Science

Ignoring Proper Channels: The Fun Side of Fluoride

When Professor Chris Miller began his address to the less than capacity crowd in the Caspary Auditorium at Rockefeller University I couldn’t help noticing this felt underwhelming. This same auditorium has seen talks by countless Noble Laureates, at which times the room has suffered from such sever overcrowding that the lectures were halted until people were removed.

Now, an older gentleman looked out on the modest crowd with bright eyes and explained he would be talking about an ion channel (a designated avenue to move a specific element in or out of a cell) that allowed the passage of fluoride (a largely ignored element in biology) in bacteria, plants, protists, and simple invertebrates (all the types of life that have the least in common with human cells). This lecture had all the makings of an arcane and esoteric ramble in an uninteresting and unimportant field of biology.

But Dr. Miller is as much a showman as he is a world-renown scientist, and for the next forty-five minutes he proceeded to engage and enlighten the audience, proving why his lab has a tendency to produce legions of excellent researchers and teachers. Fluoride, Dr. Miller contends, has never gotten it’s time in the sun. Overshadowed by the heavier and more notorious chloride ion, fluoride is present everywhere in amounts as high as 100 micromolar (just under 1 part per million), and it is a known inhibitor of several essential cellular processes, namely metabolism and reproduction; or as Miller said, “it blocks food and sex.”

fluoride

Fluoride

Because of the chemistry of the cell, fluoride can enter a cell by permeating the membrane in the form of hydrogen-fluoride. Once it enters the cell, the hydrogen is stolen away and the potentially toxic fluoride is left to its own devices. Luckily, as Miller discovered, these cells have exhaust valves for fluoride – specific channels made of protein acting like pores to release the fluoride out of the cell. Channels allow passive movement (requiring no energy) where transporters are proteins that actively move ions (requiring energy). Dr. Miller’s channels, named FLUCs, (pronounced “flukes”) regulate the internal fluoride concentrations and effectively save the cells.

This in-and-of itself is a great finding; however Dr. Miller was taken by certain oddities about this channel. For the remainder of the lecture, Miller painted a beautiful picture of how this weird channel defied convention in numerous ways – it was incredibly specific; it works very fast; it has an “antiparallel” architecture, in which the two subunits are identical but the interact with each other when rotated 180 degrees; the ‘channel’ actually has four internal pores! Each of these findings is interesting to a hard-core physiologist or biophysicist. Dr. Miller managed to make each impressive to an even broader audience.

miller

Chris Miller PhD is a professor at Brandeis and has trained a generation of biologists.

In a talk peppered with nerdy jokes (“at least in Massachusetts, we do not violate electronegativity”) acknowledging the at-times cumbersome nomenclature (“it’s not voltage-dependent, not calcium-dependent, not N-A-P-O-D-whatever dependent” – NADPH is an import substrate that stands…for something) and even prone to editorial (“this channel just sits there like a moron with it’s mouth open!”) Miller managed to jam enough fundamental cell biology in to make even the surest biologist confident they were learning something. His delivery mimicked Lewis Black, from his intonation, to his hand waving, to his occasional excoriation of some unseen foe (“‘channel, transporter, same thing’ – NO THEY’RE NOT the same thing!”)

Having studied biophysics, to me Miller did the unthinkable – he made an hour-long lecture about an ion-channel incredibly fun and informative. His approach and mentality are key – I was fortunate to speak with him after the lecture and ask him some questions and he relished in the opportunity to further discuss FLUCs, fluoride, and anything even remotely related to his research. The enthusiasm he has is true and unfettered.

Perhaps most impressive is the fact that he is able to inspire so many graduate students, post-docs, fellows and researchers to continue in this field. Many are drawn to sexier and higher-paying research targeting cancer, or heart disease. As Miller put his work, “it is completely removed from the bothersome problem of human health. That way, I can enjoy the protein for itself!”

FLUC.jpg

The actual FLUC channel as represented with protein structure software (memprotein.org). The white/grey sphere is an oddly placed central sodium ion. Weird!

