Author: russhodge

I am a science writer at the Max Delbrück Center for Molecular Medicine in Berlin, author of fiction and popular science books, an artist, and a professional musician who performs on the viola da gamba and Medieval and Renaissance stringed instruments. I edit manuscripts of all types and teach the full range of scientific communication skills. I am doing theoretical work in this subject - see for example https://goodsciencewriting.wordpress.com/2018/03/11/ghosts-models-and-meaning-in-science/

Mating with Neanderthals

Today, April 1, Nature Communications reports on another study on those sneaky Neanderthal genes that crept into the modern human genome, probably by climbing up a tree in the yard and entering through a bedroom window. In a popular article describing the project, Emily Willingham writes:

…Khrameeva and her colleagues noted that speculation regarding some Neanderthal-H. sapiens gene flow through sexual reproduction is “appealing.” And experts in the field generally agree that the idea is plausible, even if it’s not their favored explanation.

Now most Homo sapiens wouldn’t consider mating with a Neanderthal very appealing, but we do have to consider that about 4% of our genome derives from Neanderthals, so I’m guessing about it appeals to about 4% of the population. Since some governments are considering expanding the definition of marriage to include relationships with other species, at least when submitting their tax returns, it’s time for this minority to speak up and be heard.

Some little-known facts about Kansas

These remarks were short-listed from the Science Cabaret. Quite a while ago I offered them to the Kansas Board of Tourism to use as an endorsement for our state, free of charge. I am still waiting for a response.

Kansas occupies the exact geographical center of the continental United States. And on the maps they show us in grade school, the US is at the center of the world. This is somewhat inconvenient for the Russians, whose country is split in half – sometimes to go just a little distance from east to west, you have to travel all the way across the world in the opposite direction – but hey, we paid for the map. In cosmological terms, astronomers tell us that if you look up at the stars, all the galaxies in the sky are flying away from us at tremendous speeds. Put all this information together and you discover that Kansas lies at the navel of the universe. At least until a tornado comes, carries us away, and dumps us someplace else.

People are proud of this location but you shouldn’t make a big deal out of it. You have to remember we didn’t choose to live there. A long time ago when the government drew Kansas on a map, that’s where they stuck us. We would have preferred to be closer to one ocean or the other, but nobody asked. Somebody has to live at the center of the universe, and it just happens to be us. Anyway, we have lots of other things to be proud of. Right at the moment I can’t think of any, but ask me again in a couple of weeks. I’ll do some research.

This explains a lot about Kansas. For example, why we get lots of aliens. Imagine you’re zooming across the galaxy, at thousands of times the speed of light, experiencing extensions of time and your bladder. At some point you need a rest stop. We’re conveniently located, we have good coffee, and clean restrooms. And excellent steak, the cheapest in the universe. So aliens drop in all the time. About 25 percent of Kansans claim to have been abducted by aliens. They’re not trying to hurt us. It’s a mistake, they think we’re fast food. If nobody’s at home when they come by, they take one of your cows instead.

Some more little-known facts about Kansas: the state flower is the sunflower, the bird the Meadowlark, and our state song is “Home on the Range.” We learn it in the first grade, and it goes like this:

Oh give me a home where the buffalo roam
And the deer and the antelope play…

When they teach us this song you think, is this really about Kansas? Sure, we have a lot of deer; if you live in the outer suburbs they come right into your yard. Your dogs think they’re toys you’ve brought home, just for their enjoyment. In deer season, people shoot them. But you have to be careful. It’s easy to mistake your neighbors’ lawn ornaments for a deer, and people are quite sensitive about having their lawn ornaments shot to pieces. In deer season it is not unusual to see statues of the Virgin Mary, garden gnomes, and bird feeders dressed in fluorescent orange hunting jackets.

One odd thing about the song is that we know that the plural form of deer is deer. Nobody, even in Kansas, puts an –s on deer. But antelopes… We’re not so sure about that one. “Antelopes” sounds fine to me. So in the song, they’re either talking about one specific deer and one specific antelope, or a bunch of deer and that one particular antelope.

Try as I might, I have never seen that animal. And I’ve looked for it, believe me. Every time I drive through my state, I keep a sharp eye out. But I’ve never seen the antelope. And where are the buffalo that are supposedly roaming around all over the place? Your teacher says, “We killed them all.” Doesn’t seem like nice behavior towards an animal featured prominently in your state song, right there in the first line, but there you have it.

And the song neglects some of the other prominent species in our state. Right now, for example, Kansas is up to its neck in llamas. Everywhere you go these days, somebody’s started a llama farm. I don’t think you can milk one, and their eggs are inedible, but a llama must be good for something. Whatever it is, we should consider changing the state song. For example,

Oh give me a home where the buffalo (used to) roam
And the deer and the camelids play…

The song goes on to say,

…Where seldom is heard
a discouraging word
and the skies are not cloudy all day.

