Yen, J.H., Barr, A.R., 1973. The etiological agent of cytoplasmic incompatibility in Culex pipiens. J. Invertebr. Pathol. 22, 242–250.
Since our last post, two months ago, we here at Sick Papes have been riding the highs and lows of an almost indescribable emotional voyage from which we have only recently emerged, bursting with joy and self-knowledge.
It all began, like most of our emotional experiences, while we were blasting the Chances With Wolves radio show (which, in case you don’t know, plays the best music on the planet) at full volume while dissecting crickets under a microscope. All of a sudden, a song by Jonathan Richman called "Fly Into the Mystery" came on. This song, like many others by Jonathan Richman, is about the beauty and longing of summer nights in Boston. And it began to haunt me.
Driven by an unknown urge, I embarked on a literature search of other beautiful things that have happened on Boston summer evenings. This obviously led me to this 1924 pape, where two dudes took a break from their Great Gatsy-era shennanigans to look through a microscope for one GodDamn second an observe a strange bacteria living inside the ovary cells of the mosquitoes living around Boston and Brookline. These bacteria, subsequently named Wolbachia, remained mostly a curiosity for the next 60 years, thought to only exist in a handful of insect species. It wasn’t until the 1990s, when dudes figured out how to use molecular methods to identity cryptic bacterial species, that the trippy truth emerged: Wolbachia infect ~1 million species of insects (and other arthropods and nematodes), and are probably the most abundant endosymbiotic bacteria on the planet. And more importantly, their insane evolutionary success is largely because they can directly manipulate the reproductive behavior of their hosts.
Somes jokes, like the one about re-captioning every single New Yorker cartoon with “Christ, what an asshole!” stay hilarious no matter how many times you hear them. And it’s the same for some research topics: as far as I can tell, every pape that has ever dropped about Wolbachia is fucking amazing. It was in the vortex of insanely hot papes about Wolbachia that we have been trapped for the past two months, unable to stop clinking through to other hot references. It’s pointless to try to pick the best of the bunch, but this 1972 pape right here is straight up astounding. (OK, Wolbachia weren’t totally ignored until the 1990s, but they were definitely a left-field kinda thing.)
The background is that different populations of mosquitoes from around the world often can’t successfully mate with each other. This isn’t really a mind-blower - it’s the early stages of speciation, where the different populations still look like the same species, but their genomes have independently evolved to the point that they can no longer fit together quite right when they mate.
What IS a mind-blower is that, in this case, the reason these different populations can’t reproduce is because of the specific strains of Wolbachia that live in the ovaries of the different populations. If you simply feed the mosquitoes antibiotics, all of a sudden they can reproduce with the other populations. In other words, the Wolbachia bacteria is causing the formation of new insect species. This is also the case in Nasonia wasps, where three totally different species instantly become interfertile if you give them antibiotics.
If you ask me, one of the stupidest ideas out there is that of the “Man Cave.” The fact that a mainstream portion of my society thinks that the definition of manhood involves sitting in a specific room and watching TV and burning these remote-control-themed scented candles (or these ones) is nauseating, and I ask you to join me in weeping for the future generations of boy-children who will be raised with this double-whammy addiction to football and fucked-up aromatherapy.
That said, I’ll be DAMNED if there isn’t some seriously dope-ass research out there about some of the (actual) differences between men and women, and X-chromosome inactivation has got be near the top of the Hot column in this century’s “Research Topics: Hot-or-Not” list.
In mammals, XY individuals - those we often call “males” - carry a Y-chromosome, which contains a gene that initiates the cascade of developmental events leading to the growth of a male (including the development of male-specific organ known as the Butt). This is fine (and dandy), but because of this, females have twice as many X chromosomes in every one of their cells, which is not necessarily dandy because twice the chromosome means twice the mRNA levels of every gene on that chromosome, which could really harsh one’s mellow. In order to balance out the amount of transcription from genes on the X-chromosomes, every cell in the embryo of a female mammal shuts down one of the two X-chromosomes, completely silencing its expression. This is X-chromosome inactivation.
