Zombie cockroaches

Just when you thought the zombie apocalypse couldn't get any worse... now we have roaches to worry about!  Fortunately, zombie roaches in the wild are not aggressive, brain-sucking insects. It turns out that the wasps that make the zombies are what we should really be concerned about.

Jewel Wasp (A. compressa)
Image courtesy of Morphbank.net

The Jewel Wasp (Ampulex compressa) has an elegant and extremely sophisticated method to secure a good home for its eggs.  It attacks and injects a cocktail of neurotransmitters into the brain of a roach, effectively turning it into the slave of the wasp (Educated Earth has a good video of this process, see here).  The wasp then drags the roach to a suitable location and lays its eggs in the abdomen. The roach is hypokinetic for several days until the larvae hatch and then they slowly consume the host.  Interestingly, the larvae eat the internal organs in a way that maximizes the lifespan of the roach.  It's a morbid process, but how the wasp achieves this zombification is truly incredible.

The wasp actually stings the roach twice.  The first sting is to the thorax and produces a mild and very transient anesthetic that paralyzes the front legs.  A study by Moore et al. (abstract) showed that the active components of the first sting activate GABA receptors (GABA itself, and receptor agonists beta-alanine and taurine).  During the minute or so of action, the wasp then stings the roach again, but in a very precise location within the brain.  In a sense, the wasp is acting like a brain surgeon, who needs their patient to remain still while a precise operation is done.  This second injection is a cocktail of neuroactive compounds that have very specific effects on the roach's brain.  After the anesthetic wears off, the roach grooms itself excessively and then becomes lethargic.  It is not paralyzed, just sluggish.  When the first studies on A. compressa were done, there was a great deal of controversy over whether the venom was delivered to the central nervous system, or directly to the site of action in the brain.  In an elegant study by Haspel et al. (abstract), they milked the venom from wasps and injected them with radiolabeled carbon (14C).  This meant that the fresh venom produced by the wasp would contain the radiolabel.  Haspel could then visualize the location of the venom in the roach brain by taking pictures of brain slices.  Those of you who think that would be cool as hell, raise your hand!!

  Anyhow, it was found that the neurotoxin attacks the brain directly, with the most venom at the supra-esophageal ganglia (SupEG) and the sub-esophageal ganglia (SEG).  In insects, these areas are thought to provide "higher order" brain function.  A recent study by Gal et al.(abstract) found that the venom affects the drive to initiate and maintain walking.  Other motor skills (like flying, swimming, self-righting) were not affected.  Based on the electrochemical difference between stung and unstung wasps, they concluded that stung wasps had a deficit in the ability to "reach a decision" to walk.  There must be human versions of this wasp because I swear, there are days when I have trouble reaching the decision to get off the couch.

A follow-up study by Gal et al in 2010 (PLoS article) made another very interesting discovery.  Roaches who had their brain ganglia removed were stung for a much longer period of time (196 sec) than normal roaches (39 sec).  Why?  Because the wasp was actively seeking this part of the brain and couldn't find it!  What does it search for?  A specific morphology?  A defined depth within the brain?  Nobody knows.  Furthermore, why is it so important for the wasp to target this region so specifically?  The answer is also still open to speculation but this has zombie written all over it.  The wasp needs the roach to be compliant to move it into the proper position for incubation of the larvae, but resist the urge to flee for several days.  So, the venom basically takes away whatever "freewill" the roach might have had.

Octopamine
 (image courtesy of Wikidocs)

So, what is this supernatural cocktail?  Not a whole lot is known about the composition of the venom (another great project for biohackers or kids looking for obscure science fair projects). I will post more details later but one key component appears to be an antagonist of the octopamine receptor.  Octopamine is a monoamine neurotransmitter that is specific to invertebrates and OA levels are known to be associated with the hypokinetic state.  Several years ago, Rosenberg et al. (abstract) gave roaches a octopamine receptor agonist and found that motor activity in stung subjects was at least partially restored.  Other receptor agonists and antagonists had little effect.  This is certainly one clue about how A. compressa makes zombie cockroaches but for now, the rest of the process is all voodoo.

Discovery of an upside down, carnivorous plant in Brazil

I've always been a fan of carnivorous plants.  Pitcher plants, Venus flytraps... very cool.  An article just published in PNAS describes a very bizarre plant that has been recently characterized as carnivorous.  The flowering plant, from the genus Philcoxia, is a pathetic specimen.  Found in dry savannas of the cerrado in central Brazil, the stems are leafless, which means it resembles many of my potted plants here at the house.

It turns out that the leaves of Philcoxia are actually underground! Most plants would find this adaptation ridiculous.  The primary function of a leaf is to capture sunlight and produce energy through photosynthesis.  What kind of freakish plant would put the leaf underground where there is no light?  A murderous plant, of course.

What Pereira et al. show in the PNAS paper (abstract) is that the leaves of Philcoxia have evolved to trap and eat nematodes in the soil.  The data to support this comes from an elegant study using nematodes that had been fed nitrogen-15 (15N), an isotope of natural nitrogen.  Releasing the nematodes in the vicinity of the plant, they measured the change in 15N in the leaves after two days.  They show that the absorbed 15N increases from nearly undetectable levels before the experiment to about 15% of all nitrogen content by Day 2.  They talk in the methods about how they extensively washed and dried the leaves to remove all traces of 'nematode remains', but the greatest risk in this experiment is that the 15N they are measuring is simply from the residue of dead worms on the leaves.  Nevertheless, they also show that the leaves are covered  with a sticky sap and that enzymes on the surface are available to break down the corpse for consumption, as found in other carnivorous plants. Interestingly, the glands that produce the sap are also similar to those found on other carnivorous plants.  So, it certainly seems plausible that another plant has found its way to the dark side.  Better call NCIS (that's Nematode Criminal Investigative Service).

Maybe I'll just start telling people that the dead plants I have around my house are rare Philcoxia from central Brazil and that they are supposed to look dead.  Maybe I'll tell them that I have re-engineered them to eat, um, larger prey. I wonder if carnivory could be engineered into grass?  That would keep the neighbor's dog off of the yard!! Ahh, the possibilities...

Bioluminescent Light Bulbs?

There is a news blurb going around about using flasks of bioluminscent bacteria to light your house.  I mentioned this type of thing in the Foxfire post, but Philips has been working on this for some time.  The lighting system consists of a wall of hand-blown glass flasks, coupled to methane lines that are sourced locally (ie, from the users trash).  The bacteria have been engineered to glow when methane is present, so users can control the lighting.  Although this is impractical for general use at the moment, it is probably the beginning of the next revolution in lighting. Some of the articles talk about the most likely first application, which would be for safety lighting near buildings or on roadways.  I think it would be cool to have trees or shrubs engineered to glow as well... it would be awesome to have glowing bushes near our front walkway!  If you want to see how the bioluminscent bacteria fit into the Microbial Home, see the link at Philips' web site ( link), it's pretty trippy stuff.  If you want to try your hand at growing bioluminescent algae at home (or for a cool science fair project!), here is a good starting place (link).  If you want to see what a team from Cambridge University did for their iGEM project last year (hint: it's on making bioluminscent products) check out this link.

