The Allen Institute, the Chan Zuckerberg Initiative and the University of Washington have launched a collaboration called the Seattle Hub for Synthetic Biology, with the goal of using genetically modified cells to capture a DNA-based record showing how they change over time.
If the project works out as hoped, it could lead to a deeper understanding of the mechanisms behind cellular processes — including, for example, how tumors grow — and point to new methods for fighting disease and promoting healthy cell growth.
Over the next five years, the Seattle Hub for Synthetic Biology will receive $35 million from the Allen Institute, and another $35 million from the Chan Zuckerberg Initiative, founded by Meta CEO Mark Zuckerberg and his wife, Priscilla Chan.
Jay Shendure, a professor of genome sciences at UW Medicine, will serve as the hub’s executive director. Other members of the leadership team include Marion Pepper and Cole Trapnell, researchers at UW Medicine; and Jesse Gray, a veteran of Ascidian Therapeutics and Harvard Medical School. The collaboration will build on technology pioneered at the Allen Discovery Center for Cell Lineage Tracing and the Brotman Baty Institute for Precision Medicine.
Shendure compared the genetically modified cells to flight recorders on airplanes. He said such cells could, for example, be combined with CAR-T cells to track the progress of cancer therapy.
“You could imagine layering them into CAR-T cells to provide a record of what happened, in the context of trying to deliver a certain therapeutic,” he told GeekWire. “And then you could imagine components of these cells, or more sophisticated versions, actually being used as part of the therapy — where, when and how a therapeutic turns on or off is modulated at some level by a much more sophisticated set of machinery.”
A new channel for checking cells
That sort of application is far down the road. In the nearer term, SeaHub’s researchers aim to develop a new channel for chronicling the changes that cells go through. This channel would take an approach that’s different from existing methods that depend on microscope imaging or sequencing a cell’s entire genome.
Shendure and his colleagues at UW have already created two techniques that could help turn elements of the genetic machinery inside cells into tiny time-lapse recording devices.
One of the techniques, known as DNA Typewriter, was the subject of a research paper in the journal Nature last year. The system makes use of gene-editing tools to lay down short snippets of DNA in chronological order, moving along a molecular string like the clicks of the carriage on an old-fashioned typewriter.
“If you insert a five-base-pair sequence, that’s four to the fifth, or 1,024. So there are 1,024 possible symbols that we could insert,” Shendure said. “When you punch a key, so to speak, you write a symbol — one of those 1,024 possible insertions. That’s like the recording of information. And the same edit moves the ‘type head’ one unit down the tape. You’re not just firing letters at a piece of paper, you’re actually typing them in some coherent order.”
The second technique is Engram. “Without Engram, DNA Typewriter is like a monkey at a typewriter, just hitting keys,” Shendure said. “But with Engram, at least for some of the keys, we can say you’re more likely to type this key if this particular signaling pathway is active, or you’re only going to type this key if you’re this particular cell type. So, we’re starting to learn how to assign meanings to keys, and to build a vocabulary of triggers between biological signals and symbols on our keyboard.”
To read the recording, researchers could extract some of the recorder cells and check the sequence of DNA letters that were inserted over time.
What the recorders could reveal
Early practical applications of the cell-recording technologies are likely to focus on studying how cells multiply and develop into tissues under normal conditions, and how things go wrong due to disease.
Studying the growth of a cancerous tumor would be a great example, Shendure said. “If you want to probe the history of one tumor — obviously this would be in a model organism, but it could be a human cell transplanted in a mouse — trying to accumulate that history over time is something that you would want to do,” he said.
Researchers could track the development of different tumors on the cellular level, and study how different treatment strategies affect their growth. For that scenario, a strain of mice could be genetically engineered with cell-recording capability.
“We make a mouse line that essentially has all this stuff stably, and the recording device can be ‘turned on’ at any point,” Shendure said. “You could have it constituently on, so it switches on at the beginning, or you could use a small chemical to turn it on, like doxycycline.”
Such methods could also be used to fine-tune tissue engineering. “If we’re trying to make skin in a dish, or something like that, what’s working? What’s not working? And how do you modulate it to improve the process?” Shendure said.
Using such techniques for clinical treatment in humans is a long-term strategy. But how long-term? “I don’t think they’re as futuristic as they might seem, given everything that’s going on,” Shendure said.
Sharing the science
Findings from the research effort will be shared widely within the scientific community. “It’s all going to be open science, fitting with the philosophy of the Allen Institute and CZI,” Shendure said.
The Chan Zuckerberg Initiative’s backing for the Seattle Hub for Synthetic Biology builds on the philanthropic organization’s history of supporting big-picture biotech projects — including a $3 billion effort aimed at curing, preventing and managing all diseases within a generation, and $15 million in grants that were awarded in 2018 to support a global research effort called the Human Cell Atlas.
“By developing new technologies to measure and understand the history of our cells over time, including how they are impacted by the environment around them, genetic mutations and other factors, we can expand scientists’ understanding of what happens at the cellular level when we go from healthy to sick, and help pinpoint the earliest causes of disease,” CZI co-founder and co-CEO Priscilla Chan said in a news release.
Rui Costa, president and chief executive officer of the Allen Institute, said he and his colleagues are “incredibly excited to enter this new era of collaboration to tackle big moonshot projects in partnership with others.”
UW President Ana Mari Cauce said the project “demonstrates the enormous potential impact of values-driven partnerships, and it represents a new way of thinking about how we can solve problems more quickly and effectively through scientific collaboration.”
“Our shared values, paired with our complementary perspectives and strengths, are a recipe for success, and I can’t wait to see what this team will accomplish together,” Cauce said.
The effort should yield noticeable results within five years, Shendure said.
“It could lead to basically a library of tools for engineering cell types, specific expression, et cetera. … I think there’ll be these deliverables that are broadly useful for the field,” he said.
Shendure hopes researchers at the Seattle Hub for Synthetic Biology will come up with specific bodies of information relating to cell lineages, including cancer cell lineages, that would be impossible to obtain using more conventional technologies. But he also has a bigger goal in mind: “Gaining acceptance for a new modality of measuring things over time, using DNA as a recording medium.”
“That’s been kind of a niche interest of technology development groups,” Shendure said. “We’re trying to really move that toward the mainstream.”