Here, we’re talking outright lies. I’ve heard a lot of discouraging words in my time – most, it is true, from foreigners from places like Paris and New York, but every once in a while a native will rip you with a criticism. And we do have clouds. There is the tall and majestic variety, which look like clipper ships, or six-packs of beer, or Snoopy on his Sopwith Camel, and other times they’re low and grey, hiding tornadoes and hail and all sorts of other unpleasant things.

Or perhaps I’ve misinterpreted this line. Maybe the intent is, “all day long.” To be even clearer, the phrase might mean something like: “All right, we have clouds, but they never stay in the sky all day long, because eventually the wind pushes them into Missouri.” In any case, you have to admit, the original is either a lie or is highly ambiguous.

The state motto is Ad astra per aspera, which is interesting because the number of Latin speakers in Kansas is approximately the same as the number of ancient Romans. If you say it really fast, with a Kansas twang, it sounds like “a disaster for aspirin,” but now we have Google Translate and it’s easily cleared up. Run the motto through the website and you discover it means, “To the stars with difficulty.”

They got that right. It’s difficult for anybody to get to the stars, but it’s a special challenge in Kansas. We don’t have any mountains. If you climb a mountain the stars are still far away, but they’re just a little bit closer. States with mountains have an unfair advantage when it comes to going to the stars.

Twang science 2: Communication (Fake paper 2)

Dear editor,

I am writing with regard to the recent publication in your journal concerning the acquisition, maintenance, and loss of a type of speech called a twang. Terris et al. make only cursory mention of – and thus fail to do justice to – a hypothesis that speaking with a twang might be associated with a retrovirus or another pathogen. Our lab has been pursuing this question for over 20 years and I would like to clarify the current status of the debate.

Our search for a pathogen involved in language perception and speech began with a series of observations on the phenotype: in many ways, the spread of the phenotype resembles an epidemic that is tied to particular regions. For example, Valley Fever, or coccidiodomycosis, is caused by a fungus found in dry areas of the Southwestern United States. The fungus forms spores that are spread by winds, particularly when the soil has been disturbed by storms, construction, agriculture, four-wheel drive offroading, motorbiking, or other sports activities. Inhaling the spores leads to an infection in some people.

It is estimated that about a two-thirds of the population of some regions of the Southwest will test positive for the fungus Coccidioides spp. at some point in their lives. Only a fraction develop flu-like symptoms. In severe cases, nodules form on the lungs. Their onset and their severity vary from person to person, likely for genetic reasons, which also play a role in whether the pathogen affects organs beyond the lungs. A weakened immune system greatly increases susceptibility. Symptoms may disappear and reappear over the course of a lifetime.

In many ways the spread of the twang resembles such diseases, which are caused by a pathogen restricted to a particular geophysical niche. There are “hotspots”, particularly in the Midwest, where penetrance reaches nearly 100 percent, surrounded by zones of variable penetrance. Geographical barriers may play a role in limiting its spread. The Rocky Mountains, for example, divide an eastern region of pronounced twang from western areas where it is hardly found at all. There is some evidence that following the Dust Bowl, which saw massive migrations from Oklahoma to California, the pathogen was transported to the western coast, where it was responsible for the rise of “Valley Girl” speech. It has been estimated that in their clothing and shoes, immigrants brought approximately two tons of Oklahoma dust to California. The pathogen may have come along for the ride.

Infants seem particularly susceptible; virtually every child born in a hotspot will acquire the twang, independent of his or her genetic background. Some studies indicate that the degree of penetrance is associated with socioeconomic factors. This, too, is common for pathogens associated with dirt or a lack of sanitary infrastructure. An intriguing observation comes from recent epidemiological work that links the severity of a family’s twang to the number of open beer bottles and pizza boxes lying around the house. Another correlation is the number of rusty cars parked behind the house. In each case, the higher the number, the more severe the twang.

Those exposed during early childhood typically suffer from the twang to some degree their entire lives. Interestingly, those who leave a hotspot for many years – usually decades – may lose many of its features. However, if a person returns home, for example during Thanksgiving, he or she experiences a dramatic but temporary increase in twang speech patterns. This likewise reflects the behavior of some pathogens: removed from their ideal environment, they reproduce only slowly or enter a phase of latency. Contrarily, someone who moves to a hotspot later in life may at some point begin to show symptoms, but only after prolonged exposure.

The hypothetical pathogen does not seem to be transmitted from person to person. Children raised by twang-positive parents in a twang-negative environment do not typically show symptoms. Weaker phenotypes that are occasionally observed might be explained by transmission through contact with fomites such as dust-ridden clothing, furniture, or beer bottles that have accompanied the family without being properly cleaned before a move.

The findings of Terris et al. are intriguing but do not in any way contradict the pathogen hypothesis. A range of infectious agents are known to affect CpG methylation patterns and the expression of genes. Tumors in particular regions of the brain that affect speech patterns may cause symptoms by disturbing neural networks, but they may also be accompanied by changes in the epigenetic regulation of genes.

