Virus World

Scientific American is the essential guide to the most awe-inspiring advances in science and technology, explaining how they change our understanding of the world and shape our lives. Tara Ghormley has always been an overachiever. She finished at the top of her class in high school, graduated summa cum laude from college and earned top honors in veterinary school. She went on to complete a rigorous training program and build a successful career as a veterinary internal medicine specialist. But in March 2020 she got infected with the SARS-CoV-2 virus—just the 24th case in the small, coastal central California town she lived in at the time, near the site of an early outbreak in the COVID pandemic. “I could have done without being first at this,” she says. Almost three years after apparently clearing the virus from her body, Ghormley is still suffering. She gets exhausted quickly, her heartbeat suddenly races, and she goes through periods where she can't concentrate or think clearly. Ghormley and her husband, who have relocated to a Los Angeles suburb, once spent their free time visiting their “happiest place on Earth”—Disneyland—but her health prevented that for more than a year. She still spends most of her days off resting in the dark or going to her many doctors' appointments. Her early infection and ongoing symptoms make her one of the first people in the country with “long COVID,” a condition where symptoms persist for at least three months after the infection and can last for years. The syndrome is known by medical professionals as postacute sequelae of COVID-19, or PASC.

People with long COVID have symptoms such as pain, extreme fatigue and “brain fog,” or difficulty concentrating or remembering things. As of February 2022, the syndrome was estimated to affect about 16 million adults in the U.S. and had forced between two million and four million Americans out of the workforce, many of whom have yet to return. Long COVID often arises in otherwise healthy young people, and it can follow even a mild initial infection. The risk appears at least slightly higher in people who were hospitalized for COVID and in older adults (who end up in the hospital more often). Women and those at socioeconomic disadvantage also face higher risk, as do people who smoke, are obese, or have any of an array of health conditions, particularly autoimmune disease. Vaccination appears to reduce the danger but does not entirely prevent long COVID. The most common, persistent and disabling symptoms of long COVID are neurological. Some are easily recognized as brain- or nerve-related: many people experience cognitive dysfunction in the form of difficulty with memory, attention, sleep and mood. Others may seem rooted more in the body than the brain, such as pain and postexertional malaise (PEM), a kind of “energy crash” that people experience after even mild exercise. But those, too, result from nerve dysfunction, often in the autonomic nervous system, which directs our bodies to breathe and digest food and generally runs our organs on autopilot. This so-called dysautonomia can lead to dizziness, a racing heart, high or low blood pressure, and gut disturbances, sometimes leaving people unable to work or even function independently....

Scientific American is the essential guide to the most awe-inspiring advances in science and technology, explaining how they change our understanding of the world and shape our lives. Since the novel coronavirus began its global spread, influenza cases reported to the World Health Organization have dropped to minuscule levels. The reason, epidemiologists think, is that the public health measures taken to keep the coronavirus from spreading also stop the flu. Influenza viruses are transmitted in much the same way as SARS-CoV-2, but they are less effective at jumping from host to host. As Scientific American reported last fall, the drop-off in flu numbers was both swift and universal. Since then, cases have stayed remarkably low. “There’s just no flu circulating,” says Greg Poland, who has studied the disease at the Mayo Clinic for decades. The U.S. saw about 600 deaths from influenza during the 2020-2021 flu season. In comparison, the Centers for Disease Control and Prevention estimated there were roughly 22,000 deaths in the prior season and 34,000 two seasons ago.

Because each year’s flu vaccine is based on strains that have been circulating during the past year, it is unclear how next year’s vaccine will fare, should the typical patterns of the disease return. The WHO made its flu strain recommendations for vaccines in late February as usual, but they were based on far fewer cases than in a common year. At the same time, with fewer virus particles circulating in the world, there is less chance of an upcoming mutation, so it is possible the 2021–2022 vaccine will prove extra effective. Public health experts are grateful for the reprieve. Some are also worried about a lost immune response, however. If influenza subsides for several years, today’s toddlers could miss a chance to have an early-age response imprinted on their immune system. That could be good or bad, depending on what strains circulate during the rest of their life. For now, future flu transmission remains a roll of the dice....

