Tag Archives: protein

Scientists make paralyzed mice walk again, in groundbreaking treatment

A team of German researchers have achieved something once thought impossible: they’ve enabled mice paralyzed after spinal cord injuries to walk again. The designer protein (a cytokine) could be used to regenerate injured nerves in the spinal cord.

Neurons don’t naturally regenerate their axons (the long slender projections that conduct electrical impulses). So in the case of an injury that severs these axons, the damage was thought to be permanent. For decades, researchers have looked for a way to repair these connections, but haven’t had much success — until recently.

In 2013, neuroscientists in Germany published a study suggesting that a signaling protein (cytokine) could promote regeneration of optic nerve axons. But the study was carried out in lab cultures, not in real mice.

Breaking new ground

Now, the approach has been demonstrated in real mice. The team of researchers from Ruhr University Bochum administered the treatment to paralyzed rodents. After two to three weeks, the rats started walking.

The treatment is essentially an injection of genetic information that instructs the brain to produce the protein (called hyper-interleukin-6). This gene therapy is administered just one time, and the protein is then distributed via branching axons to even the distant, inaccessible parts of the central nervous system.

This is one of the main achievements of the work — that it not only stimulates the nerve cells it reaches to produce the protein, but that it is also carried farther (through the brain) to inaccessible parts. So with a relatively small injection, they can stimulate large parts of the brain, researchers say.

The team is now investigating if the treatment can be improved in any way, such as grafting to the spinal injury site. After these trials, and after a satisfactory form is reached, the treatment will then be trialed on larger mammals (such as pigs, dogs, or primates). If it is also successful, the treatment could then be trialed on humans, if it is proven safe.

The study “Transneuronal delivery of hyper-interleukin-6 enables functional recovery after severe spinal cord injury in mice” has been published in Nature Communications.

Researchers identify a protein that may be the link between anxiety and depression

Researchers at Karolinska Institutet in Sweden report on a new protein that could tie stress to depression and anxiety.

A 3D-printed human brain. Image via Flickr / NIH Image Gallery.

The team has identified a protein in the brains of mice that regulates the release of both serotonin and cortisol, which are the feel-good hormone and stress hormone, respectively. This protein, p11, was previously discovered by the same team, who showed that it plays a key role in the functioning of serotonin. The present study showed that mice lacking p11 show depression- and anxiety-like behaviour, which was treatable in part with antidepressants.

The findings could help us better understand the biochemical mechanisms behind depression and anxiety, and to develop new medicine to treat them.

P11 giveth, p11 taketh away

“We know that an abnormal stress response can precipitate or worsen a depression and cause anxiety disorder and cardiovascular disease,” says first author Vasco Sousa, researcher at the Department of Clinical Neuroscience, Karolinska Institutet. “Therefore, it is important to find out whether the link between p11 deficiency and stress response that we see in mice can also be seen in patients.”

Individuals that have experienced trauma or episodes of very severe stress are known to sometimes develop an abnormal (i.e. excessive) response to stress in the future. Those who also suffer from anxiety or depression are more likely to show such responses. However, in order to find out how to help them, we must first understand how our bodies create and regulate stress.

The authors report previously observing that depressed patients and suicide victims tend to have lower-than-average levels of the p11 protein in their brains. In order to find if there’s a link there, they engineered lab mice to produce low levels of p11. Further testing confirmed that these animals showed behavior consistent with depression and anxiety.

Mice with p11 deficiency also showed a stronger reaction to stress, exhibiting higher heart rates and more anxiety-related behavior when presented with a stressful situation, than unaltered mice.

The protein is directly involved in the initial release of cortisol in mice, the team explains, as it dictates the activity of neurons in the hypothalamus, an area of the brain heavily involved in controlling hormone levels in the body. It also — through its activity in a completely separate pathway in the brainstem — dictates the release of adrenaline and noradrenaline (also known as epinephrine and norepinephrine), two other hormones involved in the stress response.

Keeping p11 levels in the brain in check could thus be a promising avenue to treat patients suffering from depression, anxiety, and those who are struggling with chronic anxiety and stress from past experiences. This is especially heartening news as many such patients report that currently-available antidepressants are not effective in managing or treating their conditions.

“One promising approach involves administration of agents that enhance localised p11 expression, and several experiments are already being conducted in animal models of depression,” says Per Svenningsson, professor at the Department of Clinical Neuroscience, Karolinska Institutet, who led the study.

“Another interesting approach which needs further investigation involves developing drugs that block the initiation of the stress hormone response in the brain.”

The paper “P11 deficiency increases stress reactivity along with HPA axis and autonomic hyperresponsiveness” has been published in the journal Molecular Psychiatry.

Debunking the soy-estrogen problem and other soy myths

Soy is a unique food that can have both estrogenic and anti-estrogenic effects on the body. Studies sometimes present unclear or conflicting evidence, but the evidence suggests that in healthy individuals, soy provides significant benefits, especially as an alternative to red meat.

Not soy fast

Soy has been consumed in Asian countries for thousands of years — there’s evidence that it has been consumed since 9,000 BC. In recent decades, soyfoods have also become increasingly popular in non-Asian countries, largely because they are versatile and rich in protein. Soy protein is better than many other sources of protein as it contains all the essential amino acids.

At the same time, soy is often shunned for fear that it interferes with hormones. While some small-scale studies have cast some doubt on soy’s beneficial properties, recent large-scale studies have helped us understand soy’s effects on the body much better.

There have been several large-scale studies on the health effects of soy. These results suggest that soy has either a beneficial or at worst, a neutral effect on various health conditions.

Soy is a nutrient-rich food that can be safely consumed multiple times a week and is likely to provide health benefits, especially when consumed as an alternative to red meat. While the extent of its benefit remains a matter of scientific debate, soy scaremongering has no scientific basis to stand on. Studies have shown that in moderate or even high quantities (an average of 1-2 servings per day), there is no relevant adverse effect in healthy individuals.

Tofu, one of the most popular soy products, can be an important part of a healthy diet with no significant drawbacks. Image credits: Anh Nguyen.

Is soy healthy?

The macronutrient composition of the soybean is different from other legumes, which is also why it’s so sought after. Soy is very rich in protein (comparable with meat in that regard but without the saturated fat and cholesterol). Soybean is also a good source of essential fatty acids and soy compounds that lower cholesterol levels. Studies have consistently found that reducing the animal protein and replacing it with plant protein from soy reduces cardiovascular risk, which is one of the main reasons for soy’s increasing popularity.

The soybean is also a good source of a variety of vitamins and minerals, such as potassium (which is notable because intake of this mineral is often suboptimal) and iron.

It’s hard to isolate the effects of soy from other parts of the diet, particularly as soy can be cooked and processed in multiple ways, and not all are similar.

“Soyfoods have long been recognized for their high-protein and low-saturated fat content, but over the past 20 years an impressive amount of soy-related research has evaluated the role of these foods in reducing chronic disease risk. Much of this research has been undertaken because the soybean is essentially a unique dietary source of isoflavones, a group of chemicals classified as phytoestrogens. The estrogen-like properties of isoflavones have also raised concern, however, that soyfoods might exert adverse effects in some individuals,” a recent study noted.

However, the concerns stem primarily from studies on animals, whereas human research supports the safety and benefits of soyfoods on healthy individuals.

Even in the most vulnerable categories, soy consumption seems safe. Approximately 20–25% of U.S. infants receive at least some soy-based formula (not soy milk) in their first year, and several studies documenting this have reported no negative health issues associated with this practice in babies or in adults who consumed soy-based formula as babies. Studies have found little to no differences between babies fed soy or cow’s-milk-based formula.

However, soy can be consumed in different forms, and some are not as healthy as others. Processed burgers generally tend to be far less healthy than things like tofu, for instance.

The bottom line on ‘is soy healthy’: Soy is an excellent source of nutrients, although processed forms may be far less healthy. The benefits of soy may depend on the form in which it is consumed.

Soy and female hormones

The effect of soy on women’s bodies has been often questioned. The reason is that soy contains phytoestrogens, plant hormones somewhat similar to estrogens. These are mainly two isoflavones (genistein and daidzein), and soy is far from the only plant to contain these hormones — studies have shown that a wide variety of fruits and nuts contain the same hormones. However, plant estrogens typically make a low percentage of the total ingested estrogens, especially in the Western world. Most of the estrogens we eat come from milk and dairy products; compared to that, soy only plays a minor part.

