The Virus Hunter: Erica Ollmann Saphire takes on deadly threats
Deep in the thicket of west Africa, on a bamboo bridge strung over raging waters, Erica Ollmann Saphire groped through the dark toward a village where pestilence can snuff out life with ruthless efficiency.
She was looking for rodents. The Scripps Research Institute biologist wanted to know how and where her enemy spreads viral hemorrhagic fever: things like Ebola and Lassa, diseases that can kill. Soon, she got what she came for. Standing in a hut, Saphire looked low and saw holes that vermin had burrowed close to where people sleep. Mice and rats were on a hunt for food.
"I already knew that the virus spreads," Saphire said on a recent morning, recalling her 6,700-mile trip to Sierra Leone. "I went because I might learn something about where the virus is, how it changes, something that would help me later."
Awe crept into her voice: "The number and variety and changeability in viruses is almost unknowable. They're outpacing us, and we cannot fight them without the best minds and best technologies."
Saphire has one of those brains, say colleagues from Scripps Research to Tulane to Harvard. With a breathiness that is rare in science, they describe the 40-year-old Texan as a brilliant, tenacious star in the world of virus fighters. Scholars also say that Saphire - a 5-foot-10 dynamo - is one of the few laboratory scientists who will tromp around in a rainforest in search of clues. It leads her to take on scientific challenges others find too daunting.
"Erica has one of the best minds of her generation," says Robert Garry, a microbiologist at Tulane University in New Orleans.
Sean Whelan, who holds a similar post at Harvard, says, "A lot of people would give up on the kind of problems she takes on. Erica does not give up - ever."
They point to her work.
Saphire figured out the structure of the "gateway" protein that allows Ebola to invade cells, helping drug makers. She succeeded after growing 50,000 protein samples that are so delicate they could "shatter and smush into applesauce if you poked them with a cat's whisker," Saphire said. She finally found one sample that let her work out the structure of the protein, which is called "spike" because of the way it penetrates cells and spreads illness and, usually, death. That species of Ebola is 50-90 percent lethal.
Saphire also spent years studying b12, an antibody that can neutralize HIV. She eventually determined the structure of the antibody, thrilling scientists because b12 could neutralize many types of HIV.
A third blockbuster discovery might be coming, and this one would greatly change how scientists think of human biology if it pans out. Saphire and a colleague have collected data that disputes the age-old belief that proteins - which control how cells behave - adopt a single shape, which confers a single function. They believe that some proteins rearrange themselves into many shapes, each of which play a different role. Such a finding would reveal a great deal about how information is encoded in our genome, and about the nature of viruses.
The breakthroughs are bringing Saphire a lot of attention, which isn't easy to do at Scripps Research. Her office is a brief walk from the labs of three Nobel Prize winners, and several others who might someday win the award.
She doesn't particularly embrace the limelight, saying, "I don't think I'm any different than anyone else. Maybe I just don't get scared that easily."
Broadly speaking, Saphire is a steel magnolia, alternately tough and soft, and often funny and outspoken. Sitting near a coffee mug that bears the words, "Keep Austin Weird," she remembers being "large and loud" during her undergraduate years at Rice University in Houston. She could chug an entire beer in 3.5 seconds. Work hard, play hard - that was her mantra.
Twenty years later, Saphire is married to a fellow scientist. They have two young children. She hustles to care for them, rather than rushing off to play rugby, as she once did. But she retains a sense of humor. While visiting the White House to pick up a science award, Saphire sidled up to President Barack Obama and told him he could find jobs in her lab for his two daughters.
Saphire also is self-assured, something that comes across in the clothing she wears. Two years ago, she wore a hot pink skirt while giving a major address at an international science conference.
"It looked good on stage," Saphire said. "I remember the days when I thought I had to look like a man or blend into the wall to succeed in science."
Saphire has a striking appearance. But it is her mind that colleagues talk about, and the discipline she shows while studying proteins in the tough-yet-fragile field of X-ray crystallography.
Proteins can do bad things, such as letting a virus enter a cell or shutting down your immune system. Scientists are all over it. But proteins are hard to study because they're so small. Even a powerful microscope cannot clearly resolve the structure of a protein. And without that information, it is difficult to design drugs that attach to a specific spot and perform a specific task.
The situation is not hopeless; scientists can use X-rays to indirectly learn the three-dimensional structure of proteins, an undertaking that's part science and part art, or "black magic," as Saphire jokingly says.
Researchers have to coax hundreds of thousands of these proteins into arranging themselves into crystals, and the proteins must end up ordered, like an army, all in formation. If the scientist gets that far, the crystal is bombarded with X-rays. The radiation scatters in specific directions when it hits the crystal. That pattern indirectly reveals the structure of the protein.
