October 23, 2013
In recent years, scientists have found out all sorts of remarkable things about a group of creatures that are entirely invisible to the naked eye: the trillions of bacteria that colonize every surface of our bodies.
New science, though, is indicating that the relationship goes both ways. These microorganisms affect us, but our underlying genetics also control which species of bacteria are able to thrive in and on our bodies.
One of the most striking examples of this was published today in the journal PLOS ONE. In the study, a group of researchers from Ohio State University analyzed the species of bacteria that lived in the mouths—either in saliva, on tooth surfaces or under gums—of 192 volunteers.
By sequencing all of the bacterial DNA present in a sample swabbed from each person’s mouth, the researchers detected 398 different bacteria species in total. Each volunteer, on average, harbored 149 different species of oral bacteria.
But perhaps the most interesting finding was that there was a tremendous amount of diversity between individuals—only 8 species were present in every single participant’s mouth. “No two people were exactly alike. That’s truly a fingerprint,” Purnima Kumar, the study’s lead author, said in a press statement.
This bacterial diversity, though, wasn’t entirely random: It correlated with the ethnic group of the volunteer. In other words, people from each of the four different ethnic groups represented in the study (all participants self-identified as either Caucasian, African-American, Chinese or Latino) generally had similar species of bacteria, especially underneath the gums.
As a result, simply by counting which varieties of bacteria appeared in this area, the researchers developed a model that was able to guess a person’s ethnicity with an accuracy significantly better than chance—it got it right 62 percent of the time. Some groups were even easier to identify via the bacteria than others: It could correctly identify Latinos 67 percent of the time and African-Americans with 100 accuracy.
The variation along ethnic lines, they believe, is a reflection of genetics, not environment. That’s because, if you assumed that the mouth microbiome is totally dependent on environmental factors, you’d expect that members of the same ethnic group would have different mixes of bacteria depending on whether they were first-generation immigrants to the U.S. or had family histories that stretched back generations in the country. Instead, people’s background—in terms of foods they ate and other lifestyle trends—didn’t seem to have any correlation with the bacterial communities in their mouths. But their ethnicity and thus their similar genetics matched their microbiome more often than chance.
Interestingly, the original goal of this research wasn’t to find new differences between people from different ethnic groups, but to examine the bacterial traits shared between people with good oral health (the researchers are mostly from OSU’s School of Dentistry). But when the researchers analyzed the data, they were struck by the ethnic similarities. Although they sampled bacteria from all regions of the mouth, those found under the gumline had the strongest correlation to ethnicity (and thereby genetics), likely because they’re the least disrupted by environmental factors such as diet or smoking.
The surprising ethnic finding could yield benefits for oral health. The fact that people of different ethnicities harbor different sorts of oral bacteria could lead to medical treatments that are tailored to a patient’s genetic background. If research eventually reveals that someone with certain oral bacteria species in high quantities is predisposed to certain ailments, for example, he or she could be proactively screened for these diseases.
October 21, 2013
For decades, public health officials have puzzled over a surprising fact about HIV: Only about 10-20 percent of infants who are breastfed by infected mothers catch the virus. Tests show, though, that HIV is indeed present in breast milk, so these children are exposed to the virus multiple times daily for the first several months (or even years) of their lives.
Now, a group of scientists and doctors from Duke University has figured out why these babies don’t get infected. Human breast milk naturally contains a protein called Tenascin C that neutralizes HIV and, in most cases, prevents it from being passed from mother to child. Eventually, they say, the protein could potentially be valuable as an HIV-fighting tool for both infants and adults that are either HIV-positive or at risk of contracting the infection.
The research, published today in Proceedings of the National Academy of Sciences, was inspired by previous work by other researchers showing that, both in tissue cultures and live mice, breast milk from HIV-negative mothers was naturally endowed with HIV-fighting properties. Scientists suggested that a few different proteins in the milk could potentially be responsible, but no one knew which one.
