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 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 now 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 at HHMI's Janelia Farm 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 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 the most recent breakthrough. 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 1 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.
Helicos has already resequenced the genomes of a virus and three bacteria. And the company expects to resequence the human genome shortly. Although sequencing one person’s genome will cost about $60,000 at first, 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.
At Janelia Farm, Harris will have two priorities. One is to get his boat into the Potomac, since he is a sculler. The other 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.
Harris 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."
RESEARCH ABSTRACT SUMMARY:
Tim Harris, Director of the Applied Physics and Instrumentation Group, says "applied physics is here at Janelia to develop tools for other scientists' research." Although the physics team collaborates with scientists in most of Janelia's research projects, its current emphasis is on inventing ways to study neural circuits at work in living organisms. "The problem is so complex that no circuit is completely observable," Harris notes.
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Photo: Paul Fetters