Since the time of Linnaeus, scientists have loved classifying the world around them. But while centuries of biologists have worked to collect and categorize the plants and animals of Earth, all that work likely only covers about a minute fraction of our planet’s life. As much as 99 percent of the biodiversity on Earth is smaller than 2 microns - bacteria, viruses, and tiny eukaryotes - and most of these remain to be discovered by humans. There are more microbial cells on earth (1 nonillion, or 1×10^30) than there are stars in the sky, and all of this new life exists in soil, in seawater, and inside animals, plants, and even us.

“You are mostly microbes,” Jack Gilbert told the Institute for Genomics and Systems Biology in a lecture last month. “The world is mostly microbes, and yet we have less of an understanding of how microbes run the universe than we do of the universe itself.”

Gilbert, an assistant professor of evolution and ecology at the University of Chicago, is part of an international project to remedy that shortage of knowledge about the microbial world. The Earth Microbiome Project, a group bringing together scientists from several different institutions, is dedicated to filling in these gaps in the tree of life and, more importantly, figuring out how they may be secretly pulling the strings of Earth’s ecosystems. In his talk, Gilbert rapidly narrated the group’s aims and his own research projects until he ran out of breath, leading an hour-long tour around globe in search of nature’s smallest and most abundant participants.

Classically, microbiology has taken place in cell culture dishes and incubators, as scientists grew bacteria in the laboratory in order to study its identity and function. But the field has benefited greatly in recent years from genetic advances opening up new paths of discovery. As the price of accurately sequencing DNA and its products has exponentially dropped - driven largely by the demand for human genomics - ecologists interested in microbes have borrowed the technology for their own uses. Now, instead of growing bacterial populations in the laboratory, microbiologists can take a genetic sample of whatever environment they wish and use the genes in that sample to reconstruct its microbial denizens. This process is called “metagenomics,” and it is expanding our knowledge of the bacterial world in leaps and bounds, Gilbert said.

“We can take a sample, sequence it, look at the microbial taxa in there, and identify things we couldn’t culture,” Gilbert said. “There are four trillion base pairs of genetic information in a millileter of seawater, in one teaspoon. In a gram of soil, there are about 4 quadrillion base pairs.”

With so much information out there waiting to be discovered, one of the most important questions is where to start. The Earth Microbiome Project is overseeing dozens of projects, each with their own hypotheses and environmental targets. Gilbert outlined just a few: analyzing samples from near the site of the Gulf of Mexico oil spill; comparing soil samples - some as old as 135 years old - from China, France, Australia, and South America; characterizing the microbial communities from the vaginal canals of fertile and infertile pandas in the San Diego Zoo (seriously). Importantly, the procedures used to analyze such widely different samples are being standardized by the project to ensure that comparisons between different research groups and samples are possible.

“The goal of this project is to systematically approach the problem of characterizing microbial life on Earth,” Gilbert said. “We’re reaching a zenith point in our ability to do things individually, and if we want to start generating synthesis of our understandings, we need to start working as a team, as a group, like the physicists do. We want to do the same thing: Come together as a group and say ‘we have a really good idea, a life-changing idea that will change the way we live on this planet, we just need to do it in a systematic and well organized fashion.’”

As a discrete example, Gilbert offered one of his own research projects, conducted before he relocated to Argonne National Laboratory last summer. As senior scientist at Plymouth Marine Laboratory in England, Gilbert and his team studied a section of the English Channel that has been sampled by scientists every week since 1864 - interrupted only by the two World Wars. Since 2000, the team has taken samples suitable for metagenomic analysis, and has methodically characterized what microbes live in this patch of water and how that population changes.

read more

Alien Life & Scientific Skepticism: The Sequel

In a bit of deja vu this week, a new paper stirred up fevered online debate about the existence of aliens among us - and the traditions of scientific publications. This time, ground zero for the debate was not the bacteria of arsenic-laced Mono Lake, but microscopic filaments on a rare group of meteorites collected in Antarctica in the 80’s and 90’s. In a paper published last Friday by the Journal of Cosmology, NASA scientist Richard Hoover argued that these filaments are bacterial fossils, of species that fell to Earth with the meteorite - a conclusion that was breathlessly reported by Fox News with the lede “We are not alone in the universe.”

Panspermia, the idea that life on Earth may have been seeded by alien organisms that arrived on the backs of meteorites, is a seductive idea. But as the old saying goes: once bitten by reports of alien bacteria, twice shy. Far fewer science reporters fell for the meteorite alien bacteria as they had on the arsenic-based bacteria story of last December, perhaps because of a lesson learned or merely because of the lower-profile journal in which the new paper appeared. And while the criticisms over the arsenic study took a few days to seep from science blogs to mainstream media, the travel time was much shorter this time around - Phil Plait’s skepticism on his Bad Astronomer blog was quickly trailed by an AP story that carried a chorus of criticism. Questions about the qualifications and objectivity of the author and the journal soon followed, as the Columbia Journalism Review recaps.

As with the arsenic story, the meteorite episode was almost more fascinating for what it says about modern scientific communication than what it said about science itself. On the surface, the Journal of Cosmology appeared to take some progressive steps for publishing research, including making the article free and open access and soliciting commentaries from “100 experts” on the findings, 24 of which were published soon after the original article. That move would appear to address one of the critiques of the team that published the arsenic bacteria paper, regarding their attitude that criticism was only valid through traditional (and slow) peer-reviewed channels, instead of online discussion that is able to react more immediately.

