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Genomic Study Points to Natural Origin of COVID-19

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COVID-19 Update

No matter where you go online these days, there’s bound to be discussion of coronavirus disease 2019 (COVID-19). Some folks are even making outrageous claims that the new coronavirus causing the pandemic was engineered in a lab and deliberately released to make people sick. A new study debunks such claims by providing scientific evidence that this novel coronavirus arose naturally.

The reassuring findings are the result of genomic analyses conducted by an international research team, partly supported by NIH. In their study in the journal Nature Medicine, Kristian Andersen, Scripps Research Institute, La Jolla, CA; Robert Garry, Tulane University School of Medicine, New Orleans; and their colleagues used sophisticated bioinformatic tools to compare publicly available genomic data from several coronaviruses, including the new one that causes COVID-19.

The researchers began by homing in on the parts of the coronavirus genomes that encode the spike proteins that give this family of viruses their distinctive crown-like appearance. (By the way, “corona” is Latin for “crown.”) All coronaviruses rely on spike proteins to infect other cells. But, over time, each coronavirus has fashioned these proteins a little differently, and the evolutionary clues about these modifications are spelled out in their genomes.

The genomic data of the new coronavirus responsible for COVID-19 show that its spike protein contains some unique adaptations. One of these adaptations provides special ability of this coronavirus to bind to a specific protein on human cells called angiotensin converting enzyme (ACE2). A related coronavirus that causes severe acute respiratory syndrome (SARS) in humans also seeks out ACE2.

Existing computer models predicted that the new coronavirus would not bind to ACE2 as well as the SARS virus. However, to their surprise, the researchers found that the spike protein of the new coronavirus actually bound far better than computer predictions, likely because of natural selection on ACE2 that enabled the virus to take advantage of a previously unidentified alternate binding site. Researchers said this provides strong evidence that that new virus was not the product of purposeful manipulation in a lab. In fact, any bioengineer trying to design a coronavirus that threatened human health probably would never have chosen this particular conformation for a spike protein.

The researchers went on to analyze genomic data related to the overall molecular structure, or backbone, of the new coronavirus. Their analysis showed that the backbone of the new coronavirus’s genome most closely resembles that of a bat coronavirus discovered after the COVID-19 pandemic began. However, the region that binds ACE2 resembles a novel virus found in pangolins, a strange-looking animal sometimes called a scaly anteater. This provides additional evidence that the coronavirus that causes COVID-19 almost certainly originated in nature. If the new coronavirus had been manufactured in a lab, scientists most likely would have used the backbones of coronaviruses already known to cause serious diseases in humans.

So, what is the natural origin of the novel coronavirus responsible for the COVID-19 pandemic? The researchers don’t yet have a precise answer. But they do offer two possible scenarios.

In the first scenario, as the new coronavirus evolved in its natural hosts, possibly bats or pangolins, its spike proteins mutated to bind to molecules similar in structure to the human ACE2 protein, thereby enabling it to infect human cells. This scenario seems to fit other recent outbreaks of coronavirus-caused disease in humans, such as SARS, which arose from cat-like civets; and Middle East respiratory syndrome (MERS), which arose from camels.

The second scenario is that the new coronavirus crossed from animals into humans before it became capable of causing human disease. Then, as a result of gradual evolutionary changes over years or perhaps decades, the virus eventually gained the ability to spread from human-to-human and cause serious, often life-threatening disease.

Either way, this study leaves little room to refute a natural origin for COVID-19. And that’s a good thing because it helps us keep focused on what really matters: observing good hygiene, practicing social distancing, and supporting the efforts of all the dedicated health-care professionals and researchers who are working so hard to address this major public health challenge.

Finally, next time you come across something about COVID-19 online that disturbs or puzzles you, I suggest going to FEMA’s new Coronavirus Rumor Control web site. It may not have all the answers to your questions, but it’s definitely a step in the right direction in helping to distinguish rumors from facts.

