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Leprosy’s drug resistance and origin revealed by genome analysis

Leprosy is an infectious disease with gruesome symptoms. It damages the skin, peripheral nerves, the upper respiratory tract, and the eyes. Despite being curable with multidrug therapy, leprosy still persists in many developing countries, with more than 200,000 new cases every year and increasing drug-resistant strains of the leprosy bacterium, Mycobacterium leprae, emerging.

To fight leprosy, scientists need to better understand the biology of M. leprae, and specifically how it interacts with its host and resists antibiotics. However, studying the bacterium is difficult, as it cannot be grown in a lab.

Now, an international team of scientists led by Stewart Cole’s lab at EPFL’s Global Health Institute have isolated, sequenced and analyzed the genomes of 154 strains of M. leprae from around the world. The study found several genes that are associated with resistance to antibiotics, including new genes that might point to previously unknown mechanisms of drug resistance.

“This is an important finding,” says Stewart Cole. “The way clofazimine, one of the main leprosy drugs, works is completely unknown but now we have a new lead to investigate thanks to this analysis of multidrug-resistant M. leprae.”

Isolating M. leprae DNA was a challenging task, as the amount of bacteria in skin biopsies is generally low and varies greatly between patients. And after extracting the DNA, the researchers had to separate the bacterial DNA from the patient’s. They did this with two techniques, one that increased the bacterium’s DNA and one that decreased the patient’s DNA. Once the bacterium’s DNA was isolated, the researchers were able to sequence it and compare it with that from other samples.

The scientists also found eight strains of M. leprae whose genomes harbored an incredibly large number of random mutations, accumulated over a period of a few years or perhaps decades. These eight strains are all resistant to multi-drug therapy, and were the only ones in the study in which a gene that is responsible for DNA repair is disrupted.

“It’s a fascinating survival strategy against antibiotics,” explains Andrej Benjak, the study’s leading author. “Disrupting DNA repair will result in a storm of random mutations, increasing the chance that the right gene mutates at the right spot and lead to drug resistance. But random mutations can be deadly, so it’s like a desperate, genetic Russian roulette for the bacterium.”

The researchers also discovered that leprosy itself might have originated in the Far East. Several bacterial strains from East Asia belonged to the ancestral lineages of the leprosy bacilli. “People naturally assume that old human diseases originated in Africa, but for leprosy, the evidence points to Eurasia,” says Charlotte Avanzi, one of the study’s authors from Cole’s lab.

Narrowing down the location of the origin will facilitate the reconstruction of the spread of the disease. “We need more samples from Central Asia and the Middle East, but these are hard to get due to current geopolitical issues,” says Avanzi. “For Europe, where leprosy is eradicated, we have to rely on ancient human remains. But it’s possible — we have developed the tools, and now we are ready to sequence even more samples.”

Journal Reference:

  1. Andrej Benjak, Charlotte Avanzi, Pushpendra Singh, Chloé Loiseau, Selfu Girma, Philippe Busso, Amanda N. Brum Fontes, Yuji Miyamoto, Masako Namisato, Kidist Bobosha, Claudio G. Salgado, Moisés B. da Silva, Raquel C. Bouth, Marco A. C. Frade, Fred Bernardes Filho, Josafá G. Barreto, José A. C. Nery, Samira Bührer-Sékula, Andréanne Lupien, Abdul R. Al-Samie, Yasin Al-Qubati, Abdul S. Alkubati, Gisela Bretzel, Lucio Vera-Cabrera, Fatoumata Sakho, Christian R. Johnson, Mamoudou Kodio, Abdoulaye Fomba, Samba O. Sow, Moussa Gado, Ousmane Konaté, Mariane M. A. Stefani, Gerson O. Penna, Philip N. Suffys, Euzenir Nunes Sarno, Milton O. Moraes, Patricia S. Rosa, Ida M. F. Dias Baptista, John S. Spencer, Abraham Aseffa, Masanori Matsuoka, Masanori Kai, Stewart T. Cole. Phylogenomics and antimicrobial resistance of the leprosy bacillus Mycobacterium lepraeNature Communications, 2018; 9 (1) DOI: 10.1038/s41467-017-02576-z

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Materials provided by Ecole Polytechnique Fédérale de LausanneNote: Content may be edited for style and length.

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Health

What Magnetic Fields Do to Your Brain and Body

(Credit: pippeeContributor/Shutterstock)

There’s no escaping magnetic fields—they’re all around us. For starters, the Earth itself is like a giant magnet. A spinning ball of liquid iron in our planet’s core generates the vast magnetic field that moves our compass needles around and directs the internal compasses of migrating birds, bats, and other animals. On top of that, ever-industrious humans have produced artificial magnetic fields with power lines, transport systems, electrical appliances, and medical equipment.

We may not be able to see, hear, feel, or taste the magnetic fields that surround us, but some may wonder whether they can still exert effects on our bodies and brains. This question becomes more pertinent, and the answers more tantalizing, as the strength of the magnetic field in question gets cranked up.