However, a very thorough, critical commentary by microbiologist Rosie Redfield (who also sounded the first alarm about the arsenic bacteria research) has not been published by the journal, while some very odd commentaries have, such as one concluding “Hoover’s findings are incompatible with the creationist model of life based on biblical Genesis and Aristotelian philosophy.” The journal has also reacted petulantly to criticism, posting an editorial called “Have the terrorists won?” that claims “Only a few crackpots and charlatans have denounced the Hoover study.” So while the latest alien bacterial invasion of Earth’s media is showing some steps in the right direction, it also signals that the growing pains of adapting scientific discussion to a faster media age are still present.

Elsewhere…

Last week, the Medical Center was part of a four-way kidney swap that spanned the country, from the Bronx to California (we should have a video of the event posted next week). Coincidentally, in a New York Times editorial published Sunday, the Medical Center’s Lainie Ross argued that such swaps or “donor chains” were a better option than proposed revisions to the current organ allocation system that would prioritize younger recipients.

read more

An elephant fish embryo and its yolk (courtesy Andrew Gillis)

Billions of years of evolution has produced an incredible diversity of life - “endless forms most beautiful and wonderful,” as Darwin famously put it. But a fascinating thing about evolution is it has produced such a wide variety of species with a relatively small amount of tools. Many of the roughly 23,000 human genes can be found in species as different as mice and flies, and those genes control embryonic processes that are remarkably similar despite the vastly different outcomes for an insect or a man. But sometimes, finding out just how deep this homology runs requires deep exploration.

Members of Neil Shubin’s laboratory are no strangers to adventure. The search for Tiktaalik, the famous fossil of a transitional species between fish and land-dwellers, took Shubin and his collaborators to remote stretches of the Canadian Arctic. So when J. Andrew Gillis, then a graduate student in Shubin’s laboratory, wanted to study an obscure aquatic relative of sharks with famously hard to acquire eggs, the evolutionary biologist could hardly turn him down.

“I remember when Andrew said ‘I want to get some holocephalans in the lab,’ and I thought ‘yeah, right.’ Everybody’s tried this for years; there’s a long line of people who have always wanted to get holocephalans in the laboratory,” said Shubin, the Robert R. Bensley Professor of organismal biology and anatomy at the University of Chicago. “It’s not like you can buy them at a store, it’s not like you can breed them easily in a lab. They breed on the bottom of the ocean, so you have to find places where the eggs are accessible.”

Holocephalan eggs are prized by evolutionary biologists because of a small but significant anatomical difference from their cousins, the sharks. Both share skeletons made of cartilage and other structural features, but split in terms of appendages called branchial rays, structures that grow outward from the skeletons’ central gill arches. While sharks form several sets of these rays, holocephalans only grow a single set near their head, which eventually forms the support for gill covers. Finding the genetic switch that triggers this anatomical difference, as Gillis, Shubin and colleagues did in a PNAS paper published yesterday, would shed light on the origins of appendage development across the animal kingdom, from fins to wings to limbs.

But first, a scientist needs to leave the safe world of their laboratory in order to find those precious eggs. Gillis’ quest for the embryos of the holocephalan species elephant fish, named for their prominent snout, led him halfway around the world and under the water, on SCUBA expeditions in Australia and New Zealand. Based on anecdotal information collected from local fisherman and marine biologists, Gillis was able to score a precious few eggs to take back to the laboratory for his experiments - but it wasn’t easy.

“Diving for elephant fish eggs was not always a pleasure trip,” said Gillis, now a postdoctoral researcher at the University of Cambridge. “Unfortunately, elephant fish like to lay their eggs in cold, muddy, shark-infested bays, so we spent months seeking out sites like this in southeastern Australia and New Zealand. When you finally find a few eggs in the muck, it feels like winning the lottery.”

Back in the comfort of the laboratory, the mood was still tense, as Gillis had to get all of his experiments working just right so as not to waste the valuable cargo from his expeditions. Previous work by Gillis and Shubin discovered that shark embryos use a gene called sonic hedgehog (Shh) to control the development of branchial arches. The next step was to test whether elephant fish embryos also use this genetic switch to mediate the growth of their less robust appendages.

read more

The immune system relies heavily on memory and recognition, with its success dependent on marshaling defenses against only the right infectious invaders. Scientists are finding that this memory requires a lot of moving parts, including molecules that grab pieces of bacteria and viruses, specialized cells that can determine whether those pieces are dangerous or not, and cells that attack and kill those microbes if they are ruled to be a threat. The key at each step of this complex system is specificity; if each component only binds or attacks certain types of molecules, it makes the process of remembering the correct response that much easier. As with a condo building, having the right locksmith can make all the difference.

Bacteria are largely made up of proteins and lipids, and when they first get inside a cell, the initial defense system strips them down to these parts. For proteins broken up into smaller pieces called peptides, the MHC molecules are the designated grabbers, binding the molecules and bringing them to the cell surface for recognition. But for lipids, a different group of molecules, the CD1 family, performs this task. Because lipids make up the bacterial cell wall - the critical outer barrier of the microbe - they are good, reliable candidates for jogging the immune system’s memory and initiating a response.

“It’s a really excellent way of recognizing a bacterial lipid, because they look a lot different than what they look like in us,” said Erin Adams, assistant professor of biochemistry & molecular biophysics at the University of Chicago. “If you are a bacteria, you can mutate your protein to evade the immune response and not be recognized any more, but it’s really difficult to change the structure of a lipid. If you screw it up too much, then the bacteria doesn’t survive.”