Validating the twang-pathogen hypothesis will require studies of the metabiome of those affected compared to controls. We have recently carried out such studies using a cohort similar to the patients and controls described in the paper by Terris et al. Our preliminary work, which is currently being revised for publication, has identified three potential candidates: the strongest correlation involves a retrovirus which bears some similarity to the feline leukemia virus, and there is a somewhat weaker association to two species of fungi whose spatial distribution closely matches that of the twang. At the moment we cannot rule out combinatorial effects caused by multiple pathogens, whose lifecycles depend on a delicate balance between body homeostasis and external factors in the environment.

Sincerely,

Bob Luser

News and views: From the frontiers of Twang science (Fake paper 1)

The historical origin of the word “twang” is thought to be an example of onomatopoeia: a word that sounds like what it represents. A twang is the kind of tinny, nasal sound produced by an instrument such as a banjo. It also refers to a type of speech usually associated with the English-speaking population of regions of the Midwestern and Southern United States, as well as several country music singers. The behavior required to produce a twang is complex: speakers apply a nasal quality and usually a rise in pitch to several vowels. Acquiring a twang requires physiological mechanisms ranging from perception (infants hear the speech of those in their environment) to a feedback mechanism (imitation and self-correction) and all the body parts used to produce vowel sounds: the tongue, nasal cavity, mouth, and more extensive pharyngeal structures.

Complex speech phenotypes may have a molecular basis within cells and tissues. Speaking with a twang likely involves several regions of the brain associated with speech and learning as well as those responsible for the coordinated muscular activity of the tongue and soft palette and other parts of the mouth and nasal cavities. Researchers have proposed various mechanisms to account for twang acquisition and performance among speakers. Since the behavior is acquired and can be lost again through training or relocation to an environment where speakers have a different “accent”, it is feasible that epigenetic alterations of genes must be involved. (An early study proposing a retrovirus has been discounted.) There is also some evidence that lesions can be associated with the gain of a temporary or long-term twang, or to the loss of a preexisting twang, which may help in identifying regions of the brain that are involved in its performance.

In a study in the latest issue of Nature Genetics, Terris et al. have studied epigenetic markers around genes that have been implicated in language perception and production in previous studies. They compare the status of these genes in regions of the brain thought to play a part in speech and pronunciation to regions less likely to be involved in these behaviors.

The list of candidate genes was obtained from a database hosted at the Quantitative Neuroscience Lab of Boston University (http://neurospeech.org/–sldb). Additional candidates were obtained through a computational analysis of the PubMed literature, harvesting articles meta-labeled with tags such as the following: twang, speech, language, pronunciation, and nasality.

Tissue samples were obtained from speakers who had undergone brain surgery and were judged to have a pronounced twang (or not) by a mixed audience of native (US-born) linguists. Results were compared between this group and five sets of controls: speakers who had never had a twang, those who had had a twang earlier in life but had lost it, native speakers of French (whose speech is not estimated to have a “twang” but is highly nasal), and a few individuals who had lost or acquired a twang through a stroke or other type of cerebral damage. Evaluations were performed using a standardized “Twang scale” developed at a school of performing arts in Los Angeles. (This program was developed to remove the twang of young actors.) Speakers were graded on a scale of 0 to 10 (0 = British accent; 10 = Bob Dylan).

The lab carried out a comprehensive analysis of methylation patterns across the genome from brain tissue samples from target and control regions for all five groups. The primary method used was bisulfite sequencing, which is based on the treatment of DNA with bisulfite. This causes a chemical conversion of cytosine residues to uracil, but only if the cytosines are non-methylated. Methylated cytosines are protected from the change. Comparing the sequences of treated vs. non-treated DNA permits a base-by-base readout of loci where Cs have been transformed to Us, and those which have not. The results from each group were combined and averaged and filtered for significance. They were compared to each other and to a mixed population of all groups.

The resulting patterns were compared on a chart, which revealed spikes (upward = higher methylation, downward = lower) at specific genomic locations. Both extremes are interesting because the twang phenotype might be due to either higher levels of methylation at particular loci, lower levels, or some combination.

Interestingly, the study revealed a number of significant differences between these patterns in “plus-twang” and “minus-twang” groups. The most extreme variation was found in cells of the superior temporal gyrus and primary auditory cortex, with somewhat smaller (although still significant) peaks in adjacent tissue of the brain region known as Wernicke’s area. The highest difference was found in a region ca. 1 Mb from the FOXP2 gene on chromosome 7, a gene which is highly implicated in many aspects of language acquisition and performance. A bioinformatics analysis of this region revealed a high statistical likelihood that it plays a regulatory role in FOXP2 activation, and contains putative FOX transcription factor binding sites. Both this region and the FOXP2 gene have closely related orthologs whose sequences and relative positions are well conserved between mice and humans. Follow-up studies in mice revealed that deleting the putative regulatory region inhibited expression of the orthologous gene in several areas of the brain, and resulted in a shift in squeaking pitch.

