Approaching the genome like an engineer

Broad fellow Jason Buenrostro’s technology-inspired journey of decoding diseases, investigating one cell at a time.

Casey Atkins
Credit: Casey Atkins

It was during a class trip to a genome sequencing company that Jason Buenrostro found his true calling: developing technologies to decode the complexities of biology and genetics.

Buenrostro, who was pursuing degrees in biology and engineering at Santa Clara University, had wondered how both fields could be combined in a meaningful way. But on the trip, he found himself fascinated by DNA sequencing, a classic example of the interdependence between biology and technology.

“When I saw a scientist in a cleanroom suit show us silicon wafers which they developed to deposit pieces of DNA and the process of how they used fluorescence microscopy to sequence the genome, it really blew my mind,” said Buenrostro.

The trip — to Mountain View, CA-based Complete Genomics — offered him a window into an end-to-end platform, where researchers were both developing new biological methods and new instruments for genome sequencing.

Ten years later, now a Broad Fellow at the Broad Institute of MIT and Harvard, Buenrostro leads a lab positioned squarely at that intersection. His team integrates methods from computer science, engineering, and molecular biology to develop the next generation of biological tools.

“We are trying to understand the mechanisms of gene regulation that ultimately lead to disease, and we are doing that at the single cell level,” said Buenrostro.

For the most part, biologists have operated under the assumption that all cells within a single tissue or cell population are basically identical. However, genetic-profiling tools developed in the last five years have helped scientists discover the myriad of molecular differences between similar cells within a tissue — differences, scientists now understand, that significantly impact the cells’ properties, responses, and functions. Buenrostro is one of the researchers building such tools.

He and his lab hope that the kinds of single-cell profiling methods they are developing will allow researchers to gain additional insights into the mechanisms behind various diseases and develop therapies targeted to specific cell types.

In this short video Buenrostro talks about his journey in science, the invaluable support of family, and the importance of mentorship.

An unexpected journey

Buenrostro was born in Stanford, CA, to immigrant parents from Mexico, and from an early age wanted to become a doctor. During his college days, he became certified as an emergency medical technician and logged many hours volunteering at clinics. In 2009, he earned his bachelor degrees as a first-generation college graduate.

Aiming to enter medical school with a few years of work experience, he was soon looking for a full-time science job while preparing for the medical school entrance exams and continuing to volunteer at clinics during his free time. He found a research assistant position with Ron Davis and Hanlee Ji, renowned biologists at the Stanford Genome Technology Center.

Six months into the job, however, he realized how much he enjoyed genomics research. The field gave him the first opportunity to apply both his engineering and biology degrees. And he was finally gaining expertise in DNA sequencing technologies, which had caught his attention during that class trip to Complete Genomics.

“The best part of this job was getting the opportunity to work with two amazing people from both areas of my interest,” said Buenrostro, “While Hanlee Ji brought in expertise from the clinic and tumor genetics, Ron Davis was a bioengineer pioneering biotech methods.”

When Ji and Davis gave him the opportunity to stay in the lab for an another year, he readily accepted. Much to his family’s surprise, Buenrostro decided not to go to medical school and pursue biomedical research instead. While his parents were supportive, many in his extended family were not convinced about his career choice. In fact, one relative asked him, “Why are you throwing your life away?”

“The economically successful career path for many first-generation immigrants is believed to be medicine, law, or engineering — not academic research,” Buenrostro said.

He had not forgotten about his original goal of helping patients. But he began to realize that while as a physician, he could improve the quality of life for individual patients, as a scientist, he could develop new technologies to help diagnose and cure diseases benefiting many.

“The possibility of developing technology to advance the quality of healthcare became the biggest motivating piece of my journey forward,” said Buenrostro.

Stanford, science, and sequencing

As a brand new Ph.D. student at the Stanford University Department of Genetics, Buenrostro attended a departmental retreat in 2011. During a poker match, he sat next to geneticist William Greenleaf, who was just starting his own lab. Greenleaf convinced Buenrostro to join his lab as a doctoral student.

“I think I may have tricked Jason into joining my lab,” said Greenleaf. “After hearing about the work he did at the Stanford Genome Technology Center and the techniques he had mastered, I definitely wanted to recruit him.”

Buenrostro was Greenleaf's first graduate student. He entered with many skills, serving as an enormous resource by teaching sequencing methods to new lab members.

“He really formed some of the foundations of both the culture and the scientific projects for the lab during his doctoral days,” said Greenleaf.

But, while Greenleaf recalls meeting Buenrostro as simply a serendipitous moment, his former student has a different story to tell.

Buenrostro had seen Greenleaf’s work presented at a conference the year before, and had been thrilled by the advances Greenleaf was making in genome sequencing. Buenrostro knew he wanted to work with him.

“Sitting next to Will during the poker match was not an accident,” he said. “I’m pretty sure I convinced Will to offer me a position in his lab, versus the other way around.”

During Buenrostro’s doctoral years in Greenleaf’s lab, the mentor-mentee duo designed experiments to better understand the human epigenome — the information layer, made up of chemical compounds and proteins that can attach to DNA, that tells the genome what to do and when.

This work ultimately led to Buenrostro pioneering an epigenome profiling method called ATAC-seq (for “assay for transposase accessible chromatin sequencing”), a robust and sensitive technique which scans the epigenome and provides scientists with an intricate view of gene regulation.

