Found in Translation
A new laboratory building is helping Thayer engineers create better medical technologies by putting them into direct contact with doctors.
By Michael Blanding
To the eye, breast cancer tissue looks just like normal tissue. The only way surgeons can tell the difference is by palpating it—feeling it with their hands. Even then, sometimes when the cancer is deep inside the breast, it’s difficult to feel from the surface; and some cancer you can’t feel at all. That makes it very difficult for surgeons performing a lumpectomy to make sure they’ve removed all of the cancerous cells from a breast tumor. Studies have shown, depressingly, that more than a third of the time, surgeons leave behind cancer cells on the margins of a lumpectomy—leaving patients to go through the trauma of cutting all over again. “It’s not good for the patient, it’s expensive, and it’s painful,” says Dr. Rick Barth, a cancer surgeon at Dartmouth-Hitchcock Medical Center.
Part of the problem, he says, is the way that surgeons are guided. Radiologists traditionally scan patients in an MRI machine while they are lying on their stomachs with their breasts hanging down—inserting a wire to pinpoint the location of the tumor. But when patients enter surgery, they are placed on their backs. “It’s not a very accurate technique,” says Barth. “The breast looks a lot different.” There had to be a better way, thought Barth. To find it, he traveled a few miles up the road to Thayer to talk with Professor Keith Paulsen Th’84 ’86, who had for years been working on new techniques to use imaging to guide brain surgeons. What if women were scanned lying on their backs, asked Paulsen, and then a 3-D model of cancer in the breast was created similar to the way neurosurgeons create a model of brain cancer.
Paulsen tasked Thayer research scientist Venkat Krishnaswamy with developing the system, which included a video screen that Barth could consult during surgery and use of a tracker on his scalpel to make sure he was cutting in the right place. A study published by the team a few years ago showed that the technique was just as accurate as palpation; now they are a year into a clinical study comparing it head-to-head with the wire technique. As promising as it was, however, the technique still had its limitations. Chief among them was that Krishnaswamy had to be in the OR during surgery, constantly performing the proper mathematical equations in order to make the image render correctly. “We realized this had to be simplified drastically,” Krishnaswamy says.
After going back to the design table for several months, the team developed an even simpler technique: a 3-D printed shell that is customized to each patient, slipped over her breast to show the location of the tumor. Named the Breast Cancer Locator, it has pre-cut holes that allow the surgeon to mark the edges of the cancer on the breast surface, insert wire directly into the middle of the cancer, and inject blue dye under the skin surface to guide the surgeon to more accurately remove the cancer. Now, after using the technique on more than 10 patients, Barth says it is proving to be very accurate. “We think with this Breast Cancer Locator, the positive margin rate will be less than 10 percent,” says Barth. “It’s a way to make the surgery much more precise, so patients won’t have to come back for another surgery and will have an optimal cosmetic result as well.”
The concept of “translational medicine”—turning discoveries made in the laboratory into practical tools to help patients in the clinic—is a goal often strived for and rarely achieved. To create breakthroughs such as the one Paulsen, Krishnaswamy, and Barth made takes countless hours of meetings and consultations to refine devices and plan clinical trials—with all of the driving back and forth between engineering lab and hospital that entails. “Even two or three miles does not seem like a large distance, but that matters a lot,” says Krishnaswamy. “We refine this device with patients on a day-to-day basis as we go. Proximity is a force multiplier.”
Dartmouth took a giant leap forward in facilitating such collaborations with the construction last fall of the Williamson Translational Research Building, a new project by the Geisel School of Medicine to bring scientists directly into contact with doctors. The building is literally connected to the main arcade of the Dartmouth-Hitchcock Medical Center (DHMC); the seventh floor houses a dedicated space for Thayer School engineers, including an 8,000-square-foot open laboratory with work stations, offices, live animal housing, and advanced equipment that the engineers are using to develop new ways to diagnose and fight cancer.
My lab has been at the hospital for 20 years, but I didn’t have a desk,” says Thayer Professor Brian Pogue, who is also a professor of surgery at Geisel. “If I needed a desk, I had to go to the cafeteria and get a cup of coffee. Now we have desks and a physical laboratory co-located in the hospital. That’s something 90 percent of engineering schools don’t have.”