Understanding more about how these CD1 molecules function could be helpful in building better vaccines or treatments against bacteria and viruses. But the traditional scientific approach of taking a snapshot of these molecules (through the method of X-ray crystallography) was frustratingly difficult. So a multi-disciplinary team led by Louise Scharf in Adams’ laboratory set about using some molecular engineering to solve that problem, and their work was published last month in the journal Immunity.

The mission was to catch one of the CD1 family, CD1c, in the act of binding with a bacterial lipid; in this case, a component of the bacteria that causes tuberculosis called mannosyl-ß1-phosphomycoketide (MPM, for much-needed short). The protein was normally too unstable for crystallography, so Scharf and colleagues meticulously changed pieces of CD1c to create a more stable structure, without betraying the molecule’s original function.

“We did a lot of tests to make sure that the protein that we made, our Frankenstein protein, was only Frankenstein in the bits that didn’t count, the structural parts of the protein,” Adams said. “We had to keep validating along the way, step by step, to make sure we weren’t creating a monster.”

read more

ScienceLife ran 219 posts in 2010, and choosing the best of them is as hard as picking a favorite gene.  So here’s a month-by-month scan of a busy year at the University of Chicago Medical Center, full of exciting discoveries in the laboratory and the clinic. The impact of some of this research is already being felt by patients receiving improved, evidence-based medical care. For other studies, the clinical benefit may be years in the future, and may take unpredictable forms. As a closing message for 2010, we’ll re-quote the recently departed Eugene Goldwasser, whose laboratory research isolating and purifying the hormone erythropoietin has helped millions of people worldwide.

“It is a particularly impressive example of how basic research can pay a dividend that could not be anticipated at the start,” Goldwasser wrote about his life’s work, “and it is a pity that the lesson still has not been learned by those who control public funding of science.”

January: Tong Chuan-He looked at how cancer may result from cells who don’t want to grow up. Scientists studied how sleep affects the language learning skills of starlings (with painstakingly acquired video of the experiment!). Richard Jones combined two laboratory staples - Western blots and DNA micro-arrays - to develop a new method for studying protein networks. While physicians such as Tammy Utset treat patients with lupus, UChicago scientists are looking for the genetic origins of the autoimmune disorder.

February: Many Medical Center employees returned from volunteering with relief efforts in Haiti, and we filmed video interviews with Rex Haydon, Tiffany Cupp, Richard Cook, and Dima Awad on their experiences. Most of the human genome is “junk” between protein-encoding regions, but Marcelo Nobrega developed a way to find important regulatory elements in that genetic sea. Like birds, human learning can be affected by sleep, and Leila Kheirandish-Gozal reported on the impact of obstructive sleep apnea upon learning in children. Can a single protein in the brain create behaviors associated with drug addiction in rats?

March: Everyone knows air travel is stressful, but did you know that eastbound flights cause stronger cortisol changes than westbound trips? The laboratory of Milan Mrksich found a way to direct stem cells to form fat or bone by shaping them into stars or flowers, a brilliant example of bioengineering. Computational neuroscientists discovered how touch is like vision in the brain, knowledge that could be used to someday re-engineer Luke Skywalker’s robot hand. Dartmouth president and Partners in Health co-founder Jim Yong Kim visited to talk about a new, needed area of research: health care delivery.

April: Researchers at the Field Museum and the University of Chicago teamed up for the Emerging Pathogens Project, an effort to find new viruses in animals before they jump to humans. Cardiologist Martin Burke tested out a new type of internal defibrillator device that can go under the skin, instead of into the heart (the clinical trial, reported in May, was a success). In a lecture to the MacLean Center of Clinical Medical Ethics, transplant surgeon J. Michael Millis described his efforts to bring American organ transplant practices to China.

May: A trial testing the erectile dysfunction drug Viagra for a rare, untreatable lung disease failed, but pulmonologist Imre Noth found a silver lining. Lauren Sallan and Michael Coates uncovered evidence of a previously unappreciated mass extinction event 360 million years ago that changed the path of life on Earth. Researchers from the University of Chicago and around the world presented science at the frontier of biotechnology at the annual BIO conference.

June: In a study that is literally the size of an entire country, epidemiologist Habibul Ahsan measured the toll of a tragic, accidental exposure of millions to arsenic in Bangladesh. Putting a gene from fireflies into the pancreas of mice isn’t mad science, it’s an imaging tool that will help study cures for diabetes. Epigenetics, the modifications that turn genes on and off, took off in 2010, and cardiologists Stephen Archer and Jalees Rehman linked one epigenetic factor to pulmonary artery hypertension.

July: Scientists don’t often get to see the fruits of their research in the flesh, but the Celebrating the Miracles gathering of diabetic children weaned off injected insulin thanks to genetic research was a moving exception (video of the event can also be viewed). Another hot topic in science and medicine this year was the use of computational analysis to sift through rapidly accumulating data, topics explored by Gary An and Andrey Rzhetsky. Or you can build a computer model of a brain network to study the dynamics of epilepsy, like neurologist Wim van Drongelen.

August: Air pollution is a problem indoors as well as outdoors in developing countries where dung and firewood are used to cook food - a problem being tackled in a project led by Sola Olopade. A study of the hormonal changes induced by a stressful test revealed a surprising protective effect of marriage and long relationships. Microbiologist Olaf Schneewind’s laboratory developed two new strategies against MRSA, the most-wanted cause of hospital-acquired infections.

September: To study multiple sclerosis, neurologist Brian Popko’ s laboratory developed a new mouse model that can replicate the disease, then spontaneously recover. Meanwhile, a new drug to treat MS, originally isolated from fungus found in wasps, was approved by the FDA and is being studied for broader uses at the Medical Center. The micro-organisms that live in humans were analyzed as part of a “microbiome” study looking at the protective effects of breast-feeding against a intestinal disease.