The authors remain cautious about their findings. In the paper’s discussion they report: “The exact molecular mechanisms underlying differential methylation remain to be understood, as does the quantitative significance of the identified loci in twang acquisition (or loss).” To address the mechanistic interplay between methylated regions, their regulators, and the twang-phenotype, the group has developed transgenic Cre mice in which particular methylated regions, methyltransferases, and methyl binding proteins can be deleted in a neuron-specific manner. Additionally, libraries of small molecules are being screened for specific effects on squeaking pitch as a phenotypic marker for twang in the mouse model.

Ideally, a potential twang modulator might be found among approved drugs or natural substances, which can be used to study the methylation status of the FOXP2-associated region. The next step would be to assemble a cohort of patients (twang-plus and twang-minus) who have already tried the drug or substance, checking to see whether this exposure has altered their speech patterns.

The author would like to thank Robert Zinzen for critical review of this article.

Craig Venter and the Alien Zombies from Mars

©  2014, Russ Hodge

(sorry, Hollywood: I thought of it first!)

I don’t know about you, but I’ve really missed Craig Venter. Oh where have you been, oh guru, oh Guitar Hero of molecular biology? I just haven’t been able to think of Craig in any other way since that article in Wired magazine, which described him thus:

You are standing at the edge of a lagoon on a South Pacific island. The nearest village is 20 miles away, reachable only by boat. The water is as clear as air. Overhead, white fairy terns hover and peep among the coconut trees. Perhaps 100 yards away, you see a man strolling in the shallows. He is bald, bearded, and buck naked. He stoops every once in a while to pick up a shell or examine something in the sand …

That’s our Craig! If you’ve missed him too, HE’s BACK! And once again, he’s making news from the cusp, the cutting-edge, the very BRINK of modern science. Most people keep a respectful distance from the brink, in fear of falling off, but not Craig Venter. The man has no fear of heights at all. He’s even willing to lean way over the edge… It’s the fastest way to get your picture back on the cover of Time magazine. Maybe this time in the nude.

Craig has been off the grid, popping up from time to time in an airport with his pet monkey (no, wait, that was Justin Bieber). Maybe he’s been spending time on that huge yacht he bought with his profits from the human genome. He deserved it. Single-handedly deciphering the human genome is hard work!

But now we know that as he’s been roaming the open seas and idyllic, deserted beaches, he’s been doing a lot more than obtaining the perfect tan, equally distributed across all parts of his body. He’s also been thinking: What next? What’s the next Big Problem facing mankind? If you’ve got a biomedical megacorporation at your disposal – do something with it, man!

He considered a couple of options. He was thinking about curing death, for example, but Google beat him to the punch. Google would be stiff competition, with all their considerable expertise in the life sciences. You wouldn’t want two companies competing with each other to solve the problem of death, now would you? Remember when that happened with the human genome?

Uh, it got finished a lot faster that way…

Then he thought about cloning dinosaurs, but Michael Crichton and Steven Spielberg grabbed that one up. Old news. The second guy to try something NEVER makes it to the cover of Time magazine.

That left only one problem of sufficient importance to attract a Big Thinker like Craig: extraterrrestrial life! Craig decided to go find it, and not only that – to bring it back to Earth! And grow it in the lab! What could possibly go wrong???

For those of us who might think this sounds crazy, well, we just have simpler, less visionary minds than Craig. Behind this beautiful idea is a complex thought process that most of us just aren’t capable of. Here are the steps:

  1. It’s hard to find alien life on Earth unless it is very large, resembles a cross between a reptile and an insect, and starts eating people.
  2. Therefore, we’ll have to look for it someplace else.
  3. Mars is close, so let’s look there. (Adhering to that fundamental scientific principle: If you drop a coin, look for it in well-lighted areas, even if you dropped it somewhere else.)
  4. All life is based on DNA.
  5. Climate change on Mars has probably killed all the big animals, except the ones that look like rodents and jelly donuts. To catch them you’d need a mousetrap or a donut box. But it would cost 10 trillion dollars to send the mousetrap or donut box back to Earth. And why should you do that, when we already have plenty of rodents and donuts here at home?
  6. We can send a DNA sequencer to Mars. (Since it will be dropped onto the planet from orbit, wrap it in lots of bubble packing. The best thing would be to design a DNA sequencer that is completely made of Legos, which can be assembled by the mechanical arm on the rover.)
  7. Collect some Martian DNA with a Q-tip. (Also pack the Q-tip in bubble packing, because it might get bent.)
  8. Have the sequencer analyze the Martian DNA and send the complete sequence back to Earth by radio. (Preferably broadband, at a rate a lot faster than my modem.)
  9. Make sure you only have DNA from one organism, rather than thousands of different ones. Otherwise you may get a cross between a rat and a jelly donut. (Hmm… have to think about that one.)
  10. Fire up the DNA synthesizer in your lab and rebuild the DNA of the Martian organism.
  11. Implant the DNA in… an Earth cell? (…Have to think about that one, too.)
  12. Clone it and let it grow into an alien. (Helpful tip: since you don’t know how big it will grow to be, use a really big Petri dish.)
  13. Try to contain the alien in the lab. (Install a nuclear device so that you can destroy the lab if it escapes.)

What could possibly go wrong?