The controversy stems from the fact that the two isoflavones can act like estrogen (the female sex hormone) and estrogen plays a role in many biological processes from breast cancer to reproduction. However, these phytoestrogens have a much weaker effect than human estrogen — and while they share similarities to human hormones, they are structurally different. Furthermore, in some instances, phytoestrogens may even block the action of estrogen, which further complicates the issue.

Basically, while high levels of estrogen have been linked to an increased risk of breast cancer, soy foods don’t contain high enough levels of isoflavones to increase the risk of breast cancer.

“Soy has a relatively high concentration of certain hormones that are similar to human hormones and people got freaked out about that,” says Isaac Emery, a food sustainability consultant, for The Guardian. “But the reality is you would have to consume an impossibly large amount of soy milk and tofu for that to ever be a problem.”

Unfermented soy foodsIsoflavone content (mg)Protein (g)
soy milk, 1 cup67
tofu (bean curd), soft, 3 ounces208
soybeans, mature, boiled, ½ cup5515
soybeans, dry roasted, 1 oz.4011
edamame, boiled, ½ cup1611
soy cheese, 1oz.24
soy burger, 1 patty514
It’s worth noting that not all soy foods are alike. Source: Harvard University.
Fermented soy foodsIsoflavone content (mg)Protein (g)
miso, 3 oz.3710
natto, 3 oz.7014
tempeh, cooked, 3 oz.3013
soy sauce, 1 tbsp0.020

Several studies have looked for this but failed to establish a connection — and furthermore, some studies suggest that soy might actually reduce the incidence of some types of cancer (though that evidence is still unclear).

High soya intake among women in Asian countries has been linked to a 30% lower risk of developing breast cancer compared to US women, who eat much less soya. For example, the average intake of isoflavones in Japan is 30-50 mg per day, compared to 3mg in Europe and the US.

At any rate, the best existing science at the moment suggests no reason to associate soy consumption with cancer risk. According to the American Cancer Society (ACS), while our understanding of estrogen is still improving, soy does not seem to pose any cancer risk.

Across the ocean, similar studies have come to similar conclusions. A recent review of the European Food Safety Authority found that isoflavones do not adversely affect the breast, thyroid, or uterus of postmenopausal women. No effect was found on endometrial thickness or the histopathology of the uterus after 30 months of supplementation with 150 mg/day of soy isoflavones.

Soy has also been sometimes regarded as a risk to the endometrial tissue. However, studies suggest otherwise. A review of 25 clinical studies found that isoflavones do not adversely affect the endometrium. Furthermore, a recent meta-analysis of 10 observational studies found that soy intake was inversely associated with endometrial cancer risk. Regarding endometriosis, studies have found either a neutral or a positive effect associated with soy milk.

It’s sometimes claimed that while soy is a healthy option for most women, it can be dangerous for women right before or during menopause. However, this has been disproven. A study in which women ingested 900 mg of soy isoflavones per day found “no significant changes in mean values for estrogenic effects or other laboratory measurements” — and 900 mg is essentially impossible to get through diet, no matter how much soy you eat.

In fact, some studies have found that soy isoflavones can help with menopause. Asian women who consume soy regularly have much lower rates of menopausal symptoms such as hot flashes, although the studies are contradictory and it’s still unclear if soy is responsible for this protective effect. The average blood concentration of the isoflavone genistein in Asian women is about 12 times higher than that of US because of higher soy consumption, although the possible benefits of soy remain uncertain.

Another study on obese postmenopausal women found that replacing at least some of the consumed animal protein with soy offers clears advantages in terms of regulating insulin and cholesterol.

However, very large quantities of soy consumption (more than 15 servings/week) might disrupt ovarian function, one study found.

“Although the levels of phytoestrogens typically found in soy foods pose minimal risk in the adult female, the female reproductive system is dependent on hormones for proper function and phytoestrogens at very high levels can interfere with this process.”

The bottom line on soy and female hormones: studies have found no reason for concern unless soy is consumed in extremely large quantities. Soy is linked to positive outcomes for women, though the extent of these effects is still being researched.

Soy and male hormones

The idea that soy is not good for men, that it will alter their hormone levels or make them grow “man boobs” is owed to advertising more than real science. The alleged evidence for this comes from two isolated case reports of elder Japanese men whose caloric intake came almost exclusively from soy. Yes, if all you eat is soy, you’re bound to have health problems — but that can be said for everything, if you just eat one food, you’re bound to get in trouble. A thorough review found that “that isoflavones do not exert feminizing effects on men at intake levels equal to and even considerably higher than are typical for Asian males.”

Concerns that the consumption of phytoestrogens might exert adverse effects on men’s fertility (such as lowered testosterone levels and semen quality) have been addressed in several studies.

Soy burgers have become increasingly popular lately.

The controversy was fueled by one highly circulated 2008 study quoted by the Daily Mail which found that in men with a low sperm count, soy was associated with an even lower sperm count (though not leading to infertility). However, the study had important limitations: it’s limited to only 99 men, the majority of participants 72%) were overweight or obese, and other dietary and lifestyle parameters were not factored in (for instance, red meat or junk food are also suspected of reducing sperm count, as is a sedentary lifestyle).

The study was contradicted by more recent research that found no such association. As it so often happens, this small study was misinterpreted as “soy kills your sperm,” although evidence suggesting otherwise is much more robust. Asian populations have regularly consumed soy for generations without exhibiting any fertility disorders and primate studies also found no connection between soy and the quality, quantity, or motility of sperm.

In one University of Minnesota study from 2009, fifteen placebo-controlled treatment groups were compared with a baseline. In addition, 32 reports involving 36 treatment groups were assessed in simpler models to ascertain the results.

The researchers found no indication of a hormone alteration, regardless of the type of soy that was consumed.

“No significant effects of soy protein or isoflavone intake on testosterone, sex hormone-binding globulin, free testosterone, or free androgen index were detected regardless of the statistical model,” the researchers wrote. “The results of this meta-analysis suggest that neither soy foods nor isoflavone supplements alter measures of bioavailable testosterone concentrations in men.

In a 2010 review of the medical evidence, researchers wrote that “isoflavones do not exert feminizing effects on men,” while a study on babies who were fed soy milk found no “estrogen-like” hormonal effects in the soy drinkers.

Another interesting study on patients with prostate cancer assessed how much phytoestrogens would need to be ingested to alter testosterone and estrogen levels in men — it would be almost impossible to consume that much. No effects on estrogen levels have been noted in numerous clinical studies in which men were exposed to as much as 150 mg/day isoflavones (which is already a huge quantity). Even when a study analyzed a dose of 450 – 900 mg of phytoestrogens per day for 3 months, it found only a small detectable change in testosterone levels and no feminizing effects.

“The intervention data indicate that isoflavones do not exert feminizing effects on men at intake levels equal to and even considerably higher than are typical for Asian males,” the study concluded.

To put that into perspective, 450 mg of phytoestrogen is a huge amount. The average consumption of isoflavones in Asian society is 15-50 mg per day, while in Western countries only about 2 mg per day. You could have yourself a soy feast every day and you still wouldn’t reach it:

  • 1 cup of cooked soybeans = 94 mg
  • 6 ounces of tempeh = 74 mg
  • 2 cups of soy milk = 60 mg
  • 6 ounces of tofu = 40 mg
  • 2 soy hot dogs = 22 mg
  • 4 oz of soy cheese = 8 mg
  • total = 298

Overall, the impact of soy on male hormones is nonexistent or negligible and it is strongly overshadowed by the positive nutritional advantages of soy compared to equivalent foods.

“These data do not support concerns about effects on reproductive hormones and semen quality,” one review concluded.

If you’re worried about your hormone levels and feminization, you’d be better off reducing the amount of alcohol you consume. Alcohol has been repeatedly linked to hormone disorders, and ethanol is essentially a testicular toxin known to disrupt testosterone and reduce fertility.

The bottom line on soy and male hormones: The weight of evidence suggests no association between soy and feminization or hormonal issues. If your calories don’t come exclusively from soy, you should be alright.

Soy and cardiovascular disease

Image credits: Kien Cuong Bui.

Soy has been found to reduce the incidence of cardiovascular diseases, although it’s still debatable to what extent this effect is owed to the soy itself or to the fact that soy is often replacing more harmful foods like red meat.

The first major study to support this was a 1995 meta-analysis of 38 controlled clinical trials, which found that eating 50 grams of soy protein per day (over a pound of tofu) reduces cholesterol by 12.9%. Other studies have found a similar but weaker effect, and the problems stem from how soy is consumed — not all soy foods are alike, and some processed foods may be less healthy than others.