As part of the study, the researchers divided breast milk into smaller fractions made up of specific proteins via a number of filters—separating the proteins by size, electrical charge and other characteristics—and tested which of these fractions, when added to a tissue culture, prevented the cells from being infected by HIV. Eventually, using mass spectrometry, they found that one particular protein was present in all the HIV-resistant fractions but in none of the others: Tenascin C.
“The protein works by binding to the HIV envelope, and one of the interesting things is that we were even able to narrow down exactly where on the envelope it binds,” says Sallie Permar, the study’s lead author. Her team found that the protein binds to a crucial region on the virus’ envelope that normally locks onto a receptor called CCR5 on the outside of human T cells,allowing it to fuse its membrane with the cell’s. With the region covered up by Tenascin C, HIV’s normal route of attack is blocked, and the virus’ effectiveness is greatly diminished.
Still, the researchers say that other natural elements in milk might play a role in fighting HIV as well. “It’s clearly not the whole story, because we do have samples that have low amounts of this protein but still have HIV-neutralizing activity,” Permar says. ”So it may be acting in concert with other antiviral and antimicrobial factors in the milk.”
Whatever those other factors are, though, the finding vindicates recent changes to UN guidelines that recommend even HIV-positive mothers in resource-poor countries should breastfeed, if they’re taking anti-retroviral drugs to combat their own infection. That’s because—as statistics bear out—the immense nutritional and immune system-boosting benefits of breast milk outweigh the relatively small chance of transmitting HIV through breastfeeding. Tenascin C, it seems, is a big part of why that transmission rate is surprisingly low, and sufficient access to anti-retroviral drugs can help drive it even lower—as low as 2 percent.
The next steps, Permar says, are determining which area of Tenascin C is active in binding to HIV and whether it can effectively prevent transmission in a live animal, as opposed to a tissue culture. If it works, it could potentially be incorporated into an HIV drug with broader applications. Possible uses include giving it in a concentrated form to infants who can’t breastfeed or even administering it to those who do to increase their level or resistance. It’s even conceivable that it could someday be adapted to reduce the risk of HIV transmission in adults as well.
One immediate advantage, says Permar, is that “it’s like to be inherently safe, because it’s already a component for breast milk. It’s something babies eat everyday.” Other potential treatments, on the other hand, must be screened for toxicity.
Tenascin C’s presence in breast milk, though, prompts a deeper question: Why would milk naturally include a protein that battles HIV, a virus that evolved extremely recently in our evolutionary history, sometime in the early 20th century?
“I don’t think it’s in breast milk to combat HIV specifically, but there have been other, related infections that have passed through breastfeeding,” Permar says. “Our work has shown that Tenascin C’s activity isn’t specific to HIV, so we think it’s more of a broad-spectrum anti-microbial protein.”
In other words, Tenascin C is effective at combating a large variety of infections (perhaps related to its role in adults, where it holds various types of tissue together, necessitating receptors that can bind to a wide array of different cells). The fact that it happens to bind at just the right spot on HIV’s outer envelope so that it combats the virus’ transmission, as Permar puts it, is “a gift from evolution.”
October 13, 2013
Recently, there’s been a bunch of research indicating marijuana isn’t the worst drug in the world—long-term use of it might not harm IQ, and it can serve as an effective way to distract people from chronic pain.
That said, there are plenty of drug users—along with drug counselors and medical professional—seeking ways to aid in kicking the habit. For them, a new finding by researchers from the National Institute on Drug Abuse (NIDA) and elsewhere might be rather interesting.
As documented in a paper published today in Nature Neuroscience, the scientists used a drug to increase levels of the naturally-occurring chemical kynurenic acid in the brains of rats who’d been dosed with marijuana’s active ingredient (THC). When they did that, activity levels driven by the neurotransmitter dopamine, associated with pleasure, went down in key areas of their brains. In a second experiment, when they dosed monkeys who were able to self-medicate with the marijuana ingredient, they voluntarily consumed roughly 80 percent less of it.
In other words, by jacking up levels of kynurenic acid, the drug (with the decidedly user-unfriendly name Ro 61-8048) seems to make marijuana less pleasurable and therefore less psychologically addictive.