October: Common wisdom on quitting smoking says to stay away from cigarette-associated cues, but research from psychiatrist Harriet de Wit’s laboratory revealed that abstinence could make craving even worse. A study of how getting a good night’s rest affects dieting results suggested that “sleeping off the pounds” isn’t merely a fantasy. Graduate student Daniel Matute solved a 100-year-old riddle about how quickly new species become reproductively incompatible with each other.

November: In perhaps our favorite study of the year, geneticist George Perry found a way to acquire the genomic information of endangered species from…poop. The evolutionary biologist Leigh Van Valen passed away, but his Lewis Caroll-inspired Red Queen Hypothesis lives on. Sometimes statistics don’t tell the whole truth, as in the curious case of the aspirin paradox - why the cardio-protective drug may actually predict worse outcomes after heart attack.

December: Evolution textbooks may need a rewrite after geneticist Manyuan Long’s laboratory discovered that new genes can be just as essential as old genes. A study by neurobiologist Nicholas Hatsopoulos proved that the only thing better than a thought-controlled device is a thought-controlled device equipped with a robot arm. Ripped from the headlines: microbiologist Jack Miller weighed in on the hype over arsenic-based bacteria, and ethicist/physician/friar Daniel Sulmasy discussed the Presidential Bioethics Commission’s report on synthetic biology.

All told, it was a great year of science and medicine. Let’s do it again in 2011! Regular posting will resume Jan. 3rd. Happy Holidays.

Imagine There’s No Hunger

This post is going up around lunchtime, and you might be just now picturing what you’re going to eat. There are those healthy whole-wheat pasta leftovers in the fridge, but just down the street is a deli where you can purchase a giant Italian sub with hot peppers and cheese and a bag of chips on the side. Just the thought of that delicious sandwich is making your mouth salivate and your stomach grumble in anticipation. Wait, were we talking about you, or me?

The ability of people to make themselves hungry just by imagining food has always baffled psychologists, who would predict just the opposite response. Using imagination for habituation, the gradual diminishing of a stimuli’s power to provoke a response with repetition, is a classic tool of psychological treatment. For example, people with phobias are often instructed to repeatedly imagine the cause of their fear (spiders, heights, airplanes) until their emotional response subsides. By that theory, repeatedly imagining a delicious pizza should eventually make you less hungry for a slice, rather than increase craving.

But maybe people are just imagining the wrong thing, thought researchers from the business school at Carnegie-Mellon in this week’s Science. Instead of imagining the food before it is eaten, perhaps people could imagine actually eating that food to habituate themselves against its wily charms. Using a particularly seductive denizen of the office vending machine, M&M’s, the authors instructed their subjects to imagine eating 30 pieces of the candy in succession, like picturing the process of inserting 30 quarters into a vending machine. This tedious fantasy actually worked when the subjects were subsequently given a nice big bowl of M&Ms - subjects who imagined eating 30 pieces of candy ate less than subjects who only imagined a 3-piece snack, or no snack at all. The trick was found to be stimulus-specific, in that a session of imaginary M&M eating had no effect on subsequent eating of another snack; in this case, cheese cubes.

Aside from it’s dietary implications, the study is a pretty amazing demonstration of the power of imagination - “The difference between actual experience and mental representations of experience may be smaller than previously assumed,” the authors write. But it’s unlikely that anyone will incorporate this imagination trick into a get-thin quick diet plan, as you can’t sell a customer the ability to imagine eating unhealthy food, and therefore can’t hire Kirstie Alley to endorse it. But it is something we can all try for free, at home or at our office desk. So while I write the rest of this post, I’ll devote part of my mind to imagining the laborious consumption of that delicious Italian sub sandwich, rather than the sandwich in all it’s pre-eaten glory.

[H/T to the Wall Street Journal Health Blog for the article.]

read more

Life found on...California (photo from NASA)

By now, you’ve probably heard about the “alien” arsenic bacteria discovered in a California lake…and if you’ve been following the story closely, you might have a neck ache from all the twists and turns. When word of a NASA press conference on “astrobiology” broke last week, many hoped that the first evidence of extraterrestrial life was about to be released. But then the news turned out to be the discovery of a bacteria that can grow using the poisonous element arsenic, not little green men. But wait - the substitution of arsenic for phosphate (one of the key six ingredients for life) at least meant that the rules for life had been rewritten, still a cool finding. But wait again!

Over the weekend, scientists began lining up to take chunks out of the Science paper containing the findings from NASA and US Geological Survey scientists. First, microbiologist Rosie Redfield dissected the methodology of the paper and found it considerably lacking, if not intentionally deceptive. Science writer Carl Zimmer followed with damning comments from several scientists supporting Redfield’s take and adding more fuel to the fire…even going so far as to say that the paper should not have been accepted by a journal and published. And even more writers piled on with critiques of how NASA and Science promoted the research, and how media outlets handled the science. It’s all very confusing.

One interested observer is Jack Gilbert, assistant professor of ecology & evolution at the University of Chicago and an environmental microbiologist at Argonne National Laboratory. Gilbert uses genetic and computational techniques to study microbial function and diversity in their natural environments, a field where an arsenic-based bacterial species would be big-time news. But Gilbert finds the paper far less momentous than some of the original, breathless coverage.

“This is just another example of a microbe that has found a niche that enables it to survive in areas where other microbes would not be able to survive,” Gilbert said in a phone interview yesterday. “Bacteria are incredibly versatile, that’s all this paper is really saying.”

