Pardis Sabeti, the Rollerblading Rock Star Scientist of Harvard
The recipient of the Smithsonian American Ingenuity Award for natural sciences blazed a new view of how to treat infectious diseases via genetics
- By Seth Mnookin
- Smithsonian magazine, December 2012, Subscribe
(Page 2 of 3)
At the time, the main way scientists studied natural selection in human beings was by developing theories to explain the presence of a specific version of a gene in a population. This method dated back to the 1940s, when the British geneticist and evolutionary biologist J.B.S. Haldane speculated that the reason red blood cell disorders, such as sickle cell anemia, were more common in tropical environments where malaria was endemic was that the gene causing those disorders also conferred some protection against malaria—the “malaria hypothesis.” Beginning in the 1980s, researchers began developing more sophisticated tests to identify “signatures” of natural selection, but these were blunt tools that had difficulty detecting evolutionary changes that had occurred in the past 10,000 years—precisely when many diseases that ravage humans arose.
Sabeti was convinced that there was a way to pinpoint when more recent changes in the human genome had occurred and that this knowledge could lead to breakthroughs in fighting disease. Specifically, she wanted to use the makeup of neighborhoods of genes (called haplotypes) to determine if a specific gene variation (called an allele) in a given neighborhood had recently come to prominence in a population because it conferred an evolutionary advantage. This should be possible, she thought, by using the never-ending process of genetic recombination—the breaking and rejoining of DNA strands—as a kind of clock to measure how long ago a given mutation had swept through a population. If a widespread mutation had appeared recently—for instance, the mutation that enabled adult human beings to digest the lactose in cow’s milk, a nutritional advantage for many people in Europe after cows became common there—fewer recombination events would have occurred since it was introduced. As a result, the mutated version of that allele should be on a stretch of DNA that was more or less identical for everyone in a population. If the mutation had appeared a longer time ago, recombination would dictate that the area around the mutated allele would have gone through more random recombination events and it would be on a stretch of DNA that was more varied across the population.
It was a radical approach: Instead of using existing tools to analyze new data, she was trying to develop new tools to use on available data. When she was at Oxford, “Everybody thought what I was trying to look for was dumb,” Sabeti says. “It seemed as if I was just going to go nowhere. I know everyone has a hard time at some point when they’re in graduate school, but I was on the higher end of the hard time early on in my PhD.”
Nevertheless, Sabeti returned to Boston to attend Harvard Medical School and kept at it, taking “a series of little steps,” she says. “I was just charting my path in my own weird ways.” Then, early one morning, she plugged a large data set related to the DC40L gene, which she’d already linked to malaria resistance, into an algorithm she’d developed and watched results showing it was associated with a common haplotype—indicating it had recently been selected for—come into focus on her computer screen.
“I was just sort of beside myself with excitement,” she says. “It’s a really exciting moment when you know something about the whole world that no one else does. I wanted to call somebody, but didn’t know anybody I felt comfortable calling at 3 a.m.”
***
There’d be plenty of people eager to talk to Sabeti before long. That October, she was the lead author on a paper published in Nature that laid out her discovery’s “profound implications for the study of human history and for medicine.” For the first time, researchers could look for evidence of positive selection by testing common haplotypes even if they didn’t have “prior knowledge of a specific variant or selective advantage.” By applying this approach to pathogens, there was the possibility of identifying how diseases had evolved to outwit the human immune response or develop drug resistance—knowledge that would open up new avenues to combating disease.
All of a sudden, the previously unknown 26-year-old was a superstar. David Hafler, a Yale neurologist and immunobiologist who has worked with Sabeti, compares her approach to that of a preternaturally gifted athlete, the hockey great Wayne Gretzky. “He was asked, ‘Why are you always where the action is?’ And he responded, ‘I don’t skate to where the puck is, I skate to where the puck is going to be.’ That’s the reason she’s able to make all of these fundamental contributions.”
By 2006, when Sabeti became just the third woman in the history of Harvard Medical School to graduate summa cum laude, she was working with Lander at the Broad Institute. Using the massive amounts of data being made available by next-generation genetic sequencing, Sabeti and her colleagues developed a tool to pore through the entire human genome (as opposed to just a handful of haplotypes) to locate gene variations that appeared to have been under recent selection pressure.
In a 2007 paper also published in Nature, they zeroed in on three clear examples in which genes involved in a common biological process underwent selection in the same population. The first gene pair, SLC24A5 and SLC45A2, played a role in skin pigmentation in Europeans. The second pair, EDAR and EDA2R, was involved in the development of hair follicles in Asians. And the third gene pair, LARGE and DMD, was related to susceptibility to infection by the Lassa virus in West Africa.
Sabeti’s background in malaria and interest in infectious diseases pushed her to focus on Lassa, an acute viral hemorrhagic fever first identified in the Nigerian town of Lassa in the late 1960s. The U.S. Centers for Disease Control and Prevention identifies Lassa virus as one of only a handful of Category A agents, which “pose a risk to national security” because they’re deadly, can be easily transmitted between humans and “might cause public panic or social disruption.” Like the Ebola virus, Lassa virus is often referred to as an emerging pathogen, because the documented human cases have occurred relatively recently.
As Sabeti would quickly discover, working with Lassa presented a unique set of challenges. “I realized that I had become interested in a [virus that has]...very few people working on it,” she says. “In order to do that I just had to figure out how to do it myself.”
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Comments (4)
More than any other reading material, I am addicted to Smithsonian magazine. The stories about the Ingenuity Awards are all wonderful, but I was particularly struck by Pardis Sabeti. The story about this brilliant woman's scientific and interpersonal successes is educational and inspiring.
Posted by Judi Culver on January 11,2013 | 06:15 PM
Yes, commentator NT, the magazine is copyedited, and "pore through" is correct. Per Webster's, the verb "pore" means "to read or study carefully," and that is the meaning intended, though "pore over" is the more common phrasing. Thanks for the close reading.
Posted by Terence Monmaney on December 13,2012 | 10:10 AM
"developed a tool to pore through" Does nobody copyedit at the Smithsonian anymore? That should be "pour through."
Posted by NT on December 8,2012 | 12:03 PM
I was struck by the picture of Sabeti. Looks like a copy of Mona Lisa. Or is it that same enigmatic look? William
Posted by William Knottnerus on December 6,2012 | 02:32 PM