Probably the most famous manifestation of X-chromosome inactivation in action is the Calico Cat (editors note: complex internal rhyme unintended). The beautiful colors that besplotch the majestic Calico result from fact that pigmentation genes are located on the X-chromosome. During development, random cells throughout the cat inactivate either one or the other X-chromosome (each of contains a specific pigmentation gene), leading to the differential expression of pigment alleles in random patches of color on the adult’s fur. (Thus, all Calico cats are female, a fact that may surprise some of our readers who don’t already subscribe to Cat Fancy magazine).
The present pape addresses the molecular mechanism by which the X-chromosome shuts down. This process is known to involve a long, non-coding RNA (i.e. it doesn’t encode a protein product, but instead performs its biochemical handjob as an RNA) called Xist. Xist is transcribed from a specific location on the X-chromosome and then, in a bit of particularly trippy biological mystery, spreads to cover the entire chromosome over a period of hours like an iTunes visualizer, correlating with the cessation of transcription.
In this pape, a couple of major players in the game with, from what I can tell, infinity money, developed a technique to do time-lapse, deep-sequencing-based analysis of how the Xist RNA spreads to cover the X-chromosome during the process of X-chromosome inactivation. The first surprising thing is that Xist RNA doesn’t just leak outwards from its source along the length of the chromosome (like, for example, a two-dimensional pee stain on one’s shorts), but rather accumulates in very defined, specific spots across the chromosome (much like, for another example, forming a careful pee pattern in a snowbank).
The truly sick part of this pape, though, is that the regions where the Xist RNA accumulates are in fact the closest regions of the X chromosome in 3D physical space (not in 2D sequence space)! Because remember: the chromosome is packed into the nucleus like a crazily efficient, unknotted brick of uncooked Ramen noodles, so two points that are physically close in the nucleus may not actually be next to each other along the linear length of the chromosome. The model that the authors propose from their data provides quite heady visuals indeed, and we thank the authors for the opportunity to heartily update our mental imagery of one of the trillions of incredibly small machines working away in our cells.
Limits to sustained energy intake. XVIII. Energy intake and reproductive output during lactation in Swiss mice raising small litters. Zhao ZJ, Song DG, Su ZC, Wei WB, Liu XB, & Speakman JR (2013). The Journal of experimental biology, 216 (Pt 12), 2349-58 PMID: 23720804
Although binging is often attributed to weak human character, a substantial binge can also help a man get in touch with his/her reckless animal roots. Whether it involves a steaming heap of elk intestines or 3 seasons of Arrested Development, there are some treats that evolution has wired animals to consume beyond the point of reasonable satiety. Giving in to these deep urges is one of the many so-called flaws that the Catholic Church utterly failed to eradicate from our animal constitution.
A recent binge was triggered by the current issue of The Journal of Experimental Biology, which contained no less than IV sick papes about mouse lactation from Dr. John Speakman and colleagues. Further research revealed that, over the past decade, Speakman’s lab has published XVIII papers on this subject, each possessing the formulaic title: Limits to sustained energy intake., etc. This linear corpus of papes is ideally suited to sautéing an entire day in thick fatty mouse milk.
Each of these papes poses the same basic question: which factors determine an animal’s physiological limits? Speakman and colleagues study this question in lactating mice, who expend a massive amount of energy to produce milk for their thirsty pups. Two initial proposals were that milk production is limited by (I) the ability of the gut to digest food or (II) the efficiency of the mammary gland itself.
In this pape, the authors test the hypothesis that energy intake is limited by the capacity of an animal to dissipate heat. They increased the ability of lactating female mice to dissipate heat by shaving them bald as porpoises. Shaved mice ate more heartily and produced more milk, which in turn increased the size of their adorable mouse children. This result contradicted the long-held views that nursing performance is limited by the efficiency of the mother mouse’s digestion and subsequent milk production.
Although these initial results suggested that there might be one or a couple limitations to energy expenditure, the most recent papes (XIV - XVIII) show that the story is actually much more complicated. Under different environmental conditions, lactation efficiency and offspring growth are limited by several overlapping factors. There are also important differences across mouse strains. Despite the lack of simplicity in the underlying biology, the narrative organization of these XVIII papes that ask the same, seemingly basic, question, demonstrate an experimental doggedness that you got to respect.