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Science

Eastern Promises – Tai Chi Rehab

The 500+-year-old martial art of Tai Chi, practiced for self-defense and self-preservation, and once considered for demonstration in the Olympics, may be a new therapy for the aging world population. A new study in the Annals of Internal Medicine describes how patients diagnosed with chronic knee pain and osteoarthritis enjoyed significant relief after a Tai Chi regiment. Patients randomized into either a Physical Therapy group or a Tai Chi group to combat their pain and arthritis both reported significant relief on scales of pain and discomfort.

Deniro

Robert De Niro, in a diverse group of Brooklyn natives, practices Tai Chi in the heartwarming 2015 comedy “The Intern”, saving his knees for further movies.

Both groups in this trial, totaling 200 individuals, reported pain relief. Interestingly, however, the individuals who practiced Tai Chi for 12 weeks reported much better scores for depression and mental well-being after 1 year. Tai Chi employs a number of mental objectives that may help arthritis-sufferers better cope with their pain and relax their bodies. The art of focusing thought and motion can combat many physical ailments, or so many cultures believe, but this was almost certainly one of the first controlled scientific studies documenting the real health benefits of Tai Chi. The “Taiji Philosophy” may offer individuals across the world relief from pain, both mental and physical. Further studies are certain to follow, but it can’t hurt to start!

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Science

Scientists 2/3 of Way to Making South Park’s Manbearpig

When South Park‘s parody of Al Gore warned the world of Manbearpig in 2006, show creators Trey Parker and Matt Stone probably didn’t imagine that within 10-years genetic engineers would actually be mixing porcine (pig) and human genomes. Despite a moratorium by the National Institutes of Health (NIH), through which the government agency essentially decided not to fund research on human-animal chimeric genome editing, a group from UC-Davis is moving forward introducing human stem cells into pig embryos. The BBC reported these experiments after gathering material for the program “Medicines Big Breakthrough: Editing Your Genes” for Panorama.

The UC-Davis team introduced stem cells from humans into the embryos of pigs. The goal of such experiments is to have the pigs develop human organs that could be implanted into humans without the transplant rejection often associated with animal organ donations, or “xenografts”.

The science team first genetically modified the pig embryo such that it would not develop a pancreas; then they injected human embryonic stem cells. Their hypothesis is that the human cells will be called upon to fill the void and begin to develop a functional and integrated pancreas. Sows were implanted with the chimeric pig embryos, and the team will let the embryos develop for 28 days, or almost 25% of a porcine pregnancy, by which time the pancreas should begin developing. The research team will then analyze the progression of embryonic pancreatic development.

The BBC’s own press release on Monday discusses in greater depth the science of these experiments, the great impact this could have on organ transplantation, the ethical treatment of lab animals for organ generation and harvesting, and the moral conundrums of beginning to make animals with human features. For now though,  the threat of Manbearpig is still distant.

manbearpig

South Park‘s fabled Manbearpig, as described by an earnest caricature of Al Gore in 2006, is the exaggerated but feared byproduct of human/animal chimeric research.

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Science

A Rose at Any Other Temperature…

Stop and smell the roses…while you still can. A study from Alon Cna’ani at the Hebrew University suggests that the rise in global temperature will take a toll on floral fragrance. In his work, published last year in Plant, Cell & Environment, Cna’ani’s group demonstrated that at different temperatures the production of scent in petunia flowers changes. Their work identified a gene important in the regulation of scent production; through genetic manipulation, Cna’ani was able to not only show that the gene could be re-engineered to make floral scent temperature-independent, but also that the same gene played a role in the expression of pigments in petals (as described in a separate paper in The New Phytologist). The genetic linkage between the scent and color traits may indicate an evolutionary advantage, allowing flowers to respond to their specific environment and climate.

petunia

The temperature change in the experiment (a mere 6 Celsius) was enough to notably decrease production of fragrance-creating enzymes. Thus, as global temperatures rise, fragrance may decline. While floral smells may seem the least pressing concern with imminent flooding, arctic restructuring, and weather destabilization, there is a delicate role fragrance plays in pollination, germination, and the spread of flora in ecosystems.