Reference:
[1] The proximal origin of SARS-CoV-2. Andersen KG, Rambaut A, Lipkin WI, Holmes EC, Garry RF. Nat Med, 17 March 2020. [Epub ahead of publication]

Links:

Coronavirus (COVID-19) (NIH)

COVID-19, MERS & SARS (National Institute of Allergy and Infectious Diseases/NIH)

Andersen Lab (Scripps Research Institute, La Jolla, CA)

Robert Garry (Tulane University School of Medicine, New Orleans)

Coronavirus Rumor Control (FEMA)

NIH Support: National Institute of Allergy and Infectious Diseases; National Human Genome Research Institute


Tackling Fibrosis with Synthetic Materials

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April Kloxin
April Kloxin/Credit: Evan Krape, University of Delaware, Newark

When injury strikes a limb or an organ, our bodies usually heal quickly and correctly. But for some people, the healing process doesn’t shut down properly, leading to excess fibrous tissue, scarring, and potentially life-threatening organ damage.

This permanent scarring, known as fibrosis, can occur in almost every tissue of the body, including the heart and lungs. With support from a 2019 NIH Director’s New Innovator Award, April Kloxin is applying her expertise in materials science and bioengineering to build sophisticated fibrosis-in-a-dish models for unraveling this complex process in her lab at the University of Delaware, Newark.

Though Kloxin is interested in all forms of fibrosis, she’s focusing first on the incurable and often-fatal lung condition called idiopathic pulmonary fibrosis (IPF). This condition, characterized by largely unexplained thickening and stiffening of lung tissue, is diagnosed in about 50,000 people each year in the United States.

IPF remains poorly understood, in part because it often is diagnosed when the disease is already well advanced. Kloxin hopes to turn back the clock and start to understand the disease at an earlier stage, when interventions might be more successful. The key is to develop a model that better recapitulates the complexity and irreversibility of the disease process in people.

Building that better model starts with simulating the meshwork of collagen and other proteins in the extracellular matrix (ECM) that undergird every tissue and organ in the body. The ECM’s interactions with our cells are essential in wound healing and, when things go wrong, also in causing fibrosis.

Kloxin will build three-dimensional hydrogels, crosslinked sponge-like networks of polymers, peptides, and proteins, with structures that more accurately capture the biological complexities of human tissues, including the ECMs within fibrous collagen-rich microenvironments. Her synthetic matrices can be triggered with light to lock in place and stiffen. The matrices also will make it possible to culture the lung’s epithelium, or outermost layer of cells, and connective tissue that surrounds it, to study cellular responses as the model shifts from a healthy and flexible to a stiffened, disease-like state.

Kloxin and her team will also integrate into their model system lung cells that have been engineered to fluoresce or light up under a microscope when the wound-healing program activates. Such fluorescent reporters will allow her team to watch for the first time how different cells and their nearby microenvironment respond as the composition of the ECM changes and stiffens. With this system, she’ll also be able to search for small molecules with the ability to turn off excessive wound healing.

The hope is that what’s learned with her New Innovator Award will lead to fresh insights and ultimately new treatments for this mysterious, hard-to-treat condition. But the benefits could be even more wide-ranging. Kloxin thinks that her findings will have implications for the prevention and treatment of other fibrotic diseases as well.

Links:

Idiopathic Pulmonary Fibrosis (National Heart, Lung, and Blood Institute/NIH)

April Kloxin Group (University of Delaware, Newark)

Kloxin Project Information (NIH RePORTER)

NIH Director’s New Innovator Award (Common Fund)

NIH Support: Common Fund; National Heart, Lung, and Blood Institute


Giving Thanks for Biomedical Research

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This Thanksgiving, Americans have an abundance of reasons to be grateful—loving family and good food often come to mind. Here’s one more to add to the list: exciting progress in biomedical research. To check out some of that progress, I encourage you to watch this short video, produced by NIH’s National Institute of Biomedical Imaging and Engineering (NIBIB), that showcases a few cool gadgets and devices now under development.

Among the technological innovations is a wearable ultrasound patch for monitoring blood pressure [1]. The patch was developed by a research team led by Sheng Xu and Chonghe Wang, University of California San Diego, La Jolla. When this small patch is worn on the neck, it measures blood pressure in the central arteries and veins by emitting continuous ultrasound waves.

