On a Saturday afternoon in March, as Covid-19 was bearing down on New York City, a dozen scientists anxiously crowded around a computer in a suburban drug company's lab.
They had spent weeks frantically getting blood from early survivors across the globe and from mice with human-like immune systems — all to test thousands of potential treatments.
Now it was time for results.
The screen flashed totals of glowing green dots, hundreds or thousands in most samples. Then they saw some 10s, some twos and finally, zeroes.
The researchers cheered and their boss sent out for champagne.
No dots meant no infected cells. The scientists had found antibodies that block the coronavirus.
This was the start of a drug that would, eventually, go into the arms of a US president and others fighting off Covid-19.
Antibodies are substances the immune system makes to bind to and help eliminate a virus, but it takes several weeks after infection or vaccination for the most effective ones to form.
Drugs like the one these scientists at Regeneron Pharmaceuticals Inc. were developing are intended to help right away, by supplying concentrated doses of one or two antibodies that work best.
The drugs, administered by IV, are being tested to prevent infection in people at high risk of it who can't yet get a vaccine, such as housemates of Covid-19 patients. They're also being tried as a treatment soon after infection to avoid serious illness.
They are some of the most complex medicines that exist, made in a tedious, high-tech process with the risk of ruin at every step.
Unlike chemicals that are simply mixed in a lab, antibodies are coaxed from living cells.
Companies have used cells from a whole menagerie — monkeys, hamsters, mice, horses, cows, llamas.
Each drug starts with a single coronavirus survivor.
Eli Lilly, for example, worked with AbCellera, a company in Canada that got a potent antibody from an early case there.
GlaxoSmithKline and Vir Biotechnology found one in blood frozen for years in a Swiss lab from a survivor of SARS, another coronavirus that caused a deadly outbreak in 2003.
Regeneron's two-antibody drug is unique: One came from a Covid-19 survivor in Singapore and the other from the company's genetically modified mice.
People make hundreds or thousands of types of antibodies after infection but “most of them are not very good” at blocking the coronavirus, said Christos Kyratsous, a microbiologist who helped lead Regeneron's work. “You're looking for the needle in the haystack” to find one that does, he said.
The quest began in January when Chinese scientists identified the novel virus.
Dr Sumathi Sivapalasingam, a Regeneron scientist who had worked at the US Centers for Disease Control and Prevention, started seeking blood samples from people who'd been infected early on, long enough ago to have made good antibodies.
“We were essentially calling people from all over the globe” — China, Thailand, the United Kingdom, Europe — with no luck, she said.
Out of the blue, they got a call from Dr David Lye of Singapore's National Center for Infectious Disease.
He knew Regeneron had antibodies for Middle Eastern Respiratory Syndrome or MERS, a similar coronavirus disease.
Covid-19 cases were starting to mount and “I was thinking what else there was to do” because no treatments had yet been shown to help, Lye said.
The scientists quickly ruled out using the MERS antibodies but agreed to seek some for the new virus.
Lye asked three of his patients — two men and a woman who had recovered from Covid-19 pneumonia — to give blood.
It was dicey. Blood cells survive for roughly two days and the flight to New York takes 18 hours.
The samples then would have to clear customs and be driven to Regeneron's lab in Tarrytown, New York.
“It was exciting” yet terrifying, Lye said.
“I was concerned whether a flight delay or any mistake along the way would render the samples useless.”
“The blood was warm in the tube” when a courier rushed it to the Singapore airport, Sivapalasingam said.
It arrived on March 13, the day Covid-19 was declared a national emergency in the United States.
Sivapalasingam was working late at home when she got an email from colleagues at the lab.
“They were jumping up for joy because the cells were fresh and viable and perfect,” she said.
Meanwhile, others were working with what Regeneron's chief executive calls its “magical mice,” animals bred to have human-like immune systems.
When vaccinated with a piece of the virus, they don't get sick but make “almost identical antibodies to what humans would make,” Kyratsous said. It takes just 20 to 30 of these mice to develop a drug.
Blood from the mice and patients contains B cells, and each makes a specific antibody that's carried on its surface.
The goal is to find antibodies that stick to the virus and block it from infecting cells.
Scientists first screen the B cells by mixing them with part of the spiky protein that covers the virus and sorting out cells with antibodies that connect.
Next, researchers decode the genetic recipes for each antibody. The genes are put into a type of hamster cell widely used in the drug industry because they grow very rapidly and churn out the chosen antibody-like mini-biofactories.
Then comes the big challenge: testing each antibody by mixing it with uninfected cells and a “pseudovirus” — a tame virus that's been modified to carry the spike protein and to glow green if it gets inside a cell.
Each antibody goes into a well in a gridded, plastic container like a massive ice cube tray.
A computer attached to a microscope counts how many cells in each well are infected to see how successfully each antibody blocked the virus.
These are the results Kristen Pascal went to the lab to get on Saturday, March 14.
She recalled that she had “brought in pizza and pie for Pi Day,” a day scientists celebrate because 3, 1 and 4 are the first three digits of pi, an important number in math.
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