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UC San Diego Health Sciences

Tag: Research

— Research

Seeing is Understanding

For the first few months of the pandemic, SARS-CoV-2 was called simply “the novel coronavirus.” “Novel,” meaning scientists hadn’t seen it before

For the first few months of the pandemic, SARS-CoV-2 was called simply “the novel coronavirus,” “novel,” meaning scientists hadn’t seen it before. And yet the ability to see — really see, at the atomic level — what a microbe looks like and how it interacts with human cells is crucial in helping researchers design better methods to prevent or disrupt those interactions.

Rommie E. Amaro, PhD, professor in the UC San Diego Department of Chemistry & Biochemistry, and collaborators, were among the first to get a close look. They created models of the virus and its interactions with human cells, based on structural data generated from cryo-electron tomography and cryo-electron microscopy — leading-edge techniques that allow researchers to glimpse molecular structures at unprecedented resolution — and a combination of computer modeling and molecular dynamics simulations.

The models revealed a trove of information. For example, SARS-CoV-2’s infamous spike protein, protrusions that help it grab hold of human cells, is coated in sugar molecules known as glycans. These glycans change the spike protein’s shape — important information for researchers trying to target it with new drugs, or drum up antibodies against it with vaccines.

A

THE VIRUS. The spike proteins protruding from the virus’ spherical lipid bilayer are shown in gray, with glycans highlighted in dark blue.

B

The spike protein. This is the SARS-CoV-2’s spike protein in its open state. The spike protein is shown in cyan and the sugars forming a so-called “glycan shield” are depicted in dark blue. The spike is embedded in the viral membrane, shown at the bottom as multicolored carpeting.

C

The infection. SARS-CoV-2 (top) latches onto the ACE-2 receptor (yellow), a molecule on the surface of human cells that the virus uses like a doorknob to gain entry and establish infection.

A. THE VIRUS
Image credit: Lorenzo Casalino
Modeling credit: Abigail C. Dommer, Lorenzo Casalino
Zied Gaieb, Rommie E. Amaro

B. THE SPIKE PROTEIN
Image credit: Lorenzo Casalino
Modeling credit: Lorenzo Casalino, Zied Gaieb, Rommie E. Amaro

C. THE INFECTION
Image credit: Lorenzo Casalino
Modeling credit: Lorenzo Casalino, Abigail C. Dommer Zied Gaieb, Emilia P. Barros, Rommie E. Amaro

— Research

Seeing is Understanding

For the first few months of the pandemic, SARS-CoV-2 was called simply “the novel coronavirus.” “Novel,” meaning scientists hadn’t seen it before

— By Scott LaFee with David Pride, MD

Q&A

  • Question

    In the beginning of the pandemic, there was much concern and angst regarding COVID-19 testing in terms of accuracy of results, capacity and timing. You were deeply involved in developing and advancing testing throughout the pandemic. How would you describe that experience, the highs and lows?

    Answer:It was very difficult for clinical laboratories like ours early in the pandemic. We are accustomed to evaluating tests much more deeply than we were able to do before we started offering some of the tests we did earlier in the pandemic. It was also very problematic not to be able to give physicians definitive answers when they asked about the sensitivity and specificity of our tests. They simply hadn’t been studied well enough for us to have those answers. It was also quite problematic for laboratories like ours to have so many different tests simultaneously that all checked for the same virus. In general, we evaluate all the available tests and choose the one that works best or that best suits our institutional needs. Because there was such a limited supply of testing available, we often had to choose tests, even before we were able to evaluate how well they worked. This was, in essence, a lab director’s worst nightmare. In retrospect, we are relieved that most of the tests we chose work really well, and most importantly, are still available on the market because of their superior performances.

  • Question

    There is talk of an almost instantaneous breath test for COVID-19. Do you think that might happen, maybe before the next pandemic?

    Answer:It will be difficult for a COVID-19 breath test to rival the sensitivity/specificity that we have with our assays based on quantitative PCR. We find for many of the more rapid antigen assays the sensitivity would likely be too low to have a performance that would give us confidence in telling people they are not infected.