A resistance to the poisonous effects of arsenic would be helpful for the bacteria, called GFAJ-1 (pictured at right), to survive in its natural habitat of Mono Lake, where arsenic levels are extremely high. But the experiments published in Science don’t look at GFAJ-1 in its natural environment, but rather in the laboratory, where researchers artificially removed the element phosphate (used in building DNA and many important proteins) and replaced it with increasing levels of arsenic. The big finding was that this inhospitable environment did not kill the bacteria - and at some arsenic concentrations, it could actually grow and reproduce, purportedly by building DNA and proteins with arsenic instead of phosphate.

One of Redfield’s main objections is that the treatments used in these experiments probably didn’t remove all of the phosphate, and trace amounts left behind could have allowed the bacteria to survive with no novel biological tricks. Gilbert said he hadn’t yet read Redfield’s post, but agreed that he would have requested the authors run more experiments and controls to shore up their conclusions. But now that the paper has been published, he agrees with the authors when they say that the proper forum for criticism is through the peer-reviewed journals.

“As an impatient person, I find peer review incredibly frustrating, but it’s there for a very good reason,” Gilbert said. “Peer review enables us to question the findings in other research articles, and that’s essential if we want to figure out if the piece of work isn’t up to scratch.”

read more

If a parasite infected the brains of 2 to 3 billion people, up to one-half of the world’s population, one would probably consider it a pretty serious public health emergency. But such a situation already exists, with the parasite Toxoplasma gondii, the cause of the disease toxoplasmosis. The parasite is the most common infectious cause of retinal damage, and can cause brain damage or death in its most severe forms.

Most people hear of toxoplasmosis from cases of mother-fetus transmission, the reason why pregnant women are advised to stay away from cats, who are known carriers and dispersers of the parasite. Toxoplasmosis can also flare up in people with compromised immune systems, due to diseases like HIV, cancer, and autoimmune disorders. But the Toxoplasma gondii parasite is also an apparently quiet, untreatable houseguest in the brains of billions more people, where its possible role in seizure disorders, schizophrenia, and memory loss is just starting to be investigated.

With a widespread infection where the proven effects are already scary and the unproven effects may be even worse, it would be great to have vaccine protection against toxoplasmosis. But while vaccines are typically designed for unwelcome visitors of bacterial or viral form, they are not normally used to prevent infection from protozoan parasites like Toxoplasma gondii. That did not discourage the laboratory of Rima McLeod, who has recently published three papers with collaborators on two separate potential vaccination strategies against toxoplasmosis.

The most direct vaccine strategy - used against polio and chicken pox, for example - is to take a live pathogen and render it harmless. When introduced into a subject as part of a vaccine, the defanged invader inspires the immune system to respond as it would the real thing, increasing its defenses for when the actual virus attacks.

In a paper published at PLoS ONE, a group led by Samuel Hutson created a strong candidate for this type of vaccine by creating a mutant Toxoplasma gondii. Constructs created by collaborators in the Netherlands modified the promoter of a ribosomal protein in the parasite so that scientists could place it in a state where it became unable to proliferate. When injected into mice, this “trapped” strain disappears within 10 days, but not before educating the immune system on how to fight off subsequent infection by the real parasite.

“It is extraordinarily, robustly protective,” McLeod said. “It was 100 percent protective for mice against large numbers of the homologous parasite strains, and it was also very good at protecting against heterologous parasites as well. It made a very effective live vaccine.”

read more

Even before the very rules of life were changed by the discovery of an arsenic-based microbe in a California lake (or were they? More next week.), this week seemed to be full of strange and interesting science involving animals. While ScienceLife works on a bunch of research that is under embargo until later this month (disclaimer: none of them involve extraterrestrial life), here are a few bullet-pointed studies that inspired awe and wonder this week.

• Optogenetics is the technique of creating mutant mice with cells that can be modulated with flashes of light, which is awesome. For example, a scientist can introduce a gene into a mouse strain that makes motor neurons sensitive to light, and when light is shined at those neurons, the mouse starts running. Now, researchers from Stanford and UT Southwestern have used optogenetics in the frontal cortex of a mouse strain, and found a way to produce anti-depressant-like effects (pdf). As covered by David Dobbs at Wired, the technique may offer a new non-invasive way of treating depression way down the line; for now, optogenetics requires a brain implant, which is less than ideal clinically.

• Telomeres, the long repeated sequences at the end of chromosomes, were a fashionable scientific buzzword before optogenetics was even a glimmer in science’s eye. With their companion enzyme telomerase, telomeres were hyped to be the genetic key to the  “fountain of youth,” the biological source of the cell damage that accompanies aging. But despite being the subject of last year’s Nobel Prize in Physiology or Medicine, the excitement about telomeres seemed to have faded out. But an exciting new study published in Nature this week may reignite that flame, as scientists at Harvard reversed the premature aging of a special mutant mouse with telomerase treatment. Wired, Ars Technica, and the Wall Street Journal discussed this “Ponce de Leon” effect, but Discover blog 80beats urges patience for those waiting on anti-aging pills.

• Scientists have long used animal models to study the neurobiology of fear in laboratory settings. But how do you realistically recreate situations that would cause a rat to be scared in the wild in the predator-free world of the animal facility? For one group of scientists, the answer was Robogator, a simulated predator designed to leap out at rats as they moved foraged for food in their lab environment (you can download video clips here). Researchers looked at how close the rat would approach Robogator before and after a lesion of the amgydala, a brain region thought to be involved in fear response. Before the lesion, the rats would only get food 10 inches or less from the entrance to their chamber, but after the lesion, they would go as far as 50 inches, sometimes even approaching and investigating the robot (video) without fear.