  Philips is not the only company looking at commercializing bioluminescence for non-medical applications.  A company called BioLume (link), based in Research Triangle Park, NC is trying to put bioluminescent proteins in food.  Yeah, that's right.  Glowing food.  They use examples like candy and alcohol as likely products, as well as makeup.  Sounds like a Rave Gone Wild! The company has IP around many different bioluminescent proteins (mostly luciferases) found in marine life.  I imagine that they formulate it in a way that the enzyme becomes active when there is a change in the environment.  They mention a calcium-induced reaction of a enzyme-substrate fusion, as well as fusions with fluorescent proteins.  I'm sure that the proprietary chemistry and photophysics involved in these products is really cool!  I do hope the metabolized product is non bioluminscent... there is nothing more scary that glowing pee!

Red wine in a pill: Metabolic effects of resveratrol in humans

Remember back in July I talked about a future where simply popping a couple of resveratrol tablets gave the same benefit as a walk around the block?  That future may be closer than we think!  A recent paper in the journal Cell Metabolism describes the results of a very small study of resveratrol in humans and the data is pretty exciting.  Let me repeat that caveat... this was a small study!  Still, the metabolic effects described in this work clearly emphasize the need for further research on this and other magical polyphenols.

The paper published by Timmers et al. (abstract) is the first to study the metabolic effects of resveratrol (RES) in a clinical setting.  Eleven obese men were given either RES (at 150mg/day) or placebo for 4weeks, followed by a 4-week washout and then the treatment was switched (this is known as a crossover study).  Patients and doctors were both blind as to what treatment was being administered and during treatment, a variety of metabolic tests were conducted.  There is a lot of data in the paper (and it looks like the pdf is free, so check it out yourself!) but let me hit a few highlights:

1) Patients taking RES show an increase in mitrochondrial efficiency, particularly in fatty acid oxidation of muscle fats, and decreased levels of triglycerides and glucose levels.  Significantly, these changes are seen at the gene level, suggesting that it is the overall metabolic pathway that is improved, not just a downstream clearance of metabolic markers.  A similar pattern of changes has been noted in athletes undergoing endurance training (they reference Dube et al, 2008 and Meex et al, 2010).  This is fairly consistent with the Momken paper I blogged about back in July, ie, RES acts like an exercise mimetic.

2) Changes in glucose and insulin levels are modest.  Timmers et al. report a statistically significant drop in serum glucose and insulin levels in the patients taking RES, but this effect is pretty modest.  There is also a shift in peak glucose and insulin levels after a liquid test meal, suggesting some changes in glucose homeostasis, but they could not draw definitive conclusions.  If you recall, the rat data from Momken et al. was also pretty weak with regard to insulin/glucose levels.

3) RES also showed other health benefits:  This study also demonstrated a significant effect of RES on lowering systolic blood pressure and mean arterial blood pressure, as well as decreases in resting energy expenditure and sleeping metabolic rate.  The later two effects are also seen in studies of calorie restriction and further illustrate the metabolic changes induced by RES.  Calorie restriction is also associated with increased lifespan in animals, so these observations may be pointing to another possible health benefit of RES.  They also observed a decrease in markers of inflammation, further suggesting an overall improvement in health. Although this is interesting, I still think the catechins are the more potent player here... I'd like to think that as the flavinoids polymerize during aging, the wine gets better and better for your heart. It would be interesting to see how some of these molecules perform in a study similar to this.

Taken together, this paper highlights some of the metabolic effects of RES in humans and may offer some insight into the health benefits of this polyphenol.  Much like the rat study, however, this is a very high dose (the equivalent of >100 glasses of wine per day) and so who knows if there are long term side effects at this dose.  The fact that they see statistical significance with only eleven patients is also very surprising.  Clinical studies usually need hundreds, or even thousands of patients to provide enough statistical power to draw conclusions like this.  Personally, I would find taking a pill much less satisfying that enjoying a nice glass of Cabernet. Since that glass of Cab is a veritable grab bag of Redox goodies, I think it is also very likely that there are many other 'good' polyphenols in wine that scientists haven't studied as rigorously as RES.  So as dozens of trick-or-treaters descended upon our neighborhood on Halloween night, I had to raise my glass to our ancient ancestors who discovered the wonderful winemaking process, and the scientists who now try and tease apart how it does what it does. I may have also stolen a chocolate or two... in the interests of science, you know.

A gene important for creating zombie caterpillars

Advancements in zombie science are coming fast and furious!  An email from a colleague (and fellow reader) noted that I missed a recent article in the journal Science concerning zombies.  The article, titled "A Gene for an Extended Phenotype", seemed pretty innocuous, however, after going back and reading it more carefully it turned out to be a pretty cool discovery.

First, a bit about zombie caterpillars.  There have been several documented reports of zombie-like behavior in moth larvae.  This report is focused on the infection of the gypsy moth (Lymantria dispar) by a baculovirus (known as LdMNPV).  During the various stages of molting, larvae typically hang out on the ground and away from The Very Hungry Birdie, but climb up into the trees at night to feed on leaves.  After infection by the baculovirus, their behavior changes (noticing a pattern here?).  As the virus replicates and ravages the inside of the caterpillar, the infected host climbs up into the leaves during the daylight hours and eventually dies.  The body then liquefies, and virus-laden particles rain down on the uninfected victims below.  Yeah, you can't script horror much better than that.

Ok, so Hoover et al. (from Penn State, see abstract) were interested in identifying which genes were important for the change in behavior.  To do this, they infected caterpillars with wild type baculovirus, as well as virus that had been genetically engineered to be missing certain genes.  The caterpillars were placed in 1 liter soda bottles equipped with a fiberglass screen for climbing (in true DIYbio fashion!!).  Interestingly, when a gene called egt was removed, the caterpillars died at ground level, suggesting that the behavioral control of the virus had been altered.  To make sure it wasn't an artifact of the mutated virus, they re-engineered the mutated constructs so that the egt gene was present again and the zombie caterpillars climbed up the mesh and died.  It would appear that the egt gene in the virus has evolved to make the caterpillars engage in high-risk behavior, and to place the caterpillars in a location where rain/gravity/hungry birdies can maximize viral spread. Genius.

The next step is to figure out the mechanism.  Interestingly, Hoover et al. mention that the egt gene encodes an enzyme which deactivates a hormone (20-hydroxyecdysone) involved in the process of molting.  It is intriguing that the virus blocks the molting process in order to give itself time to replicate inside the host, but it was hard for me to understand how the modification of the hormone leads to behavioral changes.  Perhaps entomologists already know that part.  Coincidentally, the hormone is also reported to have a variety of biological effects in humans, even though we do not molt and lack the endogenous receptor. What would the modified enzyme do in a human?  Until we find this stuff out, it's probably a good idea to check the trees around your house, particularly if you hear a dripping sound... and if your neighbor has been missing awhile.

Yes, there are zombies all around us.

How about a GFP cat to go with your GFP beagle?



The GFP cat:
From Figure 2 of Wongsrikeao et al.



