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.

Through the first X papes in the series, Speakman and his jolly giants tested these hypotheses, as well as a couple other clever theories they dreamed up. My favorite among this back-catalogue is the evocatively titled: Limits to sustained energy intake. X. Effects of fur removal on reproductive performance in laboratory mice.

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. 

SICK PAPES SPECIAL ON CONTROVERSY: PART 1

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

VERSUS

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, GW and Ephrussi, B. 1936. The differentiation of eye pigments in Drosophila as studied by transplanation. Genetics 21(4) 225-247.

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. 

Blackiston DJ, & Levin M (2013). Ectopic eyes outside the head in Xenopus tadpoles provide sensory data for light-mediated learning. The Journal of experimental biology, 216 (Pt 6), 1031-40 PMID: 23447666

Our pals in the Department of Futuristic Neuroscience have recently attracted a lot of attention for a whacky pape that demonstrated that one rat could (sort of) learn to detect signals recorded from another rat’s brain. The main finding of this study, that animals connected by electrodes tend not to ignore each other, is fuzzily heartwarming, but ranks close to Feline papillomavirus on the grand scale of illness.

A much more compelling example of the brain’s dynamic ballsiness (i.e., the ability of neural circuits to learn to detect unfamiliar sensory stimuli), is described in a recent exercise in sickness by the duo of Blackiston and Levin. These pre-pubescent-frog-loving maniacs surgically removed the eyeballs of a couple hundred tadpoles, and then transplanted donor eyeballs onto different regions of the tadpole body (fanny, haunch, etc). The donor eyeballs were labeled with a fluorescent protein (RFP), so they could monitor the axons of the transplanted optic nerve. Most of the resettled eyeballs did not successfully innervate the central nervous system, but about ¼ of them managed to connect to the gut, and another ¼ innervated the spinal cord.

Blackiston and Levin then tested the population of chimeric tadpole beasts with an associative learning task that required the tadpoles to detect light in order to avoid an electric shock. A small number of the 200 freak tadpoles could learn to avoid red light, despite the fact that they did not have normal eyes. All of the successful learners had transplanted eyeballs that innervated the spinal cord.

It’s already incredible that transplanted eyeballs can successfully wire up to the spinal cord; the fact that tadpoles can then use the whimsical retina/spinal cord circuit in a behavioral task seems, at first glance, to defy the 14^th amendment of biology. But we’ve known for a long time that the nervous system is able to adapt to novel inputs. For example, the visual cortex of blind people can be colonized by auditory and somatosensory inputs, allowing them to fluently read using touch (Braille) and echolocate like bats (??).

The interesting question is not whether animals can learn to detect exogenous signals (e.g., spikes transmitted from a Brazilian rat’s brain), but how the hell the nervous system pulls out such meaningful signals of hope against the noisy background of torrential chaos and despair. This is some boring biology shit. In the meantime let’s get psyched about building an exoskeleton for the World Cup and teaching Big-Dog to throw cinder blocks.