Overall, however, soy has been linked to a lower risk of heart disease compared to protein from animal sources. Even though soy protein may have little or even no direct effect on cholesterol or artery health, it is generally good for the heart and blood vessels if it replaces less healthful choices like red meat, especially as it comes with plenty of vitamins, minerals, and is low in saturated fats.

It’s also noteworthy that cardiovascular protection was observed in women more than men. But, for both men and women, the discussion is about how and how much soy helps cardiovascular health, not about problems associated with consumption.

The bottom line on soy and cardiovascular health: some studies have reported positive effects associated with soy consumption. While the extent of that is being actively researched, soy is a healthier alternative to red meat.

Soy and cancer

In animal and cell studies, high dosages of isoflavones tend to stimulate cancer growth. But in real humans, it’s a completely different thing, and most studies suggest a protective effect rather than the opposite.

For instance, the Shanghai Women’s Health Study (the largest and most detailed study of soy and breast cancer risk) followed 73,223 Chinese women for over 7 years. It found that women who ate the most soy had a 59% lower risk of premenopausal breast cancer compared to those who ate the lowest amount of soy. The Breast Cancer Family Registry, another prospective study following 6,235 women diagnosed with breast cancer in the US and Canada found higher survival rates in women who consumed more soya.

Another concern links soy and the risk of prostate cancer — however, here too, the studies suggest the opposite: regular soya intake is associated with an almost 30% reduction in the risk of developing prostate cancer (though again, this is difficult to attribute directly to soya, it could be linked to the lower intake of red meat or more general lifestyle). The strongest evidence here comes from a meta-analysis of 30 case-control and cohort studies from the US, Europe, Japan, and China, which found that phytoestrogen is significantly associated with a reduced risk of prostate cancer.

Curiously, it’s not clear how this happens. Soya intake doesn’t affect testosterone levels in men, so it could simply be that a diet containing more soya is often healthier overall (although isoflavones have been found to inhibit metastasis).

The bottom line on soy and cancer: soy is associated with a reduction in the risk of breast and prostate cancer.

Traditionally-served tofu in Japan.

The Conclusions

It’s always challenging to study the health impacts of a particular food or ingredient. There have been hundreds of studies on the health impacts of soy, some bigger and more thorough, some a bit more shallow, all with their own limitations. Studies often show correlation without causation, but the weight of evidence strongly indicates health benefits from eating soya — even if it just replaces unhealthier foods.

The phytoestrogens in soy play a complex role in the human body and the mechanism, but most studies find neutral or positive effects. However, in some niche situations, specialy attention must be paid to soy (for instance soy may interfere with thyroid hormone medication). Evidence indicates soyfoods can be safely consumed by all individuals except those who are allergic to soy protein, which is a rare allergy.

Aside from the phytoestrogens, soy contains plenty of vitamins, minerals, and nutrients. Soy can also be prepared in different types of foods — and some are healthier than others.

As is always the case, soy is best consumed in a balanced diet. Any food consumed in extremes will likely lead to negative health outcomes.

A protein in our pancreas and lungs could help treat asthma

Research using animal models and human tissue samples found a new potential avenue of treatment for asthma and chronic obstructive pulmonary disease (COPD).

Human alveolar tissue seen under the microscope.
Image credits Yale Rosen / Flickr.

An international research team reports that activation of a protein called free fatty acid receptor 4 (FFA4) in lung tissue can help reverse hallmark symptoms of asthma such as inflammation and obstruction of the airways in patients resistant to current treatments.

While the effect has not yet been confirmed in living human patients, the results warrant continued research into drugs that can target and interact with this protein, say the authors.

A breath of fresh air

“By the identification of this new mechanism we offer the hope for new effective medicines for those patients that are not responsive to our current treatments,” says Professor Christopher Brightling, an author on the paper from the University of Leicester.

The study identifies an existing class of medication that can interact with the FFA4 protein in model animals and human tissue samples to address the condition. FFA4 is found in cells in the gut and pancreas and helps to control blood glucose levels. Dietary fats, most notably omega 3 oils from fish, are known to activate this protein.

First, the team found that this protein is also present in lung tissues, which they called “surprising”. Furthermore, they found that activating FFA4 in mouse lung tissue causes smooth muscle surrounding the airways to relax, allowing more air to flow in. This effect also worked to reduce inflammation caused by exposure to pollution, cigarette smoke, or allergens. Cells in human lung tissue reacted in a similar way, they add.

Because this mechanism is different from the ones used for current asthma and COPD medication, it could prove to be an effective avenue of treatment for unresponsive or severe cases.

“It was indeed a surprise to find that by targeting a protein — which up to now has been thought of as being activated by fish oils in our diet — we were able to relax airway muscle and prevent inflammation,” says Andrew Tobin, Professor of Molecular Pharmacology at the University of Glasgow. “We are optimistic that we can extend our findings and develop a new drug treatment of asthma and COPD.”

With air pollution reaching worrying levels across the world, asthmatic patients are likely to see worsening symptoms. Such medication could help complement our current treatments to help preserve their health and quality of life.

The paper, “Pathophysiological regulation of lung function by the free fatty acid receptor FFA4,” has been published in the journal Science Translational Medicine.

A mutated coronavirus, better at infecting cells, is now “dominant” in the world

A strain of the coronavirus seen in Europe and the United States is significantly more infectious than the initial virus, according to findings from Scripps Research.

cryogenic electron microscope image of a SARS-CoV-2 spike protein.
Image credits Andrew Ward lab / Scripps Research.

The strain is characterized by a mutation that dramatically increases the number of spike proteins on the virus’ surface, explains senior author Hyeryun Choe, a virologist at Scripps. These spikes represent the biochemical mechanism via which the virus gains entry into human cells.

More of a bad thing

“The number—or density—of functional spikes on the virus is 4 or 5 times greater due to this mutation,” says Hyeryun Choe, PhD.

“Viruses with this mutation were much more infectious than those without the mutation in the cell culture system we used.”

The coronavirus gets its name from these spikes, which resemble a crown. Apart from their aesthetics, these spikes enable the virus to access our cells using the ACE2 receptors on their membrane.

The mutation identified by this study, called D614G, doesn’t directly influence the number of spikes. What it does do, however, is to cause a different amino acid to be used in these spikes — glycine instead of aspartic acid — which makes their structures more flexible. Due to this, more spikes can survive from the moment the virus is produced to when it infects a host as they’re less likely to break off.

So although the mutation acts on the flexibility of these spikes, the net result is a virus that’s much more stable over time and retains a greater ability to infect cells.

No such link has yet been confirmed or infirmed, but the team says that such mutations could help explain why outbreaks in Italy or New York were rampant and quickly overwhelmed the medical resources available, while other areas fared much better, at least initially.

Still, to the best of our knowledge today, the SARS-CoV-2 variant that spread in the earliest outbreaks lacked the D614G mutation, but it is now dominating in much of the world, the team explains. In February, no sequences deposited to the GenBank database showed the D614G mutation. By March, it appeared in 1 out of 4 samples. and in 70% of samples by May, the team reports. ICU data from New York and elsewhere reports a preponderance of the new D614G variant as well, they add.

Mutation is a natural part of biology and that all viruses acquire tiny genetic changes as they reproduce. Most don’t have any bearing on the virus’ ability to infect our cells.

The team further notes that the findings are based in lab experiments with harmless viruses engineered to produce key coronavirus proteins. Further research would be needed to determine whether this mutation also impacts the transmissibility of the virus in real-world situations. For now, however, serum isolated from infected people worked just as well against engineered viruses with and without the D614G mutation, suggesting that potential vaccines should protect against both strains.

It is still unknown whether this small mutation affects the severity of symptoms of infected people, or increases mortality, the scientists say.

The paper “The D614G mutation in the SARS-CoV-2 spike protein reduces S1
shedding and increases infectivity” has been published in the pre-print site bioRxiv and is undergoing peer-review.

First identified biomarker for PTSD could hold the key to treating the disorder

New research from the Centre for Addiction and Mental Health (CAMH) and the Canadian Institutes of Health Research (CIHR) may lead to the first clinical diagnostic tool for post-traumatic stress disorder (PTSD) and novel, reliable treatments.

Art therapy mask created at the National Intrepid Center for Excellence (NICoE) depicts demons coming out of the brain of a PTSD patient, a serviceman, who created it.
Image credits Department of Defense / Katie Lange.

PTSD is a debilitating mental health condition that can be triggered by either experiencing or witnessing extreme trauma. However, there are no clinical diagnostic tools for PTSD today, and treatment options are limited and of limited efficacy.