Well, that didn't take long.  I blogged last month about a paper describing GFP beagles that were able to glow under the control of a tetracycline promotor.  Now, a new Nature Methods paper describes a GFP cat!  The basic point of the paper (here's the abstract) was to demonstrate gamate-targeted transgenesis in cats and to use this ability to make a transgenic feline model for HIV research.  The HIV part was interesting, as they introduced the gene for a protein from the rhesus macaque known as TRIM5.  I studied TRIM5 pretty extensively when I was doing HIV research as it is a species-specific restriction factor that is effective at stopping HIV replication.  Cats don't have an analogous TRIM protein (that we know of) so by introducing this protein into the cat, researchers can study the transmission of FIV (the cat version of HIV).

The cool part was the GFP expression.  Wongsrikeao et al. wanted to see if they could introduce multiple genes, and since GFP is a convenient marker, they could also study the presence of the transgenes in progeny cats.  As I mentioned in the Beagle post, fluorescent proteins have been introduced in animals previously (see here and here for cats) but the efficiency in the present work is better.  I'm certainly no expert on transgenics, but the general trend over the last few years is clear... we are moving from the realm of the nearly impossible to the land of the challenging but doable.  Glowing cats, dogs, hamsters, bunnies, you name it are going to be popping up in your pet store relatively soon.  Lost your dog?  No problem... just look for the glowing blob in the woods.  How about a government program to develop a GFP opossum?  Think of how much road kill would be eliminated if you could see these animals before they got up close and personal with your tire.  Think about how cool the forest would be if all of the little woodland creatures glowed bright green. Think about how easy it would be to hunt.  I wonder how screwed up the food chain would get. I guess we would have to make GFP plants for the little GFP bunnies to hide in. Man, this would make a really cool dystopian/biopunk story!

Can gut bacteria make zombies?



L. rhamnosus: Not a zombie-
producing bacteria...yet.



If T. gondii weren't enough to worry about, now there is evidence that bacteria in our gut can influence brain function.  Lactobacillus and other probiotic organisms have long been speculated to have beneficial in vivo effects, and are most commonly known for improving the health of the digestive tract.  L. acidophilus is probably the most widely known, since it is used to make yogurt, but there are many other types of lactobacilli with alleged health benefits ranging from lowered cholesterol to improved mood.  Some of these benefits are speculative, and for many years any benefit (such as improved gut health) was thought to be due to local effects or secreted chemicals.  However, the impact of these bacterial colonies may be much more far-reaching.

A Proceeding of the National Academy of Sciences (PNAS) paper published by Heujtz et al. last January (abstract) showed that microbial colonization in the mouse gut led to the activation of signaling pathways involved with motor control and emotional response.  This was the latest in a growing body of literature that suggests gut bacteria could influence how we think and act.  Now, in the August edition of PNAS, Bravo and colleagues take this one step further (abstract).  They show that Lactobacillus rhamnosus can directly influence the expression of GABA receptors in the brain.  GABA is the primary neurotransmitter for regulating many physiological and psychological activities in humans.  For example, caffeine inhibits GABA and results in an overall increase in neurotransmitter activity.  In contrast, alcohol and sedatives tend to increase GABA activity, leading to reduced neurotransmitter activity. Bravo et al. showed that feeding mice L. rhamnosus reduced GABA expression in some areas of the brain, while increasing it in others.  The overall effect was to make the mice more calm.  Here in the Dark Lab, we would test this by subjecting the rats to endless episodes of Jersey Shore, Barney and Friends, and The Jonas Brothers, and then asking how long it takes before they fall into convulsions.  Bravo measured stress-induced hyperthermia (rise in core body temperature from stress) after a battery of different tests, including  forced swimming and mazes (less barbaric than listening to the Barney jingle, but presumably effective at producing stress) and showed that the L. rhamnosus-fed animals exhibited less stress during these activities.

The final point of the paper was what I found most interesting.  Some of the animals had the vagus nerve cut prior to the start of the experiment.  This nerve is a direct link between the gut and the brain and is responsible for transmitting signals about hunger and satiation.  In these animals,there was absolutely no effect from consuming L. rhamnosus.  No changes in GABA expression and no behavior changes versus the control animals.  This means that the probiotic bacteria that colonize in the gut might actually use this nerve to signal directly to the brain.  Although these bacteria appear to provide a health benefit, I can certainly imagine other strains that are more nefarious.  Yeah, I'm talking about zombies again.  This phenomenon is not all that different from what is seen in T. gondii or the zombie ants... microbial agents that manipulate the brain function of the host.  If a probiotic strain can mimic the effect of caffeine-overstimulation or, even worse, caffeine-deprivation, then that would be a whole new kind of scary.  Anyone who has seen me before that first cup of coffee knows what I'm talking about... it's bad enough to give a zombie nightmares!

Zombie rats are horny!

You may remember a very early post on zombies, where I talked about a parasite known as Toxoplasma gondii.  I just read a new article published in PLoS that is really mind-blowing.  It also should fall in the category of science known as what-kind-of-PhD-do-I-need-to-study-this-shit.  Very interesting, very strange, and very cool.  Here's the abstract to check out for yourself (abstract).  As you know, rats that are infected with T. gondii lose their fear of cats.  This is important for the parasite because part of its life-cycle occurs in the gut of the cat.  This report takes that one step further.  House et al. show that as part of this shift in rat behavior, the rats are actually attracted to cat urine.  Not attracted like "this smells like roses" but rather "yowsa, hot babes" (rats do say 'yowsa'... I've heard them).  Yes, the parasite changes the way the rat brain responds to the smell of cat urine.  Neurons in the ventromedial hypothalmus, dorsomedial part (mercifully abbreviated as VMHdm), which normally are active in response to fear, are silent when infected rats are exposed to urine.  In contrast, the area in the brain the DOES light up is the posterodorsal medial amygdala.  These are the same neurons that light up when rats watch porn (or are exposed to estrous females, but somehow that doesn't sound as sexy).  Their conclusion is that T. gondii makes rats think that if they follow the cat pee, they will get laid.  Although that may work in some dive bars, for these rats it ultimately leads to just a single dinner date.

These results are also consistent with other findings that show an increased level of dopamine in infected rats.  Dopamine is, of course, the primary molecule in behavioral reward so it seems reasonable that this pathway would also be effective at shifting rat behaviors.  They cite a 2006 paper by Webster et al. (abstract) where it was shown that dopamine receptor antagonists prevent the attraction to cat urine.  Could this receptor be the first therapeutic target for treating zombies?  I'll have to propose that at the next New Target meeting. 

The ability of T. gondii to alter brain function and behavioral response is incredibly cool and a little bit scary.  Why scary?  Because it is estimated that at least one third of the human population has been exposed to the zombie-inducing T. gondii (and no, it's not just pop stars and politicians).  Even subtle changes in behavior on that scale can lead to massive changes in society.  Although it is unclear how well this study translates to humans, it does suggest that in the event of a zombie apocalypse, it's probably not a good idea to hide out in the girls' bathroom.

