Empowering Optical Microscopy for Living Tissues
You joined MIT in 2021 as an assistant professor of electrical engineering and computer science. She focuses on developing optical imaging tools to enable noninvasive, faster and richer visualization of diseases and other dynamic biological processes.
As an undergraduate, Sixian You was fascinated how optical microscopes could capture beautiful color images of cells and their surroundings within slices of biological tissue. As a doctoral candidate, she built experimental microscopy systems that could take these images within living animals.
When she first tried out her microscope on a rodent model of cancer, You's expectations were low. Not seeing any action in the video stream, she went to lunch. But when she returned, "I saw the cells were moving like crazy," she says.
She watched the animal's immune cells pouring out of its blood vessels toward the tumor cells. You and her colleagues also soon found they could even track the tiny sub-cellular bodies called extracellular vesicles that can take cancerous cargoes out of tumor cells.
We are trying to see the sweet spots that can best leverage all the advances in optical physics, engineering and machine learning.
Moreover, nothing in the animal model had been labeled with chemicals. "All the colors we see are intrinsic signals from the biological tissue," says You. "We were merely engineering the light to get intrinsic contrast from the tissue."
"This is a very powerful example of how advanced optic microscopy can reveal things that we didn't know," You says. "Visualizing these things in living bodies is very important for understanding disease mechanisms and therapy strategies."
"We are trying to see the sweet spots that can best leverage all the advances in optical physics, engineering and machine learning," You says. As she develops these tools, she'll seek partners to move them into medical research and clinical applications.
Optical microscopy has been the gold standard for tissue examination, in both clinical practice and biomedical research. But it's typically done on preserved tissue samples that have been stained with chemicals to bring out contrasting textures or colors. "A lot of diseases can be much better studied and diagnosed if we can do this in living animals and living humans," You says. "But this just has not been done, mostly due to the fundamental technical limitations of optical microscopy such as depth, flexibility and size."
She works to overcome these limitations, developing imaging systems from source to algorithms, collecting image data inside the body and deep into tissues, retaining the sub-micron microscopy resolution that can aid research and diagnoses—and still not requiring chemical labels.
Her previous work used a customized pulsed laser source to deliver a method she and her colleagues at the University of Illinois at Urbana/Champaign engineered called "simultaneous label-free autofluorescence-multiharmonic" (SLAM) microscopy.
SLAM microscopy builds on a technology known as "multiphoton imaging" that can boost the ability for imaging to penetrate into tissues, offering better functional and structural clues about the biological processes underway. With a newly developed and applied fiber-based light source, SLAM microscopy enabled real-time and simultaneous detection of functional and structural signals from living tissues.
Today, You’s Computational Biophotonics Laboratory at MIT aims to further empower deep tissue microscopy by developing learning-based laser sources, adaptive light delivery systems and image reconstruction algorithms.
One goal is to build an ultra-thin miniscope, with a dramatically decreased footprint compared to what’s currently available. Such a tool might pay off in performing in vivo needle biopsies in cancer screening, imaging neural activity in living brains, and acting as a gastrointestinal endoscope for humans and even for small animal models used in medical research.
One goal is to build an ultra-thin miniscope, with a dramatically decreased footprint compared to what’s currently available.
Advanced optical microscopy also may pay off in another use where tissue access is more straightforward: offering quick "point of procedure" diagnoses in surgical operations. For instance, surgeons who perform lumpectomy operations for breast cancer try hard to remove only the cancerous cells. But during the surgery, the surgeons may not be able to get definitive proof that they have achieved clear margins around the tumor cells. Often a follow-up operation is required, which is a huge burden for patients and the medical system, You says.
While You was earning her doctorate at the University of Illinois, her system was converted by co-workers Yi Sun and Darold Spillman into a prototype microscopy cart that they could roll into an operating room. This portable system let the researchers look directly at the tumor margins, within the 15-minute workflow limit of the surgery. But eyeballing wasn't definitive enough, "so we developed an AI algorithm that can get a reliable real time diagnosis by just looking at the image for maybe 10 milliseconds," You says.
You joined Apple in between achieving her doctorate and starting her postdoctoral position. She greatly enjoyed her time at the tech giant, which brought home the major payoffs of jointly optimizing hardware and software.
One advantage of this combined strategy is lower cost, as we're seeing in mobile phones that cut down on expensive hardware components and compensate for performance by using software, You says. Advanced medical microscopes designed this way could become far more accessible for primary physicians, people at home, and those in developing countries. And once developers know what images a device will obtain, they can apply artificial intelligence algorithms and do end-to-end optimization to get peak performance.
Several types of corporate collaborations appeal to You. One is in wearable everyday health sensors such as the devices offered by Apple and FitBit that already feature multiple optical sensors. She suggests that hyperspectral imaging (analyzing a wide spectrum of light, rather than just primary colors, for each pixel) might offer new ways to monitor health.
Another related area is imaging-based diagnosis, for example to check out skin growths that might be cancerous. "In skin cancer, the key is early detection," You notes. "If you have a suspicious area, and you can use either phone or your watch to monitor its spectroscopy data, that could give you molecular information that machine learning algorithms could use to tell you if this is worth a doctor appointment."
Her high-resolution non-invasive microscopes also might aid research on skincare in general. If a manufacturer of facial products wants to see the effects of a skin cream or other treatment, these microscopes could easily visualize all the layers of skin and track the layers over time, says You.
In applications like these, combining her cutting-edge microscopy research with industry input could make the systems more innovative and more practical. "I'm super excited to work with industry collaborators who are interested in bringing these technologies to fruition," You says.