Machine learning and the microscope

With recent advances in imaging, genomics and other technologies, the life sciences are awash in data. If a biologist is studying cells taken from the brain tissue of Alzheimer's patients, for example, there could be any number of characteristics they want to investigate - a cell's type, the genes it's expressing, its location within the tissue, or more. However, while cells can now be probed experimentally using different kinds of measurements simultaneously, when it comes to analyzing the data, scientists usually can only work with one type of measurement at a time.

Working with "multimodal" data, as it's called, requires new computational tools, which is where Xinyi Zhang comes in.

The fourth-year MIT PhD student is bridging machine learning and biology to understand fundamental biological principles, especially in areas where conventional methods have hit limitations. Working in the lab of MIT Professor Caroline Uhler in the Department of Electrical Engineering and Computer Science, the Laboratory for Information and Decision Systems, and the Institute for Data, Systems, and Society, and collaborating with researchers at the Eric and Wendy Schmidt Center at the Broad Institute and elsewhere, Zhang has led multiple efforts to build computational frameworks and principles for understanding the regulatory mechanisms of cells.

"All of these are small steps toward the end goal of trying to answer how cells work, how tissues and organs work, why they have disease, and why they can sometimes be cured and sometimes not," Zhang says.

The activities Zhang pursues in her down time are no less ambitious. The list of hobbies she has taken up at the Institute include sailing, skiing, ice skating, rock climbing, performing with MIT's Concert Choir, and flying single-engine planes. (She earned her pilot's license in November 2022.)

"I guess I like to go to places I've never been and do things I haven't done before," she says with signature understatement.

Uhler, her advisor, says that Zhang's quiet humility leads to a surprise "in every conversation."

"Every time, you learn something like, 'Okay, so now she's learning to fly,'" Uhler says. "It's just amazing. Anything she does, she does for the right reasons. She wants to be good at the things she cares about, which I think is really exciting."

Zhang first became interested in biology as a high school student in Hangzhou, China. She liked that her teachers couldn't answer her questions in biology class, which led her to see it as the "most interesting" topic to study.

Her interest in biology eventually turned into an interest in bioengineering. After her parents, who were middle school teachers, suggested studying in the United States, she majored in the latter alongside electrical engineering and computer science as an undergraduate at the University of California at Berkeley.

Zhang was ready to dive straight into MIT's EECS PhD program after graduating in 2020, but the Covid-19 pandemic delayed her first year. Despite that, in December 2022, she, Uhler, and two other co-authors published a paper in Nature Communications.

The groundwork for the paper was laid by Xiao Wang, one of the co-authors. She had previously done work with the Broad Institute in developing a form of spatial cell analysis that combined multiple forms of cell imaging and gene expression for the same cell while also mapping out the cell's place in the tissue sample it came from - something that had never been done before.

This innovation had many potential applications, including enabling new ways of tracking the progression of various diseases, but there was no way to analyze all the multimodal data the method produced. In came Zhang, who became interested in designing a computational method that could.

The team focused on chromatin staining as their imaging method of choice, which is relatively cheap but still reveals a great deal of information about cells. The next step was integrating the spatial analysis techniques developed by Wang, and to do that, Zhang began designing an autoencoder.

Autoencoders are a type of neural network that typically encodes and shrinks large amounts of high-dimensional data, then expand the transformed data back to its original size. In this case, Zhang's autoencoder did the reverse, taking the input data and making it higher-dimensional. This allowed them to combine data from different animals and remove technical variations that were not due to meaningful biological differences.

In the paper, they used this technology, abbreviated as STACI, to identify how cells and tissues reveal the progression of Alzheimer's disease when observed under a number of spatial and imaging techniques. The model can also be used to analyze any number of diseases, Zhang says.

Given unlimited time and resources, her dream would be to build a fully complete model of human life. Unfortunately, both time and resources are limited. Her ambition isn't, however, and she says she wants to keep applying her skills to solve the "most challenging questions that we don't have the tools to answer."

She's currently working on wrapping up a couple of projects, one focused on studying neurodegeneration by analyzing frontal cortex imaging and another on predicting protein images from protein sequences and chromatin imaging.

"There are still many unanswered questions," she says. "I want to pick questions that are biologically meaningful, that help us understand things we didn't know before."

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