A need for speed
A patient’s genetic sample holds great promise – but to capitalize on it, researchers need to crack open the information within, analyze it, and return the data to doctors in time to influence critical healthcare decisions. Broad Institute researcher Chris Friedrich and his team are challenging themselves to find ways to deliver information faster than ever before, efforts that in the future could help patients. They have streamlined the entire process by which a sample’s DNA is obtained, prepared, and sequenced at the Broad, reducing the workflow to its most essential parts. They call this ultra-fast method Exome Express – and promise the delivery of data in 21 days or less.
Many projects need samples sequenced fast, especially those involving clinical research samples from patients. Other researchers may need results quickly in order to meet deadlines, apply for funding, or produce a publication.
“We found ourselves with lots of projects where people want data much faster, as fast as possible,” said Friedrich. “There’s a growing emphasis on the need for speed.”
The speed of Exome Express gives Friedrich’s team and all of their colleagues in the Broad’s Genomics Platform a flexible space in which to try out tweaks and adjustments to the method. It operates on a small scale, which means that the investment of time and resources is much lower while trying out a new way of doing things.
“There is a large investment of time and resources required to make a change in a high-throughput process,” Friedrich explained. “Using Exome Express, we can test, validate and implement changes much faster because the team is focused on a single application. This allows us to adapt to the evolving needs of the customer and focus on doing what is best for each sample.”
In this way, Exome Express complements the Broad’s strong, stable, and high-throughput platforms that are used to sequence tens of thousands of exomes, whole human genomes, and more. The “exome” in Exome Express refers to the 1.5 percent of the genome that codes for protein. In many cases, this is the part of the genome that clinicians or researchers are primarily interested in.
Before Exome Express, it would take about seven weeks to sequence the exome of a sample at the Broad. For projects in which a researcher needs information on a large batch of samples, this timeframe is often sufficient. But for clinicians and patients looking for data that may help them make treatment choices, seven weeks is an eternity.
Nikhil Wagle is an instructor in medicine in the Department of Oncology at Dana-Farber Cancer Institute and an associated researcher at the Broad. Wagle is part of a group effort known as the CanSeq initiative – a Broad, Dana-Farber Cancer Institute, and Brigham and Women’s Hospital collaboration. His group’s need for quality data in a short period of time helped drive the development of Exome Express.
Previously, Wagle and his colleagues would scan samples looking for specific mutations known to cause cancer. The genes in which these influential mutations lie are called oncogenes, and the “map” that researchers at the Broad and Dana-Farber Cancer Institute created of where these genes fall in the genome is known as OncoMap. Clinicians at cancer research centers around the world use tools like OncoMap to look for “actionable” mutations in the genomes of cancer patients: these are mutations against which drugs either have been or are being developed. This means that patients who test positive for a particular mutation can be given a drug specifically tailored to their tumor or can be enrolled in a clinical trial designed for patients like them.
However, Oncomap and other tests like it are limited to a pre-specified set of genes, and adding new ones has been very challenging. Wagle and his clinical colleagues wanted a more expansive test, one that could help them spot mutations anywhere in the coding regions of the genome. They also needed a method that could turn around this information fast, allowing them to follow up on interesting leads with FDA-approved tests that could more definitively confirm telltale mutations. They teamed up with the Broad’s Genomics Platform last summer to try out Exome Express and get a first glimpse of the genetic landscape of their samples.
“We’ve been thrilled to be one of the first users of Exome Express,” said Wagle. His team’s goal is to sequence samples from between 150 and 200 patients this year.
Exome Express’s nimbleness is made possible not only through advances in sequencing technology, but also through a deliberate reimagining of the process by which samples make their way through the Broad. CanSeq researchers place patients’ tissue samples in pre-arranged kits sent over from the Broad Institute and enter information about the samples into an online portal. Samples are then couriered over to the Broad Institute. And that’s when the real streamlining begins.
“Last summer, we mapped out our workflow and we realized we had 46 steps,” Friedrich explained. These steps include adding reagents to a test tube, running preliminary analysis steps, and checking back and forth between researchers at the Broad and users about the quality of the data. Friedrich and his colleagues were able to slim down this workflow to about a dozen essential steps by using a value-added approach to workflow design. This approach allowed the team to objectively assess which steps increased the quality of the final product.
“We not only reduced the time to get the end result, but we also reduced the total work, the man hours that go into processing,” said Friedrich. “When you take that approach, you effectively reduce the cost.”
Of course, Friedrich and his colleagues are endlessly tinkering, refining, and perfecting. “Exome Express is up and running and already we’re working on new versions to make it even better,” he said. “We’re striving for operational excellence while being on the cutting-edge of science. And we love what we’re doing: we love generating results.”
In addition to Friedrich, the Exome Express team includes: Emily Wheeler, Tamara Mason, Teni Dowdell, Katie Larkin, and Cassandra Crawford.
The CanSeq initiative is a collaborative project made possible through the efforts of many individuals including: principle investigator Levi Garraway; computational biologist and medical oncologist Eli Van Allen; and project manager Jen Fostell.