Other great technologies featured in the video include:

Laser-Powered Glucose Meter. Peter So and Jeon Woong Kang, researchers at Massachusetts Institute of Technology (MIT), Cambridge, and their collaborators at MIT and University of Missouri, Columbia have developed a laser-powered device that measures glucose through the skin [2]. They report that this device potentially could provide accurate, continuous glucose monitoring for people with diabetes without the painful finger pricks.

15-Second Breast Scanner. Lihong Wang, a researcher at California Institute of Technology, Pasadena, and colleagues have combined laser light and sound waves to create a rapid, noninvasive, painless breast scan. It can be performed while a woman rests comfortably on a table without the radiation or compression of a standard mammogram [3].

White Blood Cell Counter. Carlos Castro-Gonzalez, then a postdoc at Massachusetts Institute of Technology, Cambridge, and colleagues developed a portable, non-invasive home monitor to count white blood cells as they pass through capillaries inside a finger [4]. The test, which takes about 1 minute, can be carried out at home, and will help those undergoing chemotherapy to determine whether their white cell count has dropped too low for the next dose, avoiding risk for treatment-compromising infections.

Neural-Enabled Prosthetic Hand (NEPH). Ranu Jung, a researcher at Florida International University, Miami, and colleagues have developed a prosthetic hand that restores a sense of touch, grip, and finger control for amputees [5]. NEPH is a fully implantable, wirelessly controlled system that directly stimulates nerves. More than two years ago, the FDA approved a first-in-human trial of the NEPH system.

If you want to check out more taxpayer-supported innovations, take a look at NIBIB’s two previous videos from 2013 and 2018 As always, let me offer thanks to you from the NIH family—and from all Americans who care about the future of their health—for your continued support. Happy Thanksgiving!

References:

[1] Monitoring of the central blood pressure waveform via a conformal ultrasonic device. Wang C, Li X, Hu H, Zhang, L, Huang Z, Lin M, Zhang Z, Yun Z, Huang B, Gong H, Bhaskaran S, Gu Y, Makihata M, Guo Y, Lei Y, Chen Y, Wang C, Li Y, Zhang T, Chen Z, Pisano AP, Zhang L, Zhou Q, Xu S. Nature Biomedical Engineering. September 2018, 687-695.

[2] Evaluation of accuracy dependence of Raman spectroscopic models on the ratio of calibration and validation points for non-invasive glucose sensing. Singh SP, Mukherjee S, Galindo LH, So PTC, Dasari RR, Khan UZ, Kannan R, Upendran A, Kang JW. Anal Bioanal Chem. 2018 Oct;410(25):6469-6475.

[3] Single-breath-hold photoacoustic computed tomography of the breast. Lin L, Hu P, Shi J, Appleton CM, Maslov K, Li L, Zhang R, Wang LV. Nat Commun. 2018 Jun 15;9(1):2352.

[4] Non-invasive detection of severe neutropenia in chemotherapy patients by optical imaging of nailfold microcirculation. Bourquard A, Pablo-Trinidad A, Butterworth I, Sánchez-Ferro Á, Cerrato C, Humala K, Fabra Urdiola M, Del Rio C, Valles B, Tucker-Schwartz JM, Lee ES, Vakoc BJ9, Padera TP, Ledesma-Carbayo MJ, Chen YB, Hochberg EP, Gray ML, Castro-González C. Sci Rep. 2018 Mar 28;8(1):5301.

[5] Enhancing Sensorimotor Integration Using a Neural Enabled Prosthetic Hand System

Links:

Sheng Xu Lab (University of California San Diego, La Jolla)

So Lab (Massachusetts Institute of Technology, Cambridge)

Lihong Wang (California Institute of Technology, Pasadena)

Video: Lihong Wang: Better Cancer Screenings

Carlos Castro-Gonzalez (Madrid-MIT M + Visión Consortium, Cambridge, MA)

Video: Carlos Castro-Gonzalez (YouTube)

Ranu Jung (Florida International University, Miami)

Video: New Prosthetic System Restores Sense of Touch (Florida International)

NIH Support: National Institute of Biomedical Imaging and Bioengineering; National Institute of Neurological Diseases and Stroke; National Heart, Lung, and Blood Institute; National Cancer Institute; Common Fund


Body-on-a-Chip Device Predicts Cancer Drug Responses

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Body-on-a-Chip
Credit: McAleer et al., Science Translational Medicine, 2019

Researchers continue to produce impressive miniature human tissues that resemble the structure of a range of human organs, including the livers, kidneys, hearts, and even the brain. In fact, some researchers are now building on this success to take the next big technological step: placing key components of several miniature organs on a chip at once.

