Bruce and Cole Trapnell have teamed up, with support from the Chan Zuckerberg Initiative, to study the biology of chronic inflammation at the single-cell level.

Family Ties: A Father and Son Search for the Cellular Fingerprint of Fibrosis

On the surface, Cole and Bruce Trapnell’s research couldn’t be more different.

Cole, a computer scientist, builds powerful software tools for studying single cells — the building blocks of life — by the millions. He shares those tools with other biologists and uses them himself to investigate the genetic programs that guide the transformation of cells during development.

Bruce is a clinician-scientist and a world expert in rare, often incurable, lung diseases. He has spent decades uncovering the genetic and biological basis of those rare diseases and translating his findings into new treatments.

But the father-and-son pair have recently partnered to study chronic inflammation and its devastating effects on the human body, especially fibrosis. By combining their expertise at the leading edge of single-cell biology and translational medicine, they hope to break open the study of fibrosis, an all-too-common complication in chronic diseases of the liver, lung, kidney, and other organs.

Despite decades of research, scientists are still short on the insights they need to prevent, diagnose and treat fibrosis, says Bruce, an attending physician at Cincinnati Children’s Hospital Medical Center. “Even though it’s an important clinical problem, the molecular and cellular biology of fibrosis, especially in these disparate diseases, is not well understood. We’re so close to the beginning of our understanding of it,” he says.

Cole isn’t surprised that he and Bruce have found scientific common ground. “Toward the end of my postdoc, it started to become clear that there wouldn’t only be an opportunity to work together, but there’d be many. My lab develops tools that can often help us understand the mechanism of a particular disease and also about human biology, and that’s Dad’s whole M.O. He uses rare lung diseases to learn about healthy human biology,” says Cole, who studied software engineering before “getting excited about biology.” He is now an Associate Professor in the Department of Genome Sciences at the University of Washington.

When he writes a new grant, Cole always sends it to Bruce: “He’s an extremely smart person that doesn’t especially care much about the technology for technology’s sake. He cares what scientists get from it and what the field learns. And that’s focusing.”

The Chan Zuckerberg Initiative’s Single-Cell Biology program is supporting the Trapnells’ research project. They are one of 29 teams of scientists, engineers, and clinicians, funded through CZI’s Inflammation program, using single-cell analysis to study the role of inflammation in maintaining health and triggering disease. The father-and-son team is investigating the inflammatory processes that lead to fibrosis and organ failure in idiopathic lung fibrosis (IPF) and NASH, a type of nonalcoholic fatty liver disease. They are working closely with Yiing Lin, a surgeon-scientist at Washington University School of Medicine in St. Louis and an expert in liver disease.

Cole brings an arsenal of tools and technologies in single-cell biology and data science to the project, which offers a new way to probe inflammation. Collectively, Bruce and Yiing have decades of experience in the lab and clinic, which allows them to integrate new biological insights with medical intuition and their patients’ lived experiences. It’s a potent combination.

“It’s exciting because it’s a completely new strategy,” says Bruce. “We are taking rare diseases that are individually quite different and looking across them to see if they share a common signature at the genetic or cellular level. And we’re applying a novel approach to this question: the high-throughput single-cell sequencing method that Cole and his colleagues developed. It’s not that often that you have a new way of approaching something.”

From Rockets to Rare Diseases

This research project isn’t the first time Cole and Bruce have teamed up — in the lab or the field.

Visits to NASA’s Goddard Space Flight Center and the Smithsonian National Air and Space Museum near his childhood home in the Washington, D.C., area fueled Cole’s interest in rocketry, a pastime he shared with Bruce.

Cole did his first gel electrophoresis, a lab technique for separating fragments of DNA by size, at six years old. At the time, his dad was completing a fellowship at the National Heart, Lung, and Blood Institute in Bethesda, Maryland. A weekend trip to the lab was a way for them to spend time together. “We would go to the lab because [my dad] had an experiment to run. While we were waiting, we’d hang out and do a science experiment of our own,” recalls Cole.

A framed picture of that gel sits on Cole’s desk in Seattle — 2,000 miles and three time zones from his dad’s lab in Cincinnati.

Later, Cole and Bruce moved on to model rockets. Cole and Bruce have built and launched many of them over the years. The largest one, made by Cole, was 7 feet long and 7 inches in diameter.

Bruce still dabbles in rocketry; Cole has moved from pushing the limits of technology skyward to pushing it inward. He pioneers new measurement technologies that can sequence the genetic information in millions of individual cells in a single experiment. He also develops new algorithms for analyzing the resulting data.

