Crisis in the Red Zone

by Richard Preston

  Pardis Sabeti planned to publish on the Internet all the genome sequences of all the Ebolas they’d found. This was so that other research groups could study the Ebola code and perhaps make discoveries themselves. “There’s a lot of siloing that happens during an Ebola outbreak,” Sabeti explained. Siloing is when a scientist guards her data, and doesn’t release it for other scientists to see or use. Ebola scientists were well known for being secretive, for withholding their discoveries about Ebola until they could publish their discoveries in a prestigious journal and get credit. Sabeti felt that this practice gave an advantage to the virus. “We want to try to break down silos and encourage everybody to work together,” she said.

  A second shipment of blood samples from Kenema had arrived at Harvard on June 24. This shipment contained eighty-four tubes of sterilized blood serum. The serum had been collected from sixty-six individuals who had tested positive for Ebola. The individuals had lived in the Makona Triangle or its outskirts. Sabeti’s team immediately put the samples into the sequencing process.

  By July 1, the team had obtained deep sequences of the Ebolas that had been replicating in the blood of a total of seventy-eight sick people. This was a movie clip of Ebola with seventy-eight frames, enough to see a small portion of the swarm as a four-dimensional image of the virus changing through time. Sabeti and her people made a list of all the mutations that had appeared in the Ebolas that had inhabited the seventy-eight people. The list covered just two sheets of paper. They made photocopies of the sheets and passed them around at the Broad Institute.

  CAMBRIDGE

  July 1

  Sabeti and her team spent the day staring at the photocopied sheets of paper. The problem they faced was very simple and very hard. They were looking at the mutations in the Ebola code and trying to understand the meaning of what they were seeing. It was like staring at a cryptic text on an ancient papyrus in which you can read the letters but you don’t know what the words mean.

  The Ebola code had been shifting as the virus went from one person to the next—a letter changing here, a letter changing there, random errors popping up in the virus’s 18,959 letters of code. The errors were propagating; the swarm seemed to be changing. What did the errors mean? Was Ebola evolving in some way?

  One of the people who stared at the sheets of paper is a genomic scientist named Daniel Park, who was working in the War Room Team. He dabbed at the sheets with colored highlighters, putting marks on the letters of code that had changed. “Our first question was, What questions should we be asking?” he recalled. “What would be the most helpful for the people dealing with the outbreak? There was a lot of loud talk. We were walking into each other’s offices, saying, ‘What do you think this means? Is this a transmission chain? Can we piece together a transmission chain?’ ” Park said. Sabeti and her team began to detect chains of transmission: They could see how a variety of Ebola had gone from one person to another, and then to another.

  They tried to identify exactly how the virus was jumping from person to person. Was it really being transmitted only through contact with fluids, or could the virus also be traveling in other ways, maybe through the air? “Being scientists, we were skeptical,” Daniel Park said. “We said, ‘Is there some other way the virus is being transmitted?’ ”

  As the team studied the Ebola code, Pardis Sabeti was constantly in motion, in and out of people’s offices and talking loudly in the hallways with shifting knots of her team members. They were worried by what was happening in Africa. They worried that Ebola could experience a big mutation, could really change its character, perhaps becoming more contagious. Sabeti’s voice, clear and vibrant, could be heard all over the sixth floor of the Broad Institute. She had sung in her band, Thousand Days, for eight years, and she used her lungs while she analyzed Ebola code, too.

  The team became convinced that the outbreak had started in one place, presumably with the little boy in Meliandou, and that the virus had come from an animal reservoir, most likely a bat. It would have been nice to know whether the virus in the Makona Triangle would respond to vaccines or drugs—except that there weren’t any vaccines or drugs that were known to work against any kind of Ebola, mutant or not.