X-ray crystallography work has led to 28 Nobel Prizes. But failure is common. So is frustration. Saphire hangs in there, largely because of an "a-ha" moment that occurred during her senior year at Rice. It suddenly became apparent to her that X-ray crystallography was one of the most powerful tools that can be used to solve hard questions in biomedical research.
The first major project she took up was among the most difficult in virology - determining the shape of b12, an antibody discovered by Scripps Research scientist Dennis Burton. It was the mid-1990s, and AIDS research was making progress. But as Burton points out, scientists were struggling with the harsh reality that "a virus is a masterpiece of evolution. It changes."
Saphire was a graduate student at Scripps Research, and up for a challenge. She decided to earn her doctoral degree by solving the structure of b12, which was a risky decision. Students in her field typically have about five years to earn a doctorate. She got 4.5 years down the line without developing any crystals that would scatter X-rays well enough to reveal the antibody's shape.
"I was concerned that she wouldn't get anything good before her Ph.D and that she should maybe switch to something that would guarantee some success," Burton said. "She stuck with it and not only succeeded, but became the first person to solve the structure of an entire human antibody. It was a tour-de-force. I don't think I've ever been associated with another student who had her steeliness." Twelve years later, it's still the only crystal structure of an entire human antibody.
Her next major project was equally difficult - resolve the structure of a single protein on the surface of Ebola, the protein that served as a gateway between the outside world and the interior of cells. Cracking the problem is essential to drug design, and to finding ways to protect the country against biological attack.
As before, years passed without success, partly due to the composition of the Ebola protein. It is covered with sugars that inhibit crystallization.
Saphire played a hunch, suspecting that she could grow the crystals she needed if she somehow locked the proteins in place. After a lot of setbacks, she found an antibody that did just what she wanted. She soon had the structure of the key protein, a breakthrough that made the cover of the journal Nature. Many gifted scientists go their entire career without achieving that honor.
"That was a pretty creative approach to solving the problem," said Harvard's Whelan. "It's telling us a lot about Ebola."
Where does this persistence and steeliness come from?
Saphire, who grew up near Austin, Texas, is not big on psycho-analyzing herself, preferring to describe her toughness as innate. But some of it likely comes from her father, Taylor, an independent-minded college mathematics professor who encouraged Saphire and her brother to stand up for themselves and, if something is important, to make it work, "come hell or high water."
Her toughness isn't negative. "She isn't arrogant or offensive," Burton said. Scientists point instead to her team-building skills. She arranged for her large staff to have black laboratory coats that bear the symbol of the Ebola virus. It was meant to build camaraderie, and focus.
There's a lot at stake. Although she's a prized researcher, the National Institutes of Health only funds six percent of the grants awarded in her field. Like others, she worries about whether the money will dry up.
"You have to open up a can of whoop ass and write a grant that is so awesome that they have no choice but to fund it."
Colleagues say the sketchy funding situation doesn't stop her from taking on projects that can be hard to get funded. She also goes for the heart of problem, rather than working around the edges, churning out lots of scientific papers.
Saphire has only published 37 scientific papers. A person of her age, in her field, typically has 50 or so. But each of her papers had a higher impact on scientists in her field.
"Rather than 'strip-mining,' in which there's always a little more data if you dig in the same place every year, we tend to be 'oil drillers,' looking for the gushers,'' Saphire said.
Kartik Chandran, a microbiologist at Albert Einstein College of Medicine in New York, admires her gutsiness.
"When I started my lab, my strategy wasn't to go for the big kill," Chandran said. "I set my sights lower. I'd publish papers that wouldn't blow people's doors off, but signal that I was here. Erica goes for the throat of a problem. That takes cajones."
Chandran doesn't see that changing.
"One can get lost in the details of science and lose touch with the greater realities of the world," Chandran said. "With Erica, that's less likely to happen. She's not a doctor, she's not a public health official. But she went into the jungle. Ten years from now, she'll still be at the cutting edge of explaining how these viruses work. She's emotionally invested in this."
Invested enough to gross some people out. On a recent Thursday, just before lunch, Saphire turned to a visitor and said, "I don't suppose you want to see some dead rats in Africa?" She didn't wait for answer. Instead, Saphire tapped away at the keys of her laptop, calling up the gruesome sight of rats scattered outside a food concession in a street in Sierra Leone.
It was an appalling sight. Saphire leaned forward just a bit to make sure she could see it all.
"I made my life studying these things. I should see where they are."