Highlights from the Protein Society Symposium

A week ago, I attended the 25th annual symposium of the Protein Society in Boston.  I've gone to this meeting three times and this was the best yet.  Very, very cool stuff.  I also got to see a lot of old friends from grad school, including my graduate advisor.  It was great to hear him talk fondly about the 'good ol' days' (ie, when I was his student) as I distinctly remember them being less fond and more frantic.  I think finishing a PhD thesis is the mental equivalent of giving birth to an elephant while running a marathon, but for several obvious reasons I will never be able to test the hypothesis.  I also met some cool new people.  I talked politics with a girl from Poland in a loud Irish pub and met another girl who is some kind of flute prodigy from a well-known coffee empire.  At the reception, I met a guy from, well, some European country who had done a postdoc in San Diego and I knew many of the trails he had hiked.  We tried watching the Red Sox game from the 50th floor of the Prudential building... great view but when the outfielders look like fleas on a green dog, it's really hard to see what is happening.  We kind of made it up as we went along and since the Polish chick didn't know the game, it was all good.  He still owes me pictures of Fenway.  The poster session was crazy, with two overlapping sessions and the very friendly (but bored) vendor who bribed me with chocolate every time I passed her booth.  I was also a poster judge this year, so I missed most of that session, but tracked the presenters down later to ask questions.  It's a little awkward at the coffee breaks, since everyone is staring at the nametags trying to find people they want to talk to.  I would try and catch a glimpse of their badge over the rim of my coffee and hope they were not offended when I simply walked away.  It's a very unusual hierarchy at conferences.  There is absolutely no guessing about where you stand in the pecking order.

Anyhow, I can't talk about the things I found most exciting because I was there for work, and work stuff has to stay off the radar.  However, let me briefly describe two (not work-related) things that were pretty cool.  One was a talk by Della David at UCSF on protein aggregation as a part of aging.  I don't know a lot about this field, but one of her early slides really caught my attention.  She was discussing the role of protein "aging" in inducing aggregation using C. elegans (a worm) as a model.  As the worm aged, she showed that the concentration of over 400 different proteins increased in the insoluble fraction.  In simpler terms, if you take all of the proteins out of the worm, many of them are soluble but some fraction are in an aggregated form, which is not soluble.  Although the total amount of protein seemed fairly constant with age, the proportion of aggregated protein increased and seemed to disrupt the natural process of homeostasis.  Then came the kicker... to show that this was an active process (that is, controlled by a cellular system) she used a C. elegans that had been engineered to have a specific mutation in the Daf-2 receptor.  These worms had twice the life span of a normal worm.  Whoa!  Sign me up for that mutation! Imagine living 160 years!  It turns out that the fraction of aggregates is independent of the lifespan, suggesting that the process is controlled.  Two things here... Daf2, which is part of the insulin/IGF-1 signaling pathway, can regulate lifespan (possibly related to the observation that mice that eat less live longer?) and that protein aggregation as a result of aging could also be controlled.  Here is a review on insulin/IGF-1 signaling in aging (abstract) and here is David's recent open-access paper covering some of this story (PLOS paper).  Listen folks, please hurry up with this important work... I'm not getting any younger.

The other talk I liked was by Ken Dill (a long-time favorite of mine and also from UCSF).  I'm used to him talking about transfer free energies and lattice models for proteins but this time he was talking about the stability of the proteome.  He (and others) have shown pretty convincingly that on a macro scale, protein stability is roughly dependent on the length of the protein.  (Seems simple but it has taken decades to model it in a way that makes physical sense).  Armed with this model, he determined the stability of the entire proteome and found that it is only marginally stable.  Over 500 proteins have stabilities less than 3 kcal/mol, which means they are barely folded and functional.  The implication of this result is that even slight increases in temperature can cause many of these proteins to unfold.  The resulting denaturation catastrophe overwhelms the cell and causes cell death.  This is the most plausible explanation yet for why slight increases in temperatures cause such problems (even for humans, an increase in body temp of 7-8 degrees can be fatal).  I asked him about the proteome of thermophilic bacteria and whether it might explain their ability to survive extreme temperatures and he said he is working on that now.  I'm guessing that might explain some of the adaptability, although the detailed mechanism is still a mystery.  For you DIYbio people out there, this model provides a pretty simple way to do this type of analysis yourself. The simplicity of the model, and the fact that minor ensemble changes can be magnified into major improvements for the organism tell me that life might be lurking everywhere there is an energy gradient (I'm looking at you, Titan).  On the flip side, it shows how sensitive life can be to slight changes in the environment. Here are the links to the articles (proteome stability and Dill's model)

  Dill also started off with a joke: "There are three kinds of mathematicians... those that can count, and those that can't."  Nothing like a geek joke to start off a talk... but hopefully his material will be better in San Diego next year.

GFP Beagles: Disease model or designer pet?

A recent paper in the journal genesis describes the production of transgenic beagles that glow when exposed to UV light (abstract).  The eGFP transgene was introduced into a beagle embryo using a similar (but much improved) technique that was used to clone Dolly the sheep.  Making a puppy that glows is not really new, as it has been demonstrated by the same group in 2009 (abstract) and others (in dogs, as well as other small mammals) but there are two cool things about the recent work.  First of all, they put the transgene under a promotor.  This means that the puppy does not glow green until the gene gets switched on, in this case by the drug doxycycline.  Feeding the dog low levels of doxycycline induced the expression of the GFP protein (green glow) and the effect could be turned off simply by removing the drug from the dog's diet.  This is pretty easy to do in small animals (like rats and mice) but pretty complicated in large animals. 

  In a separate article, also in genesis, they report the transmission of the transgene to offspring (abstract).  This was also interesting, as the GFP-containing females were totally fertile and had normal pregnancies and births.  The dads were wild type beagles so roughly 50% of the offspring carried the transgene.  This is consistent with stable germline transmission.  This result suggests that we are really not far off from having designer dogs.  The initial cloning will be hard (efficiency is still in the 1-5% range) but if the transgene is stable, simple breeding techniques should be enough to make zillions of glowing puppies!  Although this is a crude example, one can envision a vastly different world where hair color, facial and body features, and perhaps even personality traits could be engineered.  Genetic defects and disease determinants could be engineered out.  One could build the perfect dog.  You did realize I was still talking about dogs... right?

Foxfire: Chemistry of the undead



Ghostly mushrooms



I am currently approaching the half way mark in my current work-in-progress (WIP-2) and have been making particularly heavy use of foxfire.  I didn't start out to write about that... in fact, this book started out as a humorous middle grade adventure and quickly turned into a dark, YA biopunk.  Write what you know, I suppose.  One of the emerging themes is the struggle between the protagonists and the technologically-advanced fungi that exists in their (slightly dystopian) world.  So, I found it a little coincidental that a report came out a week ago by Marina Capelari and colleagues about a type of ghost mushroom that had been re-discovered in a Brazilian rainforest after being extinct for over 150 years (abstract in the journal Mycologia).  The mushroom, formerly known as Agaricus gardneri, is notable for its bright and constant bioluminescence.  To understand why this is unusual, here is a brief description of how foxfire comes to be:

Bioluminescence is generally accepted to come from a 2-step reaction.  A chemical called luciferin (L) is first reduced (to LH₂) and this reaction is catalyzed by an enzyme called reductase.  NADH is a molecule (di-nucleotide, actually) that is a cofactor in many redox reactions.  Its basic function is to move protons around (you're a geek if you noticed the chemistry pun).

