Cancer Warriors

Biomedical Cover StoryEngineers, life scientists, and medical doctors converge to fight a common foe.

Imagine a wormlike robot as long as a human thumb, blazing hot at one end, navigating its way through your brain. Sound unnerving? For brain cancer patients, who on average survive for less than a year, it could one day be a lifesaver. The robot uses its tip to burn off deep-seated brain tumors and then sucks up debris with a small vacuum tube. It has no electromagnetic components, so doctors and surgeons can operate it while a magnetic resonance imaging machine, or MRI, takes photos of the brain’s interior in real time to help guide the surgery.

The robot is the creation of mechanical engineer Jaydev Desai, of the University of Maryland, College Park, and neurosurgeon J. Marc Simard and radiologist Rao Gullapalli from the university’s medical school in Baltimore. The idea came to Simard when he saw plastic surgeons on TV using maggots to remove damaged tissue. Tested successfully in pig cadavers but still years away from clinical trials, the robot is one of several cancer-fighting devices being developed at Desai’s Robotics Automation & Medical Systems (RAMS) lab. Another is a better sensor for detecting breast cancer progression that could help physicians get more accurate biopsies.

RAMS is but one of many examples of how engineers are being mobilized to battle cancer, which killed an estimated 580,350 Americans in 2013 and was diagnosed in 1.7 million. Tapping breakthroughs in nanotechnology and imaging, engineers are developing, among other innovations, technology that can target tumor cells in the bloodstream, a “micropump” that can deliver precise doses of cancer drugs to pediatric patients, tumor-shrinking nanoparticles, and an endoscope capable of producing tiny, high-resolution images.

No one can predict for certain whether these new technologies will accelerate the slow decline in cancer death rates. But they hold the promise of more accurate diagnoses, a better understanding of the progress of the disease in each patient, and less painful and debilitating treatment, if not cures.

Desai and his colleagues also typify an increasing partnership–called “convergence” – between engineering and other fields, including the physical and life sciences. Nanoparticles, new imaging techniques, and microchips were all once largely an engineer’s domain, but now life scientists and doctors are reaching into that toolbox not only to fight one of humanity’s deadliest diseases but also to confront other 21st-century challenges, from climate change to demands for energy and clean water.

Engineers and life scientists are living together, talking together, and learning from each other more now than ever, says William Heetderks, associate director for science programs at the National Institute of Biomedical Imaging and Bioengineering (NIBIB). A 2013 report from the American Academy of Arts and Sciences notes that transdisciplinary relationships are key in emerging fields like precision medicine – involving tailoring treatment to an individual patient’s genetics, personal history, and behavior – which “will require approaches from physical sciences, engineering, information sciences, environmental sciences, and social sciences, together with an ever more sophisticated understanding of the underlying biology.”

Speaking the same language

Engineering robots for cancer treatment was “the next big thing” in Desai’s field when he came to Maryland and started his lab in 2006, but exploration at the time was limited, he says. RAMS has gone a long way to change that, with support from the National Institutes of Health – which provided a $2 million grant for the brain surgery robot – and the NIBIB, a sub agency of NIH.

Creating an MRI-compatible robot that’s small and flexible enough to navigate the brain’s deepest recesses and perform tissue-removal surgery at the same time poses many engineering challenges, Desai says. For instance, electromagnetic motors that could be used on any other robot were off the table because they might distort MRI images. The most recent prototype is instead controlled by cables, springs, and pulleys constructed from a specially made material that can alter its shape in response to temperature changes. Such an apparatus would be located outside the MRI’s field of view to maximize the image quality. Another challenge lies in creating a tiny robot that still has a wide range of movement in order to remove hard-to-reach tissue. The current prototype has multiple hinges, almost like a human finger, Desai says.

For his part, Desai communicates easily with collaborators from other disciplines. “As I interact with [the neurosurgeons and radiologists], they learn about my work and vice versa. We learn something new every time we get together. There are too many components in this project which need to be addressed, and at the end of the day, we hope to have something that’s really good.”

Not all researchers reach Desai’s comfort level. “Historically, communication between [engineers and life scientists] has been difficult, and almost as difficult as people who speak different languages,” says Heetderks. Problems can arise, he says, because most engineers and physical scientists tend to approach a problem more from a quantitative, numbers-based perspective, while many life scientists rely on descriptive measurements.