A new study into the physiological roots of PTSD and preventive measures against it could set that right, however. The authors report identifying a protein complex that’s elevated in the bodies of PTSD patients. The team developed a peptide compound that targets and disrupts this protein, which has proven effective in preventing the formation or recall of traumatic memories in early tests in mice.

Chemical bliss

“The discovery of the Glucocorticoid Receptor-FKBP51 protein complex provides a new understanding of molecular mechanisms underlying PTSD,” said Dr. Fang Liu, the study’s corresponding author. “We believe this protein complex normally increases after severe stress, but in most cases, levels soon go back to baseline levels.”

“However, in those who develop PTSD, the protein complex remains persistently elevated, and so this could be a blood-based biomarker for PTSD as well as being a target for pharmacological treatment.”

Back in 1915, English psychologist Charles Myers coined the term “shell shock” to describe the state of soldiers who were involuntarily shivering, crying, fearful, and experienced constant intrusions of distressing memories following their service in the hellscapes of World War One. “Shell shock” isn’t in current psychiatric use any longer as it has been rolled into the wider-ranging concept of PTSD. However, it can be seen as its intellectual forerunner.

We now know that such symptoms aren’t limited to army personnel. Victims of violent or sexual assault also often develop PTSD, as do survivors of non-assault based trauma (such as natural disasters), albeit less often.

PTSD is characterized by persistent and intrusive memories or nightmares of the traumatic event, heightened levels of anxiety and vigilance, general emotional unresponsiveness, and persistent avoidance of stimuli related to the trauma. The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) lists 17 different symptoms of PTSD, and requires at least one (of the five) re-experiencing symptoms, at least three (of seven) avoidance symptoms, and at least two (of five) arousal symptoms to be present for one month for a diagnosis to be made.

Some of the other masks created at NICoE. Patients are encouraged to express their experience through the masks. Many depict a split sense of self or chaotic thought patterns.
Image credits Department of Defense / Katie Lange.

It’s still a very current problem. The team examined statistics from 24 countries and found that Canada currently has the highest prevalence of PTSD among the lot. Around 9.2% of Canadians will develop PTSD during their lifetimes, they explain. A 2017 study estimated that around 6.8% of Americans will develop PTSD during their lifetime.

The authors of the new paper report that individuals with PTSD have heightened levels of a complex protein formed from the glucocorticoid receptor (GR) and the FKBP51 binding protein compared to healthy controls, people who were exposed to trauma without developing PTSD, and patients with major depressive disorders. Fear-conditioned mice also showed heightened levels of this protein complex, they add. These findings strongly suggest that the complex is a mediator for the disorder.

In order to validate their findings, the team designed the peptide TAT-GRpep (think of peptides as being chunks of protein) that binds to and disrupts the function of the GR-FKBP51 complex. TAT-GRpep works by binding to the GR, effectively taking up the spot that the protein complex needs to bind to in order to elicit a response in the body. They tested this peptide on lab mice and report that it was “able to decrease GR-FKBP51 complex levels in both blood and brain tissue from mice,” suggesting that it could also prove effective in humans.

“Because our interfering peptide can block the consolidation of fear memories, we propose that it or a therapeutic analog could be given to patients exposed to severe trauma, as a prophylaxis against the future emergence of PTSD,” the paper reads. “The protein complex could also be a treatment target for established PTSD symptoms and as a biochemical diagnostic marker for PTSD.”

“Any of these advances would significantly improve on current clinical approaches to this important brain disorder.”

Dr. Liu and her team plan to further test and refine the peptide before conducting human clinical trials.

The paper “The glucocorticoid receptor–FKBP51 complex contributes to fear conditioning and posttraumatic stress disorder” has been published in the Journal of Clinical Investigation.

Rare genetic mutations and the fruit fly explain how Zika causes microcephaly

In the early part of 2016, the World Health Organization’s Emergency Committee (EC) under the International Health Regulations (2005) (IHR 2005) discussed the clusters of microcephaly and Guillain-Barré Syndrome (GBS) cases that have been temporally associated with Zika virus transmission.

Brazil, France, the United States of America, and El Salvador provided information on a potential association between microcephaly and other neurological disorders with Zika virus. The recent cluster of microcephaly cases was considered a Public Health Emergency of International Concern (PHEIC). Several months later, the WHO confirmed in a scientific consensus that the Zika virus is linked with microcephaly as well as Guillain-Barré syndrome.

Three years and several studies later, researchers at Baylor College of Medicine revealed one way how in utero Zika virus infection can lead to microcephaly in newborns. The team discovered that the Zika virus protein NS4A interrupts the growth of the brain by taking control of a pathway that regulates the generation of new neurons.

Rare genetic mutations helped explain how Zika causes microcephaly

Zika virus protein NS4A interacts with ANKLE2, a protein linked to hereditary microcephaly.

“The current study was initiated when a patient presented with a small brain size at birth and severe abnormalities in brain structures at the Baylor Hopkins Center for Mendelian Genomics (CMG),” said Dr. Hugo Bellen, professor at Baylor, investigator at the Howard Hughes Medical Institute and Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital.

This patient and others in a cohort at CMG had not been infected by Zika virus in utero. They had a genetic defect that caused microcephaly. CMG scientists determined that the ANKLE2 gene was associated with the condition.

Several years ago, Dr. Bellen and colleagues discovered in the fruit fly model that the ANKLE2 gene was associated with neurodevelopmental disorders. In a subsequent fruit fly study, the researchers demonstrated that overexpression of Zika protein NS4A causes microcephaly in the flies by inhibiting the function of ANKLE2, a cell cycle regulator that acts by suppressing the activity of VRK1 protein. Since very little is known about the role of ANKLE2 or VRK1 in brain development, Bellen and his colleagues applied a multidisciplinary approach to tease apart the exact mechanism underlying ANKLE2-associated microcephaly.

The fruit fly helps clarify the mystery

This image shows the two lobes of the brain of a fruit fly larva with hundreds of neurons, colored green, and stem cells, colored magenta. 

To figure out how Ankle2 mutations were influencing brain formation, the researchers went back to flies. Normally, Ankle2 works with a series of other genes to control the division of neuroblasts — stem cells that give rise to neurons. These cells are crucial for proper brain development.

Mutations in the Ankle2 gene, though, messed with neuroblast division. Larval flies with the mutation had fewer neuroblasts and smaller-than-expected brains. Further analyses revealed more details about how Ankle2 regulates asymmetric neuroblast division. They found that Ankle2 protein interacts with VRK1 kinases, and that Ankle2 mutants alter this interaction in ways that disrupt asymmetric cell division.

The Zika connection

In the future, a drug that protects this protein could stop Zika’s damaging developmental effects, says Dr. Hugo Bellen.

“For decades, researchers have been unsuccessful in finding experimental evidence between defects in asymmetric cell divisions and microcephaly in vertebrate models. The current work makes a giant leap in that direction and provides strong evidence that links a single evolutionarily conserved Ankle2/VRK1 pathway as a regulator of asymmetric division of neuroblasts and microcephaly. Moreover, it shows that irrespective of the nature of the initial triggering event, whether it is a Zika virus infection or congenital mutations, the microcephaly converges on the disruption of Ankle2 and VRK1, making them promising drug targets.”

Researchers finally figure out the protein that senses cold temperatures

New research is homing in on the biochemical mechanisms that allow mammals to feel cold.

Image credits Antonio Jose Cespedes.

The study is the first to identify a protein that responds to extreme cold. The gene is evolutionarily conserved across species, including humans.

Chilly

“Clearly, nerves in the skin can sense cold. But no one has been able to pinpoint exactly how they sense it,” said Shawn Xu, a faculty member at the University of Michigan Life Sciences Institute and senior author of the study. “Now, I think we have an answer.”

It’s vital for our bodies to be able to perceive temperature. When it gets too chilly outside, we need to feel that uncomfortable ‘cold‘ sensation so that we’ll seek shelter, warmth, and not die from exposure.

It falls to receptor proteins in the nerves of our skin to perceive this change and then relay the information to our brains. This mechanism holds true from humans down to very simple organisms, such as the millimeter-long worms that researchers study in Xu’s lab at the Life Sciences Institute: Caenorhabditis elegans.

We seek warmer environments when we’re cold, and Xu’s worms do the same thing: when they sense cold, they engage in avoidance behavior and move away, seeking warmth. However, unlike us, C. elegans have a simple and well-mapped genome, and a short lifespan, making them a valuable model system for studying sensory responses.

Previous efforts to find the receptor for cold have been unsuccessful because researchers were focusing on specific groups of genes that are related to sensation, which is a biased approach, Xu said. Instead, he and his team relied on the simplicity of C. elegans for an ‘unbiased approach’.