There are always skeptics around who will point out niggly things like the fact that the Martian soil contains up to about 15% iron, about three times that on Earth. Scientists have reported that excess iron damages DNA in an animal’s body, so it has to be controlled – for example, by the hemoglobin molecules in our blood cells that grab hold of it and glue it into big crystals. But evolution always finds an answer, even on Mars. Martians probably have blood cells the size of basketballs.

Some people are even skeptical about #4 – the idea that Martian life would be based on DNA. Wouldn’t the environment of Mars a couple of billion years ago have been different? Isn’t some other type of self-replicating chemistry possible? Does the starting recipe of the primoridal soup matter? Won’t any environment inevitably produce DNA, if you cook it long enough? (Try this in your kitchen.)

But those are just the skeptics talking. They don’t know about the paper written by Francis Crick and Leslie Orgel back in 1973, after a week in which they drank waaay too much coffee. The two biochemists proposed that there’s an alien spaceship that floats from galaxy to galaxy, seeding planets with DNA. It’s the reason why on Star Trek, most of the aliens look human, except for the funny ears. They also have different wrinkles on their faces. They also behave strangely, but then, aliens didn’t have the benefit of growing up in an Earth family that teaches you proper manners.

That paper didn’t make it into Nature. It was close, but one of the referees wrote: “I am well aware of Francis Crick’s reputation as a Nobel laureate. His eminent qualifications do not, however, prevent him from occasionally being a dingbat. I refer you to another paper in which he explains dreams.”

Crick’s is only one version of the Panspermia hypothesis. Other scientists think that DNA might not have originated on Earth, but this didn’t require an alien spaceship. It could have been assembled in a gassy cloud in space, probably the Crab Nebula – it certainly looks sinister, like it’s up to something.

That DNA floats around, maybe passes through a black hole or a wormhole, and when it comes out it glues itself to an asteroid. Or maybe dark matter. Then it goes on to inseminate the entire universe.

There’s yet another version of panspermia called “Necropanspermia”, which proposes that not only did DNA originate with aliens, but that the aliens were zombies. Here, too, the magazine Wired provides science with titillating new information: The article begins this way: “Life on Earth could have grown from the broken remains of alien viruses that, although dead, still contained enough information to give rise to new life.” Ergo: zombie viruses. Actually, I’m really hoping that Craig Venter will find their DNA on Mars and fax it back to Earth. That’s just what we need, a bunch of alien zombies on the loose.

MicroRNAs micromanage the pancreatic β-cell

The Poy lab shows that a complex microRNA pathway governs the body’s response to insulin resistance

 

Our daily lives are marked by cycles – wakefulness and sleep, activity and rest, eating and fasting – through which most biological activity must continue in a balanced way. We don’t have to eat all the time because our cells can store nutrients for later use. Eating causes a quick rise in glucose, one of the body’s main sources of energy, but too much sugar in the bloodstream is toxic. When levels surpass a certain point, cells should absorb glucose. They are told to do so by the hormone insulin, which is produced by specialized beta cells in the pancreas. But in the disease diabetes type 2, cells become resistant to insulin stimulation and don’t respond properly. The body tries to compensate by creating more beta cells, which then secrete more insulin. It’s as if cells have become deaf, and the body raises the volume of the signal in hopes that the message will get through.

How the body senses insulin resistance and stimulates the production of more beta cells has been unclear. Matthew Poy’s lab at the MDC has now solved a crucial part of the puzzle. In a recent article in Cell Metabolism, the scientists unravel several layers of regulation by which cells control the production of specific proteins and respond to insulin resistance.

The study demonstrates that beta cells require a protein called Ago2 to begin this type of proliferation. Normally the production of Ago2 is braked by a small RNA molecule (miR-184). During insulin resistance, however, beta cells stop creating miR-184. As a result they release the brake on Ago2, which stimulates their proliferation and the secretion of more insulin.

Understanding this process required that the lab unravel the details of an intricate, switch-back route by which the information in genes leads to the production of proteins (or not). Proteins such as Ago2 are encoded in genes, which can be transcribed into messenger RNA molecules and then translated into proteins. But our genome also encodes at least 2,000 short microRNA molecules (miRNAs) which can block this process. MiRNAs have sequences that cause them to dock onto messenger RNAs and trigger their destruction before they can be translated into proteins.

In recent years scientists have discovered that miRNAs target many – if not most – human messengers and thus play a crucial role in fine-tuning the amounts of proteins produced by cells. MiR-184 apparently docks onto Ago2 messenger RNA and limits its production in this way.

Matthew and his lab have been studying the influence of miRNAs on beta cells for several years. “Many technologies are available now including small RNA sequencing techniques that can be implemented to  detect changes in miRNAs in b-cells and study the amounts of these molecules that were being produced in disease models,” Matthew says. “A few years ago we discovered that healthy beta cells turned out large amounts of one such molecule, miR-375.”

This is where the story becomes a complicated affair of regulators regulating the regulators of regulators. (If you don’t like brain teasers, skip this paragraph and the next.) miR-375 normally docks onto the messenger of a protein called Cadm1. Cadm1 suppresses beta-cell proliferation. In other words, the production of more beta cells depends on eliminating Cadm1. Achieving that requires more miR-375.

