Rats and mice get a lot of bad press, but for Steve Conolly, a professor of bioengineering and of electrical engineering and computer sciences, the furry creatures have been stalwart pioneers in the development of a spectacular new medical research technology called magnetic particle imaging (MPI).
Conolly, working with colleagues, postdocs, and students in his lab, has devised groundbreaking imaging systems that use strong magnetic fields to light up targeted diseases anywhere in the body. MPI is extremely sensitive and quickly generates bright, high-contrast images, in many ways outperforming established methods such as computed tomography (CT), nuclear imaging and magnetic resonance imaging (MRI).
One example is MPI’s unmatched superiority in tracking migrating cells over time, an important step forward if stem-cell therapies are to succeed. White blood cell tracking could also lead to noninvasive, early detection and monitoring of tumors and inflammatory diseases such as multiple sclerosis and osteoarthritis.
The catch is that none of today’s MPI scanners are roomy enough to fit a human inside. “Right now, they can accommodate rats,” says Conolly. “Scaling up to humans is our next engineering challenge.”
Engineering for health
As a graduate student at Stanford in the 1980s, Conolly first studied communications technology, but soon discovered a more interesting challenge. “I realized that how we communicate with radio, television and other methods has a lot in common with how we peer inside the body without a scalpel.”
MRI was the technology that first caught his attention, and for over a decade he contributed so many technical advances to the field that he earned 19 patents and an Outstanding Inventor Award from Stanford’s Office of Technology Licensing. One result was a novel architecture that could produce MRI scanners at a tenth of the cost of a typical hospital machine.
In 2004 he moved to Berkeley’s Department of Bioengineering as an associate professor, where one of his first graduate students was Patrick Goodwill. Like Conolly, Goodwill was convinced that “the future is people’s health” and wanted to be part of it, although “not as a biologist. I wanted to build stuff.” He and Conolly made a natural team. In 2005, Conolly came upon an article in Nature about a new imaging technology, called magnetic particle imaging (MPI), invented at Philips Research in Hamburg, which promised to be thousands of times more sensitive than MRI. He says, “I understood immediately this would be a big deal.”
Besides magnetic sensitivity, what appealed to him most was the promise of outstanding contrast and a high signal-to-noise ratio in the resulting images. MPI uses tracers that can pinpoint targets such as a region within the lungs or the brain or a specific kind of cell, and are visible at any depth in the body. A scan sees nothing but the tracers themselves, with no shadows of bones or tissues — no background at all.
Moreover, MPI is safe. The tracers are nanoscale bits of “rust,” iron oxide that the body eventually converts to hemoglobin or other proteins, or simply excretes. Since there’s no ionizing radiation, assessing conditions like stroke or pulmonary embolism could be safer than with X-ray CT or nuclear imaging.
Conolly and Goodwill began building a series of MPI scanners of their own design. Most parts for the machines had to be acquired second-hand. At one point, a pair of permanent magnets snapped their support structure and slammed together, with Goodwill’s hand between them; after his fellow students pulled the magnets apart, they took him, bleeding, to the infirmary.
By 2009, they had built a scanner big enough to image a mouse. The breakthrough occurred when they decided to rethink the problem from scratch. The result was an entirely new and far-reaching theory of MPI. With it, they improved imaging by redesigning hardware, rewriting reconstruction software, and even determining the ideal nanoscale dimensions for tracers.
With bigger and more sophisticated “preclinical” (rat-sized) scanners, the Conolly lab produced a string of research advances with important implications for medical diagnostics. In 2014, having built the first (and only) MPI scanners in North America, Conolly and Goodwill joined with the former preclinical imaging director at Perkin Elmer, Anna Christensen, to become the cofounders of Magnetic Insight, which recently sold one the first commercial preclinical scanners to Stanford’s Molecular Imaging Program in the Department of Radiology.
A new way to fight cancer
Cancer, heart disease, and stroke impact millions of lives per year. Mortality from heart disease and stroke has been decreasing in recent decades, but the incidence of death from cancer has not improved as much. Conolly lab researchers and their colleagues have demonstrated MPI’s ability to diagnose human tumors in rats using tracers that circulate in the blood, and these studies show that MPI produces images that complement more mainstream MRI and CTs.
But, the future of cancer diagnosis lies in a different opposite direction, says Conolly: “We’d like to have the immune system target the tumor for us. Researchers believe that we all have tumor cells, but in a healthy human they’re extinguished as fast as they’re created. White blood cells already know how to find a tumor.” In fact, some therapies just emerging into the clinic include t-cell therapies that re-train the immune system to recognize certain cancers.
Conolly explains that “the white blood cells move slowly along the sides of a vein and ‘sniff out’ what’s outside, then exit between the cells of the vessel walls — there’s no loss of blood — to go after their target.” Sixty percent of white blood cells are neutrophils, which spend much of their time sensing and killing bacteria but also may attack tumors. Iron-oxide nanoparticles hitched to such cells could highlight a tumor at the earliest stage, when surgical resection is extremely effective.
Following immune cell movement and change over time may emerge to be one of the keys to early cancer diagnosis. The Conolly lab researchers have proven MPI’s cell-tracking facility by studying adult human stem cells and progenitor cells in rats. They’ve documented the trajectory of stem cells, which give rise to a variety of tissues including bone and brain, over periods ranging from several days to more than 12 weeks. No other technology can follow cells for as long, with comparable contrast, robustness and sensitivity.
By labeling white blood cells with iron-oxide nanoparticles, Conolly says, MPI’s ability to detect tumors at the earliest stage could be a major advance in biomedical imaging. “For cell tracking, MPI is the best imaging method hands down, which makes MPI the world’s most promising technology for noninvasive immune-system diagnostic imaging.”
While the promise of MPI is bright, challenges remain. When human-sized bodies are exposed to electromagnetic fields at certain frequencies, tissues can absorb energy and heat up, and nerves can be uncomfortably stimulated. While not a showstopper, Goodwill says, this imposes an “imaging speed limit” on clinical scanners.
Goodwill is confident this will not deter Conolly, whom he describes as “someone who looks at questions with fresh eyes, always looking to change and improve existing technologies. That’s his state of mind.”
On the path to achieving affordable, human-scale MPI scanners, Conolly is determined to solve existing problems systematically. Styling himself an engineer, not a scientist, he says, “I want to make things better, faster and cheaper. Right now, we’re doing all three.”