L + 2NADH <--> LH₂ + 2NAD+

Reduced luciferin is then oxidized (to LO) by an enzyme called luciferase.  This process also produces a photon of light and is the source of the creepy glow.

LH₂ + O₂ <--> LO + H₂O+ LIGHT



Illudin S: Potential substrate for ghost fungi

Why am I cryptically showing fungal luciferin as L, instead of showing the chemical structure?  Could it be that my chemistry skills are so bad, I couldn't tell the difference between L and LH if my life depended on it?  Well, yes -- but it is also true that the luciferase substrate in fungi is not well characterized. The luciferin for A.gardneri is probably a member of the sesquiterpene family, most likely an illudin.  Some of these compounds have been studied as anticancer agents but the illudins tend to be extremely toxic (possibly another reason they are called ghost mushrooms!).  Interestingly, other luciferins (such as those found in fireflies, shrimp, etc) have totally different chemical structures, which gives them different biological properties and unique spectral characteristics (ie, different colors, brightness, etc).  Changes in the luciferin structure, amino acid substitutions in the active site of luciferase, and varying levels of oxygen or water can each contribute to changes in the emission of light.  What is unusual about A. gardneri is that unlike other species, the bioluminescence is almost constant.  In fireflies, the luciferin is released when they want to blink and in the case of other species, they light up only after contact (probably a means of self-defence).  So why does this mushroom glow all the time? No one knows yet.  The biochemistry of these things is almost as mysterious as seeing their eerie ghostly glow on some rotting tree stump at midnight.

However, it provides a great real-world example of the potential technology for my story.  It doesn't take much imagination to think that these mushrooms could be engineered to be very bright or to respond in controlled ways depending on environmental input.  A basic example from my WIP is that these types of fungi are used for lighting underground.  No electricity required, no pollution, and little maintenance.  They are almost the perfect type of lighting... or are they?  Anyhow, I thought it was a pretty clever idea early on until I found out that Ben Franklin used foxfire from mushrooms to light the inside of one of the first submarines.  Was there anything this guy didn't know about?  I guess he's going to have to go on my list of card-carrying biopunks.



Resveratrol from red wine: An exercise mimetic?

I've posted before about the magic of polyphenols in wine.  A new paper out by Iman Momken et al. in the FASEB Journal (abstract)  now suggests that one of these polyphenols can protect against muscle wasting and bone loss as a result of inactivity.  The group suspended rats by the tail to prevent their hind limbs from significant weight-bearing exercise in an attempt to model the situation during spaceflight (the main focus of the paper).  One group was treated with resveratrol (aka RES, a red wine polyphenol) at 400 mg/kg per day and compared to a control group receiving no treatment or normal rats (no leg suspension).  Over a two-week period, they studied both the physiological changes in the muscle and bone, as well as biochemical pathways involved to better understand the biological function of the polyphenol. 

The physical benefits were fairly clear.  They observed significantly reduced muscle atrophy and much less bone demineralization in RES-treated rats, suggesting that the compound was protective.  The interesting aspect was in the biochemical details.  It is well known that extreme lack of muscle usage (for example, in cases of long-term bed rest) can induce insulin resistance in humans.  In this study, they claimed that rats treated with RES did not lose insulin resistance. However, I thought this was the least convincing data in the paper.  Some of the differences were significant, but I thought the overall effect on insulin/glucose levels was pretty modest.

A much more convincing effect was observed in the bone and muscle.  They monitored a number of biochemical parameters and found that suspension of the hind limb led to significant changes in the morphology and function of muscle tissue.  All of these changes were consistent with atrophy.  Rats in the control group did not have this effect.  In the RES-treated group, suspension of the hind limb was found to produce little or no changes to muscle.  Then they show that specific biochemical pathways are involved in the protective effects of resveratrol, particularly those involved in oxidative stress and fatty acid metabolism. In plain English, they found that even though there was no weight-bearing exercise to stimulate cellular activity, resveratrol was able to preserve these activities and prevent muscle degradation.  That is, it acted almost like an exercise mimetic.

Does this mean we can forget the gym and just drink our way to better health? Can we have a glass or two of wine while watching Buffy the Vampire Slayer and call it exercise?  Probably not.  The amount of resveratrol in a typical glass of wine is less than a milligram.  The 250g rats in this study received 100 mg, so the observed benefit came from the equivalent of 100 glasses of wine per day.  Your muscles are really gonna need that resveratrol if you spend every day passed out next to the TV.  However, it does further illustrate the potential health benefits of these wonderful polyphenols.  Maybe on those cold, snowy days in winter you can just pop a RES pill and get the same benefit as a walk around the neighborhood. For you health nuts, you can chase it down with a glass of good Cabernet.

Amazing new paper on Zombie Ants

As some of you may know, I’m a big fan of zombies.  Not the feet-dragging, flesh-rotting stereotypes found on B-grade horror movies (although they can be cool too) but the ones found in real life.  The ones that make you wonder whether human zombies are for real.  The science behind these phenomena is fascinating but absolutely terrifying.  Creatures that suddenly exhibit irrational behavior or complete odd and highly specific tasks.  (Don’t worry, your girlfriend is (probably) not a zombie.)  I already wrote a bit about T. gondii (link) but a recent article in the journal BMC Ecology (abstract) describes an even more horrifying example. Zombie ants. I’m thinking this would make a great sequel to A Bug’s Life.

 



Zombie ant with fruiting body



It starts with a simple fungal infection and before long the ant is no longer following the well-marked ant trails through the Thai rainforest.  It starts staggering and has the occasional convulsion but instead of heading to rehab, it falls out of the tree and onto the forest floor.  At solar noon, the ant stops its random stagger and makes a bee-line to a nearby sapling.  It clamps its mandibles into a leaf (almost always a primary vein, under the leaf, facing NNW, about 25 cm high) and dies.  Bizarre? Yes, but to the fungus it is all part of a diabolical plan (cue music).  In order to reproduce, the fungus (Ophiocordyceps unilateralis) requires a very specific temperature and humidity.  An environment not present in the canopy (where the ants are) but uniformly at about 25 cm from the forest floor.  What’s an evil fungus to do? In order to get there, the fungus hijacks the ant and manipulates its brain by releasing various chemicals and poisons as well as making specific morphological changes to the mandibles.  All of these activities are designed to get the ant out of the canopy, go to a specific environment, and have the ant remain attached there after death.  Then the fungus sprouts a fruiting body out of the ant’s head to release spores.  All in all, the amazing transformation from ant to fruiting body takes about 2-3 weeks.  Many of the details are still a mystery but the Hughes paper begins to shed some light on this process.  A process, incidentally, that is very ancient.  Another paper by Hughes (abstract) describes fossils from the Tertiary Period (from about 50 million years ago) that bear mandible scars on primary veins of leaves.  Could these be the echoes of ancient zombie ants?  Could our own legends be the echoes of human zombies?  I wouldn’t worry too much unless your spouse’s ‘honey-do’ list becomes very bizarre or your girlfriend’s new hat looks suspiciously like a fruiting body.