Pogue is codirector of the newly created Center for Imaging Medicine, which is housed at Williamson and brings together experts in optics, electronics, ultrasound, and biochemistry, including Paulsen and Krishnaswamy. Pogue’s own research investigates the use of molecular tracers injected into tissue to help guide surgeons during surgery. “Doctors are making second-by-second decisions on which tissues to remove and which tissues to leave,” says Pogue. “This could help them determine what types of tumors have this molecular biology.” Specially designed protein molecules interact with and bind to protein receptors in the tissue; when lights of different colors are used to illuminate the surgery, they can show up on the camera image, and this display can show doctors the difference between cancerous and non-cancerous tissue in real time.
Another area of research for Pogue is developing cameras to aid in radiation therapy for cancer. Patients routinely come in for radiation treatment every day, but there are few ways to tell if it is working, or even where the radiation is hitting the patient. Pogue’s invention, developed with engineering professor Scott Davis, makes use of a barely detectable glow called Cherenkov light that is released by the tumor when it is radiated. Measuring the amount of that light, the radiation therapy team could verify if they are giving the proper dosage of radiation in the exact location planned. “Verification that the treatment is being given properly is a big deal, because the treatment must be designed to limit damage in normal tissues, and small things, such as patient movements or breathing at the wrong time, can lead to large radiation delivery errors,” says Pogue. Both of these projects are currently being tested on animals, and Pogue is meeting weekly with physicians at DHMC to prepare for human clinical trials early in the fall.
That kind of contact with doctors is crucial for engineers as they develop their devices, says Thayer Professor Jonathan Elliott, who is also working on a project involving imaging molecular tracers, this time to image brain cancer. In a video, he shows how the imaging system works: As the molecular tracers move through the brain vessels and tissue, they light up like a supernova exploding in different colors. The dynamic quality of the image, says Elliott, provides much more information than the usual static images neurosurgeons work with. “There is such a rich amount of information there,” he says. “It’s seeing a whole movie instead of going into a movie for a minute at the beginning and a minute in the middle and trying to tell a friend what the movie is about.”
Still, says Elliot, it’s a challenge to convey this information in the tense environment of an operating room. Some of the tracers are only visible under infrared light, and much of the surgery is done looking through a microscope, making it impossible for a surgeon to look back and forth between the patient and a video screen. “I spend a lot of time thinking about how to visualize this data and trying to understand the optimal way of integrating these things, saying, ‘Is this going to be a distractor or is this going to be helpful,’” he says. Spending time in the OR watching how procedures are done is crucial to developing the right equipment.
“As soon as you get in there, you realize that half the things you thought were good ideas won’t work and things you thought wouldn’t make sense could totally work,” says Elliott. “Being able to work alongside the surgeon and see the whole process means ideas advance much more quickly.”
That’s true whether a device is just starting out or in the refining process. Geoffrey Luke, a new engineering professor who is in the early stages of developing a method of imaging lymph nodes to detect cancer without an invasive biopsy, says one of the reasons he came to Thayer is the ability to work closely with clinicians. “You need that feedback from the clinic about what will be most helpful,” says Luke, who works with oncologist Barth. “I’m hoping that will steer it in the right direction in the earlier stages of the research.”
In some cases, that feedback has resulted in radical redesigns of medical devices. Engineering Professor Ryan Halter Th’06 uses a technique called electrical impedance tomography to identify prostate cancer. The devices he creates send electrical currents into tissues; from differences in conductivity, clinicians can distinguish between cancerous and non-cancerous tumors. Halter first designed a side-fired prostate imaging probe that would send currents around the outside edges of a cylindrical ultrasound probe (like the exterior of a paper towel roll). But the patient had to be lying on his back with his legs in the air, a very uncomfortable position. Normally, a patients lies on his side and an end-fired probe takes images from the front of the tube (like the open end of the roll). Even though the side-fired probe takes better images, Halter knew that in order to have doctors use it, he’d need to redesign it as an end-fired probe. “The first time you put an instrument in the hands of a clinician, you start learning what works and what doesn’t work,” he says. “Clinicians were trained to do a procedure in a particular way. Unless you are revolutionizing a treatment procedure, it’s going to be tough to get them to adopt a brand-new technology.”
