Now, Medical University of Vienna professor Leopold Eckhart and colleagues have performed one of the largest comparative genomic studies to help determine the key molecular and evolutionary origins of mammalian adaptations seen in skin proteins.

In a new study appearing recently in the advanced online edition of the journal Molecular Biology and Evolution, Eckhart’s team homed in on which genes, among the dozens of mammalian keratin genes, are required for living on land or in the sea. The products of these keratin genes assemble to form the girders of the cytoskeleton in skin cells, called keratinocytes, that maintain a tight barrier between the body and the outside world.

“The results of the present study provide important new data on the evolution of keratins that control the mechanical stability of the epidermis, the outermost layer of the skin,” said Eckhart.

In terrestrial mammals, the epidermis depends on different keratins to maintain the barrier to the environment and to regenerate the epidermis if the skin is wounded. The new report proposes that fully aquatic mammals continuously use the epidermal regeneration program and therefore require only one of the two sets of epidermal keratins.

“It is surprising that the main proteins of the outermost skin layers of terrestrial mammals, including humans, are dispensable in aquatic mammals, such as dolphins, whales, and manatees,” said Eckhart. “And it is remarkable that a stress response program was the starting point of an evolutionary innovation: the new architecture of the epidermis in aquatic mammals.”

The epidermis of dolphins is approximately 50 times thicker than normal human epidermis. Keratins K1, K2, and K10 have been lost and replaced by keratins K6 and K17 in dolphins.

Both the thickening of the epidermis and the key roles of K6 and K17 are also found in human skin wound healing and in lesional skin of patients with psoriasis. In this common skin disease, so-far-unknown genetic factors predispose skin cells to trigger the evolutionarily ancient wound healing program of the epidermis.

“At this point evolutionary biology meets dermatological research, and we hope that this type of ‘translational research’ will yield further insights for the benefit of patients in the future,” said Eckhart.

The research team at the Medical University of Vienna also discovered previously underestimated complexity in the epidermal keratin composition due to so-called “alternative splicing” keratin K10 mRNA and adaptations of keratin gene sets in terrestrial mammals. However, an entire remodeling of the keratin cytoskeleton has occurred only in fully aquatic mammals.

“Our data point to a general pattern of skin evolution: proteins of innermost skin layers are the most conserved, and proteins of the outermost layers are the most diverse,” said Eckhart. “The interactions between keratins and other epidermal proteins need further studies. With progress in comparative genomics and new lines of experimental research, the evolution of the skin will remain an exciting and fruitful research topic.”

The newly discovered ability of the human protein RBBP6 to interfere with Ebola virus replication suggests new ways to fight the infection. As viruses develop and evolve proteins to bypass the body’s immune defenses, human cells in turn develop defense mechanisms against those viruses — an evolutionary arms race that has been ongoing for millions of years. This particular defense mechanism has therapeutic potential, said co-lead author Judd Hultquist, assistant professor of medicine in the division of infectious disease at Northwestern University Feinberg School of Medicine.

“One of the scariest parts about the 2014 Ebola outbreak was that we had no treatments on hand; tens of thousands of people became sick and thousands of people died because we lacked a suitable treatment,” Hultquist said. “What we envision is a small molecule drug that mimics this human protein and could be used in response to an Ebola virus outbreak.”

A small molecule drug is the ultimate goal because these are able to enter cells more easily and, therefore, be more effective.

The study will be published Dec. 13 in the journal Cell. The research was a close collaboration between Hultquist’s lab at Feinberg and labs at Georgia State University and the University of California, San Francisco.

The Ebola virus, like other viruses, invades host cells and uses them to replicate, usurping cellular processes to build viral proteins, which eventually become new copies of the virus. In the current study, Hultquist and his collaborators used mass spectrometry — a technique that identifies specific elements in a sample by mass — to search for interactions between human proteins and Ebola virus proteins. They found strong evidence for an interaction between the Ebola virus protein VP30 and the human protein RBBP6.

Further structural and computational analysis narrowed the interaction down to a small, 23-amino acid-long peptide chain. This small group of amino acids alone is sufficient to disrupt the Ebola virus life cycle, Hultquist said.

“If you take that peptide and put it into human cells, you can block Ebola virus infection,” Hultquist said. “Conversely, when you remove the RBBP6 protein from human cells, Ebola virus replicates much faster.”

Emerging diseases will impact new regions as the world continues to become more interconnected and globalized, Hultquist said. In addition, the looming specter of climate change promises to broaden the reach of vector-borne diseases — by expanding the range of mosquitos, for example — requiring new strategies in curbing disease outbreaks.

Until recently, many diseases in the developing world, including Ebola virus, have been comparatively understudied, Hultquist said.

