The Calm Before the Storm

Nisa Williams, seen here in the solitude of a fifth-floor lab on UW Medicine’s South Lake Union campus, is completing a PhD project in midst of the COVID-19 crisis.

Uncertainty is a fact of life for just about any PhD student, especially in the hectic final year of a thesis project. So much can change and so much is unknown. Data shifts. Funding is fickle. The right postdoc job could require relocation to a faraway city. It’s all part of the territory for a young scientist.

Nisa Williams was beginning the final stretch of her PhD project when her mentor suddenly left the University of Washington for an opportunity on the east coast. Fortunately, Williams, a bioengineering student, found a welcoming lab where she could continue her work on cutting-edge tissue engineering methods. Crisis averted.

“That was in January,” says Williams. “Before things really got strange.”

For more than 100 years, scientists hoping to understand how the human heart grows and functions have relied on two-dimensional platforms. While these models have led to decades of insights, they do not adequately mimic the conditions that exist in our bodies. Williams is part of a movement to change that by developing more sophisticated three-dimensional representations of the heart.

“Our hypothesis is that if you give cells a home that closely resembles their natural environment, it’s more likely that natural events will occur.”

Tissue Origami

To watch nature unfold, Williams, now based in the Murry Lab in the Institute for Stem Cell and Regenerative Medicine (ISCRM), creates manmade environments in which cardiac cells feel at home enough to behave as they would in an actual heart, not unlike designing natural zoo habitats that make animals feel at home enough to behave as they would in the wild.

Williams uses tissue engineering techniques to cue cells themselves to organize themselves. Here, cardiac cells have aligned to form the conical shape of the ventricle.

In the course of testing her hypothesis, Williams has developed a type of technique that is sometimes referred to as tissue origami. Layers of cells are stacked onto flexible scaffolds, which Williams then forms into heart-ventricle shapes that attempt to recapitulate the helical architecture of the growing heart. Electrical cues are then used to signal the cells to contract and rearrange themselves as they respond to their new 3D environment.

Williams explains one application for this technique. “I make tiny ventricles in a dish that are about the size of a mouse ventricle. Using our 3D model, I can measure the force those cells are capable of generating to pump blood around the body.”

The ability to study the heart in such detail is exciting.

Particularly tantalizing, adds Williams, are the possible insights into how these heart cells remodel themselves. The 3D models potentially enable her to observe the in-between steps in cardiac development, to see how the cells fold and turn in a way that gives the heart its structure and function. “The cells remodeling themselves is what allows the heart to twist and wring, like a coiled-up towel, which gives it more force. And nobody has been able to understand how this architecture develops in embryos or how to recreate it. So to see it happen is pretty cool.”

The 3D tissue engineering technology central to Williams’s research offers scientists a game-changing tool to explore fundamental questions about the means by which complex structures like the heart, brain, and other organs develop, what causes problems in those tissues, and how to treat diseases. No surprise then, that Williams was eager to complete her thesis and make a lasting contribution to the field of biomedical research.

That’s when COVID-19 hit home.

Nothing To Do But Get it Done

By late January, Williams had settled into the Murry Lab. She was letting her cells lead her in new directions, publishing reviews and research papers, and drawing on the diverse expertise of the engineers, pathologists, and biologists who were just steps away when she was stuck or needed a sounding board for a new idea.

Three months later, her cells are still folding, twisting, and turning in their homey human-engineered environments, and a proof-of-concept paper is due out in May. Everything else, of course, has changed as ISCRM researchers join much of the world by limiting time in the lab to slow the spread of COVID-19.

Williams, top right, poses last year with other ISCRM faculty members and trainees working collaboratively on heart engineering efforts.

Williams was granted permission to continue working from her bench in the solitude of a fifth floor lab on UW Medicine’s South Lake Union campus.  “Really, there’s nothing to do but get it done,” says Williams, searching for a silver lining.  “The downside is there are no more in-person meetings, which are really important when you’re talking about data – or if you’re a visual person and like to draw to explain what you’re trying to say.”

Physical distancing is not a challenge when there are hardly any people around. Still, the reality of pursuing a PhD in a pandemic weighs on Williams. “If I hadn’t been graduating, I would shut my experiments down. Because even though there are only a few of us here, we all know it’s out there. The anxiety is real. It makes it stressful.”

For Williams, the loss of community cuts deep, too.  “In the old days, I’d pass one of my committee members or my P.I. in the hallway and just ask a question if something was on my mind. That doesn’t happen anymore.  My data has been changing in really interesting ways and I wish I could just bounce ideas off people who have expertise. Now we email, set up a Zoom, and do the best we can. It’s not bad. It’s just different.”

In the midst of all the uncertainty, there is at least one piece of the puzzle in place for Williams. After graduating, she will be joining Sana Biotechnology, where she will apply her tissue engineering expertise to a promising effort to develop a stem cell-based treatment for heart disease.

In the meantime, Williams remains grateful to be a part of a supportive research community. “It’s become very apparent to me through all this how much ISCRM takes care of its people. When I needed a workspace, they found one. When I need access to one of the cores, there is someone there to help. And the message from everyone is the same. ‘We’re still here. Even though we’re not physically here, you can still lean on us.’ I’m so thankful for that.”