When embryonic sea urchins have just 16 cells, four of them are destined to produce the skeleton. Developmental biologists including Duke’s Dave McClay know an awful lot about how those embryonic cells reach their intended fate. But years ago a post-doc in McClay’s lab uncovered a surprising twist. He devised a way to eliminate those four skeletal precursor cells only to find that the young urchins stubbornly produced a skeleton anyway. Using new genomic tools and sophisticated modeling, the McClay lab is still trying to figure out just how they do it.
“We know a lot about the gene network it takes to build this one fate,” says Dave McClay. “We have no idea how a different network trans-fates to replace it.”
McClay has joined forces with Joshua Socolar, a Physics Professor and Associate Director for the IGSP Center for Systems Biology, along with Computational Biology Graduate Student Xianrui Cheng to help sort out the problem using a complementary blend of experimentation and computational modeling. Chen represents a new breed of scientist in the making; he spends half of his time at the McClay lab bench running experiments on the urchins and the other half with Socolar sorting out how to represent the biological phenomena he has observed firsthand in mathematical terms. With both sets of tools at his disposal, he is able to “fill in the cracks between the two fields.”
One of the first steps in forging the collaboration was sorting out the language, Socolar says. From a biological perspective, the urchin cells switch from one network to another in the process of changing their fate. But, “from a mathematical point of view, not really. Both have the same DNA and are in some sense running the same program. What’s different is that the network is in a different dynamical state. By framing the question in this way, we want to understand how the complete set of network instructions guides the state a cell is in. We want to make progress in understanding the logic of the system.”
Socolar says he never dreamed the title biologist would ever be associated with his name in any way. For him, the sea urchin conundrum is inspiring because it brings up fundamental questions that have been circulating in the physics and mathematical modeling community for years. “I’ve been interested for a long time in systems that undergo interesting transitions in behavior or exhibit very complex behavior,” he says.
In the 90s, researchers showed that even random networks, in which things were wired together “willy-nilly” could generate intriguing behaviors. That led to a flurry of activity, trying to work out the fundamental properties of a network required to produce characteristics like stability and flexibility. Socolar’s interest now is to apply that kind of thinking to address the deeper principles underlying biological networks in nature.
“All along we knew there was a system, but technically we just couldn’t get at it. It was too large a problem. We were missing the genomes and the high-throughput technologies needed to look at dynamic changes in gene expression”
“These biological networks are guided by natural selection and evolution to do things that look very specific,” he says. “But, how hard is it really? Is it possible you can get those properties essentially for free if you make a complicated enough network and then all natural selection has to do is just tune the dials to make it more efficient? The random models were interesting in opening our eyes to the possibilities, but now what is really going on in these systems?”
For McClay, it is all about figuring out how cells work, using the new tools of systems biology to address long-standing questions that had just been too big to tackle before.
“All along we knew there was a system, but technically we just couldn’t get at it,” McClay says. “It was too large a problem. We were missing the genomes and the high-throughput technologies needed to look at dynamic changes in gene expression. Now, all that is available, so what we knew to exist we can actually address. To me, the challenge is to pick the right problems.”
He believes what they learn from the sea urchins will have relevance to other organisms and to the kinds of fundamental questions that preoccupy stem cell biologists of all sorts. They’ve already made progress that McClay says has shattered whatever preconceived notions he might have had about how the urchin cells operate. It isn’t that the loss of the would-be skeletal cells lends some other cell the capacity to trans-fate. Those cells probably have that all along, but the skeletal precursor cells actively prevent other cells from becoming them. “They are the gatekeepers,” he says.