Joseph DeSimone, a chemistry and chemical engineering professor at the University of North Carolina, Chapel Hill, can testify to that. After a 15-year career in polymer science and lithography, he wanted to venture into a new area of research and in 2005 started talking to researchers at UNC’s medical school. “That process was fraught with issues,” he recalls. “I had to learn a new language in working with the medical school, so to speak, and learn how to get new types of funding and be relevant to a new community.”

Now DeSimone heads a lab of 30 researchers, spanning disciplines from engineering to biology to chemistry, developing new ways of producing cancer drug particles. They are doing so by taking a page from the semiconductor industry. Over the past 55 years, the industry has made transistors exponentially smaller and cheaper, slashing the cost and shrinking the size of consumer electronics, such as smartphones. DeSimone wants to manufacture particles for drugs the same way. His method, called Particle Replication in Non-wetting Templates, or PRINT, can create huge amounts of nanoparticles that are incredibly uniform in size, shape, and other physical properties. With current methods, he says, the drug manufacturing industry can’t produce such cookie-cutter shapes and sizes out of particles that are a fraction the width of hair.

DeSimone says size and shape are important when going after cancerous cells, because they have different properties from healthy cells, like their ability to be more “deformable” or malleable. Particles that are uniform in size and shape have a better chance of targeting those cells, rather than being thrown away by the body. He believes PRINT, mainly funded by the National Cancer Institute’s Carolina Center of Cancer Nanotechnology Excellence, will speed approval of new cancer drugs by the Food and Drug Administration. “The FDA hates heterogeneity, and we bring, for the first time, uniformity to particles,” DeSimone says, “We’re bridging upon the uniformity and precision from microelectronics.”

Teaming up with hospitals

UNC and other universities have found a growing willingness from NIBIB, as well as NCI’s Office of Physical Sciences – Oncology (NCI-OPSO), to fund convergent cancer research. Heetderks says his agency is especially interested in funding opportunities for engineers, physicians, and life scientists to work together. As biological research, in particular, has boomed in the past 20 years, he says, it has opened up new spaces for collaboration. Those abound at places like MIT’s David H. Koch Institute for Integrative Cancer Research, where researchers have developed a nanoparticle shown in clinical trials to shrink tumors, and at the University of California, San Diego, where the engineering school has teamed up a number of times with the Moores Cancer Center on NCI-backed projects to find better solutions for cancer treatment and diagnosis.

Boston University bioengineers have joined Massachusetts General Hospital researchers to develop technology that can target tumor cells that circulate in the blood, one of the main reasons that cancers metastasize and appear in other areas of the body. Such cells can be as rare as one in a billion blood cells, but metastasis is behind more than 90 percent of cancer deaths. BU’s engineering school recently put out a call for proposals for new cancer care technologies for diagnosis, treatment, and methods for improving a patient’s quality of life. The school plans to award up to seven grants of $50,000 each to selected projects. The department also held a contest for engineering undergraduates and graduates to create new technologies to help improve cancer patients’ quality of life. Winners included a mouthwash and taste-modification device for chemotherapy patients, developed by an electrical engineer, an acoustic engineer, a biologist, a business student, and a chemist.

A materials scientist and an anesthesia professor at Boston Children’s Hospital’s Laboratory for Biomaterials and Drug Delivery are working to create nanoparticles that can shrink to about half their size and release drugs to a specific tumor site at the same time. They shrink by being exposed to radiation, so they may be able to deliver tumor-killing drugs while a patient undergoes radiation therapy. Meanwhile, a University of Southern California biomedical engineering professor, Ellis Meng, has developed a wirelessly activated micropump to treat children with leptomeningeal metastases, a rare cancer affecting the brain and spinal cord. Currently, these patients must endure uncomfortable spinal taps several times a week. The device is the size of two small cookies stacked together, and once implanted in the abdomen, it could send frequent doses of chemotherapy into spinal fluid for direct delivery to the brain, according to an article on the website of the National Science Foundation, which funded Meng’s research. Meng’s specialty is biomedical and electrical engineering, but she originally was working with an ophthalmologist to make a miniature pump that could replace needle injections into the eye before the device was reworked for cancer medicine.

Another space where engineers are making a big impact is imaging, Heetderks says. For instance, University of Washington mechanical engineers are working on an ultrathin fiber-optic endoscope that doesn’t sacrifice size for image resolution, as some endoscopes do. Doctors would be able to navigate incredibly small areas in the brain to help better determine what differentiates cancerous cells from healthy cells.

