In this illustration of immune defense, Y-shaped proteins called antibodies attack a virus.
When we get sick, our immune system sends its soldier cells to the battlefield. Called B-cells, they "examine" the foreign particles that shouldn't be in our bloodstream—and start producing the antibodies, the proteins to neutralize the invaders.
To screen the antibodies, scientists have developed a proprietary way to make the effective ones glow – like a literal "lightbulb" moment.
The better these antibodies are at neutralizing the pathogen, the faster we recover.
The antibodies acquired from COVID-19 survivors already showed promise in treating other patients, but because they must be obtained from people, generating a regular supply is not feasible. To close the gap, researchers are trying to identify the B-cells that make the best antibodies—and then farm them in laboratories at scale.
Scientists at Berkley Lights, a biotechnology company in California, have been screening B-cells from recovered patients and testing the antibodies they release for virus-neutralizing abilities. To screen the antibodies, scientists there have developed a proprietary way to make the effective ones glow – like a literal "lightbulb" moment.
So how does it work? First, the individual B-cells are placed into microscopic chambers called nano-pens, where they secrete the antibodies. Once released, the antibodies are flushed over tiny beads that have bits of the viral particles attached to them, along with special molecules that can emit fluorescent light.
"When an antibody binds to the bead, we see a bright light on the bead," explains John Proctor, the company's senior vice president of antibody therapeutics. "So we can identify which cells are making the antibodies."
Then the antibodies are tested for their ability to counteract the coronavirus's spike proteins, which the virus uses to break into our cells. Not all antibodies are equally good at this crucial defense move—some can block only parts of the virus's machinery, while others can neutralize it completely. Proctor and his colleagues are looking for the latter.
Once scientists identify the best performing B-cells, they crack the cells open—or in scientific terms "lyse" them—and extract the genetic instructions for making the antibodies. As it turns out, B-cells aren't very efficient at pumping out massive amounts of antibodies, so scientists insert these genetic instructions into a different, more prolific type of cell.
Named Chinese Hamster Ovary Cells or CHO, these cells are commonly used in the pharmaceutical industry because they can generate therapeutic proteins en masse. Under the right nutrient conditions, which include a lot of sugar, CHO cells can keep making the antibodies at commercial levels. "They are engineered to operate in very large bioreactors," Proctor explains.
While traditional antibody screening can take three months, the Beacon System can do it in less than 24 hours.
Berkeley Lights' technology has already been used to screen the antibodies of recovered patients from Vanderbilt University Medical Center. In another example, a biotech company GenScript ProBio used the platform to screen mice engineered to have human antibodies for the coronavirus.
In addition to its small, lab-on-a-chip size, Berkeley Lights' system allows scientists to greatly speed up the screening process. While traditional antibody screening can take three months, the Beacon System can do it in less than 24 hours. "We only need one B-cell per pen and a couple of beads to see that fluorescent signal," Proctor says. "It is a more advanced way to process and analyze cells, and that level of sensitivity is unique to our technology."
B-cells secreting antibodies inside the Berkeley Lights Beacon System Nano-Pens.
While vaccines are likely to take months to develop and test, antibodies might arrive to the battleground sooner. With the extremely limited treatment options for COVID-19, antibody-based therapeutics can potentially bridge this gap.
This Jarvik-7 artificial heart was used in the first bridge operation in 1985 meant to replace a failing heart while the patient waited for a donor organ.
What might surprise you is that the origin of the artificial heart dates back decades before, when an inventive television actor teamed up with a famous doctor to design and patent the first such device.
A man of many talents
Paul Winchell was an entertainer in the 1950s and 60s, rising to fame as a ventriloquist and guest-starring as an actor on programs like "The Ed Sullivan Show" and "Perry Mason." When children's animation boomed in the 1960s, Winchell made a name for himself as a voice actor on shows like "The Smurfs," "Winnie the Pooh," and "The Jetsons." He eventually became famous for originating the voices of Tigger from "Winnie the Pooh" and Gargamel from "The Smurfs," among many others.
