Showing posts tagged sickpape

SickPapes Special on Suren N. Sehgal (1932-2003) and the discovery of the TOR pathway


Vézina, C., Kudelski, A., Sehgal, S.N., 1975. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J. Antibiot. 28, 721–726.


Laplante, M., Sabatini, D.M., 2012. mTOR signaling in growth control and disease. Cell 149, 274–293. 

In our younger and more vulnerable years, it was exciting to learn “how things work.” But, as we’ve grown older, and gotten more seriously into smoking weed, it is the discovery stories behind ”how things work” - the ways that people figured it out in the first place - that we find truly spine-tingling. We’ve said it before, and we’ll say it again: there is nothing better than choosing a hot-ass research topic, strapping yourself in, and doing a psychadelic literature search all the way back to the beginning to see how it all got started. The euphoria from the resulting “PubMed High” is, truly, nature’s candy.

Case in point: TOR signaling. TOR signaling is a highly conserved pathway that cells use to respond to nutrients and other external signals, and is therefore a central focus for tons of important biomedical research on conditions that involve cell growth and/or nutrition, things like cancer, diabetes, and obesity. There are, quite literally, shit-loads of papes about TOR - trust me, I’ve smoked them all. 

Given how “mainstream” and “biomedical” this field is, I was not at all emotionally prepared to learn how the pathway was discovered. To begin, look no further than the name of the pathway: TOR, which stands for “Target of rapamycin.” This name refers to the fact that the pathway responds to (i.e. is disrupted by) a drug called “rapamycin.” Rapamycin, it turns out, is where the story gets freaky-deaky, and leads us to the trippiest place on earth, Easter Island. And Easter Island, as we know, is where all scientific discoveries ultimately begin. 

In 1964, a team of Canadian microbiologists went to Easter Island, looking for soil microbes that produce natural antibiotics. One of the soil samples they collected contained a bacterial strain which secreted a factor with potent anti-fungal activity. Dr. Suren N. Sehgal and his team named this factor rapamycin, in honor of the local name for Easter Island, Rapa Nui.  

There is a cliche of scientific discovery stories that goes like this: an unsuspecting biologist, studying some relatively obscure organism, winds up identifying a molecule that has wildly important and far-ranging applications. Penicillin is the most famous example, but similar stories are told about Green Fluorescent Protein (from jellyfish; now used to visualize proteins in vivo), thermostable Taq polymerase (from a hot-springs bacteria; now used to amplify DNA), and CRISPR-associated enzymes (from yogurt bacteria, now used to achieve GATTACA-esque dystopic fantasies about modifying babies).

Of course, by now it has also become almost cliche to point out that this Surprise-turn-NobelPrize narrative is total bullshit, and all of these discoveries were in fact made by excellent, forward-thinking scientists who knew what they were doing. Not to say that there wasn’t some element of serendipity in how revolutionary such discoveries ultimately became, but it’s important to emphasize that these discoveries were not lucky one-offs. As many mythbusters have pointed out, even the “accidental” discovery of Penicillin was actually done by a guy who had devoted his whole career to identifying anti-bacterial compounds, and involved lots of work by others who are rarely credited. As it has been written before: “Tenacity frequently precedes rather than follows serendipity.” 

Point is: Dr. Sehgal did not just “get lucky.” While it might be tempting to imagine him as an esoteric microbiologist with no idea how important rapamycin would become, this was not how it went down at all. Dr. Sehgal ran a lab at a pharmaceutical company that was set up specifically to systematically screen for anti-microbial factors produced by other microbes. Once they identified these Easter Island bacteria, they quickly isolated the active compound (rapamycin), figured out how to produce it in quantity, and then discovered that, in addition to it’s anti-fungal properties, rapamycin worked in mammals as a powerful immunosuppressant. (Rapamycin was eventually turned into a drug to help suppress the immune system after organ transplants.) Rapamycin was soon discovered to also suppress the proliferation of some kinds of tumors. 

In the 50 years since the discovery of rapamycin, an enormous number of researchers have worked to identify the pathway that is targeted by rapamycin (the TOR pathway), and have begun to figure out the complex ways that this this pathway links external signals (like nutrition) to control of the cell cycle and other basic metabolic processes. This explains how rapamycin suppresses tumor growth (by blocking the progression of the cell cycle), and it suppresses the immune system (by blocking the proliferation of immune cells in response to antigens). That’s what we call a “hot pathway.” 

To read more about Suren N. Sehgal, check out this moving tribute to his research and life, which celebrates “his life and his contributions to mankind.”  

Contributed by benewencampen

Gert Holstege, Janniko R. Georgiadis, Anne M. J. Paans, Linda C. Meiners, Ferdinand H. C. E. van der Graaf, and A. A. T. Simone Reinders Brain Activation during Human Male Ejaculation The Journal of Neuroscience, October 8, 2003, 23(27):9185-9193.

This pape applauds itself for being the first of its kind to demonstrate that not only is the whole run up to cumming pretty great, but the main event is fun too.  Respect.  Sure, the authors didn’t normalize for the apparently limitless virility of the dudes who came twice, on cue, in a single recording session (or, conversely, for the sandpaper-like palms of the girls whose men didn’t succeed”), nor for the lack or presence of lube (but honestly, who could keep their heads still while getting a dry HJ in a PET machine?).  And strangely, neither did the guys who came nor those who didn’t “report important differences between their sexual experience under normal circumstances and in the scanner.”  The authors don’t attempt to make sense of this perverted reflection of the sexual fantasies of the men, and press ahead in their attempt to generalize the images of ejaculation collected from subjects strapped down in PET machines, getting saline injected into their forearms, to orgasm in principle.

But methodology aside, this pape helps push us towards a neurobiological answer for the sick & pressing question: why do spinal cord injured patients want to fuck even more than they want to walk?  For the irresitable cum-drive rears its tumscent head in this pape even more powerfully than the authors seem to recognize, for while they were off searching for causes and therapies for sexual impotency, assuming that ejaculation is fun because it’s involved in sexual reproduction, their fancy-ass Ecat Exact HR+ 32-ring PET scanner got incorporated into 8 different obsessional sexual fantasy / cum-producing machines.

Contributed by gagaboatly
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