Thirty-six years ago, we were, like today, in the midst of a new and still somewhat mysterious global pandemic. In the U.S. alone, more than one million people were infected with HIV, and 12,000 had already died of AIDS. At the time, we were just beginning to understand how the virus worked. But that didn’t stop some leaders from making wildly optimistic claims about an AIDS vaccine being delivered within two years. Now, with COVID-19, we are in a remarkably similar spot: 2.7 million people have been infected across the U.S., and 128,000 have died of the disease. Despite our limited understanding of how the novel coronavirus works and what it does to the human body, many are putting what I consider a disproportionate amount of faith in the possibility of a COVID-19 vaccine by 2021. My feelings today echo my feelings a third of a century ago: yes, a vaccine may be possible, but it is by no means a certainty.

Every deadly virus tells a story. As each chapter unfolds, we learn more about the possibility of developing a vaccine. The poliovirus, for example, told us early on that a vaccine would be possible. When that virus enters the body, it responds by making antibodies that can clear the pathogen entirely. It’s a hit-and-run: The virus hits you hard, then runs away for good. Once you have the antibodies, it can’t cause you harm again. With HIV, the virus told us the road to a vaccine would be long and challenging. As the outbreak unfolded, we began tracking antibody levels and T cell counts of those infected. The high levels of both showed that patients were mounting incredibly active immune responses, more forceful than anything we’d seen for any other disease. But even working at its highest capacity, the body’s immune system was never strong enough to clear the virus. Unlike a hit-and-run such as polio, HIV was a “catch it and keep it” virus—once you were infected, the pathogen stayed in your body until it destroyed your immune system and you died. While that situation didn’t mean a vaccine would be impossible, it certainly meant developing one wouldn’t be easy.

SARS-CoV-2 has echoes of both HIV and polio. We know from nearly 60 years of observing coronaviruses that a body’s immune system can clear the virus. But a coronavirus is a tricky thing. The virus distorts the immune system so that even after you clear it, the pathogen can reenter your system and cause illness again. It is not a hit-and-run or a catch and keep but a “get it and forget it” virus that is able to infect the same person multiple times....

David Veesler and their colleagues, showed a consequence of this dramatic transformation: only one of eight antibody treatments for COVID used in hospitals—which are based on natural antibodies—still bound effectively to RBDs. Other research has shown that mutations on RBDs and a second site called the N-terminal domain enable the virus to avoid antibodies gained by vaccination or infection. Thanks to Omicron’s convincing disguise, the variant had little to slow it down, and it spread with lightning-fast speed. Vaccines, however, still warded off serious illness, especially with booster shots.  It stabilized. When Omicron drastically altered its spike to hide from the immune system, those changes eliminated some chemical residues the spike needed to attach to ACE2. But other mutations compensated: RBDs formed new chemical bridges to still effectively bind to the protein, according to another study in Science. “It clearly lost some residues important for binding, but it made them up with other interactions,” says Subramaniam, who was the senior author of the paper. The spike protein also became sturdier. In other variants, two subunits within the spike, S1 and S2, are loosely connected. This allows them to split apart quickly so the spike can bury itself in a human cell when the virus encounters one. The downside of this delicate arrangement, however, is that many spikes split prematurely, before getting close to a cell. Once asunder, the spikes can no longer help the virus attach.

Mutations in Omicron led to slim molecular bridges that hold the subunits together better, according to several studies. One was published in the Journal of Medical Virology, and the others were released as preprint papers that have not yet been formally reviewed by other scientists. “This virus has really protected itself from prematurely triggering,” says Shan-Lu Liu, author of one of the papers and director of the Viruses and Emerging Pathogens program at the Ohio State University. “When the virus is in the right place at the right time, it can be triggered and get into the cell, but not prior to that.”  It slipped in the side door. Across previous variants, there was one constant: the virus relies on a protein on the surface of human cells called TMPRSS2 (pronounced “tempress two”) to help it break through the cell membrane. But Omicron did not use TMPRSS2. It took a wholly different route into the cell. Instead of breaking down the front door, it slipped in through the side. While other variants require both the ACE2 and TMPRSS2 proteins to inject their genome into a cell, Omicron bound only to ACE2. Then it was engulfed in a hollow bubble called an endosome. The bubble drifted into the cell, where the virus broke out and began a takeover.....