Everyday Exposure

A magnetic field arises whenever a charged particle, like an electron or proton, moves around. Since the electric currents running through blenders, hairdryers, and wires in the walls of our homes consist of flowing electrons, they all generate magnetic fields. Through these sources, the average person is exposed to magnetic fields reaching 0.1 microtesla in strength on a daily basis. By comparison, the Earth’s magnetic field, which we are always exposed to (as long as we remain on the planet’s surface), is about 500 times stronger. That means the magnetic force penetrating your body as you lounge around your home or spend a day at the office is decidedly insignificant.

From time to time, a scientific study finds a link between living near high-voltage power lines and illness. Heightened risk of childhood leukemia is the most commonly cited potential health consequence, but whether or not the risk is real has been hard to pin down. One glaring issue is that scientists have yet to figure out the mechanism by which such weak magnetic fields—which are still in the microtesla range for homes next to power lines—could adversely affect the human body. In 2010, the International Commission on Non-Ionizing Radiation Protection concluded that the evidence that living near power lines increases the risk of the deadly blood cancer “is too weak to form the basis for exposure guidelines.”

(Credit: VILevi/Shutterstock)

An MRI machine. (Credit: VILevi/Shutterstock)

What’s the Threshold?

Meanwhile, a team of scientists at the Utilities Threshold Initiative Consortium (UTIC) has been busy working to figure out the threshold at which the human body shows a physiological response to a magnetic field. According to Alexandre Legros, a medical biophysicist at the Lawson Health Research Institute and Western University in London, Ontario and a UTIC scientist, the smallest magnetic field that has reliably been shown to trigger a response in humans is around 10,000 to 20,000 microtesla. But crucially, to produce the effect, the field cannot be static like Earth’s magnetic field; rather, it must change directions over time. When these strong, direction-shifting magnetic fields get directed at a human, small electrical currents begin to pulse through the body. Above that threshold, the currents can stimulate super-sensitive cells in the retina, known as graded potential neurons, giving the illusion of a white light flickering even when the affected person is in darkness; these visual manifestations are known as magnetophosphenes.

The 10,000-microtesla threshold is well above the strength of any magnetic field encountered in everyday life. So in what situations might magnetophosphenes occur?

Medical Magnets

“There’s only one circumstance in which you may perceive magnetophosphenes,” says Legros: “If you’re in an MRI [magnetic resonance imaging] machine and moving your head fast.” An MRI scanner is essentially a big magnet that produces a powerful magnetic field of around 3 tesla (or 3 million microtesla) — millions of times larger than the fields we’re normally exposed to. But because it’s a static magnetic field, MRI scanners don’t exert any noticeable effect on the body. That would change, however, if the patient inside the scanner were to rapidly move his or her head back and forth. “Moving quickly induces a time-varying field, so by doing that you are inducing currents in different structures of your brain,” says Legros. Those currents may lead to nausea, loss of balance, a metallic taste in your mouth, or in some cases, magnetophosphenes.

On par with the magnetic field of an MRI is the one produced by a medical procedure known as transcranial magnetic stimulation (TMS). But unlike MRI, which makes detailed pictures of the inside of the body, the purpose of TMS is to stimulate the brain. That task requires an electric current, which is why TMS relies on a magnetic pulse rather than a static magnetic field. When this pulse is delivered via an electromagnetic coil placed against the scalp, the resulting current jolts a particular part of the brain with the aim of treating neurological diseases like depression.

Out-of-this-World Magnetic Fields

The magnetic fields associated with MRI and TMS are the strongest that a human might realistically be exposed to. Still, they are “hilariously puny” compared to those found beyond our planet, says Paul Sutter, an astrophysicist at Ohio State University and chief scientist at the COSI Science Center in Columbus, Ohio. At the extreme lies the aptly-named magnetar, which is a rare type of neutron star with a magnetic field one thousand trillion times stronger than Earth’s.

An artist's impression of a magnetar. (Credit: ESO/L. Calçada/Wikipedia (CC BY 4.0))

An artist’s impression of a magnetar. (Credit: ESO/L. Calçada/Wikipedia (CC BY 4.0))

If any human ever got close to a magnetar, they would quickly find themselves in dire straits. “Strong magnetic fields can start to do surprising things,” says Sutter. At the atomic level, the strong magnetic field would move all of the positive charges in your body in one direction and the negative charges the other way, he explains; spherical atoms would stretch out into ellipses and soon they would start to resemble thin pencils. That drastic change in shape would interfere with basic chemistry, causing the normal forces and interactions between atoms and molecules in the body to break down. “The first thing you would notice is your entire nervous system, which is based on electrical charges moving throughout your body, is going to stop working,” says Sutter. “And then you basically dissolve.”