Brenner, S., Jacob, F., and Meselson, M. 1961. An unstable intermediate carrying information from genes to ribosomes for protein synthesis. Nature (4776): 576-581. [PDF]
Francois Jacob, our hero many times over, died on April 19, 2013. Much has been written about Jacob, including the most inspiring book of all time, his own incredibly-titled autobiography, and many simply jaw-dropping remembrances of his life and career (which didn’t even begin until the age of 30, prior to which point he was fighting against the Nazis as a military doctor). In light of this, we wish to pay our humble respects to Jacob by focusing in on one of his most truly moving papes, in which he helps figure out that mRNA is the intermediate messenger between DNA and protein. As someone who has grown up learning about DNA, RNA and protein from textbooks beginning at the age of 13, it is unspeakably humbling to realize that even such awe-inspiring knowledge as this was unleashed in the form of a single Pape. Given the torrential onslaught of meaningless papes which flood our poor inboxes daily, it is mindboggling to imagine what it must have been like when a pape of this stature and dignity could simply show up in Nature one week. We are all indebted to the True Pape such as this one, and we continue to pray for many more like it. In tribute to Jacob, we heartily recommend you enjoy his wonderful papes first-hand.
By the beginning of the 1960s, it was known that the physical basis of heredity was DNA, and it was strongly believed that the sequence of bases in DNA was co-linear with the sequence of amino acids within proteins. However, it was also known that DNA doesn’t leave the nucleus, whereas protein synthesis takes place in ribosomes, which are in the cytoplasm. The question, therefore, was how does the information get from the nucleus to the cytoplasm, and what is the molecular basis of this process? The best guess at the time was that each ribosome acted as a specialized template for a specific protein. Given that ribosomes are made of RNA, after all, it made perfect sense to imagine that the ribosomal RNA contained sequence-specific information which could encode a specific protein.
[At this point, as an aside, and just out of curiosity, would any of you know how to prove that mRNA is the messenger, even knowing the right answer beforehand? Even if you could go Back to the Future 2 with the book of correct answers to biology, could you figure out how to do these experiments to prove it? I sure couldn’t. There are those who believe that science progresses largely within social constraints, and that the intellectual contributions of specific individuals should not be hero-worshipped, and that somebody else would have figured it out pretty soon anyway. This may or may not be the case (it isn’t - you should definitely hero-worship Jacob and his crew), but I dare you to let this pape wash over your brain and not “need a minute” to collect yourself].
In any case, there is a true story where Jacob visits Brenner and Crick, and he’s telling them about his latest results implying the existence a short-lived molecule between DNA and protein, and they’re all at a party (probably much like the exact opposite of the moon-tower kegger in Dazed and Confused), then someone recalls a recent pape showing that after a virus infects a cell, there is this short-lived species of RNA that arises, which the authors hadn’t known how to interpret in their own pape, and then apparently everybody at the party starts screaming and Jacob doesn’t really speak English but picks it up quickly enough, and later that night they have all of the experiments planned out, and within weeks and they’re headed to Matt Meselson’s lab to use his ultracentrifuge.
The basic set-up is this: grow a bunch of bacteria in heavy nitrogen and carbon, infect them with the virus, and then transfer them immediately to a light medium. Any new products will be light, and any old products will be heavy, and the two can be separated by density in an ultracentrifuge in a cesium chloride density gradient (ground-truthed in Figs. 2 and 3). Using this set-up, they show that upon infection with virus, a new species of RNA is formed (Fig 4), which has a short half-life on the order of 16 minutes (Fig 5), and which associates with the old, heavy ribosomes (Fig 6). That is, the new RNA does not make new ribosomes, but represents a new, previously unknown species of RNA (the messenger!). They then show, using labeled sulfur, that the newly synthesized viral proteins, together with the new RNA, are also found on the old, heavy ribosomes (Figs. 7 and 8), disproving the idea that specialized ribosomes form each protein individually. Hallelujah!