The team looked across thousands of random genetic variations to determine which affected the worms’ responses to cold. They report that worms engineered to lack the glutamate receptor gene glr-3 no longer responded when temperatures dipped below 18 degrees Celsius (64 F).

Glr-3 is responsible for making the eponymous GLR-3 receptor protein; without this protein, the worms lost sensitivity to cold temperatures, a strong indicator that it underpins the ability to sense cold.

The glr-3 gene is evolutionarily conserved across species including humans. The vertebrate versions of the gene can also function as a cold-sensing receptor, the team adds. The team determined this after adding the mammalian version of the gene to mutant worms lacking glr-3 (and were thus insensitive to cold), which made them feel cold temperatures once more.

The team also added the worm, zebrafish, mouse, and human versions of the genes to cold-insensitive mammalian cells, and all allowed the cells to sense to cold temperatures.

The mouse version of the gene, GluK2 has been documented to help transmit chemical signals within the brain. The authors further discovered that the gene is also active in a group of sensory neurons that detect environmental stimuli, such as temperature, through sensory endings in the mice’s skin. Reducing expression of GluK2 in these sensory neurons made the mice insensitive to cold, but not cool, temperatures — additional evidence that the GluK2 protein serves as a cold receptor in mammals.

“For all these years, attention has been focused on this gene’s function in the brain. Now, we’ve found that it has a role in the peripheral sensory system, as well,” Xu said. “It’s really exciting. This was one of the few remaining sensory receptors that had not yet been identified in nature.”

The paper “A Cold-Sensing Receptor Encoded by a Glutamate Receptor Gene” has been published in the journal Cell.

Eat more plant protein for a longer and healthier life, new study concludes

In recent times, the human diet has changed substantially. We have access to an unprecedented variety of foods, yet meat consumption has increased dramatically: from 20 kilograms a year in 1961, to around 43 kilograms in 2014. However, recent studies have increasingly found that meat consumption can have negative health effects, and substitute meat for plant protein can provide important benefits.

The latest study followed almost 71,000 middle-aged Japanese adults for an average of almost two decades. They split the people into five groups based on how much plant protein they ate. People who ate the most plants were 13% less likely to die during the study and 16% less likely to die of cardiovascular causes than people who ate the least amount of plants.

Furthermore, when people replaced just 4% of processed meat in their diet with plant protein, they were 46% less likely to die of any cause and 50% less likely to die of cancer.

This is hardly the first study to come up with these conclusions. Numerous previous studies have found that higher consumption of animal protein is associated with chronic diseases and mortality and higher consumption of plant protein reduces this risk. However, most of these studies were conducted on people in the Western World, where consumption of animal protein is much higher. This study, carried on people with a high plant protein consumption, showcases that more plant protein is always helpful.

Leaner meat, such as fish, is also a decent alternative, researchers say.

“Our study suggests that plant protein may provide beneficial health effects and that replacement of red and processed meat protein with plant or fish protein may increase longevity,” the researchers write.

Contrary to popular belief, many plants are protein-rich — up to the point where they rival and even surpass meat. Lean beef contains around 26 grams of protein per 100 grams, comparable to lean pork (although fatter meats have way less protein). Meanwhile, kidney beans and chickpeas have around 24 grams of protein per 100 grams — and plenty of other plants can serve as excellent alternatives.

Furthermore, it’s not just the proteins — these plants are also rich in fiber and other important nutrients which meat is lacking. Fiber, in particular, has been shown to provide important health benefits and is often lacking from meat-rich diets.

There’s also a shortcoming to this study: the participants’ diets were only assessed once, at the start of the study. It’s possible that along the road, some of their dietary patterns changed. However, this adds to the growing body of evidence regarding the negative effects of a meat-rich diet. The science is in: if you want to live a healthy life, eat less meat and more plants.

The study has been published in JAMA Internal Medicine.

Cancer.

Discovery of new “don’t eat me protein” points the way to effective cancer therapy

Stanford University (SU) researchers have found a new signaling molecule that cancer cells use to keep the immune system at bay.

Cancer.

Image via Pixabay.

Our bodies’ immune cells are, among other objectives, tasked with clearing out malfunctioning cells. In theory, cancer cells fall into this category and should be targeted; in practice, however, they use all sorts of biochemical tricks to avoid detection. Researchers at the SU School of Medicine have identified a new signaling molecule that cancer cells use for this purpose.

Cloaking proteins

Immune system cells called macrophages normally detect sick or damaged cells, then proceed to engulf and devour them. In recent years, however, researchers have discovered that proteins on the cell surface can tell macrophages not to destroy them. While this mechanism is meant for good, law-abiding cells to keep the immune system from attacking them, cancer cells have hijacked the same mechanism.

The authors’ past research has shown that the proteins PDL1 and CD47 are used by cancer cells to hide from immune system cells. The discovery of these two proteins and their role also pointed to a possible treatment against cancer: blocking them to ‘uncloak’ cancer cells. Antibodies aimed at blocking CD47 undergoing clinical trials, while treatments targeting PDL1 are already in use in oncology clinics. 

“Finding that not all patients responded to anti-CD47 antibodies helped fuel our research at Stanford to test whether non-responder cells and patients might have alternative ‘don’t eat me’ signals,” said co-author Irving Weissman, the Virginia and D.K. Ludwig Professors for Clinical Investigation in Cancer Research.

The team reports finding a new such protein, called CD24, that cancer cells employ as a “don’t eat me” sign. They began by looking for proteins that were produced in larger quantities in cancer cells than in the surrounding, healthy tissues. The hypothesis the team was working on was that cancers growing in the presence of macrophages need to produce some kind of signaling molecule to keep themselves safe. This should be reflected in a higher concentration of that particular compound in the cancer cells — and, by disrupting this compound, cancer could be made vulnerable.

Many different types of cancer produce higher levels of CD24 compared with normal cells and surrounding tissues, the team explains. They further showed that macrophage cells which infiltrate the tumor sense the presence of this protein through a specialized receptor (SIGLEC-10). They placed a mix of cancer cells harvested from patients and macrophages in a dish and then blocked the interaction between CD24 and SIGLEC-10. The macrophages immediately started breaking down the cancer cells, they explain. Lastly, they implanted human breast cancer cells in mice and blocked CD24 signaling — the mice’s macrophages attacked the cancer cells, the team reports.

Of particular interest was the discovery that ovarian and triple-negative breast cancer, both of which are very hard to treat, were highly affected by blocking the CD24 signaling.

“This may be a vulnerability for those very dangerous cancers,” said Amira Barkal, an MD-PhD student and lead author of the paper.

CD24 seems to often work as a complement to CD47 — one of the previously-identified ‘don’t eat me’ proteins — the team adds. Some cancers, like blood cancer, are highly susceptible to CD47-signaling blockage but not to CD24-signaling blockage. Others, like ovarian cancer, show the exact opposite susceptibility. This finding makes the team confident that most (if not all) types of cancers can be attacked by blocking one of these two signaling molecules.

The researchers now hope that therapies to block CD24 signaling will follow in the footsteps of anti-CD47 therapies, being tested first for safety in preclinical trials, followed by safety and efficacy clinical trials in humans. In the future, they plan to keep sniffing out such proteins in a bid to make cancers even more vulnerable by blocking several ‘don’t eat me’ proteins at a time.

“There are probably many major and minor ‘don’t eat me’ signals, and CD24 seems to be one of the major ones,” Barkal said.

Combined with novel ways of detecting the disease, such treatment avenues may finally spell the end of cancer as we know it today. Not a day too soon.

The paper “Engagement of MHC class I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy” has been published in the journal Nature Immunology.

 

The age of the designer protein is upon us — and the prospects are thrilling

In what could be a game-changer for therapies used in many diseases, scientists have created the first completely artificial protein switch. The protein can work inside living cells to modify or command the cell’s internal circuitry.

It’s the first fully artificial protein developed by humans. Credit: Wikipedia Commons

 

Researchers at the University of California, San Francisco used computational protein design to create self-assembling proteins that present bioactive peptides only upon the addition of specific molecular “keys.” The work was published in the journal Nature.

The research team installed the switch in yeast and showed that the genetically engineered fungus could be made to degrade a specific cellular protein at a time of the researchers’ choosing. By redesigning the switch, they also demonstrated the same effect in lab-grown human cells.

“In the same way that integrated circuits enabled the explosion of the computer chip industry, these versatile and dynamic biological switches could soon unlock precise control over the behavior of living cells and, ultimately, our health,” said Hana El-Samad, and co-senior author of the report.

