Medicine Nobel goes to researchers for describing transit inside a cell

New information could become essential background reading for all of medicine. 
by John Timmer

Fusing a vesicle is now known to involve a lot of proteins, shown here in color.

Tam Lab/Virginia.edu

It's tempting to think of cells as a complex bag of water and chemicals. But cells wouldn't function if their contents were just mixed together chaotically. Instead, the inside of eukaryotic cells is carefully structured, with individual compartments performing specific functions: the DNA held in the nucleus, ATP generated in the mitochondria, damaged material digested in the lysosomes, and so on. Each of these compartments has its own specialized collection of proteins that enable it to perform these functions.

This all raises a rather significant question: how does a cell know what goes where? Or, more specifically, what happens biochemically to move proteins to the right destination, whether that destination is a specific compartment inside the cell or in the cell's environment? Three researchers have won the 2013 Nobel Prize in Physiology or Medicine for helping describe evolution's solution to that problem.

The basics of the process can be worked out with a bit of microscopy. Most of the specialized structures within a cell, as well as the cell's surface, are surrounded by membranes. Within the cell, smaller bags of membranes called "vesicles" are shuttled between structures. When they encounter their destination, the vesicles fuse with the membranes of their target, pouring their contents into it. Sorting out what goes where is mostly a matter of putting the right proteins in a vesicle and then ensuring that the vesicle fuses with the appropriate target.

In 1999, Gunter Blobel received a Nobel for figuring out the protein side of things. He showed that proteins contain short tags that help the cell determine their ultimate destination and route them using the appropriate vesicles. This year's prize goes to researchers who helped understand how vesicles move to their final destination and merge with it.

UC Berkeley's Randy Schekman turned to a simple genetic system to dissect the vesicle trafficking problem. He reasoned that destroying the transit of proteins would be fatal to the yeast, but it might be possible to find mutations that only blocked transit at elevated temperatures. His lab performed screens that first looked for high-temperature lethality and then confirmed that the lethality came about in part because proteins weren't making it to the cell's surface. Over time, he built up a collection of genes that affected this process, and by testing for interactions among them, he started dividing the process into individual pathways.

Meanwhile, James Rothman (who has spent time at too many institutions to mention; he's currently at Yale) decided to take a biochemical approach. His group isolated intact membranes from cells and found conditions in which vesicles would fuse inside a test tube. Over time, these reactions were done using ever more specific fractions of the material inside a cell. When the components were pure enough, Rothman's lab started looking at which proteins were still present.

As Rothman and Schekman started to identify the genes involved, it turned out that in many cases they were working on the same things. Vesicle trafficking was as old as eukaryotes themselves, and the same proteins were used in plants, fungi, and animals.

Combined with the work of other labs, a picture emerged where both the vesicles and their targets were decorated with a specific collection of proteins that could fit together like a lock and key (the proteins have names like SNAPs, SNAREs, and VAMPs). When the right combination of SNAPs and SNAREs is brought together, they stick to each other and cause the membranes they're embedded in to fuse. Specificity comes about because vesicles meant for one destination have a combination of proteins on their surface that can only trigger fusion with an equally specific combination on their destination.

Sometimes, however, you need more than just specificity. Cells don't send out insulin and other hormones all the time, and nerves only release neurotransmitters when they're triggered by the activity of other nerves. Stanford's Thomas Südhof shares the Nobel Prize for using the nervous system to understand how the cell controls vesicle fusion. He demonstrated that at a nerve cell's synapse, vesicles filled with neurotransmitters are poised at the cell surface, ready to fuse at a moment's notice.

Südhof identified another set of proteins that interacted with SNAPs and SNAREs, blocking their ability to trigger vesicle fusion. When the right signal was received, however—in the case of nerve cells, this involves a burst of calcium ions—the inhibition gets released, and the vesicle can fuse almost instantaneously. This process ensures that signals within the nervous system get transmitted rapidly.

The prize citation notes that this process does have some medical implications. There are a number of inherited disorders that alter the process, and some neurotoxins (including Botox) target it as well. But really, knowing something as basic as how proteins get delivered to the right place in the cell is closer to something like essential background reading for all of medicine. It helps us make sense of many, many process, a lot of which have clear and direct medical relevance.

By: Unknown On 11:16 AM

Continue Reading

Weird Science chooses its drugs based on their side effects

And likes its partners to smell like family. 
by John Timmer

Scientists also uncovered this ancient sign in New Zealand.

ghewgill

You smell like you're related to my last mate, so we should have sex. That sentiment appears to apply to female fruit flies. Let's say you're a fly and you've mated once. You're given the choice of the same partner or a completely new one. What do you do? If you're a male, you go for the new partner; if you're a female, you stick with the familiar one.

