Timothy Harris has always measured things. “It’s just one of those traits that some of us were handicapped with or blessed with in this world,” he says, recalling that his childhood self counted the seconds it took to jump off a 50-foot bridge into a reservoir.
So it’s no surprise that he has spent his adult life inventing better ways to make scientific measurements or that his former research team at Helicos BioSciences achieved a goal set by scientists 20 years ago: to simultaneously sequence millions of different pieces of DNA. “The scale of what we did was completely outside current practice,” Harris says, adding that single-molecule sequencing is a key step to personalized medicine, which will allow doctors to choose the best treatment for each patient.
As the first member of his family to graduate from college, Harris opted for secure employment as a researcher at Bell Labs rather than an academic position. During his 18 years at Bell, he developed new optical methods for studying semiconductors, even though his degrees were in chemistry rather than physics. “If I needed to know something about a field that I knew nothing about, there was almost always someone in the building who had invented that field or pioneered important parts of it,” he explains.
He applied this philosophy to studies of microscopic semiconductors called quantum dots, which are included in optical switches, solar cells, and anti-counterfeiting ink. They initially were difficult to study, because their properties are determined by size, which varies widely, rather than by composition. Therefore, Harris wanted to look at individual quantum dots, even though they are only a few atoms in diameter.
In early 1990, Harris discovered that Eric Betzig (now a scientist at HHMI’s Janelia Research Campus) had arrived at Bell. Betzig was the inventor of near-field scanning microscopy, and he wanted to build a video-rate near-field microscope. Harris, however, was more interested in a microscope with sufficient sensitivity to allow single-quantum dot fluorescence. “So Eric and my talented postdoc [Jay Trautman] improved the microscope’s sensitivity 10,000 times in one step,” he says.
Quantum dots were puzzling because they emit only half the light they receive. Using the new near-field microscope, Harris, with Lou Brus of Bell Labs and scientists from MIT, discovered the unlikely fact that quantum dots blink. “I like that project,” he says, “because it showed that you could find out something fundamentally different about quantum dots that you couldn’t possibly know unless you looked at them one at a time.” Scientists later learned to minimize quantum dots’ blinking, making them more useful for commercial applications.
Upon leaving Bell Labs in 1996, Harris became interested in biological measurements that generate huge amounts of data. At SEQ (now Amersham), his team invented an automated imager that allows drug developers to see the effects on cells of thousands of compounds in one fell swoop. At the rate of 40,000 tests per day, it can screen a million compounds in a few weeks instead of years. The IN Cell Analyzer 3000 has been purchased by drug companies around the world, and it has been used to discover a compound that slows the spread of cancer cells.
The Single Molecule Sequencing technique is one of the most recent breakthroughs. Scientists had sequenced the human genome by the time Harris moved to Helicos in 2004, but not on a grand scale. “If you don’t look at a lot of individuals, you won’t see the differences,” says Harris, whose team invented a way to sequence up to one billion different DNA molecules on a solid surface viewed with a microscope. Because DNA does not have to be copied before it is sequenced, the method is cheaper and avoids a major source of errors.
Single-molecule DNA sequencing could improve the diagnosis and treatment of cancer, Harris predicts, because conventional methods find only the most common mutations in tumor samples. “If you could study [the DNA of] 50 individual tumor cells, you could find a dangerous mutation even if it were present in only 5 of those cells,” he explains.
Although sequencing one person’s genome currently costs about $50,000, the price could plummet to $1,000 (a goal set by the National Institutes of Health) with increased efficiencies and decreased reagent use. At that point, people could have their DNA sequenced to determine their disease susceptibility and whether a particular drug would likely help or harm them. It should also be possible to compare thousands of human genomes.
When Harris joined Janelia in 2008, he set two priorities. One was to get his boat into the Potomac, since he is an avid sculler. The other—which continues to engage his attention—is to find better ways to study the brain. “Brains are really complicated, and if you can’t figure out how to make a lot of measurements, you’re never going to understand them,” he says.
As director of the Applied Physics and Instrumentation Group at Janelia, one of Harris’ goals is to assemble “a world-class team of measurement experts.” Harris and his small team work with colleagues to develop and deploy new technologies to the Janelia research community. The group addresses technological problems that are not easily addressed with commercially available tools, and creates solutions that are accessible to biologists. Where practical, new tools are brought into users’ labs and disseminated broadly. The group’s current projects include an apparatus for evaluating the properties of fluorescent labeling molecules that make cells or their components visible under a microscope, and electrical probes that can simultaneously detect the activity of more than 100 neurons.
Ironically, many of the tools Harris is developing are designed to be used by neuroscientists—although Harris himself has never studied neurobiology. “But you can learn any new field as long as you have experts to teach you,” he adds. “And Janelia is full of wonderfully talented people.”