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Friday Fun Thread for January 20, 2023

Be advised: this thread is not for serious in-depth discussion of weighty topics (we have a link for that), this thread is not for anything Culture War related. This thread is for Fun. You got jokes? Share 'em. You got silly questions? Ask 'em.

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tl'dr at the bottom.

It was the early 20th century. These were heady times for biology; Thomas Hunt Morgan was doing groundbreaking work in Drosophila which culminated in the concept of the gene. Griffith reported some experiments that launched a series of investigations over the following decades by Hershey & Chase/Avery and McLeod showing that DNA, not protein, is the hereditary material in the cell. And in a lab in the Rockefeller Institute, NYC, a French surgeon was using proto-tissue culture techniques to create an immortal chicken heart.

A full century ago, some smart scientists were already asking how cellular theory intersected with aging and senescence, and whether there where limits on cell division. To great acclaim, Dr. Carrel claimed to have found the answer: he grew embryonic chicken heart cells in a stoppered flask. For 20 years the cells thrived as he fed them a steady diet of embryonic chicken fluid and claimed to the media that:

In 1921, an article in The World by Alessandro Fabbri engaged his audience with an account of how large the volume of the cells cultured could have been, telling readers that it would have been like a “rooster … big enough today to cross the Atlantic in a stride,” and “so monstrous that when perched on this mundane sphere, the World, it would look like a weathercock.” Three years later, the New York Tribune published an article to celebrate the twelfth birthday of the culture.

You might be skeptical at this juncture - maybe you learned about a certain limit in high school named after a famous scientist waiting in the wings. While it was long accepted in the 20th century that cells could divide forever and the answer to aging lay elsewhere, the development of modern tissue culture techniques in the 50s set the stage for Leonard Hayflick (I linked a great radiolab interview above - in his mid 80s, he still stored a ton of cell lines in liquid nitrogen tanks in his garage. There's probably some fascinating cell lines in there that the rest of us have forgotten about). And indeed, Leonard Hayflick showed with much more rigorous technique that differentiated cells isolated from human adults had a definite lifespan, and would naturally senesce and die after a certain number of divisions in vitro, and presumably in vivo as well. A large amount of work went into defining the 'Hayflick limit' for various cell types in different contexts, and more importantly, it was discovered that certain cancerous cells could indeed be adapted to grow in cell culture indefinitely. It turns out Carrel's protocol of adding fresh embryonic fluid to his chicken heart culture was most likely adding fresh stem cells (although we also cannot rule out fraud as the experiment supposedly could not be replicated) on a regular basis.

You may wonder, dear reader, why I bothered to lay this out for you? Well, if you think about it, there's one obvious exception to the Hayflick limit - your germ line. Your gametes represent an unbroken cellular lineage stretching all the way back to the first spark of cellular life in the primordial soup. And this week, a heroic paper described another exception to the Hayflick limit and actually succeeded in creating the immunological equivalent of Carrel's chicken heart.

When T cells recognize their specific antigen, they enable a initiate a genetic program to both rapidly divide and also release effector proteins that unleash a range of defensive mechanisms against the invading pathogen. You've probably heard of the different COVID proteins used in the vaccines; each of those proteins consisting of hundreds of amino acids is chopped up into 8-20 amino acid long 'bytes' that can be recognized by T cells. While your immune response consists of a mishmash of dozens to hundreds of T cell lines specific for different antigens (polyclonal), scientists have developed ways to track a single clone specific for a single antigen. Here, the authors infect mice with a virus (VSV) and track T cells specific for a peptide (VSV-N52-59). Techniques have also been developed to take T cells out of one mouse and transfer it to a new mouse, and the last piece of the technological puzzle missing for Carrel - a method for differentiating transferred T cells from the endogenous T cells already present in the new mouse.

So the basic outline of the study is to infect a mouse with VSV, isolate those T cells, transfer to a new mouse, infect that mouse with VSV, isolate those T cells, transfer to a new infinitum. They kept it up for 10 years, or 5 times the lifetime of a mouse - roughly equivalent to stimulating some T cells around the time Columbus landed in America and having them still be growing today. Curiously, the telomere length is unaffected despite the cells acquiring a number of markers we normally associate with dysfunction (PD-1 of cancer checkpoint blockade fame, TIM3, TOX, KLRG1, etc) and a distinct transcriptional signature. And more importantly, they're still immunologically functional and capable of further division.

How do T cells do it? Hell if I know. But the standard models of ROS, telomeres, mitochondrial dysfunction, etc. just aren't able to explain it. Like the best studies, this hints at a deeper truth we're nowhere close to uncovering, and I despair of meaningfully understanding the system in my lifetime. It's still a beautiful fucking paper though, and I pity the post-doc who's been shuffling T cells around mice for the last 8 years of his life.

tl;dr - Mice live two years, scientists have shown that you can take differentiated T cells (not stem cells!), stimulate them with a virus, transfer them to a new mouse and so on and so forth for more than 10 years (!). They calculate this to be a 10^40 fold expansion of the original group of T cells.

You're correct, but it's also just typical biologist-speak. Carrel also didn't literally culture enough cells to create a rooster that could cross the Atlantic in a single stride.

Typically, when the media is exhausted (every several days) you 'pass' the cells and throw out some fraction (from 50-95%). If you pass the cells 1/10 a dozen times and then do the math, if you hadn't killed any cells you'd have some absurd number. Here, they only transfer 10^5 cells to each new mouse and thus discard the vast majority of their T cells when they kill the old mouse, not to mention the fact that most cells will die during the isolation/sorting/transfer procedure.