  * * *

  —

  By the middle of 2014, two experimental vaccines for Ebola had been partly developed—vaccines that might or might not immunize people against the virus. One vaccine was called the VSV-ZEBOV, and the other was called the IFN-Alpha vaccine. Neither vaccine had ever been tested in a human. In addition, a dozen or so highly experimental drugs were in various stages of development, and most of them had never been inside a human body. It was widely assumed that most of the experimental Ebola drugs would ultimately fail, either because they were unsafe for humans or because they simply weren’t effective. Among the anti-Ebola drug candidates was a compound named ZMapp. It had showed some promise when it was tested in guinea pigs, though it had never been tested in a person. The story of ZMapp begins with a man named Larry Zeitlin, and with sperm.

  SPITTOON

  BALTIMORE, MARYLAND

  1996

  Larry Zeitlin today is the cofounder and president of a small biotech firm called Mapp Biopharmaceutical, Inc., which is headquartered in a group of rented rooms in a strip office park outside San Diego. Zeitlin is a soft-spoken man in his forties, with dark hair, dark eyes, and a slender frame, who wears jeans and T-shirts, and he is an expert on using antibodies to defeat infectious diseases.

  In 1996, Zeitlin was a postdoctoral researcher in a laboratory at Johns Hopkins University in Baltimore, where he was working with a team trying to develop vaginal microbicides that would kill sexually transmitted herpes virus on contact, or would kill human sperm—for use as a spermicide. Spermicides at the time weren’t very good. Sperm, it turns out, is very hard to kill. This might be expected, given the fact that sperm has been achieving success in challenging environments for around six hundred million years.

  Zeitlin was working on a spermicide that would use antibodies to kill sperm. Antibodies are proteins made by the immune systems of higher animals. The antibodies drift in the blood of an organism, and they stick to and kill invading microbes that get into the blood of the organism. Zeitlin was using human antibodies, and he was trying to see if the antibodies would stick to human sperm cells and kill them.

  Zeitlin did little experiments with sperm and antibodies. He would sit on a stool at his lab bench at Johns Hopkins with a microscope and two small plastic film canisters. He would pop open one of the film canisters. It contained a small amount of mucus collected from a woman’s cervix. Using a pipette, Zeitlin collected a small amount of the cervical mucus and dropped it on a glass microscope slide. Next he popped open the other film canister. It contained a dollop of warm semen. (“It had been donated that morning by a college student, probably on his way to class,” Zeitlin says. “He got paid ten dollars.”) Zeitlin put a drop of semen on the mucus. Then he put the slide into the microscope and looked.

  He saw sperm cells swimming madly through the mucus. It is actually one of the ancient wonders of nature. The sperm cells wriggled with unending, fierce energy. Nothing seemed able to stop them.

  Next, Zeitlin removed the slide from the microscope and put a drop of saline solution onto it. The solution had antibodies dissolved in it. Then, as quickly as he could, just an instant after he put the antibodies on the sperm, he put the slide back in the microscope and looked.

  It was too late. The antibodies had already immobilized the sperm.

  The sperm cells had gotten clumped together into large shaking balls. They were frozen in place and would eventually die. Antibodies were roughly a thousand times better at killing sperm than any chemical spermicide. Sperm cells can be thought of as invading microbes. The antibodies had stopped the invaders instantly.

  * * *

  —

  In 2000, Larry Zeitlin moved to Ca
lifornia to take a job with a biotech startup company in San Diego called Epicyte, which was developing an industrial process to make antibodies for curing diseases and killing sperm. He packed his things in a Volkswagen GTI and set off for the West Coast. One of Zeitlin’s bosses at the Hopkins lab was a mucus expert named Kevin Whaley, who also had a job offer from Epicyte. Zeitlin and Whaley rented a one-bedroom apartment near the beach in Del Mar and went to work at the company.

  The company had an industrial method for growing large amounts of antibodies in kernels of genetically modified corn. By the summer of 2003, however, Epicyte was in trouble. One problem was that anti-GMO activists didn’t like the idea of GMO corn that could kill sperm. What if a sperm-killing gene escaped from the GMO corn and got into regular corn? What would happen if people ate spermicidal corn?

  Zeitlin and Whaley began to smell bankruptcy coming, and they quit the company just before it did go bankrupt. Now jobless, Larry Zeitlin applied for unemployment benefits, and he started collecting a monthly unemployment check of $1,600.

