Center Drives Discovery by Cracking DNA of Cells

In the mid-19th century, scientists discovered that cells are the foundational building block of life for both plants and animals. In the years since, they’ve come to appreciate how, in many cases, miniscule, single-celled organisms are also the foundational building blocks of entire ecosystems. Microorganisms influence soil fertility, plant and animal health, and the global cycles of important elements like nitrogen. And in the ocean, phytoplankton–the photosynthesizing organisms that make up the base of the marine food web–produce about half of the oxygen we breathe on Earth.

Yet, even as researchers have managed to map the entire human genome, our ability to sequence the DNA within a single cell has remained limited.

“We’ve known that the cell is the basic unit of life for almost 200 years and, yet, what individual cells are actually doing is still largely a mystery,” said Greg Gavelis, a bioinformatician at Bigelow Laboratory. “They’re kind of these little black boxes.”

Bigelow Laboratory’s Single Cell Genomics Center is helping change that.

SCGC is a one-stop-shop for reading, or sequencing, the DNA within individual cells. In fact, it’s the only facility that offers open-access services and educational programs in microbial single cell genomics in the world. Since the center began in 2009, more than 100 universities, research institutes, and companies in six continents have utilized SCGC services to collectively process over 1,000,000 individual cells.

“We pioneered much of the technology in this space, and we are unique as a service provider,” said Senior Research Scientist and SCGC Director Ramunas Stepanauskas. “There’s no other place in the world where you can just go and request sequencing of individual microbial cells.”

This ability to interpret the genetic information of a single cell, encoded in what’s called its genome, has transformed scientists’ understanding of global nutrient cycling, the evolutionary history of life, and countless other environmental processes. It’s also opened up new possibilities in everything from medicine to space exploration. Using SCGC capabilities, scientists from Bigelow Laboratory and other institutions have been able to identify novel antimicrobial compounds, which could have applications for drug development. They’ve begun looking at the genomes of viruses, which are the most numerous biological entities on the planet. And, they’ve discovered genomes, which Gavelis said, looked nothing like anything previously seen in the scientific literature.

SCGC is also a core part of a massive project called the Global Ocean Reference Genomes. Similar to the Human Genome Project — just with tens of thousands of species — the team is developing a genomic atlas of microbial life in the ocean, from the surface of the tropics to the deep sea.

In December 2022, a team of Bigelow Laboratory scientists also published groundbreaking research using SCGC services that showed that a small fraction of marine microorganisms is responsible for consuming the majority of oxygen in the ocean. That work was the first time that researchers were able, at the single-cell level, to combine genomic sequencing with quantifiable information on what those individual microbial cells are doing in their natural environment.

Despite obvious interest in single-cell genomics for fundamental and applied science, SCGC remains one of a kind partly because sequencing DNA from a single cell is still really hard.

Each cell the center processes has just a mere handful of molecules of DNA, weighing just a few femtograms — that’s 15 orders of magnitude smaller than a gram — and each sample can be easily contaminated by foreign DNA. To manage that, SCGC relies on UV treatments and HEPA filters for decontamination, and much of the physical work is done by robots to avoid the number of human hands that come into contact with each sample.

“You need to operate multiple, complex, and expensive pieces of equipment to get this kind of work done,” said Senior Research Associate Brian Thompson. “Many labs are really good at managing individual steps, but it’s much harder to be able to successfully operate and integrate all of the different pieces of the workflow.”

The first, crucial step in that complex workflow is flow cytometry, which works by suspending particles in a fluid and forcing them to flow single file past a laser beam. The cells are coated with special fluorescent dyes, which light up in front of the beam to flag just the cells with characteristics the scientist is interested in.

SCGC was developed at Bigelow Laboratory precisely because the institute housed the Center for Aquatic Cytometry, the first facility of its kind dedicated to marine science. The co-location of SCGC adjacent to the flow cytometry center is what’s made this service so unique and successful.

It’s also helped make SCGC an important resource for education. For the last several years, the center has offered workshops to train scientists at different stages of their career on how to produce and use single-cell genomics data. Interest in the course has only increased each year.

“What I find most satisfying is when customers or students of SCGC become scientific collaborators, and I start interacting with them, with my senior research scientist hat on, to develop joint projects,” Stepanauskas said. “This is complex work, and to make all the pieces fit together consistently, it’s just not feasible as an individual researcher.”