But Winchell wasn't just an entertainer: He also had a quiet passion for science and medicine. Between television gigs, Winchell busied himself working as a medical hypnotist and acupuncturist, treating the same Hollywood stars he performed alongside. When he wasn't doing that, Winchell threw himself into engineering and design, building not only the ventriloquism dummies he used on his television appearances but a host of products he'd dreamed up himself. Winchell spent hours tinkering with his own inventions, such as a set of battery-powered gloves and something called a "flameless lighter." Over the course of his life, Winchell designed and patented more than 30 of these products – mostly novelties, but also serious medical devices, such as a portable blood plasma defroster.
| Ventriloquist Paul Winchell with Jerry Mahoney, his dummy, in 1951 |
A meeting of the minds
In the early 1950s, Winchell appeared on a variety show called the "Arthur Murray Dance Party" and faced off in a dance competition with the legendary Ricardo Montalban (Winchell won). At a cast party for the show later that same night, Winchell met Dr. Henry Heimlich – the same doctor who would later become famous for inventing the Heimlich maneuver, who was married to Murray's daughter. The two hit it off immediately, bonding over their shared interest in medicine. Before long, Heimlich invited Winchell to come observe him in the operating room at the hospital where he worked. Winchell jumped at the opportunity, and not long after he became a frequent guest in Heimlich's surgical theatre, fascinated by the mechanics of the human body.
One day while Winchell was observing at the hospital, he witnessed a patient die on the operating table after undergoing open-heart surgery. He was suddenly struck with an idea: If there was some way doctors could keep blood pumping temporarily throughout the body during surgery, patients who underwent risky operations like open-heart surgery might have a better chance of survival. Winchell rushed to Heimlich with the idea – and Heimlich agreed to advise Winchell and look over any design drafts he came up with. So Winchell went to work.
Winchell's heart
As it turned out, building ventriloquism dummies wasn't that different from building an artificial heart, Winchell noted later in his autobiography – the shifting valves and chambers of the mechanical heart were similar to the moving eyes and opening mouths of his puppets. After each design, Winchell would go back to Heimlich and the two would confer, making adjustments along the way to.
By 1956, Winchell had perfected his design: The "heart" consisted of a bag that could be placed inside the human body, connected to a battery-powered motor outside of the body. The motor enabled the bag to pump blood throughout the body, similar to a real human heart. Winchell received a patent for the design in 1963.
At the time, Winchell never quite got the credit he deserved. Years later, researchers at the University of Utah, working on their own artificial heart, came across Winchell's patent and got in touch with Winchell to compare notes. Winchell ended up donating his patent to the team, which included Dr. Richard Jarvik. Jarvik expanded on Winchell's design and created the Jarvik-7 – the world's first artificial heart to be successfully implanted in a human being in 1982.
The Jarvik-7 has since been replaced with newer, more efficient models made up of different synthetic materials, allowing patients to live for longer stretches without the heart clogging or breaking down. With each new generation of hearts, heart failure patients have been able to live relatively normal lives for longer periods of time and with fewer complications than before – and it never would have been possible without the unsung genius of a puppeteer and his love of science.
She figured the pain would go away. But instead, it intensified that night. Kamil's husband drove her to the Cedars-Sinai hospital, where she was admitted to the coronary care unit. It turned out she wasn't having a heart attack after all. Instead, she was diagnosed with a much less common but nonetheless dangerous heart condition called takotsubo syndrome, or broken heart syndrome.
A heart attack happens when blood flow to the heart is obstructed—such as when an artery is blocked—causing heart muscle tissue to die. In takotsubo syndrome, the blood flow isn't blocked, but the heart doesn't pump it properly. The heart changes its shape and starts to resemble a Japanese fishing device called tako-tsubo, a clay pot with a wider body and narrower mouth, used to catch octopus.
"The heart muscle is stunned and doesn't function properly anywhere from three days to three weeks," explains Noel Bairey Merz, the cardiologist at Cedar Sinai who Kamil went to see after she was discharged.
"The heart muscle is stunned and doesn't function properly anywhere from three days to three weeks."
But even though the heart isn't permanently damaged, mortality rates due to takotsubo syndrome are comparable to those of a heart attack, Merz notes—about 4-5% of patients die from the attack, and 20% within the next five years. "It's as bad as a heart attack," Merz says—only it's much less known, even to doctors. The condition affects only about 1% of people, and there are around 15,000 new cases annually. It's diagnosed using a cardiac ventriculogram, an imaging test that allows doctors to see how the heart pumps blood.