The switch created by the researchers was dubbed LOCKR, short for Latching, Orthogonal Cage/Key protein. LOCKR can be ‘programmed’ to modify gene expression, redirect cellular traffic, degrade specific proteins, and control protein binding interactions – using what the paper calls ‘its arm.’

LOCKR has a structure similar to a barrel. When opened, it reveals a molecular arm that can be engineered to control virtually any cellular process. In the paper, the researchers highlight that the switch can be used to build new biological circuits that behave like independent sensors.

“LOCKR opens a whole new realm of possibility for programming cells,” said Andrew Ng of the UC Berkeley-UCSF Graduate Program in Bioengineering. “We are now limited more by our imagination and creativity rather than the proteins that nature has evolved.”

The new switch is not the first designer protein switch ever made, but it’s the first fully artificial one — and it has a lot of applications. Having access to biotechnology tools entirely conceived of and built by humans — as opposed to editing and modifying proteins found in nature — opens a range of exciting possibilities.

LOCKR gives scientists a new way to interact with living cells, which have to control their biochemical processes to avoid death or cancer. The switch could then facilitate a new array of therapies for diverse diseases, ranging from cancer to autoimmune disorders.

 

Not a real meat burger. Credit: Beyond Meat.

Lab-grown meat market could be worth $85 billion by 2030

“Fake meat” might have sounded like a gross, even laughable idea just a decade ago. But after Beyond Meat Inc., the vegan burger maker, surpassed $200 per share last month (after a $25 offering price), who’s laughing now?

Not a real meat burger. Credit: Beyond Meat.

Not a real meat burger. Credit: Beyond Meat.

According to a new report by UBS Global Wealth Management, advances have triggered an agricultural revolution that is set to greatly expand the broader agriculture technology market, which is expected to reach $700 billion in 2030 from $135 billion today. The plant-protein (aka fake meat) market looks particularly promising, with experts estimating that it should swell from $4.6 billion to a staggering $85 billion by 2030.

And all of this is great news for basically everyone — apart from those involved in intensive animal farming.

Lab-grown food isn’t just some fad poised to come and go with the seasons. Agriculture currently accounts for 40% of land use, 30% of greenhouse gas emissions, and 70% of freshwater consumption. The world’s population is expected to hit the 10 billion mark in 2050, and billions currently living in developing countries are expected to experience higher incomes, which they’ll use to buy more meat. For instance, China’s economy has grown tremendously and this is mirrored in the country’s meat consumption. The average person in 1960s China consumed less than 5kg a year. By the late 1980s, this had risen to 20kg, and in the last few decades, this has more than tripled to over 60kg.

The world simply cannot produce this much meat, nor should it. Plant-based proteins which replicate the nutritional value, texture, and even taste of meat, fish, eggs, and dairy products will become more and more appealing as the technology improves. In the future, consumers should have access to cheaper and more “meat-like” plant-based protein, and this will be reflected in huge market growth. Simply put, real meat will turn into a luxury item while “fake” meat will be there to fill the void.

This shift in attitude is already going strong in consumer behavior. For instance, in early May, news emerged that Impossible Foods (a company at the forefront of the recent boom in fast-food meatless meat) was struggling to produce enough to meet the growing demand for their products. Their products are now sold at Burger King, White Castle, as well as chains like Red Robin. Sales of such plant-based proteins grew 10% in 2018, while the conventional meat industry grew just 2%, according to a recent report from the Good Food Institute.

The 67-page report from UBS also outlines various other avenues for market growth in agriculture as a result of digitization. For instance, UBS forecasts that by 2030, smart farming and online food delivery will grow by 16%, seed treatment by 13%, and seed science by 9%.

Scientists explore the origin of metabolism to reveal secrets of primordial life

Many scientists believe that life likely first appeared in hydrothermal vents rich in iron and sulfur. The first cells incorporated these elements into peptides which became the first ferredoxins. Credit: Ian Campbell, Rice University.

Life couldn’t exist without some form of energy to power it, and in order to access energy from the environment (i.e. food), animals and plants have had to evolve a conversion process known as metabolism. In a new exciting study, researchers at Rutgers University and Rice University reverse-engineered a primordial protein which might resemble the first biological machines involved in metabolism. In doing so, the researchers have brought us a step closer to uncovering the very origins of life itself.

“We are closer to understanding the inner workings of the ancient cell that was the ancestor of all life on earth – and, therefore, to understanding how life arose in the first place, and the pathways life might have taken on other worlds,” said lead author Andrew Mutter, a postdoctoral associate at Rutgers University’s Department of Marine and Coastal Sciences.

Mutter and colleagues studied a class of proteins called ferredoxins, which play a crucial role in supporting the metabolism of bacteria, plants, and animals by moving electrical charge through cells.

Although today’s ferredoxins are complex, scientists believe that in life’s early days, these proteins had a much simpler form. But what did they look like exactly? Similarly to how biologists compare modern birds and reptiles to infer characteristics about their shared ancestor, the researchers compared various ferredoxins found in all sorts of living things. With the help of computer models, this information enabled the team to design possible forms which the very first metabolic proteins might have taken.

A basic version of the protein was created by the researchers and then inserted into living cells. The researchers first removed the gene responsible for encoding ferredoxin from the E. coli bacteria’s genome, and replaced with a gene for their simple protein. Remarkably, the modified bacteria survived and replicated, although the colony’s growth rate was slower than normal.

The findings have important implications for synthetic biology and bioelectronics, the authors emphasized.

“These proteins channel electricity as part of a cell’s internal circuitry. The ferredoxins that appear in modern life are complex – but we’ve created a stripped-down version that still supports life. Future experiments could build on this simple version for possible industrial applications,” said co-author Vikas Nanda, a professor at Rutgers Robert Wood Johnson Medical School and Center for Advanced Biotechnology and Medicine.

The new study was published in the Proceedings of the National Academy of Sciences.

Credit: Pixabay.

New study reveals secret language of cell communication

Credit: Pixabay.

Credit: Pixabay.

Humans are complex organisms made up of trillions of cells, and each of these cells has their own structure and function. Naturally, all of these cells have to communicate with each other so that the body can properly function. Otherwise, your brain couldn’t instruct the muscles in your legs to move or there would be no way to heal when you get an injury. In a new study, researchers at the University of Connecticut have revealed new insights into the complex web of cell communication. 

While humans use words and language to communicate, cells send and receive messages or instructions by secreting proteins. But words mean very little without structure, just like language means very little without grammar. Cells also have their own conversational structure, but until recently we knew very little about it.

“This is akin to detecting what words were spoken in a sentence, but not really knowing their placement, the inflection, and tone of the message,” said Kshitiz Gupta, an assistant professor at the UConn School of Dental Medicine.

Kshitiz and colleagues employed microfluidics and computer modeling to reveal the precise wording and structure of intercellular communication. During one experiment, the researchers zoomed in on stem cells from bone marrow that can be used to treat a myocardial infarction, also known as a heart attack. The team recorded proteins that were secreted by these stem cells, as well as how these secretions changed with time.

In the lab, the researchers used this information to make a protein cocktail that could one day be used to treat an injury without the use of stem cells. While stem cells are flexible enough to change their function and behavior depending on the site of injury, it is possible to copy a particular stem cell behavior and create a cell-less therapy that only uses proteins. Such an approach could avoid some of the complications associated with stem cell transplants.

“The findings solve a fundamental problem afflicting systems biology: measuring how cells communicate with each other,” said Yashir Suhail, a postdoctoral fellow, in the Dental School’s Department of Biomedical Engineering. “The platform technology will open new lines of inquiry into research, by providing a unique way to detect how cells talk to each other at a deeper level than what is possible today.”

The findings appeared in the journal Nature Communications.

Artist illustration of Centrosaurus. Credit: Nobu Tamura.

Dinosaur fossils are rich in microbes — and this might mean we won’t ever find dino proteins

Artist illustration of Centrosaurus. Credit: Nobu Tamura.

Artist illustration of Centrosaurus. Credit: Nobu Tamura.

Paleontologists are excited by recent reports of dinosaur bones containing preserved traces of the protein collagen, as well as other soft tissues like blood and bone cells. However, these organic molecules might actually be produced by modern microbes living inside the fossils, says a new study. This means that the chances of ever finding preserved dinosaur proteins are extremely thin, or next to impossible. There goes Jurassic Park!

Evan Saitta, a postdoctoral researcher at the Field Museum, was researching how soft tissues fossilize for his Ph.D. thesis at the University of Bristol. Inspired by the interest in findings of supposed dinosaur proteins, Saitta decided to perform his own investigation.