  At this point, Zeitlin started thinking about infectious diseases. Could you make a drug from antibodies that would kill a virus that was invading the human body? Could an antibody drug work fast—almost instantly? Just the way antibodies nuke sperm in a matter of seconds?

  Zeitlin began thinking about Ebola. Suppose you could cure Ebola with antibodies? Ebola was weirdly like sperm: After a human body got “impregnated” with a few particles of Ebola, about ten days later the impregnated body would give birth to a ghoulish flood of Ebola particles, spurting, gushing, and oozing out of every pore and hole in the body.

  In 2003, Zeitlin and Whaley founded Mapp Biopharmaceutical, or Mapp Bio, with a stated purpose of curing infectious diseases, and they were going to start with Ebola. They later wondered if they’d made a mistake when they named their company Mapp Bio, because it sounded like Crap Bio. For venture capital they drew on Zeitlin’s $1,600 a month unemployment benefits. Using this money, they rented a three-room suite in an office park. One of the rooms had a garage door, which made the company immediately pre-legendary.

  The company’s biggest problem was that it was already broke. After paying the rent on the rooms, Zeitlin and Whaley had absolutely no money left over to buy scientific equipment, which is wildly expensive. They needed scientific equipment in order to have any hope of curing Ebola. There was, however, the bankrupt spermicide-corn company Epicyte. It had become a shipwreck, and shipwrecks strew cargo all over the place. When Epicyte filed for bankruptcy, its laboratory equipment, purchased by venture capitalists for large sums of money, was slated to be liquidated at distress prices at a bankruptcy auction. In preparation for the auction, the equipment got put in a locked storage room. Just before the auction took place, some of Epicyte’s equipment, in a dazzling, Star Trek–like process, dematerialized from the locked storage room and rematerialized inside the garage of Mapp Bio. Larry Zeitlin figured that the equipment would be sold for next to nothing anyway, and it might do some good advancing the fight against Ebola.

  Zeitlin and his partner wanted absolutely nothing to do with venture capitalists. Instead, they started applying for research grants from U.S. government agencies that were involved in biodefense. The general idea was that antibody drugs would be useful in defense against bioweapons. Eventually they got part of a $300,000 grant from the Defense Advanced Research Projects Agency, or DARPA. This agency is famous for investing in blue-sky research—research that has a high chance of failure but could result in a big payoff if it succeeds.

  Their plan was to start growing antibodies to Ebola in GMO tobacco plants (rather than in corn plants). They would see if it was possible to grow the antibodies in large enough amounts to make a drug feasible. They started growing tobacco plants under lights in their rented rooms, and they bought two restaurant-grade food grinders. These are machines that chefs use to puree spinach for soup. Zeitlin and Whaley used the food grinders to puree tobacco leaves into a green mush. Then they refined the mush and extracted Ebola antibodies from the mush, a delicate process that made the offices of Mapp Bio smell like a spittoon. They ended up with very small amounts of antibodies dissolved in saline solution. These antibodies might or might not kill Ebola particles; that part of the research hadn’t been worked out.

  USAMRIID, FORT DETRICK

  2000–2013

  While the scientists at Mapp Bio were growing antibodies in tobacco leaves, a space-suit researcher at USAMRIID named Gene Garrard Olinger, Jr., was working with a team, trying to discover antibodies that would kill Ebola particles. Olinger had had the same idea that Zeitlin and Whaley had, that antibodies could be a powerful defense against emerging viruses or biological weapons. In 2000, Olinger got a small research grant, and he and his team members began testing 1,700 different antibodies against Ebola in test tubes, at USAMRIID.

  The antibodies that Olinger was testing came from mice. Most of the mouse antibodies did nothing to Ebola particles, but five or six of the different antibodies made the particles clump together and die in a test tube.

  Even if mouse antibodies could stop Ebola in a test tube, there was a widespread belief among Ebola experts that an antibody drug wouldn’t be strong enough to stop Ebola in the human body. The belief was reasonable. In an earlier experiment, an antibody drug had failed to cure monkeys of Ebola. One of Olinger’s scientific advisors told him that if he kept on testing antibodies against Ebola he was in danger of dead-ending his career. “People were saying to me, ‘You’ll never have an impact with this, Ebola is just a horrible disease,’ ” Olinger says. He didn’t heed this advice. He was following a hunch. As always, the medical research was expensive and grueling. But he kept on testing antibodies.