“The really interesting finding is that when we looked at behavior, simply increasing kynerenic acid levels totally blocked the abuse potential and the chance of relapse,” said Robert Schwarcz, a neuroscientist at the University of Maryland and co-author of the study. “It’s a totally new approach to affecting THC function.”
Neuroscientists have known for some time that marijuana—along with many other drugs with abuse potential, including nicotine and opiates—induces a feeling of euphoria by increasing levels of dopamine in the brain. Over the past few decades, Schwarcz and others have also discovered that kynurenic acid is crucially involved in the regulation of brain activity driven by dopamine.
Schwarcz, working with researchers at NIDA (which is one of the few facilities in the country that can obtain and use THC in a pure form) and Jack Bergman‘s lab at Harvard (which studies the effects of THC and other drugs on animals), combined these two principles to see how kynurenic acid levels could be manipulated to disrupt marijuana’s pleasure-inducing ability. To do so, they identified that Ro 61-8048 interfered with the chemical pathway kynurenic acid takes through brain cells, creating a metabolic blockage so that kynurenic acid levels artificially rose.
When they dosed rats with this drug, they found that dopamine-driven brain activity in several key reward centers of the brain (such as the nucleus accumbens) no longer surged in lockstep with THC, as it usually does. This confirmed their hypothesis that kynurenic acid can block the same neuron receptors that dopamine usually fits into, rendering it less effective in provoking the reward centers and providing a feeling of euphoria.
Even more intriguing was the behavior they observed in both the rats and monkeys who were given the drug. By pressing levers inside their cages, the animals were able to dose themselves with THC repeatedly over time—and in the first phase of the experiment, they did so at a furious rate, hitting the levers 1.2 times per second.
But when the researchers increased their kynurenic acid levels with Ro 61-8048, they chose to consume about 80 percent less THC. After the drug wore off, and their kynurenic acid levels decreased to normal, they went right back to hitting the THC levers rapidly.
In another experiment, the scientists tested the monkeys’ tendency to relapse. First, they gave them as much THC as they wanted, then slowly dialed down the amount of THC injected with each lever push until it reached zero, leading the monkeys to eventually stop hitting the levers. Then, they gave the monkeys a small unprompted injection of THC, prompting them to start hitting the levers furiously again. But when the monkeys were dosed with Ro 61-8048 before the injection far fewer relapsed, essentially ignoring the levers—presumably because the squirt of THC didn’t provoke the same level of pleasure.
Dopamine is involved in the pleasure that lots of different drugs generate in the brain, so administering Ro 61-8048 could serve the same anti-addictive purpose when used with other drugs, the authors note. ”Currently, we’re doing some experiments with nicotine abuse, and there’s some very interesting preliminary data indicating it may work the same way,” Schwarcz said.
He cautions, though, that it’ll likely be years before this approach leads to an FDA-approved addiction treatment, in part because of the complexity of the brain and the way various neurotransmitters affect it. “Too much dopamine is bad for us, but too little dopamine is bad for us too,” he said. “You want homeostasis, so we have to be careful not to decrease dopamine levels too much.” But in the long-term, if scientists figure out how to safely increase kynurenic acid levels to limit dopamine’s effectiveness, people who suffer from addiction may have a new option when trying to wean themselves off their drugs of choice.
October 7, 2013
For years, doctors have observed a strange effect of alcohol abuse: People who drink heavily are more likely break their bones, and the risk can’t be fully explained by more frequent careless falls and alcohol-induced car accidents.
“As an orthopedic surgery resident, time after time, I see people come in with broken limbs while under the influence of alcohol,” says Roman Natoli, a doctor at Loyola University in Chicago.
Statistics suggest that their risk of a bone fracture is equal to that of a non-drinker a decade or two older than them, and they also tend to go through a slower healing process, filled with more frequent complications.
The reasons for this haven’t been entirely clear. Evidence suggested it had something to do with the way alcohol interfered with the activity of osteoblasts (the cells that synthesize new bone growth), while osteoclasts (the cells that remove old, damaged bone tissue) continued work as usual, leaving small cavities where new tissue was supposed to form. Data also indicated that the problem was dose-dependent—the more alcohol people drank, the greater the problem.
