Like many people, I have conflicted views about the reams of Supplemental Data that accompany the online versions of most papers published these days. At its worst, Supplemental Data is nothing more than a grainy video of a bat performing fellatio, overdubbed with thumping techno. At it’s best, however, a truly great Supplemental Figure reminds me of the famous scene in When Harry Met Sally where Meg Ryan loudly fakes an orgasm in a crowded restaurant, except that for me, the orgasm is real, and in those moments of ecstasy I am neither woman nor man but purely divine flesh of the GodBody incarnate. This Supplemental Text Document right here is one of those good ones which make me very glad to be living in the “Era of Supplemental Data,” as it was recently dubbed by Francis, the first pro-Open Access Pope.
To be real with you, I’ve never seen a Supplemental Document quite like this one. While Supplemental Data most often includes extra methodological details, additional controls, large datasets, or tangential experiments requested by reviewers, this one is a long-form prose essay about a decade-old scientific disagreement between these authors and a different lab. We here at SickPapes don’t take sides in this quagmire - both of these labs are outrageously hot and time-tested - but we find it surprisingly compelling to read such an emotionally honest and open piece about a genuine scientific disagreement.
Our story begins in 2001, when Paul Schedl’s lab published a paper in Cell providing evidence that a secreted protein called hedgehog is involved in guiding embryonic germ cells as they migrate towards the future gonad. In one key set of experiments, they ectopically expressed hedgehog in abnormal locations, and showed that germ cells migrated incorrectly. This was interpreted to suggest that hedgehog is sufficient to influence germ cell migration.
As far as the public was concerned, the next thing that happened was In 2007, when Ruth Lehmann’s lab published a rebuttal, with the unambiguous title “hedgehog does not guide migrating Drosophila germ cells.” In the Lehmann lab, the hedgehog ectopic expression simply did not affect germ cell migration as it did in the hands of the Schedl lab members. This was not a matter of subtle differences in methods, this was literally a direct repeat of a simple experiment, giving different answers. Both labs are highly respected, and this discrepancy was hard to explain without getting a tad bit disrespectful.
Which brings us to explaining why this new Supplemental Essay from Schedl’s lab is so sick: it explains what was happening behind the scenes at Cell the whole time. First, they reveal that the Lehmann lab’s 2007 paper actually originated as a technical comment sent to Cell in 2002 in response to the original 2001 article. The Cell editors asked the Schedl lab if they wanted to retract their paper, and the Schedl lab said “No.” Instead, they came to an agreement with Cell that an outside, independent researcher would repeat the hedgehog experiments, communicating only with Cell and not with either of the labs in question (Shout out to Stephen DiNardo, stepping in to do a major solid for the scientific community without any personal glory).
After an extended drum-roll, Dr. DiNardo told Cell that his independent experiments confirmed the original results from the 2001 Schedl lab paper, not the Lehmann results. So, what does Cell do with this important finding? Nothing. Instead of publishing this informative back-and-forth, they didn’t make any of this public, and just let everyone gossip for a decade. And, according to the Schedl lab in this Supplemental Text, this gossip-filled silence has “undermined [their] credibility in the scientific community, jeopardizing [their] careers.” Damn, Cell - that is some cold shit. I wish more folks would publish Supplemental Emotionally Honest Essays detailing the strife that various journals put them through. At the least, this might add fuel to Randy Schekman’s dope protest against journals like Cell.
With that, we here at SickPapes wish to salute any and all Sick Supplemental Data, and wish you a very happy 2014!
Beadle & Tatum are basically the Cheech & Chong of biology, in that they are complete geniuses who were way ahead of their time. These were the two heroes who showed up in the 1940s when everyone was wildly speculating about the physical nature of these mysterious things called “genes” and showed that each gene gives rise to one single protein product (the so-called “one gene - one enzyme” hypothesis). Their famous experiments were done by inducing x-ray mutations in a fungus called Neurospora, and then showing that each individual mutation could be rescued by supplying a single, specific nutrient - in other words, that a single genetic mutation causes a single, specific fuck-up in a single enzyme. They even went the extra step of confirming that each of these mutations is inherited like a Mendellian recessive and was therefore a single gene.
The spine-tingling thing about the Beadle and Tatum experiments, though, is that they are so outrageously perfect and beautiful that it is truly terrifying to anyone who has ever tried to do an experiment one’s self. When I read the first Beadle and Tatum pape, it makes me feel like I’m a particularly stupid and tone-deaf 6-year old banging on some pots and pans, hearing the congo playing on “Life’s a Gas” for the first time - i.e. that it is time to throw in the towel because I’ll never achieve anything even approaching that level of perfection.
But buddy, if you are lucky enough (and have access to enough adderall) to have read Beadle’s Noble Prize acceptance speech, you will see that the elegance and clarity of his most famous work is largely the result of a set of earlier experiments done with Boris Ephrussi, which themselves are a LOT more like experiments most of us have attempted: insanely technically challenging, time-consuming and labor intensive, and although really suggestive of something potentially important, never really coming anywhere close to actually proving that potentially awesome thing because that goal won’t be attainable for decades.
Beadle and Ephrussi worked together at Caltech, studying the genetic control of eye-color in fruit flies. Fruit flies were already a powerful system for experimental genetics, so many different mutations had been isolated which gave rise to unusual eye-colors. Working with these different mutant lines, Beadle and Ephrussi physically transplanted the eye primordia from these different mutants into host larvae of different genotypes, making three-eyed flies (this was the psychotically difficult technical part). By reciprocally transplanting between these genotypes, they showed that two of the eye-color mutants (cinnabar and vermillion) were “non-autonomous,” meaning that it was the genotype of the host rather than the donor tissue that controlled the eye color.
The next part, though, is where the scary-genius shit happens. When a cinnabar eye is transplanted into a vermillion hosts, the eye remains cinnabar-colored. But when a vermillion eye is put in a cinnabar host, the eye becomes normal colored! Although this typically shouldn’t make sense to anyone who isn’t on Peyote, Beadle and Ephrussi came up with the idea that perhaps vermillion and cinnabar represent mutations in different genes within a single biochemical pathway that ultimately produce eye pigment. In other words, their idea was that the eye color pathway would be: “Precusor Substance -> Vermillion substance -> Cinnabar substance -> Pigment.” where the substances are diffusible throughout the host body, but interpreted locally within organs, and ultimately control eye color. Even when you know the answer it’s still confusing to think clearly about how this works, so it’s really jaw-dropping how these dudes were able to figure it out from scratch, before anybody else in the entire world understood what it might mean.
These experiments and their interpretation are so hot that my computer battery starts smoking every time I open the PDF. It’s like Beadle and Ephrussi stepped into an ancient temple completely brimming with confusing symbols and death-traps, yet were instantly able to shine the laser on the one specific key symbol that opens the trap door to all the gold coins. And its particularly cool to realize that from these really complex reciprocal eye transplantations, Beadle and the boys were already thinking that genes give rise to distinct biochemical entities, and that because of this, he could design the Beadle and Tatum experiments precisely to prove what he already suspected: that each gene encodes one specific product.