Halter is now in the process of using the technology to design a new probe that will help surgeons remove all of a prostate tumor. “The surgeon can press the probe around the tissue surrounding the prostate and then produce a map that ideally will show where there is cancer left behind,” says Halter. Currently collecting data in the OR from surgeons using the device, he hopes eventually to use that data to help guide surgeons during procedures. Being based in the Williamson building has made it easier to coordinate with surgeons than when he was coming from Thayer. “We would make meetings with physicians at 1, and they wouldn’t be out of the clinic until 2:30. Now if a surgeon can’t meet, we can still do our work, and then when they are available we can meet for 15 minutes very quickly.”
The proximity of the labs to the clinics also makes it easier to tweak equipment on the fly, says Thayer Professor Shudong Jiang, who has developed a novel imaging system to gauge the effectiveness of chemotherapy on breast cancer treatment. Some tumors don’t respond to chemotherapy, but women can undergo several rounds of treatments—and harmful side effects—before that is apparent. Jiang’s system shines a laser light on the breast to measure hemoglobin, a key indicator of vasculature in a tumor that can make chemotherapy effective. “This will help them not to suffer if the treatment will not help them,” she says.
For years, Jiang had to shuttle the equipment back and forth from Thayer in order to modify it. “Before the Williamson building, all of our testing instruments and lab equipment were back at Thayer,” she says. “Now all of our tools are here; it’s so much easier.” Currently, Jiang is gathering data on breast cancer patients at DHMC using the device; the next phase of the clinical trial is to bring it to other hospitals to see if nurses or physician assistants can use the system without the researchers being present.
Having all of the engineers in one place helps not only in communication with physicians, but also with each other. Even though Thayer researchers are looking at different cancers and ways to diagnose and treat them, they are able to learn from one another as they design their equipment. “My group has already benefitted from being in this environment,” says Professor Zi Chen, who works with Paulsen and Pogue on using nanoparticles to deliver drugs into the body and on understanding how cancer cells metastasize. “My postdocs are communicating with each other and with the other PIs.”
The faculty have also already helped one another in the sometimes arduous task of taking inventions beyond usage at Dartmouth-Hitchcock. “The incentive system today is just grant to grant. It gives you money and allows you freedom to publish papers and support grad students, but there is not much incentive to work with people outside of Dartmouth,” says Pogue.
There is a well-known “valley of death” between developing technologies and commercializing them; unless an investor or a company immediately picks it up, even promising inventions often die. According to Pogue, gathering engineers together in the Center for Imaging Medicine makes it easier to help one another with the process of commercialization, including patenting technologies and seeking out investors. A case in point: Pogue and Davis have created a company, DoseOptics, to develop and commercialize their radiation dosing technology, with Krishnaswamy serving as VP of technology.
Krishnaswamy will also lead Cairn Surgical, a new company started with Barth and Paulsen to produce the Breast Cancer Locator for use in surgery, with help from the Center for Imaging Medicine and a Dartmouth SYNERGY Clinician-Entrepreneur Fellowship awarded to Barth. Krishnaswamy eventually envisions a world in which doctors can scan breast cancer patients in the MRI and send the data to their company, which will then ship a custom-designed Breast Cancer Locator back to the physicians to use during surgery.
Resources such as the Williamson Building and the Center for Imaging Medicine are critical to ensuring that inventions find their way into the world, where they can help reduce suffering and improve prognoses for cancer patients. “The most important thing is taking these innovations that have been developed at Dartmouth over the years and getting them out into the world,” says Pogue. “At Thayer, we are very good at inventions, but usually when the grant ends, the technology ends. This center will allow us to get beyond that, directly taking inventions into human clinical trials with interested physicians and encouraging translation beyond the walls of Dartmouth as well.”
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