To find out the exact nature of the issue, Natoli and a group of medical researchers from Loyola did the logical thing: They got some mice rather intoxicated.
Specifically, the doctors, who presented their findings yesterday at the American Society for Bone and Mineral Research’s annual meeting, sought to simulate the effects of a single intense bout of binge drinking on mice who’d suffered a bone fracture.
To do so, they gave mice levels of alcohol that were roughly equivalent to a human with .20 blood alcohol content, several times the legal limit for driving. For an average person, reaching this level would require drinking about 6-9 drinks in an hour, and would likely lead to confusion, disorientation, dizziness, exaggerated emotions and severe risk of injury.
We have no idea if the mice experienced mood swings, but the doctors did look closely at the way their tibias healed after an induced fracture, as compared to induced fractures in a control group of mice that hadn’t had any alcohol. They found that, in the mice who’d gone through the alcohol binge, the callus—the mass of temporary bone tissue formed by osteoblasts in the gap between the two broken bone ends—was less dense and softer.
They also uncovered a few underlying reasons why this might be the case. For one, the body generates new bone tissue by recruiting immature stem cells to the site of the break, where they develop into osteoblasts and mature bone cells. The researchers found, however, that one of the main two proteins that the body uses to bring these stem cells to the fracture site—a protein called osteopontin, or OPN—was present in much lower levels in the mice who’d had so much alcohol.
Additionally, the alcohol-exposed mice seemed to suffer from a general problem that affects a range of cellular functions: oxidative stress. In essence, this type of stress results for an overabundance of oxidizing molecules—such as peroxides and free radicals—that can damage a variety of cell components, including proteins and DNA. It’s been implicated in a huge range of disorders in humans (including cancer, heart failure and Alzheimer’s).
The mice who’d been drinking had much higher levels of a molecule that scientists use as a proxy marker for oxidative stress (malondialdehyde), which jibes with previous studies that show alcohol can lead to higher production of oxidizing molecules and interfere with the body’s ability to break them down, especially in the liver. These higher stress levels, the researchers say, could inhibit bone growth and healing for reasons we still don’t fully understand.
If these findings apply to effects of drinking on the bone-healing process in humans, they could suggest some intriguing novel therapies for speeding bone growth in people who suffer from alcoholism, and perhaps even in non-drinkers. “The basic goal is to get these fractures to heal normally,” Natoli says.
One possibility that his team plans to test in future studies is injecting mice with extra stem cells, so that even with diminished quantities of the stem cell-recruiting protein OPN, they’d be able to get sufficient levels to the healing site. Another option could be giving mice an antioxidant called NAc, which combats oxidative stress throughout the body, perhaps speeding bone healing as well.
Of course, potential remedies notwithstanding, the findings should serve as a warning: if you’re a heavy drinker, your bones are likely weaker and have more difficulty healing. The silver lining, though, comes from other research, which has indicated that the problem is reversible—simply abstain from alcohol, and your bones will eventually regain most of their density and be able to heal normally again.
September 12, 2013
For the left-handed people of the world, life isn’t easy. Throughout much of history, massive stigmas attached to left-handedness meant they were singled out as everything from unclean to witches. In Medieval times, writing with your left-hand was a surefire way to be accused of being possessed by the devil; after all, the devil himself was thought to be a lefty. The world has gotten progressively more accepting of left-handed folk, but there are still some undeniable bummers associated with a left-handed proclivity: desks and spiral notebooks pose a constant battle, scissors are all but impossible to use and–according to some studies–life-expectancy might be lower than for right-handed people.
What makes humanity’s bias against lefties all the more unfair
is that left-handed people are born that way. In fact, scientists have speculated for years that a single gene could control a left-right preference in humans. Unfortunately, they just couldn’t pinpoint exactly where the gene might lie.
Now, in a paper published today in PLOS Genetics a group of researchers have identified a network of genes that relate to handedness in humans. What’s more, they’ve linked this preference to the development of asymmetry in the body and the brain.