In one experiment, Cole and his collaborators profiled approximately 2 million cells from 61 mouse embryos to produce a map of the mouse embryo during organ formation. During this developmental period — just a four-day window in a mouse — millions of cells are generated, diversify, and mature to perform different functions. Understanding the genetic instructions that guide the transformation of these cells is a fundamental goal of biology — one Cole calls “captivating.”

Bruce has helmed a lab at Cincinnati Children’s Hospital for 24 years. He is also a Professor of Medicine and Pediatrics at the University of Cincinnati and director of a research center designed to translate basic science into new treatments for rare lung diseases.

“I just love discovery and creating things,” says Bruce, whose research focuses on the pathogenesis and treatment of some of those rare diseases, including pulmonary alveolar proteinosis (PAP), alpha-1 antitrypsin deficiency, and cystic fibrosis.

People with PAP must have their lungs rinsed out regularly just to survive. That is because their lungs fill up with surfactant, an oily substance that coats the lungs and prevents the air sacs, or alveoli, from collapsing.

Bruce’s team discovered why immune cells called alveolar macrophages don’t clear surfactant out of the air sacs in PAP. He also established the first diagnostic test, identified a hereditary version of the disease, and developed a breakthrough treatment for PAP that could be a lifeline for patients.

Cole ran his first gel, with the help of his dad, at age 6. At the time, Bruce was completing a fellowship at the National Heart, Lung, and Blood Institute in Bethesda, Maryland.

Bruce and Cole’s first scientific paper together, published in Nature in 2014, described this new class of cell therapy for the treatment of PAP. They transplanted pulmonary macrophages into the lungs of mice with a genetic form of the disease. The macrophages, which were taken from the same mice and genetically corrected, multiplied in the lungs, began clearing surfactant, and effectively treated the condition.

Bruce has since adapted this new therapy, known as pulmonary macrophage transplantation (PMT), for humans and is preparing to launch the first clinical trial.

“The opportunity to take my clinical perspective and combine that with Cole’s significant experience in technology development and in the wet lab is very satisfying. It’s just a lot of fun,” Bruce says.

Unraveling Fibrosis

At his clinic, Bruce sees the pernicious impact of inflammation and fibrosis in his patients whose lungs slowly stiffen and lose their ability to pump air.

Both are natural processes: inflammation is part of our body’s defense system, and fibrosis is part of the healing response. But chronic inflammation can lead to uncontrolled fibrosis, in which scar tissue builds up in an organ and eventually destroys normal tissue. That is what happens in the lungs in people with idiopathic pulmonary fibrosis, which is estimated to affect one in 200 adults over 70 in the United States.

“If you look at a disease where fibrosis is front and center, like idiopathic pulmonary fibrosis, it’s a terrible process that rapidly kills a person. And once you recognize the problem, there is not much you can do about it,” says Bruce.

Despite decades of research, he says scientists are still short on the insights they need to prevent and treat it. The Trapnells’ new project aims to identify the cell types involved and describe their interactions during inflammation and fibrosis.

Bruce discovered that cholesterol-busting statins can effectively treat pulmonary alveolar proteinosis (PAP), a disease that causes air sacs in the lungs to clog with surfactant. In people with the disease, fat accumulates in alveolar macrophages (red). He has also developed a cell-based therapy for the disease, which will soon enter human trials.

“Do we see specific subtypes of cells that recur in multiple diseases associated with fibrosis? What are the genes and proteins that define those cells? Can they give us any clues to the mechanism of how they came to be?” asks Cole.

They also hope to identify a cellular or genetic signature for fibrosis and follow it back to its origins. Cole’s analytical tools make that possible by allowing the researchers to compare and contrast data from multiple tissues, in mice and humans, across various inflammatory diseases.

“If we can identify biomarkers of the process at an earlier time, we can intervene earlier. And maybe the drugs that we currently have might have a chance of being clinically beneficial,” Bruce says.

The team is about a year into the research project, and the scientific insights are coming.

For Bruce and Cole, there have been personal insights, too. For example, Bruce thrives off Cole’s work at the leading edge of biology. “I get to take the pulse on different areas of science from Cole and his collaborators, and I value that a lot. As you get older in any field, especially medicine and science, we draw from younger researchers. They teach you a lot. I’m happy to be the beneficiary of that,” he says.

Cole has come to understand what spurred his dad to work so hard and what keeps him motivated after decades of research in the same field. “Now, I get it, both scientifically and having observed him interact with his patients or their care teams. I understand in a much clearer way why my dad has worked so hard on a pretty specific set of scientific problems and questions,” he says.

“It’s cool to understand what makes your dad tick — at least a little bit.”

Written by Lindsay Borthwick, a writer who specializes in science, technology and innovation.

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Chan Zuckerberg Initiative Science

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