Now, what happens when you swap out the familiar mate, and substitute one of its siblings? You get roughly the same result: males go for the novel partner, while females prefer the familiar one (although it's a weak preference). How does this work? The researchers did the same tests with flies that carried a mutation that blocked their ability to sense odors. The preferences went away entirely—for both sexes.

If it messes you up, it probably does some good things, too. This study is a bit of a two-for-one, but both messages provide a bit of perspective on why humans seem to be incapable of listening to warnings. In the first set of experiments, the researchers focused on the warning labels on cigarettes and artificial flavorings. If you show people ads with warning information and immediately ask them if they want to purchase the product, they'll buy less than controls. But if you wait a couple of weeks to ask, they'll actually buy more of it.

Something similar happens with prescription drugs (the authors used products like baldness treatments). But here, warnings about side effects had a straight-up positive effect, making people view the product as more trustworthy—but only if the products weren't on the market yet. The authors conclude that it's a matter of immediacy that makes people discount the messages in warning labels and focus on the positives in the ad. And it doesn't even matter when the delay takes place; even knowing there would be a delay is enough to get people to view a product positively.

Whiskey and lox. Two industries that are doing well in Scotland are whiskey distilleries and salmon farms. Now, chemical engineers may bring these two great tastes together. The process of making whiskey creates a lot of waste in the form of a protein-rich soup of grains that get filtered out before the distilling process begins. If everything goes well, some of those calories are going to get recycled into a food pellet that is then used by the salmon farms. Not exactly recycling, but certainly an efficient use of resources.

But think of the cats! A variety of studies into human behavior have identified factors that keep people in abusive relationships despite all the damage that they experience. Now, researchers have added another to the list: their pets. About a third of women in abusive relationships have delayed getting out in part because their partners had threatened or actually harmed the family pets. And at least one of the people interviewed for the new study had their partner kill a pet in front of her in order to make a threat.

Like the best Weird Science, this one has practical applications. Staff in shelters for battered spouses can be made aware of the issue and can take steps to help with pets that would otherwise be left behind. The study also gets bonus Weird Science points for being published in the Journal of Interpersonal Violence.

When we killed them, we lost more than the birds. In many ways, New Zealand prior to human colonization was an exotic lost world. With the only mammals present being bats, birds took over many roles in the ecosystems of New Zealand, with the giant moa reaching heights of three meters as it grazed the woodlands of the islands. Now, researchers have managed to discover what this lost world looked like using a distinctive research material: moa poop. They found a site where a collection of moa droppings (technically called copralites) was preserved, and used them to reconstruct the plants present in the pre-extinction ecosystem. They determined that the loss of major players in the ecosystem like the moas changed it dramatically, altering the plants that were present on the isolated islands.

By: Unknown On 10:48 AM

Continue Reading

Frisky male mice find youngsters’ tears a turn-off

Pheromone in tears keeps males from trying to mate with immature mice. 
by Kate Shaw Yoshida 

"You smell like you've been crying."

UCSD

Like humans, animals shed tears; there are reports of crying wolves, rats, gorillas, and elephants. But as far as we know, it isn’t out of sadness, frustration, or empathy. Instead, tears keep animals’ eyes moist and comfortable, and they help fight infection in and around the eyes. But tears also play an important role in animals’ behavior, according to a new study in this week’s issue of Nature. An international group of researchers has found that a chemical compound in mouse tears actually helps dictate sexual behavior.

The first part of the study was largely exploratory. By combing through the mouse genome, the researchers identified several genes that could produce potential pheromones. They were looking for any compounds that were expressed differently in mice of various ages, sexes, or physiological states in order to expand on what we know about how pheromones affect social interactions. One compound called ESP22 looked particularly promising: it was age dependent, with mice between two and three weeks of age showing the highest levels of expression.

ESP22 has another interesting quality as well. It is produced by a specialized set of cells in the lacrimal gland and then released into a mouse’s tears. In case you aren’t up to date on the latest research involving crying mice and sex, here’s a quick primer. Apparently, tears may play a significant role in mouse sex. In 2005, scientists identified a pheromone found in the tears of male mice that seemed to be involved in sexual behavior. A few years later, they found that this pheromone, called ESP1, makes female mice more sexually receptive when males approach them to mate.

This new compound, ESP22, had the hallmarks of another tear-based pheromone: it's secreted in the tears of just a small subset of mice. The researchers reasoned that perhaps this compound, too, plays a role in regulating sexual behavior.