In addition to figuring out one of the basic truths of life, there are two details of this pape which are particularly insane. (1) These experiments, with the exception of the sulfur stuff, were done by Brenner and Jacob in a period of four weeks, in a dirty basement, while visiting a lab that neither Jacob nor Brenner typically worked in. What’s more, the experiments completely failed for the first three weeks and the actual data was gotten in that one final week when no one believed in them. (2) The heavy carbon, which was necessary to separate out old and new ribosomes, was not just something you could buy. According to this great interview with Meselson, it did not exist anywhere in the USA or Japan, and so he got Linus Pauling to directly ask the head of the Soviet Academy of Sciences to make one gram of it for them, which they did by thermal diffusion, over the course of one full year. They delivered it to Meselson as a gas, which Meselson then turned into carbon dioxide that he fed to algae, which photosynthesized the heavy carbon into their bodies, which he then fed to yeast, which he then used to make yeast broth to feed the E. coli. Point is, these people were not kidding around at all, and we are eternally grateful for that.
There are some scientific subjects that attract recreational bedlamites like seagulls to a coastal landfill. My favorite of these is magnetoreception: the ability of an animal to perceive an ambient magnetic field. Lots of animals can do this—birds, insects, reptiles— and some of them use the earth’s weak magnetic asymmetry to achieve extraordinary feats of navigation. For example, scientific hero Ken Lohmann has shown that sea turtles navigate thousands of miles through the horrific salty ocean in order to meet their half-shelled-brethren at a specific location for an annual Bacchanalian picnic. Ken’s lab also found that if you move a spiny lobster 20 miles in any direction from its preferred hangout spot, it immediately returns directly to its headquarters using cues from the earth’s magnetic field. These and bajillions of other examples demonstrate that many of the earth’s macro-biotic inhabitants can use a magnetic sense to cruise around in magnificent style, which, in my humble opinion, is absolutely fucking fantastic.
Returning to the bedlamites. There are two dudes in particular that illustrate the fact that magnets exert a certain ineffable force upon the zanier castes of our super-organismic civilization. The first of these is shown in the video above: Mr. Harry Magnet, whose extensive pape on personal perception of magnetic fields cannot be deemed sick or otherwise, because it has not undergone rigorous peer review (but we welcome submissions).
The second example comes from Alane Jackson, the purveyor of a theory called magnetrition, which was first explained to me by a youth soccer referee who lived in a wigwam on an magnetically neutral island in the middle of an Alaskan lake. Basically, Alane’s idea is that mitochondria are magnetically charged, and that jostling our cells around causes cytoplasmic stirring, thereby promoting health. I also recommend another section of Alane’s website, titled Smoking is good.
Buried beneath all of this absolutely essential HTML is an equally intense scientific debate about the mechanisms by which real animals measure magnetic fields. So far, two basic mechanisms have been proposed:
(1) MAGNETITE. The magnetite hypothesis was inspired by the observation that some magnet-loving bacteria produce magnetite (Fe3O4) crystals that cause them to align with and cruise along the local magnetic vibe. Because magnetite has also been found in the snouts/beaks of fish and birds, it was suggested that the rotation of these crystals could be detected by mechanosensory neurons in the brain. Smaller, “superparamagnetic crystals” have also been found in bird beaks. These crystals do not have a permanent magnetic moment, and therefore do not individually rotate to align with the earth’s magnetic field. However, large arrays of these superparamagnetic crystals would attract and repulse each other under different magnetic field conditions, generating forces that could, in principle, be sensed by neurons.
(2) CRYPTOCHROME. This second mechanism is even bonkers-er. Some radical-pair chemical reactions can be influenced by magnetic forces—one example is the absorption of light by retinal photopigments called cryptochromes. The idea is that the ambient magnetic field would alter the rate of cryptochrome photo-isomerization, so that if a bird were gazing upward at a clear blue sky, it could actually “see” a hazy magnetic field image layered on top of the normal visual scene.
The argument surrounding these two mechanisms is best exemplified in the bird magnetoreception literature, which has been enriched in recent years by a flurry of combative pape-slinging. In one camp, (1) the Wiltschkos and their pals claim that birds use little magnetite particles in their beaks to detect magnetic fields, while in another camp (2) Henrik Mouritsen and his pals claim that magnetoreception arises in the retina, mostly likely through cyptochrome. (3) David Anthony Keays and his buds weighed in on side 2 of the fracas last year, when they suggested that those magnetite particles in the beak are located inside little pieces of biological irrelevance called macrophages.
