Then he met Marc Kirschner, a professor of systems biology at Harvard Medical School, at a Harvard poster session. It was a moment of serendipity: Kirschner, who studies cell growth, immediately recognized Manalis' sensor as exactly the tool he needed to figure out how cells control their size, and how that control is disrupted in diseases like cancer.
"It was a chance encounter of two satellites passing through the universe that happened to have something in common," Kirschner recalls. "He wasn't really meeting people who thought this was such an interesting problem in biology, and I wasn't meeting anybody who thought they had an interesting way to solve this problem."
Thanks to that meeting, what started as a quest for higher and higher precision measurement has led to a novel research program that could shed light on how cells grow and become cancerous.
By weighing single cells over time and correlating changes in size with molecular activity inside the cells, the researchers should be able to determine how cells control their growth. That could lead to a better understanding of what happens when cells escape those controls, as cancerous cells do. The technique could also potentially be used to evaluate the effectiveness of cancer drugs.
"This is an old subject that died out many years ago, because people couldn't make these measurements accurately enough," says Kirschner. "You really have to do it on a cell-by-cell basis to make any headway into the problem."
When the soft-spoken Manalis started working on his sensor nearly a decade ago, he had no inkling that he would end up studying cancer. He just wanted to build a measurement tool superior to anything else out there.
"I enjoy thinking about how we can make fundamental measurements in a better way — more precise, more direct, or faster," says Manalis, an associate professor of biological and mechanical engineering, and member of the David H. Koch Institute for Integrative Cancer at MIT. "I also enjoy the challenge of searching for the best possible applications for new measurements."
Manalis' fondness for tools is deep-rooted. Though his father teaches environmental science at the University of California at Santa Barbara, as a child Manalis was drawn more to technology than biology. His favorite toys were tools and electronic kits, and he spent hours at the toolbench his grandfather built for him.
After earning a bachelor's degree in physics, Manalis went on to study applied physics at Stanford, where he started out working on new approaches for imaging semiconductor chips. His interests eventually turned to biotechnology during a collaboration with Affymetrix, one of the pioneers of the DNA microarray, a tiny chip used to quickly scan for the presence of particular genes.
With a new focus on biotechnology, Manalis arrived at MIT in 1999 planning to build sensors for label-free detection of biological molecules in a fluid sample, such as blood. Detecting such molecules usually involves labeling them with fluorescent or radioactive probes, but that approach often requires complicated sample preparation, and the probes don't work with all molecules.
Manalis and one of his graduate students, Thomas Burg, decided to try weighing molecules as they bind to a scale consisting of a vibrating cantilever. To do that, they had to overcome one major obstacle: vibrating cantilevers required a vacuum in order to be sensitive, and biomolecules require solution in order to bind selectively.
Manalis and Burg solved this dilemma by turning these existing sensors — known as mechanical resonators — inside out. Fluid containing the biomolecules flows through small channels embedded within the cantilever, while the outside of the cantilever is maintained at vacuum. As molecules begin to collect on the channel walls, the frequency changes by an amount proportional to the absorbed mass.
It wasn't until several years later that Manalis and his team realized that individual cells could flow through the embedded channel and be weighed without attaching to the surface. Soon after, they were able to weigh the same cell thousands of times and thereby directly observe its growth.
The sensor can weigh cells with unprecedented resolution — as low as one femtogram (10-15 grams), or less than one percent of the weight of a single bacterium such as E. coli.
Using the sensor, Manalis is also working with MIT biology professor Angelika Amon to unravel the complicated relationship between cell growth and cell division in yeast. "People have known they're very dependent on each other for many years, but nobody really knows how growth influences cell division, and vice versa," says Amon. "Scott's machine lets us do things we've never been able to do before."
That project and Manalis' collaboration with Kirschner are part of a four-year, $200,000 per year grant from the National Institutes of Health Eureka program, which promotes the pursuit of novel, unconventional research.
Manalis' research group is also investigating other potential applications such as diagnostics for cancer and HIV. Manalis has co-founded a company, Affinity Biosensors, which has commercialized the sensor so other researchers can use it.
In the meantime, Manalis and his students continue to push their technology into new realms of sensitivity. Within six to 12 months, he expects his laboratory to be able to weigh a single virus particle, which has never been done before in solution.
"What's exciting to us is that we have a tool that can make a unique measurement," says Manalis. "And, it has been fascinating for us to learn about unsolved problems in cell biology from Amon and Kirschner."