To test this hypothesis, the researchers used a strain of knockout mice with impaired sensory systems. These mice had non-functioning vomeronasal organs, which are normally responsible for sensing pheromones. If ESP22 were a pheromone involved in sexual behavior, mice that couldn’t sense ESP22 would behave differently from those that could, at least when it came to sex.

The researchers found a definite peculiarity in the behavior of these mice. In essence, the knockouts were very interested in mating with juveniles, whereas normal mice showed almost no sexual interest in young mice. Knockout mice were more likely to mount juveniles and tended to mount them more often than normal mice did. Clearly, something was prohibiting the mice with non-functioning vomeronasal organs from recognizing that the young mice were not appropriate mating targets.

But was it ESP22? After all, the vomeronasal organ could be picking up any one of many pheromones. So the researchers used a second set of knockout mice: juveniles that didn’t produce any ESP22 at all. These young mice were also the subject of unwanted sexual advances by normal mice. But when the researchers painted synthetic ESP22 on them, the mounting behavior stopped.

Together, these findings suggest that ESP22 is a pheromone expressed in juvenile mice that affects sexual behavior via the vomeronasal system. Mating with young mice isn’t exactly adaptive, since mounting prepubescent juveniles is a waste of time and energy. ESP22 appears to suppress males’ advances toward juveniles, likely directing their time and attention to more appropriate targets instead.

The ultimate goal of this research is to understand the role of chemical compounds in human behavior, but we’re a long way from reaching that goal. Humans don’t appear to have functioning vomeronasal organs, and our sexual rituals are a bit different from those of rodents. But there is evidence that human tears contain chemicals that affect sexual behavior, and it’s likely that tear-based compounds may regulate human behavior in other areas as well. The hope is that identifying and learning about pheromones in other animals will help us understand how chemicals affect our own sensory systems, behavior, and fitness.

Courtesy: arstechnica

By: Unknown On 8:44 AM

Continue Reading

What science tells us about the safety of genetically modified foods

GMO foods are safe to eat, but they pose challenges in the environment. 

by John Timmer

Canola plants, which have trouble keeping their genes in check.

Oak Ridge National Lab

Many aspects of modern technology make people a bit uneasy, but genetically modified foods may be in a class by themselves. Labs all around the world make genetic modifications of organisms—bacteria, plants, and animals—365 days a year. And some of the results of that work have been ingested by humans for years, often in the form of life-saving drugs. But genetically modified crops remain controversial around the globe, and while they're commonly used in the US, they have almost no presence in the European market.

The worries about GMO foods largely focus on their safety, but much of the debate ignores the extensive studies that have been done to understand both the potential risks and what we've learned about them. In response to this perceived gap in understanding, a group of Italian scientists have now performed a comprehensive review of the scientific literature on GMO crops (we were made aware of the review by Real Clear Science). The results suggest that GMO crops are safe for us, but there are some remaining concerns about their environmental impact that need to be nailed down. In the meantime, the authors suggest that GMOs represent a serious challenge for science communication with the public.

To get a grip on current research, the authors searched databases for any papers on the topic that were published between 2002 and October of 2012; they came up with 1,783 of them. But not all of these spoke directly to safety. The authors note that many of the articles published on GMO crops were commentaries, and the ones that directly addressed safety concerns tended to end up in low-profile publications. Confusing matters further, there were several areas of largely unrelated research that all speak to the safety of these crops.

What you ingest

There's one obvious concern when it comes to GMO crops: we eat them. Are we ingesting anything unusual? To understand that, you have to know how transgenic plants work. They start with a piece of DNA, one that carries a gene of interest—say, one that encodes a protein that provides the plant disease or pest resistance. That DNA is packaged with additional sequences that make sure the gene can be made by plant cells, along with a gene for drug resistance that lets you track whether the DNA is present in cells. The whole package is then inserted into one of the plant's chromosomes.

Wikipedia

Once in a plant cell, the gene gets transcribed into RNA. In some cases, that's the end of it; the RNA is active in some way that's useful (for example, it might target a virus for destruction). But in many cases, that RNA is converted into protein, such as the Bt protein that is toxic to insect pests. In a few rare cases, that protein may catalyze the production of a specific chemical. One example of the latter is golden rice, which has been engineered to carry the genes needed to produce vitamin A.

So DNA, RNA, proteins, and chemicals. That's a lot to worry about, right?

Well, maybe not. Everyone's meals normally contain some DNA, but the average person only ingests between 0.1 and 1 gram of it every day. Most of that is the DNA that all plants and animals naturally contain; estimates are that the engineered DNA accounts for less than 0.00006 percent of the total. Cooking destroys most of it, and the majority of the rest is degraded in the harsh digestive environment.