Sudhir Tattikota, Thomas Rathjen, and other members of Matthew’s lab established this connection and figured out how Ago2 contributes to the process. When it’s around, Ago2 helps miR-375 establish contact with the Cadm1 messenger. So put together, the whole tortuous chain looks like this: miR-184 blocks the production of Ago2. As a result, Ago2 doesn’t help miR-375 find and block its target. That means the beta cells produce more Cadm1, don’t reproduce, and don’t produce more insulin.

Put more simply: LESS miR-184 means MORE Ago2 and MORE miR-375 activity, which means LESS Cadm1 and MORE beta cells. To simplify further, consider just the input and output: less miR-184 leads to more beta cells and more insulin. (And vice-versa.) Matthew and his colleagues have clarified the links in this pathway by revealing the roles of Ago2 and Cadm1.

The take-home message? “Insulin resistance is a symptom of the growing epidemic of diabetes type 2,” Matthew says. “The body compensates by stimulating the growth of new beta cells and increasing production of the insulin signal. We’ve shown for the first time how several layers of the miRNA pathway work together to stimulate the growth of the insulin-producing cells.”

The scientists used a mouse model in which insulin resistance could be tuned up and down. When they restored the animals’ sensitivity to the hormone, beta cells produced more miR-184 and didn’t proliferate. This demonstrates that the microRNA acts as a crucial part of the mechanism that detects insulin resistance.

The study revealed another aspect of insulin sensitivity which may open new possibilities for treating diabetes type 2. When people reduce their intake of carbohydrates, which are the main source of glucose, the liver begins converting fat into substances called ketone bodies, an alternative source of energy. This type of diet has been found effective in treating some forms of epilepsy, likely because it alters the biochemistry of nerve cells.

“The literature reports that this ketogenic diet also improves insulin sensitivity and affects glucose levels,” Matthew says. “If our mouse model is put on a ketogenic diet, we also see a rise in miR-184 levels.  This may indicate that our dietary intake  may influence pancreatic beta cells in ways that are still unclear. That offers new opportunities to investigate both the mechanisms of insulin resistance and potential therapies.”

 

– Russ Hodge

Reference:

Tattikota SG, Rathjen T, McAnulty SJ, Wessels HH, Akerman I, van de Bunt M, Hausser J, Esguerra JL, Musahl A, Pandey AK, You X, Chen W, Herrera PL, Johnson PR, O’Carroll D, Eliasson L, Zavolan M, Gloyn AL, Ferrer J, Shalom-Feuerstein R, Aberdam D, Poy MN. Argonaute2 Mediates Compensatory Expansion of the Pancreatic β Cell. Cell Metab. 2014 Jan 7;19(1):122-34. doi: 10.1016/j.cmet.2013.11.015. Epub 2013 Dec 19.

 

Link to the original paper:

http://www.ncbi.nlm.nih.gov/pubmed/24361012

 

Home page of the Poy lab:

https://www.mdc-berlin.de/14669454/en/research/research_teams/microrna_and_molecular_mechanisms_of_metabolic_diseases

 

 

 

 

 

Outtakes from my new “Science cabaret”

EVOLUTION
& the Global Atheist
mind-control
Conspiracy

Warning label

This is a totally politically-incorrect talk about evolution. Well, evolution and a lot of other things. Please check all guns at the front desk. Also fruits and vegetables and anything else that can be thrown, including your shoes. This topic causes some listeners to experience dramatic increases in blood pressure and symptoms of temporary insanity. To fully enjoy the event, self-medicate well in advance. And put on clean socks.

The evolution of the brain

I’m worried that someday, biology is going to fry my brain. Science is getting too complicated to fit in there anymore. I’m not talking about data… We gave up on that a long time ago. If you started reading your genome out loud the moment you were born, at a rate of two letters per second, you’d be 47.5 years old before you finished. And that’s without any breaks for sleep, or coffee. That’s why they invented memory sticks. So you can go to Starbucks on the weekend, and get some sleep.

No, even the basics of biology are getting way too complex for our brains. It used to be, DNA makes RNA makes proteins. Three steps, simple enough to remember. Now we’ve found all these annoying little steps in between: a microRNA inhibits the translation of a protein that would otherwise help a microRNA inhibit an inhibitor. That’s a real story, you can look it up. Try to hold that in your brain, it might drive you crazy. Look at some of your colleagues. It’s already happening.

The problem is our brains didn’t evolve to do really complicated science. Our brains evolved in prehistoric times. Science was a lot simpler back then. There were only four parts.

The first part was technology, stuff like how to build a shelter, start a fire, and make weapons to kill big animals like mammoths. Basically, you got something long, and sharp, threw it at the mammoth, and ran like hell.

The second part of prehistoric science was pharmacology. Its purpose was to tell you if something was safe to eat. The methods were much simpler. You found a new plant and made somebody else eat it. Then you watched them a while. If they turned blue or died, well, we won’t eat that. If they got high, then you gathered up as much as you could carry, and took it back to the tribe. And had a big party.