He traveled to the famous Dinosaur Provincial Park in Alberta, Canada, a region was rich in fossils that there is more bone than rock once you dig a little. Saitta had to be extra careful not to contaminate the bones he retrieved from the soil.

“To collect these bones in a very controlled, sterile way, you need a dig site with a ton of bone because you have to find the bone quickly, expose just enough of one end to know what it is, then aseptically collect the unexposed bit of the bone and surrounding rock all in one,” Saitta said.

A fluorescence microscopy image showing lit-up modern microbes found in a Centrosaurus fossil. Credit: Evan Saitta, Field Museum.

A fluorescence microscopy image showing lit-up modern microbes found in a Centrosaurus fossil. Credit: Evan Saitta, Field Museum.

Saitta found 75-million-year-old fossils of Centrosaurus—a smaller cousin of Triceratops—and brought them to the lab in order to examine their organic composition. The results were compared to chemical analyses of modern chicken bones, sediment from the fossil site in Alberta, and thousands-of-years-old shark teeth.

“We visited multiple labs, and the different techniques gave us consistent and easily interpretable results, suggesting that the aseptic collection was sufficient,” Saitta said in a statement.

The analysis showed no evidence of collagen proteins inside the fossils like there were present in the chicken bones and shark teeth. Instead, what they did find were a lot of microbes, despite the fact that Saitta’s anti-contamination measures were successful.

“We found non-radiocarbon dead organic carbon, recent amino acids, and DNA in the bone—that’s indicative that the bone is hosting a modern microbial community and providing refuge,” Saitta said.

These microbes weren’t at all like the common kind of bacteria found in the surrounding rock. For instance, 30% of the genome sequences are related to Euzebya, which is only reported in places like Etruscan tombs and the skin of sea cucumbers.

It’s not all that surprising that microbes love dinosaur bones. Such fossils are rich in nutrients like phosphorus and iron, which microbes require. Bones are also naturally porous, allowing moisture to sip through.  “These bacteria are clearly having a jolly good time in these bones,” Saitta said.

Saitta thinks that many of the organic molecules and soft tissues reported in dinosaur bones by other scientists are, in fact, of a different origin. Most likely, he thinks, these fossilized tissues are actually biofilms — microbe secretions.  “I suspect that if we began to do this kind of analysis with other specimens, it would begin to explain some of the so-called dinosaur soft tissue discoveries,” he said.

Chicken.

Researchers make chicken cells resist bird flu by snipping out a tiny bit of their DNA

Designer chicken cells grown in the lab at Imperial College London can resist the spread of bird flu.

Chicken.

Image credits Samet Uçaner.

Bird flu, as its name suggests, is mostly concerned with infecting birds. And it’s quite good at it: severe strains of bird flu can completely wipe out a whole flock. In rare cases, the virus can even mutate to infect humans, causing serious illness. As such, bird flu is a well-known and scary pathogen in the public’s eye.

Now, researchers from Imperial College London and the University of Edinburgh’s Roslin Institute have devised chicken cells that can resist infection with the bird flu virus. Their efforts pave the way towards effective control of the disease, safeguarding one of the most important domesticated animals of today.

Be-gone, flu

“We have long known that chickens are a reservoir for flu viruses that might spark the next pandemic. In this research, we have identified the smallest possible genetic change we can make to chickens that can help to stop the virus taking hold,” says Professor Wendy Barclay, Chair in Influenza Virology at Imperial College London and the paper’s corresponding author. “This has the potential to stop the next flu pandemic at its source.”

The findings could make it possible to immunize chickens to the virus using a simple genetic modification. No such chickens have been produced just yet, but the team is confident that their method will prove safe, effective, and palatable with the public in the long run.

The approach involves a specific molecule found in chicken cells, called ANP32A. Researchers at Imperial report that during a bird flu infection, viruses use this molecule to replicate (multiply) and continue attacking the host. The researchers from the University of Edinburgh’s Roslin Institute worked to gene-edit chicken cells to remove a portion of DNA that encodes the production of ANP32A.

With this little tweak, the team reports, the virus was no longer able to replicate inside the cells.

Members at The Roslin Institute have previously worked on something similar. Teaming up with researchers from Cambridge University at the time, they successfully produced gene-edited chickens that didn’t transmit bird flu to other chickens following infection. However, the approach they used at the time involved adding new genetic sequences into the birds’ DNA; while the proof-of-concept was very encouraging, the approach didn’t seem to stick, commercially.

“This is an important advance that suggests we may be able to use gene-editing techniques to produce chickens that are resistant to bird flu,” says Dr. Mike McGrew, of the University of Edinburgh’s Roslin Institute and a paper co-author.

“We haven’t produced any birds yet and we need to check if the DNA change has any other effects on the bird cells before we can take this next step.”

The paper “Species specific differences in use of ANP32 proteins by influenza A virus” has been published in the journal eLife.

Eating a lot of animal protein probably means you’ll have a shorter life

Finnish researchers found that a diet rich in animal protein, particularly red meat, increases a person’s risk of death compared to individuals who include plant-based protein in their diet.

Credit: Pixabay.

The study was performed by a team of researchers at the University of Eastern Finland, who analyzed the data from the Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD). The study included the diets of about 2,600 Finnish men aged between 42 and 60 at the start of the study in 1984. Researchers performed follow-ups with the participants up 20 years after the study’s onset.

The results suggest that men whose primary source of protein was animal-based had a 23% higher risk of death compared to men who ate a balanced ratio of animal and plant-based protein. Specifically, men who ate more than 200 grams of meat per day had a 23% higher risk of premature death during the follow-up than men whose meat intake was less than 100 grams per day. As a caveat, the study only included Finnish men who primarily consumed red meat (i.e. pork, beef), which is associated with more health problems than white meat (i.e. chicken).

Previously, researchers found that red meat (and processed meats) causes cancer, common inflammatory bowel condition, and raises the risk of premature death.

High protein intake, whether animal- or plant-based, was associated with a greater risk of death in individuals who had type 2 diabetes, cardiovascular disease or cancer at the onset of the study. High protein intake did not seem to be associated with an increase in the risk of death for healthy people.

“However, these findings should not be generalized to older people who are at a greater risk of malnutrition and whose intake of protein often remains below the recommended amount,” Ph.D. Student Heli Virtanen from the University of Eastern Finland points out.

The findings appeared in the American Journal of Clinical Nutrition. In the future, researchers would like to gain a better understanding of the relationship between different sources of protein and their health effects.

Cobweb.

Bacteria coaxed into making high-performance proteins for space missions

One team of researchers plans to use engineered bacteria to create proteins. Proteins that will take us to space.

Cobweb.

Image credits Bianca Mentil.

We tend to view biology as mushy and fragile, while everything mechanical is seen as robust. But that isn’t actually true. Natural, protein-based substances can boast mechanical properties on par with — and sometimes exceeding those of — synthetic materials. A pound of spider silk, for example, is stronger and tougher than a pound of the steel we use to make buildings or cars. So, naturally, we’d very much like to have such materials in cheap and ample supply, please.

But we don’t, because we have no idea how to mass-produce spider silk and other similar proteins. That is, we had no idea. Today at the American Chemical Society (ACS) Spring 2019 National Meeting & Exposition, one team of researchers is presenting a method they developed that uses genetically-engineered bacteria to produce proteins such as those in spider silk, and is planning to use them in future space missions.

“In nature, there are a lot of protein-based materials that have amazing mechanical properties, but the supply of these materials is very often limited,” says Fuzhong Zhang, Ph.D., the project’s principal investigator. “My lab is interested in engineering microbes so that we can not only produce these materials, but make them even better.”

Spiders, as the biology majors among you may suspect, tend to be quite tiny. They’re also not especially excited by the prospect of roommates: they turn cannibalistic if you try to keep them in groups. That’s why researchers have tried to work around using them altogether by attempting to engineer bacteria, yeast, plants, even goats to produce spider silk. So far, they haven’t yet been able to fully replicate the natural fiber’s mechanical properties. They weren’s complete disasters, but the end product fell quite short of the mark.

Part of the problem, Zhang’s team explains, is that spider silk proteins are encoded in very long, highly repetitive sequences of DNA. The spiders also evolved the biochemical means to hold these sequences stable in their genome. Other organisms, however, don’t need these biochemical mechanisms. So, when we try copy-pasting silk genes in other genomes, they degrade; usually because the host organism’s cells alter or shorten the genes. Zhang and his team of researchers at Washington University in St. Louis thought that breaking them down into shorter blocks could help keep them stable — kind of how Ikea would do it. Bacteria engineered this way would only produce sub-sections of the needed proteins. The team would manage the final assembly steps.