Snail shells that amplify bioluminescence

Hinea brasiliana - courtesy of The Scripps Institution of Oceanography

Remember when I discussed various genetic monstrosities (cue maniacal laughter) in my last post?  Here is one we don’t even have to create because Mother Nature has done a pretty remarkable job already (She is the ORIGINAL biopunk!).  Check out this link that describes some research out of the Scripps Institution of Oceanography (link).  In an article published last December (see below) they describe a unique bioluminescent snail (Hinea brasiliana) found off of Australia.  The fact that this thing glows is somewhat unusual, but how it achieves the effect is quite cool.  When the snail encounters something dangerous (a predator, a diver’s foot, a sinking ship, etc) it activates a luminous display on its body in an effort to scare the threat away.  To do this, the light must be activated in such a way that it is emitted from the shell (ie, be visible to the predator).  What is remarkable is that even though the shell is opaque and colored, only the wavelength of light from the bioluminescent signal is selectively diffused.  Even more amazing is that the shell acts as an amplifier, so that the snail appears larger than it really is! 

Obviously, trying to understand the properties of the shell and how this material specifically diffuses and amplifies the bioluminescence has broad implications in commercial development of better optical materials (fiber-optics, perhaps?).  But, can you imagine engineering these properties into the leaves or bark of a tree?  Or into specific areas on your wall or ceiling?  Soft, energy efficient lighting with little or no pollution.  Understanding and replicating this phenomenon seems like a ripe area for garage scientists.  How about a science fair project looking at the transmission of light through this (and other) shells as a function of wavelength?  Is the shell acting like a filter? A lens?  What is the chemical and structural composition of the shell? Do small pores allow the selective diffusion of light? Does the light transmit backwards through the shell?  Do related species of snails transmit different wavelengths of light?  Is the light really amplified or is it just an illusion?  Maybe it’s time to pop into the Dark Lab and answer some of these questions…

Reference: 

Deheyn D. and Wilson N., Bioluminescent signals spatially amplified by wavelength-specific diffusion through the shell of a marine snail. Proceedings of the Royal Society B (Biological Sciences), Dec 15 2010.

Be a Martian tourist!!

Wanna really get away?  Go to Mars!  You could use a commercial, deep-space rocket and travel for months in cramped quarters with a bunch of other tourists.  (Imagine getting on a plane for a 4000 hour, non-stop flight with all those screaming kids… better be lots of free booze on that flight!)  Or, you could take your touristy pictures from the comfort of home!  Check out the High Resolution Imaging Science Experiment (HiRISE).  It’s run out of the University of Arizona in conjunction with NASA and is focused on using high resolution images of Mars to study the weather, geology, topology, tectonics, and climate change.  Scientists have been using this data for years to develop models for these processes but Mars is a pretty big planet and the number of interesting sites to study is pretty vast.  I mean, we haven’t finished exploring Earth yet!  So, there is an opportunity for us Dark Lab types to dig into this treasure trove of data.  Much like the fuzzy blob site (blobs post), you can sift through pictures and highlight interesting or unusual features.  But they also take it one step further… with HiWish (link) you can actually suggest (using a Google-Mars like platform) Martian features to be photographed.  If selected, the Mars Reconnaissance Orbiter will be sent commands to zoom in on your target and take high resolution images.  Amazingly cool!  Many of the gallery pictures are really cool.  The image above is a shot of a very recent (like, within the last year) meteorite strike.  Other examples of interesting features would be odd canyons, rock formations, and that little green man with the Death Blaster.  Apparently, Martians don’t like being peeped at with telescopes.

Reverse Engineering of Neolithic Wines (or The Coolest Job in the World!)



Chateau Jiahu: A blast from the past

 I do protein engineering for a major pharmaceutical company and I love my job.  I get to work on interesting scientific questions, use the coolest technology ever, and at the end of it all, contribute to developing medicines that might help people.  What’s not to love?  Then, sometimes, I get job-envy.  That happened last week when I read about Patrick McGovern.  He leads the Biomolecular Archaeology lab at the U. Penn. Museum of Archaeology and Anthropology (link) and if he ever wants to trade jobs for a day, I’m game. (Unless it’s Wednesday, because that’s the day we get free food.) He’s been called “the Indiana Jones of ancient ales, wines and extreme beverages”.  Yeah, apparently they had Jager-bombs back then. This guy’s research involves chemistry, genetics, archeology, anthropology, and wine/beer making.  Sometimes wine was also used for healing, and he also tries to determine the pharmacological significance of these chemicals, such as their antibacterial or anti-cancer properties (but I’ll save that for another post).



Malvidin: A wine fossil?



How does he do all this?  Vessels are dug out of archaeological sites around the world (Egypt, Iran, etc) and although they are empty, there is still residue on the sides, like grape juice stains.  These residues have specific chemical signatures that can be detected (usually by mass spectrometry) even after thousands of years. Remember the magic stuff I talked about in the winemaking post (link)?  The presence of these compounds provides strong evidence for fermentation.  However, most of these exist in very small quantities, making them difficult to detect in ancient residue.  The most abundant chemicals in wine (such as tartaric acid) are present in grapes and are not necessarily a marker for fermentation (a jar of wine would look the same as a jar of grape juice).  However, a recent study (abstract) has demonstrated that malvidin or syringic acid may be better markers for evidence of grape fermentation. Malvidin is the chemical that gives red wine its color, but more importantly, it is one of those magic chemicals that polymerizes over time.  In the lab, malvidin polymers can be broken into syringic acid (which is easy to detect) and large amounts of syringic acid can suggest the pot once held fermented wine.  The identification of other compounds or even the sequencing of ancient grape DNA can provide further evidence of wine or beer production.

Although this information provides important clues for studying the rise and fall of ancient civilizations, there is another, much more interesting consequence: Reverse engineering. By identifying the components and byproducts of ancient wines and beer, it becomes possible to try and reproduce today what was made thousands of years ago. McGovern has worked with Dogfish Head Brewery to make modern versions of ancient ales. One example is Chateau Jiahu (link), a fermented beverage of rice, honey and fruit that was made based on the chemical residue found in pottery jars from a Neolithic village known as Jiahu. Chateau Jiahu is an exciting opportunity to taste a drink that has been extinct for over 9000 years! Archeology, biochemistry, and beer… yeah, that’s a cool job.

