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Nanocytomer’s Star Is Rising
ME professor Lydia Sohn’s elegantly simple pore-on-a-chip seeks out hidden cancer cells
by John Alderman
Cancer patients, more often than not, learn to tolerate an overdose of challenges and indignities, not to mention fear and heartache, as they manage their long treatment regimens. High on the challenge list are the necessary but endless lab tests, then the interminably long, tense days waiting for results. Has the cancer metastasized, and if it has, where has it migrated, and can those cells be isolated and destroyed? Locating rare, circulating cancer cells hiding in sites distant from a tumor is still a medical impossibility.
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The thumb-sized nanocytometer could boost a patient’s chances of surviving leukemia, prostate cancer, or breast cancer, particularly where the cancer has recurred.
NICK LAMMERS PHOTO
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But in mechanical engineering professor Lydia Sohn’s Nano-Biology Lab, where she says, “biology meets solid-state electronics,” an interdisciplinary team is fabricating a remarkably accurate, next-generation analytical device that could enable early cancer detection of rare, isolated cancer cells where a relapse has occurred. This thumb-sized pore-on-a-chip, called a nanocytometer, could boost a patient’s chances of surviving leukemia, prostate, or breast cancer—particularly where the cancer has recurred—by locating and separating isolated metastasized cancer cells. And it could bolt into the marketplace within five years.
“The nanocytometer lets us work at the intersection of a number of disciplines from biology and mechanical engineering to solid-state physics and chemical engineering,” says Sohn, who taught physics at Princeton before joining Berkeley’s faculty two years ago. Sohn relishes creative leaps between fields. “I’m drawn to interdisciplinary sciences because it keeps everything fresh and pushes breakthroughs in surprising ways,” she says. “Mechanical engineering, in the form of micro- or nano-electro-mechanical systems, or MEMS/NEMS, allows us to design and fabricate the nanocytometer, while physics and chemical engineering provide the tools to solve and resolve problems and nuances in design and implementation. But biology is the umbrella under which they all fall. It’s inherently nano, and a model for all things nano, because of numerous biological interactions that happen at the very most minimal levels inside the cell.”
It was at Princeton that Sohn and her former physics graduate student Omar Saleh began developing tools for the relatively new and emerging field of biosensing—a fertile area to explore, particularly with the increased demand for biosensitive detection in medicine as well bioterrorism. Biosensing inspired Sohn to make a transition from solid-state electronic devices to biology.
Delving deeper into the new field, Sohn became interested in nanopores—artificial pores that mimic nature’s very own pores. The latter are tiny filters in the cell that play protective judge and jury, monitoring which substances get the green light to pass through them. Made of silicone rubber, the artificial nanopores Saleh and Sohn created are also tiny filters that can be used for the identification of single molecules. Because of that, says Sohn, they need to be only slightly larger than those molecules themselves. “We became interested in pores because they have exquisite single-molecule sensitivity and specificity, leading us to ask ourselves what we could learn or copy from nature,” says Sohn. “There were no artificial sensors out there that could do the same job.”
Andrea Carbonaro, a 27-year-old Italian graduate student and key member of Sohn’s team, has spent the last two years in Sohn’s lab designing and fabricating the nanocytometer. “Andrea took the idea of using chips with pores and ran with it,” says Sohn. “He advanced the earlier designs that were based on previous designs Omar and I had worked on.”
Sohn and Carbonaro soon realized, however, that although these incredibly tiny pores were worthy of the “gee whiz” level of admiration scientists long for, there were significant results that could be achieved with slightly larger pores, and these would be much easier to produce. Combining their nanopores with the power of nanoelectronics—the very same electronics used to measure the electrical properties of quantum dots and carbon nanotubes—they created a “pore-on-a-chip” to filter and analyze proteins at the cellular level.
The device Carbonaro has been working on for the past two years relies on a fabrication process similar to the one used to make an integrated circuit. The nanocytometer is made of a single, tiny artificial pore, whose dimensions are commensurate with a biological cell. The pore is connected to two reservoirs, and an electrolyte solution flows through the pore.
Next to the pore are platinum electrodes that measure the current across the pore. Whenever a particle of nonconductive material goes through, there is a change in the current related to the size of that particle. Knowing the dimension of the pore, you also know the dimension of the particle.
The device also takes advantage of the natural attraction that some cells have to specific antibodies and separates cells based on this attraction. Carbonaro modified the device so that these specific antibodies are incorporated into the pore, and those cells passing through that have the matching proteins slow down in the pore. The device can detect these slow cells and separate them from the rest of the cells being interrogated.
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Sohn and Carbonaro form the core of a multidisciplinary team that is aligning the already converging worlds of biology and nanoscale mechanical engineering. “The data look really great now,” says the effervescent Sohn, who holds a joint staff appointment in the Physical Biosciences Division at LBNL.
NICK LAMMERS PHOTO
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While the nanocytometer’s uses are multiple, its form is singularly consistent. “What’s striking is its elegant simplicity,” says Sohn, who with Carbonaro is particularly eager to push engineering across discipline boundaries to accelerate therapeutic and research technologies in biology and medicine. For this, Sohn turned to close friend and physician-scientist Lucy Godley, whom Sohn has known for 21 years. The two met at breakfast on their first day at Harvard, and as Sohn says, never missed a breakfast together in their four years as undergraduates.