  • Question

    One observation you’ve made is that, even if a person isn’t infected by SARS-CoV-2, they are not virus-free. Quite the contrary: Bacteria residing in and on each of us outnumber human cells, and viruses outnumber bacteria — we each carry an estimated 380 trillion viruses. Your point is that most of these viruses are not dangerous, but simply part of the human virome. What is a virome and what’s currently known about it?

    Answer:Regardless of whether we are healthy or sick, we’ve all got viromes, which essentially are just collections of viruses that inhabit the human body. Many of these viruses infect the many bacteria that also live in the human body, and thus, we probably need to think about ourselves slightly differently than we probably do. That is, that we are collections of microbes that vastly outnumber our own cells, and that our bodies are fertile hunting grounds for viruses to attack their bacterial hosts. All of this goes on pretty much every second of every day, and we have very little insight into the fact that this is happening. We know that most, if not all human body surfaces, are inhabited by viruses. This competition for space and resources in the human body probably plays a role in our homeostasis, but this hasn’t been borne out so well by studies yet. We know that these viruses can change the bacterial communities and that these viruses can be readily shared with our close contacts. We believe that, because our bacterial microbiomes can be involved in helping determine healthy and disease phenotypes among us, the fact that viruses can attack these bacteria suggests that they may be involved in this process as well.

  • Question

    You’ve said the development of COVID-19 vaccines, and the underlying research, was the top scientific breakthrough of 2020. Why?

    Answer:Simply put, science doesn’t typically move at the speed that was observed earlier in the COVID-19 pandemic. Not only were vaccines developed in record time using existing technologies, but they were also tested in thousands of people to ensure they were safe and effective prior to being rolled out to millions across the world. This will go down as one of the top scientific breakthroughs, perhaps of all time, and we have to thank the scientists who developed the vaccines, the people who were willing to participate in these clinical trials without having foreknowledge of the potential beneficial or deleterious outcomes, and the regulatory agencies that worked closely with scientists to make all this happen. I don’t think the average person realizes how much everyone involved had to set aside their own personal biases, difficult working relationships, and even political disagreements to work together to do the most beneficial thing that they could to benefit the health of everyone.

  • Question

    Like many of your colleagues, you have cautioned about the dangers of antibiotic resistance, which you say is here to stay. But you also argue that there is much that can be done to mitigate antibiotic resistant bacteria, a public health challenge that the World Health Organization predicts might kill 10 million people annually by 2050. Antibiotics don’t work against viruses, which have different structures and methods of replication compared to bacteria. Apart from developing vaccines to prevent viral infections or reduce transmission, what is the remedy?

    Answer:Unfortunately, bacteria respond to what we do to them by developing resistance to antibiotics. It’s remarkable how bacteria will develop resistance specifically to antibiotics that are used in a particular hospital, but not some of those antibiotics that are used in other hospital systems. This reveals a key feature of bacteria: that they continually evolve to solve the problems that they are faced with, such as antibiotics. It is interesting to see that this is exactly what we are observing in the current virus pandemic. We responded by rapidly developing vaccines that had the potential to significantly reduce, if not eradicate, SARS-CoV-2. Instead of simply going away, the virus has evolved specific means to respond to what we have done. The virus has chosen to infect largely those who are unvaccinated and has even mutated to become clever enough to infect some who are vaccinated. This persistence despite our best efforts is real-time proof that this virus will continue to try to respond to what we do to eliminate it. It also strongly suggests that we must all get on the same page and have a coordinated response if we expect to eliminate it. If we do anything less, SARS-CoV-2 has proven that it will seek out refuge, mutate, and then potentially come roaring back

— Research

Seeing is Understanding

For the first few months of the pandemic, SARS-CoV-2 was called simply “the novel coronavirus.” “Novel,” meaning scientists hadn’t seen it before

— By Heather Buschman, PhD

A molecule known as ACE2 sits like a doorknob on the outer surfaces of cells that line the lungs’ passageways. Since early 2020, researchers have known that SARS-CoV-2 primarily uses the ACE2 doorknob to enter these cells and establish a COVID-19 respiratory infection. Finding a way to lock out that interaction as a means to treat infection has become the goal of many research studies.

To speed up the search, many researchers have turned to testing repurposed drugs — medicines already known to be safe for human use because they are FDA-approved for other conditions.