• Here’s a novel effect of environmental pollution upon wildlife: when ibis birds of South Florida are exposed to the most potent form of mercury, they opt for homosexual pairings over heterosexual matches.

Genomic sequencing has made incredible strides in recent years, with both the cost and the time required to sequence an individual’s entire DNA sequence dropping meteorically. Yet one rate-limiting step for securing an organism’s genome remains: in order to sequence a species’ genetic information, you need a sample to start with. In humans or laboratory animals, a sample of blood or tissue is easily obtained. But what if a scientist wants to do a genomic study on an endangered species population, in the wild, without having to “trap 0r dart” a number of the animals to take blood samples?

George Perry, a genetics researcher at the University of Chicago, pondered this dilemma in planning his own research on endangered lemurs in Madagascar. In discussions with colleagues, he considered whether a “non-invasive” sampling technique might be possible for the collection of genomic data useful for conservationists and evolutionary biologists. The process led him to an unorthodox idea.

“We started thinking, ‘Is there a way to use fecal samples but to still do genomics work?’,” said Perry, a postdoctoral researcher in the laboratory of Yoav Gilad. “Then everyone would have the flexibility to collect population genomics data from any species at any time, as long as you can collect poop.”

Believe it or not, the collection of genetic data from feces has a long scientific history. Alongside the unwanted parts of an organism’s diet, solid waste contains a small number of cells stripped from the lining of the organism’s digestive system. Scientists have extracted small segments of DNA from those cells for study, mostly from the intracellular structures called mitochondria, which have their own genes. But more extensive genetic mapping of nuclear DNA from fecal samples has been thwarted by another of its ingredients: bacteria. The dominance of bacteria over host DNA inside the digestive system carries over to its product, where an organism produces less than 2% of the DNA deposited in its droppings.

To apply the awesome power of next-generation sequencing technology to a fecal sample, the DNA you want has to be separated from all that DNA you don’t want. Perry decided to modify an existing technique known as DNA capture (which has also been used to sequence Neanderthal DNA), to accomplish this task. With DNA capture, custom-made RNA sequences are used as bait to fish specific stretches of DNA out of a mixture; metallic beads are attached to the RNA sequences, and a magnet separates out the target DNA from the unwanted material. Perry boosted the specificity of this model, incorporating extra washes and two separate rounds of DNA capture, to turn his lower-quality fecal sample into starting material sufficient for sequencing. In part, that means starting with a lot more DNA that typically used for DNA capture, which means starting with roughly 2 grams of poop from each animal. Fortunately, it’s an abundant resource.

“It’s not that you can only study rhinoceros because they have huge poop,” Perry said.

read more

Scott Brady speaks at the Chicago Biomedical Consortium symposium, Oct. 29, 2010. (photo courtesy of the CBC)

Proteins are a little like laundry: folding matters. When folded properly, proteins can go about their intended business as the machinery of the cell, responsible for its structure and function. A misfolded protein or two can be an annoyance, temporarily throwing off the order of the cell but easily handled by a cell’s internal janitors. But when those misfolded proteins pile up like rumpled clothes across a messy room, the whole system can collapse, leading the cell to an early demise.

These catastrophic failures of folding may be the cause of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and Lou Gehrig’s Disease (amyotrophic lateral sclerosis). When pathologists look at the brains of people who die from these conditions, they find unusual changes, with missing neurons and/or abnormal deposits known by names like plaques, tangles, and Lewy bodies. As imaging techniques have improved, scientists have traced these abnormalities back to protein misfolding, with the accumulated defects leading to intracellular traffic jams and even cell suicide.

Experts in the protein folding field met October 29th at the University of Chicago as part of a special symposium organized by the Chicago Biomedical Consortium, a partnership between Chicago-area research institutions. A succession of experts talked about the intricate origami of folding polypeptide structures into functional proteins, the cellular mechanisms that help regulate that process, and the consequences when those mechanisms fail and misfolded proteins are allowed to aggregate into dangerous clumps.

“The ability of polypeptide chains in vivo to fold correctly into their native states with sufficient frequency for them to be able to execute their functions in a living organism is one of the most fundamental and remarkable phenomenons in biology,” said Sangram Sisodia, professor of neurosciences at the University of Chicago. “Despite these regulatory systems, protein misfolding and aggregation do occur, particularly as organisms age, and cause devastating diseases.”

Scott Brady of the University of Illinois at Chicago illustrated those diseases with the famous people they are associated with: Muhammad Ali and Parkinson’s disease, for example, or Woody Guthrie and Huntington’s. Brady then outlined the reasons why a pile of misfolded proteins can be so troublesome to neurons - many of which are long, skinny structures (as long as a meter in humans) that must transport proteins from one end to the other. Should an aggregate of erroneous proteins occur anywhere along that long stretch, it could cause a traffic jam fatal to the cell. Brady’s laboratory has repeatedly demonstrated this process in what is, thanks to their long, wide axons, a favorite animal model of neurobiologists: the squid.

“You may be wondering what calamari has to do with all this,” Brady said. “No, squids do not get Alzheimer’s disease, but they react to the toxic proteins in Alzheimer’s just as well as mammalian systems.”

read more

A cell’s DNA is its most valuable treasure. So it only makes sense that cells keep their genetic material protected under lock and key, wrapped tightly around spools called histones. When it’s time to make proteins from their DNA recipes, the right bit of DNA is unraveled so that the cell’s transcriptional machinery can gain access to the correct genes. But the process of spooling and unspooling the DNA is under tight security, controlled by a complex array of enzymes and signals attached to the histone’s tail.