Spider silk.

The spider silk produced in this study (top; higher magnification cross-section view on bottom).
Image credits Christopher Bowen.

They spliced genes encoding two pieces of the spider silk protein into bacteria, flanking each piece with a ‘split intein’. Split inteins, they explain, are naturally occurring protein sequences with enzymatic activity. Two split inteins on different protein blocks can join (forming an intein) and then cut themselves out to weld the two blocks together. Pretty handy.

After the genes were introduced to the bacteria, the team broke them apart and retrieved the protein sub-assemblies. Mixed together, the two halves reacted, producing the final protein, which the team spun into fibers. They report that the final product has all the properties of spider-spun spider silk — it’s exceptionally stretchy, tough, and strong. Overall, the method seems to be better at making the silk than spiders themselves. The team obtained two grams of silk per liter of bacteria culture (more than they would obtain from the same ‘volume’ of spiders).

Best of all, the approach isn’t limited to spider silk. Other repetitive proteins can be synthesized by simply swapping out the silk-encoding DNA with other sequences. As a proof of concept, the team also produced a protein that mussels use to stick to different surfaces — which they say can be used as a super-strong underwater adhesive.

The team is currently trying to increase the yield of their bacteria even more. They are also trying to streamline the process so that the bacteria themselves handle the final assembly of the proteins. This would improve the efficiency and potential automation of the system because researchers wouldn’t have to purify the two pieces of the protein and then incubate them together.

“NASA is one of our funders, and they are interested in bioproduction,” says Zhang. “They’re currently developing technologies in which they can convert carbon dioxide into carbohydrates that could be used as food for the microbes that we’re engineering. That way, astronauts could produce these protein-based materials in space without bringing a large amount of feedstocks.”

SAFit2.

New study wants to tackle depression, obesity, chronic pain by blocking a single protein

New research aims to shut down a protein linked to major depression, obesity, and chronic pain.

SAFit2.

The new inhibitor (colored orange) only blocks the activity of FKBP51, which is involved in depression, chronic pain and obesity.
Image credits Felix Hausch.

One protein known as FK506-binding protein 51, or FKBP51 for short, has previously been linked to depression, obesity, diabetes, and chronic pain. A new study is looking into ways we can block its activity in mice, in an effort to relieve chronic pain and have positive effects on diet-induced obesity and mood. The new compound could also have applications in alcoholism and brain cancer, the team explains.

The problematic protein

“The FKBP51 protein plays an important role in depression, obesity, diabetes and chronic pain states,” says Felix Hausch, Ph.D., the project’s principal investigator.

“We developed the first highly potent, highly selective FKBP51 inhibitor, called SAFit2, which is now being tested in mice. Inhibition of FKBP51 could thus be a new therapeutic option to treat all of these conditions.”

Hausch said he became “intrigued” by the protein’s peculiar role in the body, especially its link to depression. So, together with his team, he set about trying to shut it down. Among others, the protein can limit glucose uptake in cells and the browning of fat, which, taken together, can make our bodies store adipose tissue instead of shedding it. It also has a part to play in regulating our stress responses, Hausch adds, so finding a way to block FKBP51 could help treat a variety of conditions.

But here’s the catch: FKBP51 is extremely similar in structure to FKBP52, even though they perform almost opposite roles in cells. It is exceedingly difficult, then, to develop a drug that interacts with only one of these proteins and not the other. To tackle this issue, the team used nuclear magnetic resonance techniques to look at the FKBP51 protein, and discovered a new binding site.

“We have this yin-yang situation,” Hausch says. “Selectivity between these two proteins is thought to be crucial, but this is hard to achieve since the two proteins are so similar. We discovered that FKBP51 can change its shape in a way that FKBP52 can’t, and this allowed the development of highly selective inhibitors.”

Based on their analysis, the team started developing SAFit2, a substance they say could work to inhibit the activity of FKBP51 — and only FKBP51. Animal testing revealed that SAFit2 can help mice “cope better in stressful situations”, Hausch reports. It reduced stress hormone levels, promoted more active stress coping, was synergistic with antidepressants, protected against weight gain, helped normalize glucose levels, and reduced pain in three animal models.

Besides SAFit2, the approach they developed could help other researchers identify similar “cryptic” binding sites in challenging drug targets in the future, Hausch says.

The findings so far are pretty exciting, the team explains, but much more work needs to be done before we have FKBP1 inhibitors that are safe to use in human tests. Until then, they are exploring the potential applications of such compounds in animals. They’re also interested in using such inhibitors to treat alcoholism and have already started digging into this idea, but the results are still too early to report on.

Hausch also says that certain types of glioblastoma tumors overexpress FKBP51. This suggests that FKBP51 inhibitors might be used to treat cancer in patients whose tumors mutate beyond what current medication can treat.

“We may be able to resensitize them to different types of chemotherapy using these specific inhibitors,” he says.

The findings have been presented at the American Chemical Society (ACS) Spring 2019 National Meeting & Exposition under the title “Selective FKBP51 inhibitors enabled by transient pocket binding.”

Credit: Pixabay.

Bedtime protein shakes might lead to more muscle gain than daytime protein without adding fat or harming sleep

Studies suggest that ingesting protein just before overnight sleep improves muscle gains in response to resistance training. However, does the timing of the protein intake really matter that much? Seems so, according to a new review of recent studies which found that overnight sleep is a unique nutritional window for boosting muscle gains.

Credit: Pixabay.

Credit: Pixabay.

The review was led by Dr. Tim Snijders, Assistant Professor at Maastricht University. In 2015, Snijders and colleagues performed their own investigation of muscle gain from nightly protein intake. Their study involved 44 healthy young men on a 12-week lifting program, half of whom were given a pre-sleep protein shake consisting of 30g of casein and 15 grams of carbs, while the other half received an energy-free drink. Both groups grew bigger quads and could lift more but the protein-before-bed group saw better gains in both muscle strength and size.

Snijders’ study begged the question: is the timing of the protein shake before bed important or is it all just about the higher intake of protein and calories? That is difficult to show directly because “a huge number of participants would be needed to prove whether a difference might exist in response to pre-sleep protein, versus protein intake at other times of the day,” explained Snijders.

However, this most recent review of relevant scientific literature suggests that there are numerous indirect indicators that pre-sleep protein is specifically important for muscle gain, with sleep playing a unique window of opportunity.

When muscles suffer trauma from resistance training, this disruption activates satellite cells located on the outside of muscle fibers to proliferate at the injury site. These cells perform the biological function of repairing or replacing damaged muscle fibers, often leading to an increase in muscle fiber cross-sectional area (hypertrophy). In order to sustain hypertrophy, muscle cells need amino acids from protein present in the blood. However, the body does not release amino acids at near-constant circulating levels. Rather, they fluctuate in peaks and valleys depending on the amount of ingested protein.

“A survey of over 500 athletes found they were typically consuming at total of more than 1.2g protein per kilo of bodyweight across three main meals, but only a paltry 7g of protein as an evening snack. As a result, lower levels of amino acids would be available for muscle growth during overnight sleep,” Snijders commented on the results of one of the studies included in his review.

Evidence suggests that pre-sleep protein intake allows muscles to absorb more amino acids at night — and this doesn’t mean that there will be less during the day.

“The muscle-building effects of protein supplementation at each meal seem to be additive. In one study we found that the consumption of ample amounts of protein (60g whey) before overnight sleep did not alter the muscle protein synthetic response to a high-protein breakfast the following morning,” Snijders said.

“What’s more, others have shown that adding a protein supplement at bedtime does not affect appetite the following morning – so it is unlikely to compromise total protein or calorie intake.”

Bedtime protein doesn’t seem to make you fat either. Surprisingly, it might have the opposite effect by speeding up metabolism. In one study, researchers compared an 8-week morning vs evening casein program and found no difference in fat mass between the two programs.

“Supporting this, another group found in 11 young active men that a pre-sleep casein shake actually increased the rate of fat burning the following day. This might be because casein ingestion reduces the insulin response to subsequent meals, which pushes your body to use more fat,” Snijders said.

The review also found that bedtime protein doesn’t interfere with sleep quality or drive onset latency.

“In conclusion, protein ingestion prior to sleep is an effective interventional strategy to increase muscle protein synthesis rates during overnight sleep and can be applied to support the skeletal muscle adaptive response to resistance-type exercise training,” the authors concluded.

The findings appeared in the journal Frontiers in Nutrition