These body-on-a-chip (BOC) devices place each tissue type in its own pea-sized chamber and connect them via fluid-filled microchannels into living, integrated biological systems on a laboratory plate. In the photo above, the BOC chip is filled with green fluid to make it easier to see the various chambers. For example, this easy-to-reconfigure system can make it possible to culture liver cells (chamber 1) along with two cancer cell lines (chambers 3, 5) and cardiac function chips (chambers 2, 4).

Researchers circulate blood-mimicking fluid through the chip, along with chemotherapy drugs. This allows them to test the agents’ potential to fight human cancer cells, while simultaneously gathering evidence for potential adverse effects on tissues placed in the other chambers.

This BOC comes from a team of NIH-supported researchers, including James Hickman and Christopher McAleer, Hesperos Inc., Orlando, FL. The two were challenged by their Swiss colleagues at Roche Pharmaceuticals to create a leukemia-on-a-chip model. The challenge was to see whether it was possible to reproduce on the chip the known effects and toxicities of diclofenac and imatinib in people.

As published in Science Translational Medicine, they more than met the challenge. The researchers showed as expected that imatinib did not harm liver cells [1]. But, when treated with diclofenac, liver cells on the chip were reduced in number by about 30 percent, an observation consistent with the drug’s known liver toxicity profile.

As a second and more challenging test, the researchers reconfigured the BOC by placing a multi-drug resistant vulva cancer cell line in one chamber and, in another, a breast cancer cell line that responded to drug treatment. To explore side effects, the system also incorporated a chamber with human liver cells and two others containing beating human heart cells, along with devices to measure the cells’ electrical and mechanical activity separately.

These studies showed that tamoxifen, commonly used to treat breast cancer, indeed killed a significant number of the breast cancer cells on the BOC. But, it only did so after liver cells on the chip processed the tamoxifen to produce its more active metabolite!

Meanwhile, tamoxifen alone didn’t affect the drug-resistant vulva cancer cells on the chip, whether or not liver cells were present. This type of cancer cell has previously been shown to pump the drug out through a specific channel. Studies on the chip showed that this form of drug resistance could be overcome by adding a second drug called verapamil, which blocks the channel.

Both tamoxifen alone and the combination treatment showed some off-target effects on heart cells. While the heart cells survived the treatment, they contracted more slowly and with less force. The encouraging news was that the heart cells bounced back from the tamoxifen-only treatment within three days. But when the drug-drug combination was tested, the cardiac cells did not recover their function during the same time period.

What makes advances like this especially important is that only 1 in 10 drug candidates entering human clinical trials ultimately receives approval from the Food and Drug Administration (FDA) [2]. Often, drug candidates fail because they prove toxic to the human brain, liver, kidneys, or other organs in ways that preclinical studies in animals didn’t predict.

As BOCs are put to work in testing new drug candidates and especially treatment combinations, the hope is that we can do a better job of predicting early on which chemical compounds will prove safe and effective in humans. For those drug candidates that are ultimately doomed, “failing early” is key to reducing drug development costs. By culturing an individual patient’s cells in the chambers, BOCs also may be used to help doctors select the best treatment option for that particular patient. The ultimate goal is to accelerate the translation of basic discoveries into clinical breakthroughs. For more information about tissue chips, take a look at NIH’s Tissue Chip for Drug Screening program.

References:

[1] Multi-organ system for the evaluation of efficacy and off-target toxicity of anticancer therapeutics. McAleer CW, Long CJ, Elbrecht D, Sasserath T, Bridges LR, Rumsey JW, Martin C, Schnepper M, Wang Y, Schuler F, Roth AB, Funk C, Shuler ML, Hickman JJ. Sci Transl Med. 2019 Jun 19;11(497).