Some projects combine nanotechnology and imaging. In an Australian lab, at the University of New South Wales, chemical engineers and clinicians are creating iron-oxide nanoparticles that can be tracked and imaged while destroying tumor cells. The particle could allow doctors to treat and help diagnose cancer at the same time, according to IEEE Spectrum.

In Europe, collaboration among engineers and physical and life scientists in cancer research is not only widespread but becoming mainstream in many institutes and an “established part of the curriculum,” according to a report by U.S. experts who toured 26 West European laboratories in May 2012. Rapidly growing projects included how fluids behave in tumors, the mechanics of cancer cells, and new devices and diagnostic tools. “Overall, despite the many funding constraints for science throughout the world, this area of research appears to be robust and in some cases even expanding,” the report states. The U.S. panel, created by NSF, NCI-OPSO, and NIBIB, has since turned to Asia and plans to release a report on 18 labs across Singapore, Taiwan, China, and Japan later this year.

 Return on investment

Convergence science doesn’t come cheap. Heetderks says it requires a lot of equipment, so universities and funding agencies want projects that can promise a big payoff. Not all engineers and life scientists have the ability and resources to collaborate, and that division tends to “put people into the haves and have-nots, so to speak,” Heetderks says.

DeSimone considers himself lucky to be at Chapel Hill, where the medical school ranks 14th in the nation in NIH funding. Still, when technologies are proven to work and survive the FDA approval process, investors and industry come calling. Just ask MIT chemical engineering professor Robert Langer, who helped start 25 companies and holds 815 patents both issued and pending that he has licensed to more than 250 firms. Yet the commercial route requires patience. DeSimone cofounded a company called Liquidia Technologies in 2004 with a team of UNC researchers to help bring PRINT to market. The company didn’t launch its first clinical trial until 2010. Currently, his lab is working to prove that PRINT can be used as a platform to make drugs for a host of maladies aside from cancer, such as influenza, respiratory problems, and multiple sclerosis.

One engineer with an established, commercially viable technology now wants to deploy it in parts of the world where cancer screening and treatment are sorely needed. Samuel Sia’s saga began when he was a “pure scientist” pursuing a biophysics doctorate at Harvard. It took a trip to sub-Saharan Africa for him to realize that he needed to turn more towards engineering in order to make a tangible impact in developing countries. He joined Columbia University’s biomedical engineering department, and about nine years ago helped create a lab-on-a-chip test for prostate-specific antigen, or PSA, that provides a 15-minute screen for prostate cancer. The credit card-sized chip needs just a pinprick of blood and contains all the chemical variations needed for detecting abnormally high PSA levels and some other factors that often point to prostate cancer. The purpose was to get rid of the days-long waiting period that patients endure for lab results, making the test ideal for developing countries, where it can be difficult getting back in touch with a patient, Sia says.

As much as of the chip itself, Sia sounds proudest of putting all the pieces of this diagnostic tool together, including a portable tabletop analyzer that takes the chip and processes the results. This “systems integration” means understanding not just all pieces of the tool but also how they interact and how to put them all together in a functioning machine. “I think most people are adept at one particular area,” Sia says, “but to do systems integration well, you have to be fearless.” In 2004, Sia cofounded Claros Diagnostics with Vincent Linder, a Swiss chemist and microfluidics specialist, and David Steinmiller, who has degrees in mechanical engineering and business, to bring the test to market. Claros was sold to a company called OPKO Diagnostics in 2011 for $49 million.

In 2007, Sia launched a four-year study in Rwanda to demonstrate the system’s viability in the developing world. Reporting in a 2011 Nature Medicine paper, Sia’s team wrote that beyond prostate cancer, it could simultaneously screen for syphilis and HIV, and needed only one microliter of blood per patient to do so. Sia, whose Columbia lab is composed of bioengineers, chemists, biologists, and mechanical and electrical engineers, clearly has no problem communicating across disciplines. But he wants researchers who share one common characteristic: They must be “just really focused towards trying to make a difference.” In cancer research, that will always be what counts.

By Sarah Khan
Illustration Collage by Lung-I Lo
Cover Illustration by Francis Igot

 Sarah Khan is assistant editor of Prism