Studying this security system is an important part of epigenetics, the growing field researching the many factors that control gene expression. Where the basic components of DNA were figured out by Watson, Crick, Franklin and their successors in the 20th century, the proteins and enzymes involved in epigenetics are still largely unknown. With dozens of enzymes that each recognize their own unique combination of signals moving in and out and changing conformation, it’s a fluid, complicated system that’s hard to pin down using traditional techniques.

But the laboratory of Anthony Kossiakoff, professor of Biochemistry and Molecular Biology, thinks it might have the method to help crack part of that epigenetic code. With a new grant totaling $7 million over 5 years from the National Institutes of Health (part of their Protein Structure Initiative), Kossiakoff and colleagues will apply their Chaperone-Enabled Biology and Structure (CEBS) technology to the complex riddle of how dynamic regulation of histone modifications regulate gene expression.

Scientists have long used the specificity of the immune system’s antibodies to create reagents that recognize and tightly attach to a target protein. Once captured, that reagent can help researchers look at the location abundance of their target in the cell. But the “natural” method of creating antibodies, by essentially tricking the immune system of rabbits or mice into producing the highly specific antibody you need, is expensive and may not always produce antibodies that work as advertised.

“Over half of those you buy don’t work, others work maybe for one application but not another that you want, and so it’s buyer beware,” Kossiakoff said.

Kossiakoff’s CEBS technology produces customized antibody-like reagents called synthetic affinity binders, or sABs, created via a process called phage display mutagenesis - akin to “evolution in a test tube.” Billions of synthetic antibody-like proteins compete for their ability to bind with high affinity and specificity to a chosen target. Instead of having the very few candidates produced by traditional monoclonal antibody production , the CEBS selections can generate as many as fifty different “synthetic antibodies” that can be used as highly specific reagents. Over the last five years, the laboratories of Kossiakoff, UChicago’s Shohei Koide, and Sachdev Sidhu of the University of Toronto have refined that process and established a pipeline where super-specific reagents can be created for virtually any stable protein a researcher would like to study.

As part of the Protein Structure Initiative, the laboratory will become what Kossiakoff called a “mothership” for research on histone modification enzymes, producing sABs useful in studying their structure and function. Some of those reagents will be used for experiments in Kossiakoff’s lab, others will go out to biologists and structural biology collaborators around the world. One goal is to generate sAB reagents to act as “crystallization chaperones” to enable the “freezing” of complex proteins for crystallization structural studies - a task that has proved difficult to impossible previously.

“Proteins are dynamic, and they can be floppy, especially if they have multiple domains, as is the case for these histone modifying enzymes” Kossiakoff said. “So many times, even with heroic efforts, you can’t crystallize them to study.”

Previous studies have succeeded in characterizing small stretches of the enzymes, but not all the domains together. Capturing the entire organization of the enzyme rather than one section at a time is an important leap forward, due to their complexity - each enzyme must read several different positions on a histone simultaneously to determine whether or not to bind and activate. It’s a flurry of activity, like a janitor with a full key ring trying to unlock three different doors at once.

“These interactions are pretty transient, on and off, on and off,” Kossiakoff said. “By having all the domains clicking into the right place, binding becomes additive. It literally is a trial and error process, and there is just so much stuff going on.”

Slowing down this whirlwind long enough to determine these complex structures could lead to new insights and understanding into how histone modifications regulate gene expression. The enzymes themselves are also major targets for drug discovery - for example, certain forms of cancer have been traced back to errors in histone modification. Some potential drugs could even be derived from the sABs, with more precise targeting than the “dirtier,” less specific compounds currently used in most pharmaceuticals. With the keys to the DNA’s security system unlocked, laboratories developing new drugs could save far more money than the amount invested by the NIH in this grant.

“One of the major shortcomings in drug development is defining what the actual target is,” Kossiakoff said. “There are many cases where drugs have been produced that worked perfectly based on what was attempted to be done, but they don’t work in terms of what they were supposed to do. We can test things out before a lot of time and money are spent developing these drugs against incorrect targets.”

In recent weeks, stem cell research has once again been drawn into a battle over political, ethical, and legal questions. Given all the controversy, it’s easy to forget that there are still many scientific questions surrounding stem cells and their potential for medical use. The ability of such cells to grow into different types of organs and tissue is exciting, but harnessing that ability has remained a challenge for scientists. Much work remains to be done in finding the control panel for pushing stem cells in a particular direction - and some of that work continues despite recent court rulings.

Mesenchymal stem cells are less controversial than their embryonic cousins because they can be harvested from adult bone marrow. But they are also more restricted in their potential, with their future limited to three destinies: bone, fat, or cartilage. Of course, those three fates alone would be very useful in medicine, with applications for orthopedic surgery, arthritis, and wound healing. So scientists are looking for the best ways to manipulate mesenchymal stem cells (MSCs) toward one of those forms.

In the laboratory of Tong-Chuan He, associate professor of surgery at the University of Chicago Medical Center, the desired outcome for mesenchymal stem cells is bone.

“Our goal is try to develop an efficient way to promote cells to making bone,” He said. “Ideally, we can create a treatment where we don’t have to use protein, deliver genes or modify cells. It can be a form of cell-based therapy.”