[2] Clinical development success rates for investigational drugs. Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J. Nat Biotechnol. 2014 Jan;32(1):40-51.

Links:

Tissue Chip for Drug Screening (National Center for Advancing Translational Sciences/NIH)

James Hickman (Hesperos, Inc., Orlando, FL)

Hesperos, Inc.

NIH Support: National Center for Advancing Translational Sciences


Teaming Magnetic Bacteria with Nanoparticles for Better Drug Delivery

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Nanoparticles hold great promise for delivering next-generation therapeutics, including those based on CRISPR gene editing tools. The challenge is how to guide these tiny particles through the bloodstream and into the right target tissues. Now, scientists are enlisting some surprising partners in this quest: magnetic bacteria!

First a bit of background. Discovered in the 1960s during studies of bog sediments, “magnetotactic” bacteria contain magnetic, iron-rich particles that enable them to orient themselves to the Earth’s magnetic fields. To explore the potential of these microbes for targeted delivery of nanoparticles, the NIH-funded researchers devised the ingenious system you see in this fluorescence microscopy video. This system features a model blood vessel filled with a liquid that contains both fluorescently-tagged nanoparticles (red) and large swarms of a type of magnetic bacteria called Magnetospirillum magneticum (not visible).

At the touch of a button that rotates external magnetic fields, researchers can wirelessly control the direction in which the bacteria move through the liquid—up, down, left, right, and even “freestyle.” And—get this—the flow created by the synchronized swimming of all these bacteria pushes along any nearby nanoparticles in the same direction, even without any physical contact between the two. In fact, the researchers have found that this bacteria-guided system delivers nanoparticles into target model tissues three times faster than a similar system lacking such bacteria.

How did anyone ever dream this up? Most previous attempts to get nanoparticle-based therapies into diseased tissues have relied on simple diffusion or molecular targeting methods. Because those approaches are not always ideal, NIH-funded researchers Sangeeta Bhatia, Massachusetts Institute of Technology, Cambridge, MA, and Simone Schürle, formerly of MIT and now ETH Zurich, asked themselves: Could magnetic forces be used to propel nanoparticles through the bloodstream?

As a graduate student at ETH Zurich, Schürle had worked to develop and study tiny magnetic robots, each about the size of a cell. Those microbots, called artificial bacterial flagella (ABF), were designed to replicate the movements of bacteria, relying on miniature flagellum-like propellers to move them along in corkscrew-like fashion.

In a study published recently in Science Advances, the researchers found that the miniature robots worked as hoped in tests within a model blood vessel [1]. Using magnets to propel a single microbot, the researchers found that 200-nanometer-sized polystyrene balls penetrated twice as far into a model tissue as they did without the aid of the magnet-driven forces.

At the same time, others in the Bhatia lab were developing bacteria that could be used to deliver cancer-fighting drugs. Schürle and Bhatia wished they could direct those microbial swarms using magnets as they could with the microbots. That’s when they learned about the potential of M. magneticum and developed the experimental system demonstrated in the video above.

The researchers’ next step will be to test their magnetic approach to drug delivery in a mouse model. Ultimately, they think their innovative strategy holds promise for delivering nanoparticles carrying a wide range of therapeutic payloads right to a tumor, infection, or other diseased tissue. It’s yet another example of how basic research combined with outside-the-box thinking can lead to surprisingly creative solutions with real potential to improve human health.

References:

[1] Synthetic and living micropropellers for convection-enhanced nanoparticle transport. Schürle S, Soleimany AP, Yeh T, Anand GM, Häberli M, Fleming HE, Mirkhani N, Qiu F, Hauert S, Wang X, Nelson BJ, Bhatia SN. Sci Adv. 2019 Apr 26;5(4):eaav4803.

Links:

VIDEO: Synthetic and Living Micropropellers Stir Up Nanoparticles for Enhanced Drug Transport Powered by Magnetism

Nanotechnology (NIH)

What are genome editing and CRISPR-Cas9? (National Library of Medicine/NIH)

Sangeeta Bhatia (Massachusetts Institute of Technology, Cambridge, MA)

Simone Schürle-Finke (ETH Zurich, Switzerland)

NIH Support: National Cancer Institute; National Institute of General Medical Sciences


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