It was Godley, a hematologist-oncologist specializing in blood-borne cancers at the University of Chicago Medical School, who first mentioned to Sohn the need for something like the nanocytometer in medical research and practice. Over the course of their careers, the two had often talked of collaborating, but nothing had ever materialized. Then at Berkeley’s Chez Panisse restaurant last year, spontaneously celebrating the 20th anniversary of their friendship over “fish, pasta, and lots of chocolate,” the two friends talked in detail about Sohn’s device.
Godley saw the breakthroughs that the small device could offer her field of cancer detection and treatment. “If we could isolate these cancer cells, we could study them and potentially learn what makes them spread,” she remembered thinking. “Right now, we can only detect large groups of cancer cells that have grown in a site away from the primary cancer—metastases—which are groups of thousands of cells. But isolating individual cells that have the capacity to lodge elsewhere would be a real advance, because it might tell us who is at risk for developing a life-threatening metastasis.”
As the friends lingered over lunch, it became obvious that Sohn’s pore-on-a-chip could replace the machine now used in most major hospitals to sort and isolate cancer cells. That sophisticated diagnostic tool is a Flow-Activated Cell Sorter, better known as a FACS machine. It’s as big as a hefty desk and incredibly pricey, says Sohn, and while the FACS has provided remarkable breakthroughs in cancer diagnoses and is considered state-of-the-art machinery, its drawbacks are significant.
Among the drawbacks, explains Godley, is that it requires a large volume of cells (i.e., lots of blood), and those cells must be tagged with a dye to identify specific antibodies or proteins. The procedure is costly and damages the cells it identifies. “Lydia’s new device involves only a small volume of blood and unlabeled cells,” she says. “The small volume of blood needed, as well as the unit’s size, could have tangible results when it comes to life-threatening diseases. Ultimately we could prick a patient’s finger in the clinic or at home and decide if the patient is in remission or not, much the way a diabetic has blood sugar tested,” Godley continues. “Right now, patients have to undergo painful bone marrow biopsies, and this technology could limit the frequency of those tests.”
The immediate advantage of replacement would be cost and size. When mass-produced using lithography, like transistors on silicon chips, a nanocytometer costs less than a nickel to make, and fits lightly between two fingers. “Our system is a very cheap one, and also very simple,” says Sohn. “Physicians will be able to use it once at the patient’s bedside, and then toss it.”
Beyond the price and ease are crucial scientific implications: By identifying and collecting cells without changing or damaging them, researchers could easily harvest and use the collected rare cells for growth and research. Godley also believes Sohn’s nanocytometer could be useful in isolating rare stem cells.
Sohn’s device is very impressive, says Godley who actually gave the device its name, godmother style. “When it comes to patients with solid tumors,” says Godley, “those circulating cancer cells are extremely rare. There may only be five or ten cells in the entire body.” This is where the FACS fails, she continues, because its statistical error rate is too high. Yet finding those cells is key, for early detection as well as monitoring patients to see if their cancer is responding to treatment. “Because the FACS machine is one of the most widely used machines in my field, the applications for Lydia’s device were obvious,” Godley recalls. From that lunch onward, Godley became an integral member of Sohn’s team.
Godley’s presence on the team and her medical specialty in blood-borne cancers made it easy to target leukemia cell detection as the first function implemented. But the team has also been working closely with Professor Marc Shuman, who presides over UCSF’s prostate cancer research center. In the long-term lineup of targeted diseases, prostate and breast cancer come next for the nanocytometer and the team.
Linking up with Shuman was the result of discussions between Berkeley and UCSF seeking ways that the two institutions could collaborate in the future. In particular, both Berkeley and UCSF were interested in nano-applications in cancer research. Sohn leads the project on cell separation and propagation and is part of the full group’s bid for a million-dollar National Cancer Institute grant for nanotechnology in cancer research.
For patients, researchers, and Sohn’s team, the stakes are high. Sohn has responded with a smart orchestration of resources and outside help. She’s drawing input from other scientists as well as making use of several key consortiums and the new Berkeley Center for Entrepreneurship and Technology (CET), whose director Ikhlaq Sidhu and a group of entrepreneurial advisors heard Sohn’s research presentation last spring.
With a patent already filed, the question for Sohn became whether to license the nanocytometer to an established company or form her own startup, the direction she now seems to be headed. “We would like to start something ourselves,” she says. “There’s something unique about the Berkeley culture. People are passionate about what they do, so they will set aside the usual reluctance, whether social or departmental, to get their research done and open up new avenues of exploration.”
Slated for December is a working prototype for isolating and sorting leukemia cells. The hope is that within three years, Sohn will be able to do the same with breast and prostate cancer cells.
By actively cultivating collaboration with friends, medical researchers, and other scientists, Sohn has taken her research in unexpected directions. “With a great biologist like Lucy Godley at your side to lead you, you can approach these problems unafraid,” she says. In this particular case, one of the unique dividends of friendship and shared expertise could be saving lives.
JOHN ALDERMAN is a San Francisco–based writer whose work has appeared in The Guardian, Japan Inc., and Wired, among others. His book Sonic Boom was a 2002 New York Times Notable Book. He is currently writing a photo book of computer history. |