Scientific American is the essential guide to the most awe-inspiring advances in science and technology, explaining how they change our understanding of the world and shape our lives. While the world waits for a COVID-19 vaccine, many researchers are focused on developing effective therapeutics that can be rolled out quickly and cheaply. Monoclonal antibodies—a potentially promising laboratory-manufactured therapy modeled on antibodies extracted from the blood of recovering patients—made headlines recently when President Trump received a not-yet-approved antibody cocktail made by the company Regeneron. And pharmaceutical giant Eli Lilly recently announced that its monoclonal antibody reduced the risk of hospitalization in 300 people who had mild or moderate symptoms of COVID-19, in a small clinical trial. But David Baker, a biochemist at the University of Washington’s Institute for Protein Design, and his colleagues think they can produce an even better therapy. They have designed a synthetic peptide—a short string of amino acids, the building blocks of proteins—20 times smaller than a monoclonal antibody that is designed to bind to the infamous “spike” protein on the surface of the SARS-CoV-2 virus particle. Doing so would directly block the virus from binding to the ACE-2 receptors on human cells, functioning much like an antibody produced by an infected person’s immune system. Baker and his colleagues described these “miniprotein inhibitors” in September in Science. Although the study only tested these synthetic proteins in the lab, mixing viral particles with monkey cells in vitro, he says that unpublished data show they can protect mice and hamsters from SARS-CoV-2 infection. 

“We built these [tiny proteins] from scratch based on ‘first principles,’ using computers to model all the biochemical details of a theoretical protein that could stick to the virus,” explains Baker, who was awarded a $3 million Breakthrough Prize earlier in September for his decades of work pioneering the field of synthetic protein design. His team used computers to digitally design more than two million candidate “miniproteins,” crunched the data using algorithms, sifted out 118,000 candidate genes that encode these proteins, manufactured the proteins from scratch, and tested them directly against the virus in the lab—finding that seven designs could effectively bind to and thus disable the virus. Over the course of 3.5 billion years evolution has produced an incredible array of proteins and peptides. In recent years biochemists have tracked down and used some of these to create new drugs, such as Eptifibatide, an antiplatelet drug administered to prevent heart attacks whose active ingredient is extracted from the venom of the southern pygmy rattlesnake. The Protein Data Bank, an online repository of protein sequences and educational tools, contains the amino acid sequences and full 3-D structures for more than 160,000 peptides and proteins—but the natural world contains hundreds of millions of proteins. 

“It’s very challenging to discover in nature a peptide that does exactly what you want it to do,” explains Gaurav Bhardwaj, also a biochemist at the Institute for Protein Design, but who was not involved in the Science study. He is trying to design a bespoke peptide that would prevent SARS-CoV-2 from replicating within human cells. “Now we can computationally explore the possible design configurations for a peptide in order to perform the exact functions that we want.” Every protein’s function depends on its structure. Interactions between the atoms of the protein’s amino acids cause these chains to self-assemble in less than a second into a complex array of spirals and pleats. As the chain of amino acids grows, these helices and rippled sheets stack on top of and around one another into a dizzyingly complex series of folds, and it is these folds that give proteins their shape and function. Yet figuring out how one amino acid sequence turns into a specific fold has been a torturously difficult task, and it was only in the 1990s—with ever expanding databases of protein information—that scientists could begin to link sequence to form. “We can make up completely new proteins that have never been seen in nature because we now understand the nature of protein folding,” Baker says. “Our ability to use computers to design ‘de novo’ proteins has really only come into its own in the last few years–we might not have been able to apply ourselves to COVID-19 if the pandemic had happened five years ago....