In previous studies, the researchers observed that patients with dyslexia exhibited a correlation between the gene PCSK6 and handedness. Because every gene has two copies (known as alleles), every gene has two chances for mutation; what the researches found was that dyslexic patients with more variance in PCSK6–meaning that one or both of their PSCK6 alleles had mutated–were more likely to be right-handed.
The research team found this especially interesting, because they knew that PCSK6 was a gene directly associated with the development of left-right asymmetry in the body. They weren’t sure why this would present itself only in dyslexic patients, as dyslexia and handedness are not related. So the team expanded the study to include more than 2,600 people who don’t have dyslexia.
The study found that PCSK6 didn’t work alone in affecting handedness in the general population. Other genes, also responsible for creating left-right asymmetry in the body, were strongly associated with handedness. Like PCSK6, the effect that these genes have on handedness depends on how many mutations the alleles undergo. Each gene has the potential for mutation–the more mutations a person has in any one direction (toward right handedness or left handedness) the more likely they are to use that hand as their dominant hand, or so the researchers speculate.
The hypothesis is a logical response to a key question: If handedness is genetic and if
right-handedness is such a dominant trait, why hasn’t left-handedness been forced out of the genetic pool? In reality, the research suggests that handedness could be more subtle than simple “dominant” or “recessive” traits–a whole host of genes might play significant roles.
What’s especially exciting is that these genes all relate to the development of left-right asymmetry in the body and brain, creating a strong case for correlation between the development of this symmetry and the development of handedness. Disrupting any of these genes could lead to serious physical asymmetry, like situs inversus, a condition where the body’s organs are reversed (heart on the right side of the body, for example). In mice, the disruption of PCSK6 resulted in serious abnormal positioning of organs in their bodies.
If physical asymmetry is related to handedness, then people with situs inversus should favor one hand more often than what you’d find in the general population. Studies show that this isn’t the case–individuals with this condition mirror the general population’s split in handedness–leading the researchers to postulate that while these genes certainly influence handedness, there might be other mechanisms in the body that compensate for handedness in the event of major physiological asymmetries.
Other animals, such as polar bears or chimpanzees, also have handedness–chimpanzees have been known to prefer one hand to the other when using tools or looking for food, but the split within a population hangs around 50/50. Humans are the only species that show a truly distinct bias toward one hand or the other: a 90/10 right/left split throughout the population.
One predominant hypothesis for this bias relates to another distinct human trait: language ability. Language ability is split between the different hemispheres of the brain, much like handedness, which suggests that handedness became compartmentalized along with language ability, For most, the parts of the brain that govern language are are present in the left-side of the brain–these people tend to be
right-handed. The few that have language skills focused in the right side of the brain tend to be left-handed.
However, William Brandler, a PhD student at Oxford University and the paper’s lead author, isn’t convinced that this theory holds much stock, as correlations between language and handedness in research aren’t well established. Brandler is more interested in learning how the permutations and combinations of genetic mutations play into humans’ likelihood to be right-handed. “Through understanding the genetics of handedness, we might be able to understand how it evolved,” he says. “Once we have the full picture of all the genes involved, and how they interact with other genes, we might be able to understand how and why there is such a bias.”
And he’s confident that even if environmental factors (like the continued hatred of lefties by two-thirds of the world) place pressure on handedness, any
baseline bias still boils down to genetics. “People think it’s just an environmental thing, but you’ve got to think, why is there that initial bias in the first place, and why do you see that bias across all societies? Why aren’t there societies where you see a bias to the left?” Brandler asks. “There is a genetic component to handedness, hundreds of different genetic variants, and each one might push you one way or the other, and it’s the type of variance, along with the environment you’re in and the pressures acting on you, which affect your handedness.” But until a larger population can be tested–hundreds of thousands, by Brandler’s estimates–a full genetic map of what controls handedness and why our population isn’t evenly split between righties and lefties can’t be determined. “It’s going to take a bit of time before these materialize—but it will happen,” Brandler says. “There’s been a whole revolution in genetics such that, in a few years time, we’re really going to start to understand the genetic basis of complex traits.”