• Claire Benjamin

Matt Wheeler: Modeling for success

Creating animal models is one of the messier aspects of life-saving research, but it is a vital step in the approval process for new treatments and therapies.

It’s an important (did we mention, messy?) job.

In Matt Wheeler’s lab at the University of Illinois, pigs undergo surgery to replicate a birth defect that causes infants’ airways to collapse, and everyone waits until the pig takes the inevitable turn for the worse.

Professor of Animal Sciences Matt Wheeler uses animal models for translational research.

“Then somebody who has got a vested interest has to do the resuscitation,” Wheeler said. “There is only one person on my team that will do that.”

And, yes, that person is Wheeler—an extremely dedicated Professor of Animal Sciences and member of the Regenerative Biology and Tissue Engineering research theme at the IGB.

He keeps the pig alive long enough to get it back on the anesthesia machine so that they can insert a 3D-printed splint that will keep the airway open, like patching a hole in a garden hose.

This work began when a baby, named Kaiba Gionfriddo, was born with this disorder, and doctors decided to test the efficacy of these airway splints ancient common ancestor.

It is possible that some of the same genes, or genes with similar functionality, will be responsive to social stimuli in all three species. Because of the known complexity of brain genomic responses to behavior, however, researchers will probably need more sophisticated ways to identify similarities. Said Associate Professor of Computer Science Saurabh Sinha, “We will probably realize that the shared molecular basis across the different species is not as simple as a gene or a set of genes being common to all of them and playing a big role, but that there is a more complex notion of molecular similarity.”

To do this, researchers will combine experimental data about gene expression and the structure of the genome with computational and statistical methods. Genes called transcription factors produce proteins that work within the cell to help control the activity of many other genes. Sophisticated analyses that take into account experimental data, along with prior knowledge about how genes are regulated, will produce a model of which transcription factors are most important for directing gene activity after a social encounter. These models, called gene regulatory networks, will be developed for the brain genomic response to aggression in mice, fish and bees.

A novel and valuable aspect of the study will be the innovation of new computational methods that allow the comparison of gene regulatory networks of different species. Sinha identified such methods as one of the important outcomes of the project: “Tools to compare this basic construct of a regulatory network across different species will play a huge role in that act of comparative genomics.”

These novel computational methods will enable researchers to detect conservation of molecular mechanisms on a yet-unexplored level of analysis, the level of gene regulatory networks. “The possibility that the same gene networks have been involved in multiple and independent evolutions of social behavior is very exciting because it would provide a new appreciation of the unity of life,” said IGB Director and Professor of Entomology Gene Robinson. Professor of Physics Yoshi Oono also emphasized the potential power of the study to yield major evolutionary insights: “The molecules and their organizations responsible for sociality will be recognized to be much older than we now naively expect; [they] could be older than Metazoa, could go back at least to Filozoa,” that is, several hundred millions of years old.

Discovering deeply conserved mechanisms of social response will also further efforts to understand human brain function and social behavior. “The findings would also provide new insights into human neurobiology and mental illnesses,” said Assistant Professor of Bioengineering Jian Ma. Associate Professor of Cell and Developmental Biology Fei Wang noted the role of his lab in the project, “to use human stem cell-based neural differentiation models to validate and confirm the findings from the animal models,” which will begin to test the connection between study results and potential biomedical applications.

The Simons Foundation, in addition to funding basic life and physical science studies, supports a funding initiative for autism research, making the GNDP study with its potential connections to human social behavior particularly aligned with the Foundation’s aims. Said Robinson, “If there are gene networks that play a strong role in social responsiveness in different species, these networks might be the ones that get perturbed in mental illnesses that involve social behavior.”

Theme members are energized by the freedom and exploration the grant will support: “Here the focus is on the grander vision of getting insights by comparing whatever we learn from each species . . . [the grant] allows us some breathing space to really think on a grand scale, which normal projects don’t often do,” said Sinha.

This energy, and the strong collaborative aspect of the project, will help GNDP continue to establish itself as a theme. “The Simons proposal grew directly out of discussions we had last summer to formulate the focus of our new theme,” said Stubbs. “This project is an almost perfect embodiment of our theme.”

In addition to the faculty mentioned, many other theme members are playing important roles in the project. Annie Weisner contributed to pilot studies in mice, and Derek Caetano-Anolles will conduct ongoing mouse behavioral and molecular work. Dr. Clare Rittschof contributed to pilot studies in bees, and will be joined by Drs. Hagai Shpigler and Matt McNeill for ongoing bee behavioral and molecular work. Abbas Bukhari may assist in conducting behavioral experiments in stickleback fish, in addition to his main role performing bioinformatics analyses. Joe Troy will also contribute bioinformatics analyses. IGB Fellow Dr. Ken Yokoyama, Charles Blatti, Laura Sloofman, and Yang Zhang will be involved in computational aspects of the project. Former IGB Fellow Dr. Qiuhao Qu will help direct work in human stem cells, and Drs. Huimin Zhang and Amy Cash-Ahmed will oversee molecular experiments.

This article originally appeared in the October 2013 Carl R. Woese Institute for Genomic Biology newsletter.