Before it became infamous for its role in COVID-19 infections, ACE2 was known to regulate blood pressure. And since prescription statins — widely used cholesterol-lowering drugs — can affect ACE2, UC San Diego Health researchers analyzed the electronic medical records of 170 statin-taking patients with COVID-19 to see what effect the medications had on virus vulnerability.

They found that statin use prior to hospital admission for COVID-19 was associated with a more than 50 percent reduction in risk of developing severe COVID-19, compared to those with COVID-19 but who were not taking statins. Patients with COVID-19 who were taking statins prior to hospitalization also recovered faster. The study, led by Lori Daniels, MD, professor and director of the Cardiovascular Intensive Care Unit at UC San Diego Health, and Karen Messer, PhD, professor and chief of the Division of Biostatics and Bioinformatics, was published in the American Journal of Cardiology.

Another UC San Diego School of Medicine team discovered that SARS-CoV-2 can’t grab onto ACE2 without a carbohydrate called heparan sulfate, also found on lung cell surfaces, where it acts as a co-receptor for viral entry. “ACE2 is only part of the story,” said Jeffrey Esko, PhD, Distinguished Professor of Cellular and Molecular Medicine at UC San Diego School of Medicine and co-director of the Glycobiology Research and Training Center. “It isn’t the whole picture.”

“It isn’t the whole picture.”

— Jeffrey Esko, PhD

Esko’s team discovered that heparin — an FDA-approved form of heparan sulfate widely used to prevent and treat blood clots — reduces the ability of SARS-CoV-2 to infect human cells cultured in the lab by up to 90 percent. Essentially, the heparin acts as bait to lure and bind the coronavirus, keeping it away from human cells. The study was published in Cell.

Elsewhere, UC San Diego physician-scientists like Constance Benson, MD, professor of medicine, and Dan Sweeney, MD, helped conduct clinical trials of remdesivir, an antiviral originally designed to treat Ebola and Marburg infections, and the first repurposed drug approved by the FDA for treating COVID-19. It was found to shorten hospital stays and recovery time.

Not every repurposed drug is a success story. Atul Malhotra, MD, research chief of pulmonary, critical care and sleep medicine at UC San Diego Health, led a Phase III clinical trial investigating whether tocilizumab, a monoclonal antibody treatment for arthritis and other inflammatory diseases, might significantly improve the outcomes of patients with severe COVID-19 pneumonia.

It did not, Malhotra and colleagues reported in The New England Journal of Medicine, though they did observe a modest decrease in length of hospital stays and days on mechanical ventilators. Even when repurposed drugs do not achieve hoped-for results, Malhotra said, lessons are learned, which can guide new studies and help focus attention where it is most effective.

— Research

Seeing is Understanding

For the first few months of the pandemic, SARS-CoV-2 was called simply “the novel coronavirus.” “Novel,” meaning scientists hadn’t seen it before

— By Scott LaFee

Some of the resistance to wearing masks during the pandemic was fueled by the notion that the nose-and-mouth coverings impaired breathing, and thus cardiopulmonary function, especially during physical activity.

But a November 16, 2020 study published in the Annals of the American Thoracic Society by UC San Diego School of Medicine researchers, with colleagues in Canada and Washington state, found that while masks might feel uncomfortable, perhaps making one’s face hot and sweaty, there was virtually no empirical evidence that they significantly impaired lung function, even during heavy exercise.

“It isn’t the whole picture.”

— Jeffrey Esko, PhD

“There might be a perceived greater effort with activity, but the effects of wearing a mask on the work of breathing, on gases like oxygen and CO2 in blood or other physiological parameters are small, often too small to be detected,” said first author Susan Hopkins, MD, PhD, professor of medicine and radiology.

Hopkins and co-authors reviewed all known scientific literature on the topic, including analyses of inhaled and exhaled gases, blood oxygen levels, effects on muscle blood flow, cardiac function and blood flow to the brain. There were no detectable physiological differences based on gender or age. The only exception were persons with severe cardiopulmonary disease in which even the smallest resistance to breathing might prompt dyspnea, the medical term for shortness of breath.

70% Reduced risk of SARS-CoV-2 infection when wearing a mask during high-risk exposures compared to not wearing a mask.