Sutter guarantees that our local neighborhood — which he defines as a radius of a few hundred light-years around Earth — has been surveyed and certified magnetar-free. None of these exotic objects are approaching us, and none of the massive stars nearby are likely to turn into magnetars when they die. The nearest magnetar is a safe distance of tens of thousands of light-years away. So, at least for the time being, we can rest easy and take comfort in our planet’s own meager magnetic field.

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Health

The Aftermath of Michael Jackson’s Antigravity Lean

The infamous lean.

In Michael Jackson’s 1987 music video “Smooth Criminal,” the legendary performer leans forward 45 degrees from a straight-up position — and comes back. It’s a feat that seemingly defies both physics and physiology, and the move has become another element of MJ’s aura of mystery.

Some type of cinematic or mechanical trick must be responsible, since most people can manage only a 20-degree forward tilt before toppling headlong. Yet Jackson performed the move live on tours around the world for years.

Lean In

In a study published this week in the Journal of Neurosurgery, three scientists examine the so-called Antigravity Lean, not from a physics but from a physiological perspective. The three neurosurgeons, all at the Postgraduate Institute of Medical Education and Research in Chandigarh, India, combine in the article their knowledge of Jackson with data on spine biomechanics.

It’s been known for years how Jackson defied gravity. His shoes had a slot that slid onto a bolt in the floor, allowing him to perform the dramatic lean.

Bending forward is limited by the erector spinae muscles, which act like cables to support forward bends up to 20 degrees, though some dancers can achieve 30 degrees, the paper says. When near the max of a bend, you can feel the strain on the Achilles’ heel as the ankles become the fulcrum for balance. People soon return to vertical or catch themselves from falling headlong.

Though Jackson’s 45-degree bend is not physically possible without trickery, the King of Pop still needed incredible core strength and leg muscles to pull it off, the authors write. Not just anyone can lock their shoes into the floor and become Michael Jackson, it seems.

“Several MJ fans, including the authors, have tried to copy this move and failed, often injuring themselves in their endeavors,” the researchers write.

Figure A shows the Antigravity Tilt (a 45-degree forward bend) and the normal limit that most people can bend forward. Jackson used shoes with a slot that slid onto a bolt in the floor. Figure B shows the shift when the body’s fulcrum is the hip and when it’s the Achilles’ tendon. (Illustration courtesy of Manjul Tripathi)

Figure A shows the Antigravity Tilt (a 45-degree forward bend) and the normal limit that most people can bend forward. Jackson used shoes with a slot that slid onto a bolt in the floor. Figure B shows the shift when the body’s fulcrum is the hip and when it’s the Achilles’ tendon. (Illustration courtesy of Manjul Tripathi)

Tough Act to Follow

Jackson’s sleight of foot inspired generations of dancers who push the limits physically. This has resulted in spinal stresses not previously seen by neurosurgeons.

This is not to point the finger at Jackson. But it does suggest the reality that injuries can occur that might require implant spinal surgery, the article says, something potentially devastating to a dancer.

But it’s not all bad news — neurosurgeons have gained a lot of new information on how to treat spinal cord injuries in recent years, something that could be in part thanks to MJ’s envelope-pushing dance moves.

“The King of Pop has not only been an inspiration but a challenge to the medical fraternity,” Tripathi says.

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Health

Your Emergency Contact Does More Than You Think

(Credit: Shutterstock)

You know when you’re filling out your medical paperwork and it asks for your emergency contact? Sure, the process might be annoying, but that emergency contact could actually be put to good use by researchers.

Since many of us use a family member, those contacts can help scientists create family trees. And they can also be used for genetics and disease research, according to a study released Thursday in Cell. Discovering what diseases are inheritable can be a laborious and expensive process — patients must be recruited and researchers must clearly determine patients’ phenotypes (physical traits that include eye color, height, and overall health and are often influenced by your genes).

To make that process easier researchers from three major New York medical centers generated family trees from millions of electronic medical records to create a database.This is the first time electronic health records have been used to trace ancestry and it’s the largest study of heritability using such records.

The More You Know

The researchers identified 7.4 million relatives with an algorithm that matched names, addresses and phone numbers from three medical centers. They found 500 inheritable phenotypes in the data just by looking at test results and observations in health records. The traits included diseases affecting skin, blood and mental health.

The data can help determine the heritability level of many common diseases. For example, researchers found that having an increase of HDL (good) cholesterol is 50 percent heritable, while LDL (bad) cholesterol is only 25 percent heritable. The study’s findings were consistent across the participating medical centers and published studies.

Previous heritability research primarily documented Caucasians of northern European descent, according to the study’s first author Fernanda Polubriaginof, but this research is much broader.

“This dataset will allow us for the first time to compute whether there are differences in other races and ethnicities,” said Polubriaginof in a news release.

Future studies could look at medical records for the hereditary contribution of any trait. Due to privacy issues, patient identifiers were removed for the data, which can only be used for research at the moment. Though, with patient consent, emergency contacts could be put to important use in the future.

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