These studies, in which Cna’ani de-coupled the natural scent-temperature dependency through genetic engineering,  also open an interesting page of the discussion around GMOs. For generations, humans have bred plants extensively to preserve the traits most desirable. Being able to genetically modify flowers to be more fragrant is akin to genetically modifying apples to be sweeter, or rice to be more nutritious (both changes that, while well-received by consumers, many anti-GMOers balk at). At the moment, noone has objected to such manipulation of flowers; however, this is further evidence that cherry-picking traits genetically can be as simple as mutating a single gene.

 

 

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Science

Jogging Your Memory: Aerobic Exercise the Gold Standard for Brain Cells

Time to stop dust off the old running shoes – a 2016 study describes the specific benefits aerobic exercise, such as running, may have on stimulating growth of new brain cells! The study, published in the Journal of Physiology by a Finnish research group, reports that mice on certain exercise routines have more adult hippocampal cells, which are essential for learning, pattern separation, and other mental functions.

A growing body of research supports the idea that aerobic exercise can increase neurogenesis (the process of neuron growth). Studies from the last few years also indicate that this neurogenesis benefits not only the hippocampus, but also the hypothalamus, and other key zones of the brain.

This study compares traditional aerobic movements, like running, with alternative types of exercise in which many adult humans might participate. The researchers developed or adapted models of running, interval training, and weight training. In human physical training, each type of training has a specific purpose.

  • Aerobic exercise has traditionally benefited the heart, muscles, and metabolism and has been considered a whole-body exercise. It is also considered a long-term solution, being low impact and low stress when done in moderation.
  • Interval training, involving bouts of intense exercise with short breaks, increases blood-oxygen capacity,  improves athletic performance and may be linked with the production of certain protective factors released in the blood and the brain. It has absolutely revolutionized certain racing sports; Ultra Short Race Pace Training has caused a remarkable change in competitive swimming and the same principles have been applied to high-level running, rowing, and biking.
  • Finally, weight training is primarily recognized for increasing muscle mass, but animal studies suggest it may also increase spatial reasoning. The changes in strength are often viewed as in direct opposition to aerobic training and specifically running.

Rat Study groups

The caveat in all such exercise studies is that mild stress can be beneficial but prolonged, unpredictable, or excessive stress is almost always associated with degeneration, loss of neurogenesis and other systemic problems. It is the difference between a jogger and a marathon runner, a weight-lifter and a power-lifter, or a recreational athlete and a professional. All groups were compared to a ‘sedentary’ group of rats.

There is one morel eyebrow-raising fold in this study: they had two different groups of test subjects. Lab rats were bred for generations, pairing the animals which chose to run the most with each other, and separating the other animals who ran less. The researchers created one population who, genetically, liked running as well as another population who, genetically, typically chose not to run!

Rat Pairs

The study found, as expected, that rats who were predisposed to run had the most notable neurogenesis after running – the results were far less impressive for interval-training and sedentary groups.  The mice who didn’t like running had a dampened response, but the neurogenesis in the running group was still impressive (better in fact than of any other group, run-loving or otherwise).

There are several take-away messages of this paper. First, aerobic exercise is more effective for neurogenesis than interval training, and weight training has almost no benefit. Second, there are definitely sub-populations in any group who respond better to exercise of all types; however, the benefit to either group is significant. So like it or not, running still helps. Finally, the amount of running is correlated to the degree of neurogenesis – so run more get smarter? Maybe not exactly, but at least so far as it has been tested, running is directly linked to certain neurogenesis.

While this study only studied adult males, previous work indicates it is likely true in females, older and younger animals, and quite likely humans. Several human retrospective studies confirm that activity often leads to improved cognitive function.