You also had biology class, but there the only topic was sex tips: “For best results, choose a member of your own species.” …Makes you wonder what was on the final exam.

So science was a lot simpler, and the criteria for evaluating it were a lot simpler. In prehistoric times they also had impact points, but it meant something different. Impact points meant the number of times you could impact a mammoth with your spear. A high number you succeeded, a low number… The mammoth killed you. You died.

Today, research isn’t evaluated by mammoths. It’s judged by old farts called anonymous reviewers. The old way was simpler, and some people would like to bring it back. You send off your paper to a journal, and a couple of days later a big truck pulls up in front of your house. Out comes this huge, hairy monster, and it’s walking up your driveway. It’s a mammoth. It’s your reviewer. You get to look him right in the face and kill him. Every scientist’s fantasy.

A journal couldn’t send a mammoth to every author’s house. Look at the list from the human genome paper. Mammoths would go extinct again. Well, maybe not. Probably the scientists would go extinct first.

Since there weren’t enough mammoths, they’d just send one to the last author. Boy, that would change things, wouldn’t it? A group leader comes up and says, Russ, I’ve decided to give credit where credit is due. I’m going to put you as last author on this paper.

All I did on the paper was correct the spelling and take out 950 commas. I say… Uh, thanks, but I really think John’s contribution was much more important. John’s the high school kid who fixed my Internet connection. Even John’s too smart to take on a big hairy elephant.

So your group leader has to go find a collaborator. Probably a guy from an American football team, a guy as big as a refrigerator, who’s been banged in the head a lot of times. He’ll agree to anything if you offer him beer.

Today most scientists wouldn’t know how to kill a mammoth. First you’d need some kind of weapon. I looked everywhere in my apartment and couldn’t find anything. It gives you a whole new perspective on your stuff. A corkscrew? Naw. A tube of superglue? You go up to the mammoth and say, Please step over here, on this very clean surface. And hold perfectly still for six seconds.

All I could find was an old PC, from the nineties, that weighed about fifty kilos. I could throw it at the mammoth. But if that didn’t work… what then? I sure as hell wasn’t going to throw my Mac at it. You’d have to go to the Genius bar at the Mac store and say, Can you fix this? And they’d say, What were you doing with the device when the problem occurred?

The Bauhaus would probably have what you’d need to make a weapon. You drive down to the Bauhaus and this guy in a red shirt comes up and says, “Can I help you?” and you say, “Show me everything you have that’s long and pointy.” And he says, “What kind of project do you have in mind?”

You stand there… Finally you say, “I need to kill an extinct elephant…”

Nothing in my apartment would be any use in making a weapon or anything else 100,000 years ago. The same thing goes for my brain. The only things in my brain are the names of a bunch of molecules. The rest is taken up with PIN numbers. If I remember those, I can do everything else with my SmartPhone.

You know how when you get a new PIN, you have this feeling of panic? For a week you can’t remember the new PIN or any of the old ones? That’s evolution talking. It’s telling you, You need to save this space in your brain for something useful, like how to kill a mammoth!

It’s why kids don’t like math class. Some boring teacher is going on and on about algebra, and their brain is whispering to them, Will this save your life? Let’s go outside and throw some spears? It’s a survival instinct. That’s evolution talking.

I know that biology has already fried part of my brain, the part that learns people’s names. That was important in early human evolution. It helped you avoid inbreeding. Say you’re in a bar and a woman comes on to you. You say, What’s your name? She says, Karen. You say, Wait a minute, aren’t you my sister?

Remembering names also helps in reproduction. You go on a second date with a woman and don’t remember her name, she thinks, Do I want my kids to be as dumb as a doorknob? You’re not dumb, you’re a biologist. But it’s too late, she’s making moves on a guy across the bar.

I don’t have room in my brain for people’s names anymore. They’ve been chased out by the names of molecules. They’re competing for the same brain space. Probably the hippocampus. If you’ve ever seen a hippocampus, it’s small. And it’s shaped funny. There’s just not enough room for both people names and molecule names. Something has to go.

Nobody tells you this when you start to study biology. And your brain doesn’t have those pop-up messages – you know when your hard disk is getting full. It would be helpful. Your brain would make a rude noise and say, To make space for this molecule, delete your mom’s name.

I used to be able to learn the names of all my university students, dozens and dozens of names. But now… some days I’ll be sitting in my office, and sitting across from me is my office mate. We’ve shared an office for two years, but sometimes I look at her and try to remember her name and all I can come up with is… Tubulin? P53?

It’s a problem in Germany. When you meet somebody you’re supposed to shake their hand and say their name. People shake my hand and say, Hi, Russ, and I stand there and say, Hi, uh… I usually just hide in my office unless there’s a conference. At conferences people wear name tags. But you shouldn’t be caught looking. You’re talking to a famous scientist and trying to read her name and she’s thinking, Is he staring at my breasts?