Although the field of magnetoreception is confusing and controversial, one cannot help but delight in the titillation-level of the questions and the unfettered academic shit-hurling. Magnetoreception is clearly the modern El Dorado, attracting both well-funded academics and itinerant kooks. There is the important possibility that everybody is right— that birds have two independent magnetic senses and so do people, and the booty will be split evenly amongst the Professors and the online gurus. It seems much more likely to me, however, that this entire field is booby-trapped, and that all the magnet-lovers will end up stalking monkeys on a raft as the river below their feet slowly transforms into a cauldron of boiling soup.
Hödl, M., & Basler, K. (2012). Transcription in the absence of histone H3.2 and H3K4 methylation. Current biology : CB, 22(23), 2253–2257. doi:10.1016/j.cub.2012.10.008
Pengelly, A. R., Copur, Ö., Jäckle, H., Herzig, A., & Müller, J. (2013). A histone mutant reproduces the phenotype caused by loss of histone-modifying factor Polycomb. Science (New York, NY), 339(6120), 698–699. doi:10.1126/science.1231382
Biology is bursting at the seams with controversy. By far the most important controversy in modern biology is whether taking steroids makes your penis smaller, or whether this is just some D.A.R.E. bullshit they told us as kids to prevent us from fully achieving the glorious manifestation of our god-granted, muscly-man physiques. For those of us who believe that, in fact, steroids may help the enlarge the penis, a sub-controversy exists over whether one should inject the steroids directly into his or her penis. (Answer: currently up for debate on numerous message-boards.) Our colleagues have recently dubbed this expanding field “Penomics,” and we believe it to be rife with promise.
Arguably the SECOND-most important controversy in modern science is related to the importance of histone modifications in gene regulation and epigenetic inheritance. Here’s the low-down: DNA is a linear molecule, but is physically wrapped around structures made of histone proteins (the entire group of histones is collectively known as a “nucleosome”). The histone proteins can be modified at specific amino acids by the addition or removal of chemical groups such as methyl-, or acetyl-, which may help them physically move so that a given piece of DNA is “unwrapped” from the nucleosome and becomes relatively available for transcription.
While there is undoubtedly a strong correlation between histone modification and transcriptional activity, skeptics have pointed out that there remains very little definitive proof that histone modifications are causally important for the regulation of the nearby DNA (i.e. whether a gene is “turned on” or not is influenced by the modifications on the nearby histones). Despite this uncertainty, many writers have gone way overboard and claimed that histone modifications represent the ultimate secret key by which gene regulation is maintained across multiple generations. The masturbatory frenzy of celebration around this field has recently been strongly criticized by the God-like Mark Ptashne in a blunt letter he wrote to the Proceedings of the National Academy of Sciences.
The reason that there is so little direct evidence for the function of histone modification function is because histone proteins are exceedingly difficult to alter in vivo. This is because there are 23 copies of the histone genes (in fruit flies). What are you crazy sons-of-bitches gonna do, mutate ALL of them at once? In fact, yes. Some ambitious lads and lasses took advantage of the fact that these 23 histone genes all lie physically next to each other on the chromosome, and they built a fly with a large chromosomal deletion spanning this entire region. Then, by adding in mutant histone proteins (which, for example, cannot be chemically modified at a specific amino acid), they can ask whether this specific amino acid modification is actually necessary for the histone function.
These two papes present very similar experiments, but report essentially opposite conclusions (sort of). In Pape 1, dudes make a fly whose entire complement of Histone3 cannot be methylated at Lysine #4 (which has been proposed to be required for active transcription at a given genomic site) - i.e. every single nucleosome along the entire genome of a given cell contains histone3 that can’t be methylated at this position at all - and yet they find that these cells can transcribe perfectly fine, and express all the right genes. In other words, methylation at H3K4 cannot be causally required for transcription. Ooh chi wally wally!
But then Pape 2 (Pig in the City) chimes in with a very similar fly, but whose Histone3 cannot be methylated at lysine #27 (another site proposed to be essential, this time for repressing genes). In these motherfucking flies, the cells have completely screwed up gene expression, exactly mimicking the effect of removing the methyl transferase that adds that methyl group. Ooh chi bang bang!!