“It wasn’t until the outbreak of 2014 that other countries started seriously worrying about the potential for a larger epidemic,” Hultquist said. “It’s no longer going to be a local problem that people can afford to ignore. We should be taking a much more proactive stance against some of these neglected viruses and be studying them in real time — so the next time an outbreak does occur, we’re ready for it.”

This work was supported by National Institutes of Health grants P50GM082250, U19AI106754, R01AI120694, P01AI063302, U19AI109664, U19AI109945, P01120943 and R01AI114814.

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The InSight lander, its heat shield and parachute were spotted by HiRISE (which stands for High Resolution Imaging Science Experiment) in one set of images last week on Dec. 6, and again on Tuesday, Dec. 11. The lander, heat shield and parachute are within 1,000 feet (several hundred meters) of one another on Elysium Planitia, the flat lava plain selected as InSight’s landing location.

This isn’t the first time HiRISE has photographed a Mars lander. InSight is based largely on 2008’s Phoenix spacecraft, which the camera aboard MRO captured on the surface of Mars as well as descending on its parachute. While the HiRISE team at the University of Arizona also tried to take an image of InSight during landing, MRO was at a much less opportune angle and wasn’t able to take a good picture.

About InSight

JPL manages InSight for NASA’s Science Mission Directorate. InSight is part of NASA’s Discovery Program, managed by the agency’s Marshall Space Flight Center in Huntsville, Alabama. Lockheed Martin Space in Denver built the InSight spacecraft, including its cruise stage and lander, and supports spacecraft operations for the mission.

A number of European partners, including France’s Centre National d’Études Spatiales (CNES) and the German Aerospace Center (DLR), are supporting the InSight mission. CNES and the Institut de Physique du Globe de Paris (IPGP) provided the Seismic Experiment for Interior Structure (SEIS) instrument, with significant contributions from the Max Planck Institute for Solar System Research (MPS) in Germany, the Swiss Institute of Technology (ETH) in Switzerland, Imperial College and Oxford University in the United Kingdom, and JPL. DLR provided the Heat Flow and Physical Properties Package (HP³) instrument, with significant contributions from the Space Research Center (CBK) of the Polish Academy of Sciences and Astronika in Poland. Spain’s Centro de Astrobiología (CAB) supplied the wind sensors.

The University of Arizona, Tucson, operates HiRISE, which was built by Ball Aerospace & Technologies Corp., Boulder, Colorado. NASA’s Jet Propulsion Laboratory, a division of Caltech in Pasadena, California, manages the Mars Reconnaissance Orbiter Project for NASA’s Science Mission Directorate, Washington.

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Until now, it wasn’t clear what molecular trigger was pulled to allow this structural remodeling in times of stress. But researchers at the University of Illinois and the University of Pennsylvania have discovered the protein responsible in the roundworm C. elegans.

“We’re using a really simple animal system to understand basic biological questions that have implications not only for nematodes, including important crop parasites, but also for higher animals, including humans,” says Nathan Schroeder, assistant professor in the Department of Crop Sciences at U of I, and author of the new study published in Genetics.

When C. elegans larvae are stressed, they stop eating, their development halts, and they enter a stress-resistant stage known as dauer. In this form, their bodies become distinctly thinner and longer and develop an outer cuticle with ridges from tip to tail.

Schroeder and his team were investigating a protein called DEX-1 for an unrelated project when they noticed worms without the protein were “dumpy” in the dauer phase: they remained relatively short and round. Intrigued, the researchers decided to characterize the protein and its function in seam cells, the cells responsible for dauer remodeling.

“When we disrupted the DEX-1 protein, the seam cells did not remodel during dauer,” Schroeder says. “Seam cells have stem cell-like properties. We usually think about stem cells as controlling cell division, but we found that these cells are actually regulating their own shape through this protein, and that has an impact on overall body shape in response to stress.”

DEX-1 is an example of an extracellular matrix protein, a type that is extruded to form the mortar between cells. These proteins exist in every multicellular organism, not only keeping cells together but also facilitating interaction between cells. Not always in a good way; it turns out many extracellular matrix proteins, including a DEX-1 analogue, are associated with human diseases, such as metastatic breast cancer.

Schroeder says his group is interested in looking more closely at metastasis in cancers due to these proteins, but as a nematologist, he gets more excited about the prospect of understanding the basic biology and genetics of nematodes themselves, particularly parasitic species that affect crops.

“For many parasitic nematodes, when they’re ready to enter the infective stage, they have a similar process. Many of the genes regulating the decision to go into or come out of that infective stage also regulate the decision to enter dauer,” he says. “This research gives us insight into their biology and how they make these developmental decisions.”

The article, “Epidermal remodeling in Caenorhabditis elegans dauers requires the nidogen domain protein DEX-1,” is published in Genetics. Authors include Kristen Flatt, Caroline Beshers, Cagla Unal, Jennifer Cohen, Meera Sundaram, and Nathan Schroeder. The research was supported by the National Institutes of Health.