I don’t say people’s names when I shake their hands, but I have an excuse. I’m an American. Everybody knows Americans don’t have manners, or even culture. Back in the 17th century, when Europeans sailed to the New World, there wasn’t enough space on the ship for cathedrals or symphony orchestras. And you didn’t take the good silverware because the pirates would just take it. We’ll have that stuff shipped over later, they said, but there was a whole country to tame. Fighting Indians and building houses and turning lots of cows into hamburgers. It was like going back to the Stone Age, but with lots of guns.

After about 200 years we finally had time for culture again, but we’d forgotten most of it. Even the most basic things, like how to use silverware. The pirates know, but we’ve forgotten. It’s why Americans invented fast food. All fast food can be eaten with your hands. While you’re driving and talking on your cell phone.

It’s a problem when we get invited to some fancy restaurant. You sit down and there’s lots and lots of silverware. Strange utensils you’ve never seen before, you don’t even know what they’re called. Okay, you can identify a fork, but you’re sitting there thinking, Right hand? Left hand? Sometimes they give you two forks. Then you just take one in each hand.

By the 20th century America had moved out of the Stone Age. We could have learned to be polite again, but it would have cost a lot of time and money. John F Kennedy could have said, Today I’m announcing a ten-year program to restore our manners. Instead he decided to go to the moon.

Nowadays we don’t have to know how to kill mammoths. They’re extinct. But scientists are thinking about bringing them back. They found a frozen mammoth in Siberia, and they’re going to clone the thing. They’re going to take some of its cells, thaw them out in the microwave, and make clones of mammoths. What could possibly go wrong? Any ten year old could tell you what could go wrong: Jurassic Park, that’s what could go wrong.

So just in case, I’m going to the Bauhaus to get some supplies.

Best of PubMed #21: Shoes and socks

This week’s entry: A “shoes and socks” special. For those of you who are new to this column, you can often find abstracts of the articles or a link to the full text by cutting and pasting the PMID number into the search box at the following site:

http:/www.pubmed.org/

 

Please, sir, pull down your socks!
Bonucchi D, Piattoni J, Ravera F, Savazzi AM, Cappelli G, Pimpinelli N, Modesti PA.
Intern Emerg Med. 2007 Dec;2(4):287; comment 287-90.
PMID: 18043875

 

Helping families get past the missing socks.
Nicholson M, Manchester A.
Nurs N Z. 2007 Mar;13(2):16-7.
PMID: 17427370

 

Choosing socks
Douglas C.
BMJ. 2000 Jun 3;320(7248):1549A.
PMID: 10834918

 

Buttered bread, odd socks and knotted rope–urban myths or scientifc fact?
Rowe RC.
Drug Discov Today. 2002 Jun 1;7(11):595-6.
PMID: 12047866

 

Perceptual responses while wearing an American football uniform in the heat.
Johnson EC, Ganio MS, Lee EC, Lopez RM, McDermott BP, Casa DJ, Maresh CM, Armstrong LE.
J Athl Train. 2010 Mar-Apr;45(2):107-16.
PMID: 20210614

 

Please pass me the onions and the socks–lidocaine toxicity.
Mack RB.
N C Med J. 1983 Aug;44(8):485-6.
PMID: 6579356

 

High heels as a cause.
Bajer D.
Dtsch Arztebl Int. 2013 Apr;110(17):296. doi: 10.3238/arztebl.2013.0296.
PMID: 23671477

 

Interference of high-heeled shoes in static balance among young women.
Gerber SB, Costa RV, Grecco LA, Pasini H, Marconi NF, Oliveira CS.
Hum Mov Sci. 2012 Oct;31(5):1247-52. doi: 10.1016/j.humov.2012.02.005. Epub 2012 Jun 27.
PMID: 22742722

 

Effect of shoe type on descending a curb.
George J, Heller M, Kuzel M.
Work. 2012;41 Suppl 1:3333-8. doi: 10.3233/WOR-2012-0601-3333.
PMID: 22317224

 

Break dancing: a new risk factor for scarring hair loss.
Monselise A, Chan LJ, Shapiro J.
J Cutan Med Surg. 2011 May-Jun;15(3):177-9.
PMID: 21561588

 

Toxic sock syndrome.
Mueller KK, Pesqueira MJ, Cobb MW.
Cutis. 1996 Nov;58(5):337-8.
PMID: 8934073

A new perspective on spontaneous blinks.
Pult H, Riede-Pult BH, Murphy PJ.
Ophthalmology. 2013 May;120(5):1086-91. doi: 10.1016/j.ophtha.2012.11.010. Epub 2013 Feb 8.
PMID: 23399377

 

Preference for newspaper size.
Tsang SN, Hoffmann ER, Chan AH.
Appl Ergon. 2013 Aug 26. doi:pii: S0003-6870(13)00157-9. 10.1016/j.apergo.2013.07.015.
PMID: 23987982

 

The uses of hopelessness.
Bennett MI, Bennett MB.
Am J Psychiatry. 1984 Apr;141(4):559-62.
PMID: 6703135