So, if you needed that extra push to go running as the weather warms, here you go: you’ll get better at crosswords, wittier at work, and you’ll remember your bank passwords (results may varying). This study does not detract from the real, physical benefits of interval training and strength training, but it does highlight the powerful role aerobic exercise has in regulating and maintaining these amazing bodies we have. Now, if only running for office could increase a person’s brain cells this country might be in luck!

Read the NY Times opinion by Gretchen Reynolds here!

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Science

How Microbes Took Your Breath Away: The Bacterial Roots of Asthma

New research in the journal Science Translational Medicine this past September raises concerns over the causes of childhood asthma.  Of the over 300-million people worldwide suffering from asthma, an immune-mediated inflammatory disease in the airways, a majority live in the developed world. This fact, along with other population-based studies, indicates that environment plays a vital role in asthma development, and our sterile first-world conditions may work against us.

It is believed in this case that environmental factors may alter human microbiota (the bacteria that live within us, specifically in our guts).  In their paper, “Early infancy microbial and metabolic alterations affect
risk of childhood asthma”, the research group proposes that altering microbiota in a critical window of human infancy compromises our natural protection and results in a lifelong immune reactivity.  An individual’s microbiome (the whole cast of bacteria living within us) is heavily influcenced by who we interact with, where we live, and the world immediately around us.

These bacteria don’t play a direct role in immune modulation; however, they produce a variety of metabolites during early life which are transported through the blood stream and facilitate many functions in growth and development.  For example acetate, a metabolite which has already been linked to the onset of asthma in animals, was found to vary in abundance depending on the composition of the gut microbiome.  Changes in bacterial metabolite production may also be linked to the incidence of allergies and other immune-linked disorders.

The Canada based research group assembled a cohort of 319 human subjects through the Canadian Healthy Infant Longitudinal Development (CHILD). Subjects were examined at one year of age, and their fecal microbiome was assessed. A large group experienced dysbiosis, or a dramatic change in microbiota composition, often due to antibiotic use. Subjects experiencing dysbiosis often exhibited symptoms such as atopy (being hyperallergic) or wheezing. Not only were the symptoms at one year predictive of the asthmatic state by age 3, but also they indicated the level of dysbiosis. Further, the group determined this response was time-sensitive – they defined a “critical window” being within the first 100 days of life, during which dysbiosis had a far stronger influence on development of asthma or allergies later in life.

The group went on to confirm that the dysbiosis in this critical window was responsible for the asthmatic symptoms.  They found four species of bacteria dubbed FLVR (Faecalibacterium, Lachnospira, Veillonella, and Rothia) were implicated in protection against developing immune-mediated conditions. In animal models the group demonstrated that removing and reintroducing FLVR could exacerbate and ameliorate asthma symptoms respectively.  Reintroducing FLVR also decreased the amount of responsive immune cells found in the lungs.

The model laid forth - gut microbiota produce metabolites, and these metabolites change in situations of early infant dysbiosis, which can lead to the development of asthma and other conditions. (Adapted from Thakur et al. J Pharmacol Clin Toxicol 2013.

The model laid forth – gut microbiota produce metabolites, and these metabolites change in situations of early infant dysbiosis, which can lead to the development of asthma and other conditions. (Adapted from Thakur et al. J Pharmacol Clin Toxicol 2013.

So the take-away message is that within the first 100 days of life children are most sensitive to disruptions in their microbiota, as certain bacteria like FLVR are required to produce the metabolites needed for healthy immune system formation.  This critical window is when the immune system is developing and the human body is trying to determine good from bad, and the metabolites produced in the gut play key roles in allowing your body to get it right.  Undergoing exposure to antibiotics and antibacterials, like many children in the Western world might, could induce dysbiosis, compromise their immune development, and predispose infants for diseases like asthma.

Clinically these findings inform doctors to be mindful of the importance of these first 100 days, and presents an opportunity for clinical and therapeutic intervention to maintain levels of FLVR and thus hopefully reduce the occurrence of asthma later in life.  Probiotic treatment of infants at this stage of development could drastically reduce the number children who contract asthma, making this finding potentially the biggest breakthrough in asthma research in years.

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