The debate rages, dudes are battening down the hatches, and our blood-soaked tax dollars continue to fuel this Amazing Race. Me personally, if I have to take sides, I bet that histone modifications are causally important, but this feeling is entirely uninformed, its just my personality!!!
Jakobsen, L., Ratcliffe, J. M. and Surlykke, A. (2013). Convergent acoustic field of view in echolocating bats.Nature. 493, 93-96.
Bats have surpassed all other some odd 6000 species of mammals by evolving the ability to fly. Bats use powered flight to streak through the night, unlike those wanna-be “flying” squirrels, sugar gliders and Brazilian daredevils. In addition to the unique ability to fly, microbats use sonar to “see” delicious insects whilst flapping about (versus the megabats aka flying foxes that presumably use vision to target juicy fruits). Microbats, although micro, come in a range of sizes (~4-16 cm, some would say). The size of a bat relates to the peak frequency of an emitted sonar beam, so that smaller bats use high frequency sonar beams and larger bats use lower frequency sonar beams. For years, bat fanatics have explained this frequency-size relationship under a dubious assumption. The story goes that, because small bats eat small insects, they need higher frequencies (shorter wavelengths) in their sonar beams to adequately reflect off the smaller prey, and vice versa for larger bats. As explained in this most exquisite batpape, this story is a damned lie!
First, even small insects will reflect echoes in the lower end of the bat’s call range. Second, by rudely removing hard-caught meals from bat stomachs, most bats are found to have eaten insects with lengths much shorter than the wavelengths in their sonar beams. To get to the bottom of this bat quandary, these ill authors used a microphone array to measure the shape of the sonar beams emitted by several different species, covering a range of bat sizes, while flying in the same flight arena. They found that each bat species could adjust the shape of the sonar beam dynamically to be wide (encompassing a large volume around the bat) or narrow (encompassing a smaller, more focused region in front of the bat). Narrow sonar beams concentrate energy, which counteracts atmospheric attenuation of high frequency sound, thereby increasing range. Wider beams are better for detecting peripheral targets at shorter ranges. In fact, each species studied used the same sonar beam shape in the fixed experimental arena, predicting that these bats were optimizing their calls to suit the environment that they were placed in.
But how does a gruesome bat change the shape of its sonar beam? There are some options: (1) the frequency of the call can be adjusted, with higher frequencies producing narrower beams than lower frequencies, and (2) the width of the mouth (gape) during a call can be adjusted, with larger gapes producing narrower beams than smaller gapes. Smaller bats have smaller mouths and cannot open as wide as their larger brethren. Smaller bats also cannot fly as fast as big bats in the open field. If you’re a fast flying bat, longer detection ranges are needed to avoid slamming into a tree or a windmill. For big bats, longer ranges are easily obtained by using lower frequency calls, which are more resilient to atmospheric attenuation, and their massive gapes can keep the beam narrow and focused. Small bats don’t have the big-mouth option; instead they must use higher frequencies to narrow the sonar beam, which explains the tendency for small bats to use higher frequency calls. In sum, this wicked batpape brings together an impressive amount of data to show that bats optimize their sonar beam shapes to suit their environments, and provides a vastly improved explanation for the relationship between call frequency and size.
Like the Joker, I am fascinated by this amazing bat technology. How do bats optimize their sonar beams on the fly? Presumably something interesting is going on in those bulging bat brains that allows them to converge on the appropriate beam for every occasion, no matter how big the bat might be.
Ahrens, M. B. and Keller, P. J. (2013) Whole-brain functional imaging at cellular resolution using light-sheet microscopy. Nature Methods.
BAM, aka “Brain Activity Map”, is the brainchild of a Mr. President Obama and colleagues (2013). First announced via the nytimes.com, and first coined by the eminent chef Emeril Lagasse, the BAM seeks, by my understanding, to record the activity of every single neuron in the brain with high temporal and single neuron resolution. Clearly, this is a good idea and everyone should contribute. Some of us (this sickest ones) have contributed more than others (the healthy people). As evidence, gaze upon these fucking splendid videos. Ahrens and Keller used new imaging and genetic methods to BAM the zebrafish larva. Zebrafish have crazy behaviors and have many of the same brain parts that humans do. Now, if you are not satisfied, then read the nature news yourself!
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.