of the remaining hepatocytes. Pharmacological hypothyroidism gives the same picture: the liver needs the hormone not to permit regeneration, but so that it proceeds quickly and without loss.
That is, the same signal closes the regenerative window in the heart, but in the liver it drives recovery. I did not find a clear explanation in the sources of how these two facts coexist in one physiology, and I will not pretend that I did. Perhaps the point is that the heart cannot afford dividing cells, while the liver cannot afford slow ones: its job is such that apoptosis and renewal are its standard operating mode.
If turning off is a setting, it means there should be animals somewhere where the switch did not trip or tripped later. Such exist, and they are mammals. The spiny mouse Acomys cahirinus regenerates skin with hair follicles, sebaceous glands, dermis, fat, cartilage, smooth and skeletal muscles. The ear closes completely: in the test with a 4-millimeter hole, all 26 females and 13 of 14 males fully restored the tissue by day 85.
The house mouse — same experiment, different ending. None of the so-called healer mice of the MRL/MpJ line (0 out of 10) closed the hole. The line that for twenty years has been dragged around conferences as proof of hidden regeneration in mammals simply scarred over at a 4-millimeter hole. It closes a two-millimeter one in three weeks, and for larger ones, it plateaus and stops. Ear regeneration turned out to be a specific setting with its own threshold for wound size.
The difference is visible at the level of the wound bed. In Acomys, a true blastema forms: active wound epidermis, porous extracellular matrix of collagen III, dividing mesenchymal cells, and restoration of innervation. In a normal mouse, a dense matrix of collagen I and a scar form in the wound. The immune system of the spiny mouse responds to damage noticeably weaker — it seems this is a condition without which regeneration does not start.
There is also a pinpoint experiment on a gene. Mice lacking p21, one of the cell cycle brakes, fully regenerate the damaged ear without a visible scar. The mechanism is written out: in the wild type, SDF1 rises in the wound epidermis and beckons leukocytes with the CXCR4 receptor; in mice without p21, this signal is muted, fewer leukocytes arrive, and regeneration proceeds from its own fate-restricted progenitors. You remove one brake — you get a different outcome, and no exoticism is needed for this.
The largest example of regeneration in a mammal, no one calls regeneration. Deer antlers are shed and regrow every year at a rate of up to 2 centimeters per day; in red deer, about 3.3 million cells of the stump periosteum yield up to 15 kilograms of tissue in 70 days. There is no dedifferentiation there: cells simply divide and build bone. Remove the periosteum — regeneration disappears completely.
A human fingertip is also regeneration, and it has been documented for a long time. Douglas's 1972 series: 29 fingertips in children 4–15 years old treated with simple dressings, average healing 22 days, part of the length and thickness of soft tissues returns due to contraction, no nail defects or sensory disturbances. Allen had 57 patients and 60 amputations: the more proximal the cut, the higher the chance of nail deformity, return to work — 18 days for distal injury and 26 for higher.
Note that biology does not decide here. The review directly says that the choice between surgery and dressing is determined by the surgeon's beliefs, the tradition of a particular school, and how the intervention is paid for. Regeneration in children works, but it is not always turned on — when there is a more familiar solution.
And yet, the scar deserves its due. It closes the wound quickly, and rapid sealing is protection against infection, which kills more reliably than the absence of a new finger. Organisms capable of regenerating also go through wound healing, just their immune response is quieter, collagen is deposited later, and the matrix is subsequently remodeled. Hence another counterexample that breaks the simple logic "regeneration is always at the expense of cancer": the small intestine replaces its epithelium in a matter of days, shedding about 40 billion cells daily, and rarely gets cancer — precisely because the rapid shedding of mutated cells is its defense. This takes about 20% of the entire body budget with 2% of the mass.
The picture is this: in mammals, the regeneration code has not disappeared anywhere, but prohibitions are placed over it. Thyroid hormones close the window in the heart, polyploidization removes cells from the cycle, p21 and the leukocyte signal direct the wound into a scar, inflammation dictates how the matter will end. Some prohibitions have already been lifted in experiments, and not only in knockout mice: in the spiny mouse, they are lifted from birth, and this is also a mammal living next to us.
What wins me over in this topic is the main thing: the question has changed form. "Why can't we" has turned into "what exactly are we paying for this and when was the bill issued". We pay with endothermy and healing speed. When the bill is issued — is visible down to the week: in the mouse, it is the interval between the first and seventh day of life, in the frog — the stage of metamorphosis.
What remained behind the scenes: in placental mammals, the genes Ras-dva1 and Ras-dva2, which work in fish and amphibians, are lost, and no one has yet shown that returning them does anything. There also remains the correlation on 41 species, where thyroxine explains a lot, but not everything. And it also seems like a stretch to me to consider the liver a direct exception to the rule: its two features — restoration up to 80% of the original volume in three months and "younger than three years" by radiocarbon — may describe different processes in different zones of the organ, it's just convenient to measure them together.