There's a small chance that some of it will survive long enough to be taken up by gut bacteria, but this is a very uncommon event (otherwise your average E. coli would have a genome swimming with corn and cow DNA). The one potential risk there is that the bacteria will pick up the drug resistance gene that's part of the initial package inserted into the plant, but that poses little risk since biologists use resistance genes that are already widespread in bacterial populations, meaning the drugs aren't used much clinically.

Similar things apply to the RNA and proteins, in that most are fully digested long before they reach the bloodstream. (In fact, the review notes that this is precisely why we have to rely on injections to get protein- and RNA-based therapies into people.) There's been a single report that plant RNA may appear in the bloodstream of mice, but the results haven't been replicated since.

Another risk is that the proteins made by the GMO plant (or some digested fragment of it) will cause an allergic reaction. For that reason, the protein sequences are tested against a large database of common allergens. The proteins are also assessed for toxicity in animals and for their ability to survive a digestive environment. As far as any chemical end products are concerned, they're generally being used precisely because the chemical in question will have a beneficial effect on humans. Because all these risks from DNA, proteins, and chemicals are identical to those posed by unmodified plants, the European Commission has concluded that "the use of biotechnology and of GE plants per se does not imply higher risks than classical breeding methods or production technologies."

The only residual uncertainty is whether the mere presence of the RNA and proteins made by the transgenic DNA alters the plants in a systematic way. In a general sense, they don't; transgenic plants pass what's called a "substantial equivalence" test, which means they are indistinguishable from the crop that they were derived from in terms of nutrients and other key components.

However, if you do a detailed analysis of every protein and chemical produced by the plants (a proteomics and metabolomics study), you can see differences between the transgenics and other crops. But similar things happen if you raise identical crops in slightly different environments, so it's not clear if this is a real result or an experimental glitch—and, if it's the former, whether that tells us anything significant. The review's authors argue that this is an area that deserves further study.

GMOs and the environment

Although it's almost impossible for the genes to spread to humans, that doesn't mean they can't spread. Crops are grown in uncontrolled environments, where they come in contact with other species, some of which can be close relatives. For most species, this DNA doesn't provide any advantages that can't be provided by the DNA that's already present in the environment. Bacteria and insects won't benefit from picking up genes for herbicide resistance or insect-killing proteins. The drug resistance could benefit the bacteria, except the genes in use are already widespread in soil communities. And at least so far, field studies haven't found any evidence of transgenes ending up in soil bacteria.

The same cannot be said for plants, or at least those plants that are closely related to crops. There have been reports of a strain of canola that contains multiple herbicide resistance genes, which presumably came about through the hybridizing of two or more GM strains. Obviously, the transgene would provide a survival advantage for any plant that was growing near agricultural areas. The same would be true for the spread of genes that encode proteins that are toxic to insects, except the latter would provide a survival advantage just about anywhere.

These genes could also cause problems for agriculture itself. Currently, resistance to insecticidal proteins like Bt is limited in part by careful crop management. If wild plants pick up the same gene, it could hasten the evolution of resistant insects regardless of how the crops are managed. Although there are some ideas about how to limit the spread, there are problems with all of them: "none of them can be considered completely effective for transgene containment and complete segregation of GE [genetically engineered] crops is not possible."

Communication breakdown

The conclusion of the review is that from the perspective of human consumption, all evidence indicates that GMO foods are safe; the primary risks are to agriculture itself, primarily from the unintended spread of some of the transgenes to wild populations.

But that's hardly the impression you'd get from the public debate. GM foods are often portrayed as untested or their safety a complete unknown. Rare, unreproducible results are often trumpeted as the final word. These are features that are shared with a number of other areas where there's been a failure of science communication, and the authors argue that scientists themselves share the blame here: "the frequent non-scientific disputes in the media that are not balanced by an effective communication from the scientific and academic world, greatly contribute to enhance the concerns on GE crops."

But the review points out that effective communication is hard because the scientific community is never 100 percent unified. The authors note that there is "animated debate regarding the suitability of the experimental designs, the choice of the statistical methods, or the public accessibility of data," and that's all a healthy sign that science is following its normal course here, even as its conclusions firm up. Unfortunately, this healthy debate has "frequently been distorted by the media and often used politically and inappropriately in anti-GE crops campaigns."

All of which makes getting the big picture—GM foods appear safe to eat—a difficult message to elevate above the noise.

Courtesy: arstechnica

By: Unknown On 7:45 AM

Continue Reading