He and colleagues tested different growth factors from the appropriately-named bone morphogenetic protein (BMP) family on the basis of their ability to drive stem cells to become bone. The majority of research and therapy development focused on two members of the family, BMP2 and BMP7. But a 2007 study by He’s lab found that a neglected underdog, BMP9, was the real heavy hitter in pushing stem cells into a career as a bone cell.

But identifying BMP9 only gave researchers the key to bone differentiation, and it was necessary to find the lock as well. A new paper published by He’s lab last month in the Journal of Biological Chemistry, in collaboration with a team of Chinese researchers, tested out different receptors for BMP9 to determine which were critical for bone differentiation. The team tested a series of type I receptors (ALK1 through ALK7) to see which ones helped BMP9 drive MSCs - harvested from adult and embryonic mice - to become bone.

read more

The human body is not just an organism, it’s an ecosystem. To the billions of microscopic bacteria, viruses and fungi living in the various nooks and crannies of our intestines, mouth, nose, and other areas, we are the world, the environment that drives their evolution. Though scientists and physicians have long known that humans are housing projects for a wide array of species, research on the clinical impact that microscopic population exerts upon its host is just starting to establish momentum. Many researchers are now exploring links between what’s become known as the “microbiome” and everything from infectious disease to diabetes and obesity to psychiatric disorders.

An official seal of approval was stamped on to these efforts by the National Institutes of Health in 2008, with the announcement of the $157 million “Human Microbiome Project.” Tuesday, the project was given another $42 million bolus of funding, $1.1 million of which went to a team of University of Chicago and Argonne National Laboratory scientists. But research into the microbiome is already yielding interesting results on the world inside your gut, and how it is affected by diet from the very start of life.

The debate over giving babies breast milk or formula has swung like a pendulum since the mid-20th-century, with medical societies now endorsing breastfeeding infants whenever possible. Studies have shown that breastfeeding has advantages in protecting infants from infection and disease and provides essential, easily-digestible nutrients. But what is the biological basis for breast milk’s superiority? Scientists have speculated that it has to do with the effect of diet on the microbes of the gut. In a paper published last month at PLoS ONE, Michael Morowitz, assistant professor of surgery and pediatrics at Comer Children’s Hospital, sought to test that hypothesis with the latest genetic technology.

Morowitz was drawn from surgery to microbiology after witnessing the damage caused by a frightening infant disease: neonatal necrotizing enterocolitis (NEC). Seen often in premature babies, NEC causes intestinal inflammation that can require surgical removal and may lead to lifelong complications or death. As the surgeon on such procedures, Morowitz said he became interested in ongoing research on how to reduce the number of NEC cases.

“You say to yourself, ‘How can you prevent it?’ The literature tells you there aren’t many ways other than supporting breast milk usage,” Morowitz said. Others had proposed a link between breast milk, gut bacteria, and protection against NEC, but until recently the technology did not exist to take a full census of the microbial world, he said.

For the PLoS ONE paper, Morowitz and his team decided to study the effects of breast-milk versus formula on the microbe population in the intestines of piglets. By recording a “transcriptome” - a snapshot of gene expression - from the intestinal fluid of the piglets, Morowitz’s team could detect which bacterial species were present and active in the two groups.

read more

What infectious disease causes the most deaths in the United States? Most would probably guess HIV, or after last year’s H1N1 scare, influenza. But the deadliest infectious disease in our country is actually MRSA, the antibiotic-resistant form of Staphylococcus aureus sometimes referred to as a “Superbug.” Nearly one percent of the U.S. population is colonized with MRSA, and infection with the bacteria causes more than 100,000 hospitalizations and nearly 20,000 deaths each year.

What’s worse, MRSA is incredibly hard to treat, as its name suggests. For the last three decades, hospitals have seen more strains of S. aureus resistant to methicillin and similar antibiotics, and some strains have even shown resistance to vancomycin, the current last resort antibiotic. Even when a MRSA infection is successfully cleared, it has a high rate of relapse, as unlike other infections the body does not acquire immunity after the initial attack. A vaccine against the bacteria would thus be a valuable medical tool, a protection to prevent the infection from establishing a foothold.

Two recent papers from the laboratory of Olaf Schneewind, professor and chair of microbiology at the University of Chicago, offer promising strategies for how such a vaccine would work. We talked about Schneewind’s research back in April, when he presented the story of the MRSA vaccine search to the MacLean Center for Clinical Medical Ethics (video here). The new papers demonstrate the first signs of success for those strategies, with protection against the insidious bacteria seen in animal models.

One strategy, published today in the Journal of Experimental Medicine, turns one of MRSA’s most dangerous weapons against itself. Proteins on the cell surface of each MRSA bacterium help trick the cells of the body’s immune system into holding off their attack, and even helping to disperse the bacteria to other organs. Immune cells called B cells typically attach to surface proteins to generate specific antibodies that recruit “killer” T cells to attack the intruding infection. But when those B cells bind a MRSA surface protein called Protein A, a chain reaction leads to B cell death rather than antibody creation.

Schneewind and his colleagues decided to try to turn the tables once more against MRSA by using Protein A as the key component of a vaccine strategy. Critical genes for Protein A’s interaction with B cells were genetically scrambled, creating a non-toxic form of the protein that loses its deadly influence over the immune system. Instead, exposing animals to this neutered Protein A allows the immune system to generate protection against the normal Protein A, such that subsequent infection with MRSA is blunted. Mice injected with the modified Protein A and then later exposed to MRSA strains that cause infections in the US and Japan exhibited fewer bacterial abscesses and reduced mortality compared to control mice.

“I believe that Protein A may be the key to making a staphylococcal vaccine,” Schneewind said.

read more