Scientists don't fully understand what causes Takotsubo syndrome, but it usually occurs after extreme emotional or physical stress. Doctors think it's triggered by a so-called catecholamine storm, a phenomenon in which the body releases too much catecholamines—hormones involved in the fight-or-flight response. Evolutionarily, when early humans lived in savannas or forests and had to either fight off predators or flee from them, these hormones gave our ancestors the needed strength and stamina to take either action. Released by nerve endings and by the adrenal glands that sit on top of the kidneys, these hormones still flood our bodies in moments of stress, but an overabundance of them could sometimes be damaging.
Elaine Kamil
A recent study by scientists at Harvard Medical School linked increased risk of takotsubo to higher activity in the amygdala, a brain region responsible for emotions that's involved in responses to stress. The scientists believe that chronic stress makes people more susceptible to the syndrome. Notably, one small study suggested that the number of Takotsubo cases increased during the COVID-19 pandemic.
There are no specific drugs to treat takotsubo, so doctors rely on supportive therapies, which include medications typically used for high blood pressure and heart failure. In most cases, the heart returns to its normal shape within a few weeks. "It's a spontaneous recovery—the catecholamine storm is resolved, the injury trigger is removed and the heart heals itself because our bodies have an amazing healing capacity," Merz says. It also helps that tissues remain intact. 'The heart cells don't die, they just aren't functioning properly for some time."
That's the good news. The bad news is that takotsubo is likely to strike again—in 5-20% of patients the condition comes back, sometimes more severe than before.
That's exactly what happened to Kamil. After getting her diagnosis in 2013, she realized that she actually had a previous takotsubo episode. In 2010, she experienced similar symptoms after her son died. "The night after he died, I was having severe chest pain at night, but I was too overwhelmed with grief to do anything about it," she recalls. After a while, the pain subsided and didn't return until three years later.
For weeks after her second attack, she felt exhausted, listless and anxious. "You lose confidence in your body," she says. "You have these little twinges on your chest, or if you start having arrhythmia, and you wonder if this is another episode coming up. It's really unnerving because you don't know how to read these cues." And that's very typical, Merz says. Even when the heart muscle appears to recover, patients don't return to normal right away. They have shortens of breath, they can't exercise, and they stay anxious and worried for a while.
Women over the age of 50 are diagnosed with takotsubo more often than other demographics. However, it happens in men too, although it typically strikes after physical stress, such as a triathlon or an exhausting day of cycling. Young people can also get takotsubo. Older patients are hospitalized more often, but younger people tend to have more severe complications. It could be because an older person may go for a jog while younger one may run a marathon, which would take a stronger toll on the body of a person who's predisposed to the condition.
Notably, the emotional stressors don't always have to be negative—the heart muscle can get out of shape from good emotions, too. "There have been case reports of takotsubo at weddings," Merz says. Moreover, one out of three or four takotsubo patients experience no apparent stress, she adds. "So it could be that it's not so much the catecholamine storm itself, but the body's reaction to it—the physiological reaction deeply embedded into out physiology," she explains.
Merz and her team are working to understand what makes people predisposed to takotsubo. They think a person's genetics play a role, but they haven't yet pinpointed genes that seem to be responsible. Genes code for proteins, which affect how the body metabolizes various compounds, which, in turn, affect the body's response to stress. Pinning down the protein involved in takotsubo susceptibility would allow doctors to develop screening tests and identify those prone to severe repeating attacks. It will also help develop medications that can either prevent it or treat it better than just waiting for the body to heal itself.
Researchers at the Imperial College London recently found that elevated levels of certain types of microRNAs—molecules involved in protein production—increase the chances of developing takotsubo.
In one study, researchers tried treating takotsubo in mice with a drug called suberanilohydroxamic acid, or SAHA, typically used for cancer treatment. The drug improved cardiac health and reversed the broken heart in rodents. It remains to be seen if the drug would have a similar effect on humans. But identifying a drug that shows promise is progress, Merz says. "I'm glad that there's research in this area."