Traditional epigenome profiling techniques are complex, time consuming, and need millions of cells for running each experiment. Buenrostro’s approach, however, can profile epigenomic regulation within individual cells, and can do so with a speed and efficiency to make it useful in the clinic.

Buenrostro continues to advance this technology in his own lab, now at the Broad. For instance, in a recent study published in Cell, Buenrostro and his collaborators used ATAC-seq to study single cells from human blood and bone marrow samples. The team presented a granular view of how stem cells differentiate, improving understanding of human hematopoiesis (how blood cells develop).

In another study, published this year in Nature Medicine, Buenrostro and co-authors used ATAC-seq to study the differences in T cells (cells responsible for immune response) collected from leukemia patients and healthy volunteers, underscoring the value of this technique in cancer research and clinical applications.


Buenrostro working with his mentee Yuliya Sytnikova in the lab (Credit: Casey Atkins)

Moving biology to a digital format

For a scientist like Buenrostro who approaches biology with the mind of an engineer, “technology development” has three parts — developing new technologies, building computational tools to enable new discoveries, and applying these methods to answer key questions in biology.

“When you develop new experimental methods, you will generate new data, and with new data types you need new computational tools to analyze them,” said Buenrostro. “For me, a project is not complete until the computational tools are as stable as the experimental methods developed.”

His Broad lab specializes in both of those components: experimental and computational.

“Typically in an academic research lab like ours, the principal investigator will specialize in one of those two things, and will have some knowledge about the other,” said Fabiana Duarte, a postdoctoral researcher in the Buenrostro lab. “But with Jason, he knows both really well.”

Buenrostro’s group further uses computational tools to integrate data from single-cell genomic studies into new models of cellular networks. These model networks help map different biological interactions and provide researchers beyond his own group with a deeper look into normal cell biology and disease progression.

Buenrostro is fascinated by the idea of being able to move biology to a digital format. He is constantly thinking about the unmet needs in disease biology and how his lab can solve them.

“A simple experiment using single-cell genomics can tell us so much about a disease process,” said Buenrostro. “We want to develop tools that can help the larger communities of researchers and clinicians.”

The fellowship of the Broad

The magnitude of resources, breadth of knowledge, and extent of institutional support available through the Broad Fellows Program had made it an obvious next step for him after Stanford. The program allowed him to start and run his own lab straight out of graduate school, without first working years as a postdoc. This eventually became one of the most valuable experiences in his scientific journey.

“Jason is one of the few students I knew who could handle running his own research effort right out of grad school,” said Greenleaf. “He is a great guy to have in science. It’s important that he be given free rein to explore his own ideas, because he is incredibly creative.”

The learning curve in the Fellows Program, however, was steep.

Buenrostro realized that just because someone is technically savvy and highly motivated, that does not always mean he or she will be able to manage a lab well.

“I had a fairly good idea of what I wanted to do scientifically, but I did not know how to lead a group,” said Buenrostro. “In the last few years, I have been learning to be a leader, and that is a unique experience.”

Buenrostro has been fortunate to have great mentors as his academic career progressed.

Eric Lander, president and founding director of the Broad Institute, and Aviv Regev, core institute member and chair of the faculty at the Broad, were Buenrostro’s first mentors when he arrived in Cambridge. Lander and Regev had spearheaded development of the Broad Fellows Program and brought in Buenrostro as the first fellow. They further helped Buenrostro define his project and vision for a lab.

“It is really important for a young researcher to get exposure to both great science and a supportive community of mentors,” said Buenrostro. “Coming to the Broad made all that possible for me — learn from mentors like Eric and Aviv, build collaborations, and advance my own research program.

“Over time, the level of independence Aviv and Eric gave me has been more of a dial than a switch,” he continued. “That is the best part of the Fellows Program — learning to strike a balance between leading and being led.”

Buenrostro feels that just by observing how Regev and Lander interact with other scientists and their own students, he has learned a lot.

“From Eric, I learned that science is not just about doing research. It is also about teaching and inspiring others,” he said. “What I admire the most about him is his ability to speak about science in a very human way.”

He hopes that over time, he might be lucky to have a little bit of Lander’s leadership style “rub off on him.”

Regev’s mentorship has taught Buenrostro how to look at the various aspects of scientific projects with different lenses, moving from technical details in the lab to big-picture applications in the clinic.

“It’s impressive to watch how Aviv can go from leading large groups of people to defining the vision for an individual student’s project,” he said.

Now, as a mentor himself, Buenrostro tries to follow Regev and Lander's examples.

“Jason is a great mentor who wants us to try different approaches to do science and learn from our experiences,” said Duarte. “He gives us a lot of freedom, but then if we need more direction, he is always around to provide that.”

So what is next for this engineering-minded biologist?

Buenrostro ultimately wants to be a tenure-track research professor at an academic institution. He thinks that the Fellows Program has equipped him well with a lot of visibility, connections, and a space to do great science.

He reflects on “how far he has come” in biomedical research, and how none of this would have been possible without the amazing support of his family, partner, mentors, mentees, and colleagues.

“As a Broad fellow, I am putting my small stamp on science, but at the same time there are big shoes to fill,” said Buenrostro.