Find the bubbles and fuzzy red blobs

Wow~ bubbles, green knots, red blobs

I mentioned in an earlier post that it had never been a better time to participate in exciting research projects.  Unfortunately, this no longer involves injections of semi-purified plant extracts in an effort ‘to see what happens’.  Today, you can participate in important research efforts in the comfort (and safety!) of your own home.  The common term for this is ‘citizen science’, which is a (dorky) term I hate.  The research doesn’t have to be dorky.  NASA Science News just highlighted one such effort called The Milky Way Project (link) where volunteers can contribute to the analysis of deep sky pictures obtained by the Spitzer space telescope.  After a free sign up, you view images taken by this instrument (many of them never before seen by a human) and identify interesting features in the picture.  One particular project is looking for ‘bubbles’ in interstellar gas.  A simple tutorial explains how to identify and mark the images, which are then submitted for further analysis.  What is so great about this is that anybody can do it!  I’ve ‘bubbled’ quite a few of these images and I can tell you, some of them are truly breath-taking.  The process reminds me of those gem mining attractions in the mountains of North Carolina (I’m sure they’re everywhere).  You get a bag of dirt and sift through it in a slough.  Most bags contain a number of small emeralds or rubies, but every once in awhile you find a honker.  That’s the scientific term for a big-ass emerald.  These images are much the same.  Some are pretty dull, some have a number of interesting features, and every so often you find a honker.  All of these ‘bubbled’ pictures are then fed back through the image analysis software with the ultimate goal of figuring out what the bubbles are, how they are formed, what purpose they serve in star formation. 

Two UFRBs (unidentified fuzzy red blobs)

Bubbles are boring?  You also learn to identify green knots of gas, which are unknown objects that scientists are very interested in learning more about.  These are a fairly new discovery as are the so-called ‘fuzzy red objects’,  which is the technical term for ‘WTF is that red blob’.  Somewhere there are happy graduate students who no longer have to stare at these images 24/7 until they start drawing bubbles in the freckle patterns of their significant others.  What’s in it for you?  Aside from the opportunity to contribute to research on the cutting edge of astronomy, there is also a chance to discover something totally new.  Something unknown to mankind.  Something which may contribute to a major breakthrough in the origin of the universe.  New data comes in from these instruments on a regular basis, so get off Facebook, pull up a chair next to your favorite astrophysicist and stare into the unknown.  I find that a good cabernet goes well with the fuzzy red blobs.

Winemaking: Science or Magic?

Red wine necklace --
 (from madewithmolecules.com)

Last night I attended a networking event advertised through the San Diego Biotech Network and sponsored by PGC200.org (link).  The topic of discussion?  The Biotechnology of Enology (Oenology for you Brits).   Some days, when experiments are particularly uncooperative, I wonder what it would be like to own a winery.  Seems like a good fit since I like wine, I like science, and I like growing things.  However, I have always been intrigued by how different wines can taste even though they are made from the same grape.  There is also huge variability in different vintages from the same winery.  And unlike beer, if you let wine sit in a bottle for a few years, it can become extraordinary.   How does this happen?  I mean, how hard can it be?  Pick some grapes, stomp them with your feet, pour the shit in a vat and wait a couple years.  Seriously.  The grapes come from the same plant each year so their genetic makeup is the same.  The winemaker knows how to prepare the grapes, add the yeast, control the temperature, uses the same bins, etc.  Budweiser can make the same beer year after year… why can’t the winemakers?

Reading the abstract for the talk (biochemical pathways, genetics, chemical reactions, blah, blah, blah) I figured science must have the answers to this.  Then I saw the bit about wine tastings and immediately signed myself up.  I’ve been to a ton of scientific conferences and let me tell you, almost any mind-numbing talk can be improved with a glass or two of wine.   The speaker was Kerith Overstreet, co-founder and CSO of Bruliam Wines (link)(Bruliam sounds like something off the periodic table, but is actually a portmanteau of her children’s names).   Her talk was nothing short of fantastic.  Life-altering, in fact.   She was an MD (pathology) before switching careers to winemaking and had a sense of humor as dry as a good cabernet.  We gathered in a beautifully modern conference room and during the reception, we admired the views of the surrounding mini-mountains.  She started us off with the 2009 Hayley Pinot Noir.  It was light and pleasant (she described it as feminine).  Lucy, my partner in crime on this trip, described it as kind of bitchy.  Not sure what that means but she knows a hell of lot more about wine than I, so I just nodded knowingly.  Maybe it had too much whine.  (Thank you, thank you.  I’m here all week.) Next up was the 2009 Doctor’s Vineyard Pinot Noir.  This was from the Monterey area (Santa Lucia Highlands) and we both agreed it was really nice.  Bruliam Wines has only been operational for three years and even I can tell that these wines kick ass.  After a couple glasses of wine and some great food, we were all ready for a nap – I mean, the talk.

(The scientifically squeamish may want to sit down now.  Or skip ahead a few paragraphs.)

Kerith started us off gently, talking about how the root stocks were different from the vines and that the two are actually selected independently, like picking out a top and a bottom.  Then she went into fermentation like a bat out of biochemical hell.  Early on, it’s all about the glucose pathway.  The added yeast converts sugars to ethanol and the genetic composition of the yeast determines the speed and efficiency of the process.    Alcohol is toxic to yeast, so there is a beautiful biochemical feedback loop at this stage.  As the yeast becomes stressed, pathways are activated (and are up-regulated by the dropping sugar concentrations) that release fatty acids, sterols, and other chemoprotectants (let’s call this ‘the good stuff’).  During the fermentation process, oxygen is bad – unless you are trying to make vinegar -- however, there is always a little bit in there and so some of ‘the good stuff’ gets oxidized to make “magical stuff” (ie, tannins).  These are my scientific terms, not Kerith’s.  You know when a girl gives you that “come hither” look?  That’s the female equivalent of a tannin.

Pretty simple so far, right?  Just control the reaction and you get your wine.  Not quite.  After the yeast is done, you then have to add bacteria for the second fermentation.   This step stabilizes the wine by converting nasty biochemical byproducts to more storage-friendly chemicals.  In the case of red wine, this is also where the magic occurs.  As the sugar level is crashing and the yeast are starting to die, you sprinkle bacteria ‘like fairy dust’ into the fermenting goo.  Choice of strain is again critically important (homofermenters, heterofermenters, malolactic strains, zzzzz) but whatever you add activates different biochemical pathways which, in turn, gives you different levels of “good stuff” and “magical stuff”.  Timing and balance is everything.   You can’t let the yeast or the bacteria over-process the biochemical byproducts or you wind up with wine that is “all alcohol and no sex”.   I’m calling these chemicals “magic” because honestly, people don’t know what most of these chemicals are or why they are important.  But they are mission-critical for body, flavor, mouthfeel, and aging, particularly in red wine.  These magic tannins are the key to turning a good bottle of cab into a mind-blowing experience.  How does that work?

Catechin - one of the magic molecules

One wine characteristic I know well is the dry, leathery feel of a cabernet.  It makes your mouth feel weird and some really young cabs are like drinking liquid desert.  The a-ha moment in Kerith’s talk came at the end when she was talking about aging.  When a cab is young, there are a lot of tannins in there and the taste can be very harsh.  That sensation in your mouth is because tannins bind very strongly with proteins in spit, so they cling to the sides of your mouth.  One of the magic tannins is from the flavin-3-ol subgroup  of flavinoids (not to be confused with the famous rapper) and is commonly known as catechin.  Catechin is a small chemical (see picture) but when it gets oxidized, it can form a dimer.  Dimers can be oxidized to form trimers, and so on.  As the chemical polymerizes, it has a harder time binding to the proteins in spit.  So as the wine ages, it seems “softer” or more mellow.  Other phenols and flavinoids can also be oxidized and combine to form very exotic chemicals that cause changes in the character of the flavor (more chocolate, less berry, hint of woodsmoke, etc).  I can’t even begin to comprehend how many different combinations of chemicals you could create inside that bottle.  You might be wondering how this happens -- I said that oxidation was bad (vinegar) and oxygen levels are low during fermentation.  Where does this tiny bit of oxygen come from?  The cork.  The OTR (oxygen transmission rate) of the cork results in micro—oxygenation of the wine.  These magic tannins are basically buffering the wine from a slow oxygen leak, protecting it from the bad types of oxidation that lead to enological disaster and creating tasty flavinoids in the process.  The more tannins in the wine, the longer it can be stored and potentially the better it gets.  Wine is truly an amazing witches’ brew! 