  MAGIC SWORD

  When a 3-D image of an antibody protein is constructed using a supercomputer, you see a lumpy nugget that typically has the shape of a “Y,” like a fork with two prongs. The Y-shaped nugget drifts in the blood. The tips of the fork are like the teeth of a key, and have a truly vast number of different possible 3-D shapes. If the teeth of an antibody match something on the outside of a microbe, the antibody sticks to the microbe, fitting its teeth onto the enemy the way a key fits a lock. Antibodies are very small. If a human cell was the size of a watermelon and an Ebola particle was the size of a piece of spaghetti, then a single antibody protein would look like a speck of finely ground black pepper stuck to the spaghetti.

  Human blood is thick with antibodies. A person’s blood is about 2 percent antibodies by volume, and they really do thicken the blood. A droplet of blood large enough to cover a person’s little fingernail contains about 50,000,000,000,000,000,000 (fifty quintillion) individual antibody proteins. When a human baby is born, its mother produces a special milk called colostrum. Colostrum is a sort of paste made of antibodies. As the baby swallows the colostrum, the mother’s antibodies go straight into the baby’s bloodstream, and they thicken the baby’s blood. The baby’s blood has been primed to destroy any invading life form that could hurt the baby.

  When a virus starts multiplying in a person, the person’s immune system kicks into action and starts making antibodies to the virus. The person’s immune system throws all kinds of shapes of antibodies at the invader, antibodies with hundreds of different kinds of key-teeth. Almost all of the shapes fail to work—their teeth don’t fit anything on the surface of the invading virus, and so they don’t stick to the virus and can’t hurt it. However, a few of the antibodies do stick to the virus. These are the killer antibodies, the ones with teeth that fit the lock. The immune system goes into overdrive and starts making huge numbers of the killer antibodies, and they fill the bloodstream, sticking to virus particles, covering the particles, and killing them. The antibodies are wet nanobots programmed to destroy anything biological that gets into the human body that doesn’t belong there. At USAMRIID, Gene Olinger and his team were making secret Ebola-killing antibodies and testing
them in mice. In San Diego, Larry Zeitlin and his team were also making secret antibodies to kill Ebola particles. There was yet another team working on secret antibodies for Ebola, too.

  WINNIPEG, CANADA

  2009–2014

  In fact, a quiet race to find a cure for Ebola had begun. The Public Health Service of Canada has a state-of-the-art Biosafety Level 4 laboratory facility in Winnipeg called the National Microbiology Laboratory. The chief of pathogens of the Canadian lab was then a French Canadian Ebola expert named Gary P. Kobinger. Kobinger, working with a small team, was testing antibodies against Ebola, too. Thus there were three teams trying to cure Ebola with antibodies—led by Larry Zeitlin at Mapp Bio, Gene Olinger at USAMRIID, and Gary Kobinger at the Canadian lab. They knew they were in a race to find a cure for Ebola, and they kept their formulas secret.

  Lisa Hensley was then working at USAMRIID, collaborating with Olinger on Ebola research, and she knew him well. She also knew Kobinger well, and she began to think that the rivals should start working together, since it might speed up progress at finding a cure. Hensley began urging them to meet and talk. In the summer of 2012 at a conference in Chicago, they took her advice and went to a bar to get some beers. “This is where I guess we both sized each other up, under the guidance of Lisa Hensley,” Olinger says. At the bar in Chicago, and afterward, the two men made a tentative decision to share some of their data. Hensley also urged them to talk with Larry Zeitlin, at Mapp Bio in San Diego.

  Soon afterward, Larry Zeitlin and Gene Olinger teamed up for an experiment: They infected mice with Ebola, then gave the mice an antibody that Zeitlin had extracted from tobacco mush in his garage-lab. The drug cured some of the infected mice of Ebola.