  So, is winemaking driven by science or magic?  If it’s science, is sure isn’t governed by classical mechanics.  There is little to no predictive power and the system is far too complex to control.  Even comparing it to quantum mechanics is a stretch.  Every batch that is set up will come out different because at the end, the distribution of tannins (type and concentration) cannot be predicted.  It will taste generally like a cabernet, but the specific taste will be different from batch to batch and sometimes even bottle to bottle.   Since there are multiple biochemical pathways involved, each with interdependent feedback loops, and the final output is so exquisitely dependent on the initial conditions, I wonder if the process is actually chaotic.  What if winemaking was described by something like a Lorenz attractor?  These non-linear dynamical systems are characterized by being globally deterministic (it tastes like a cab) but locally unpredictable (I taste bell peppers!).  The weather is a good example as is the stock market.  This means that good winemaking will likely come from empirical observations, intuition, and a little luck.  I do wonder if someday scientists will understand which tannins correspond to what taste or sensation.  One could then make synthetic wines using a simplistic fermentation process followed by the addition of supplemental tannins to create the right body.  But somehow, I don’t think that scientists will ever be able to, um, convincingly fake it.

The final bottle of the night was a 2009 Rockpile Rocky Ridge Zinfandel – “a zin for cab lovers”.  The description said it was “the perfect yin-yang of dark berries and savory spices” with “spectacular structure, layered complexity, and balance”.  Blah, blah… whatever.  This stuff was orgasmic. I really didn’t care what the hell was in there.   If that’s what a really good Zinfandel tastes like, I might be a believer.  So I poured myself another glass, let it open up a bit, and chalked one up for magic.

Zombie science!

In addition to my day job as a scientist, I am also an aspiring writer of Young Adult fiction.  I like the concept of the teenage biohacker, because there is so much fertile ground to work with.  Science fair projects that go horribly wrong or the biology teacher who has an odd obsession with road kill.  In my first novel, a group of teens create primitive life in their basement lab.  The protagonist’s mom is a scientist studying extremophilic bacteria, and he learns from her that it is pretty easy to make long chains of amino acids (ie, proteins) using a temperature cycler.  When he tries to do this himself, disaster strikes and they force the system to evolve into an organized, self-replicating structure with life-like characteristics.  A prominent scientist learns about their discovery and steals it for his secret research on zombies. 

Sound crazy?  Check out the new book by Dr. Steven Schlozman called The Zombie Autopsies.  CNN interviewed the Harvard/Mass Gen psychiatrist about the book (see link) and I think it should be essential reading for any high school AP Biology class.  He uses a very scientific framework to discuss the pathogenesis of the disease, the mathematical models that predict how fast it could spread, and, of course, offensive and defensive strategies for our survival.  (Spoiler alert: The odds are pretty good for the zombies.) 

So, what is his take for the root cause?  Interestingly, he uses infectious proteins called prions as a source.   A paper published in 1982 by Stanley Prusiner first described these infectious proteins, and at the time it violated many dogmas of molecular biology (he won the Nobel Prize in 1997 for this work).  Prions are the culprit behind Creutzfeldt-Jakob disease, fatal insomnia (how awful!), Gerstmann-Straussler-Scheinker (GSS) disease, bovine spongiform encephalopathy (the technical term for Mad Cow disease), and probably other diseases and conditions that have not been linked yet.  Infectious prions are simply misfolded proteins that get into the brain and result in amyloids (aka ginormous blobs) that destroy brain tissue.  But they aren’t just any ginormous blob, they actually have a pretty well-defined structure and are quite stable.  The current thinking is that the infectious prion serves as a template that allows normal prion proteins in the brain to structurally convert to the infectious form.  However, even today the exact mechanism remains controversial.   What is known, however, is that as the infection spreads the brain disintegrates.  In CJD, this results in the slow death of the patient but in Schlozman’s book, it results in a zombie.  He makes a compelling case that if a different prion variant were to evolve such that the brain gets chewed down to the core, the patient would remain alive but would no longer be capable of cognitive thought.  All that would be left is basic brain function, an unquenchable hunger, and a dysfunctional fight-or-flight response (a “drunk crocodile” was Schlozman’s description). 

So does this mean that future college biology majors will be using Schlozman’s book for courses in Zombie Biology?  Maybe.  Although prions make for a compelling zombie disease, there are also other pathogens that have been suggested to turn your awkward, hormone-crazed, teenage neighbor into a clumsy, teenage zombie.  (Trust me, there’s a difference.)  In many zombie apocalypse movies, a virus causes people to wig-out and, just like rabies, is transmitted to hapless store clerks (and other minor characters) through a bite or a scratch.  This is also a very real possibility, since there are many brain-damaging viruses in circulation.  A few mutations in one of these guys and the brain buffet is open for business.  There are some scientists who also speculate that prion diseases are initially triggered by viruses. 

Then there is Toxoplasma gondii.  T. gondii is a parasitic protozoa whose primary host is the cat but requires a rat host as part of the full lifecycle.  Rats have a natural aversion to cats and are hard-wired to avoid areas with evidence of feline activity.  So how in the world does T. gondii manage to thrive?  Yup. Zombies.  When rats are infected with T. gondii, the infection affects brain function.  Instead of aversion, there is strong scientific evidence that rats become attracted to cats and lose their sense of risk aversion (for example, see Berdoy et al, “Fatal attraction in rats infected with Toxoplasma gondii.” Proc. Biol. Sci, Vol 267 pp1591-4, 2000).  If they could write, these zombie rats would carry little signs that say “Eat me… nom, nom, nom”.  Human infection by T. gondii usually has mild, flu-like symptoms but in some cases, it can produce symptoms very similar to schizophrenia (for a recent review, see Henriquez, et al., 2009 “Neuropsychiatric disease and Toxoplasma gondii infection.” Neuroimmunomodulation, Vol 16, pp122-133).  Crazy, unihibited humans?  Only a small step from zombies... or college freshmen.

Anyhow, this is a great example of some really cool, but offbeat, science. Yeah, this is on the fringe and is half-entertainment and half-science, but in reality, zombies are not only plausible, but something we may actually have to contend with someday.  A  prion-like protein that my protagonist discovered may be one of the catalysts.  Will he and his friends find a way to stop the zombie apocalypse?  Will his girlfriend become the first victim… or the first zombie!?  Let’s just hope she doesn’t own a cat.