Understanding the Genetic Circuits that Regulate Life

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First launched in 2004 with seed funding from the Government of Ontario, the International Regulome Consortium (IRC) is a Canadian-led international research project that has set out to definitively map the genetic pathways and control systems that govern all cellular and biological functions.

Building on the work of the Human Genome Project, which in 2001 produced a detailed description of the genes in the human body, the IRC includes 58 researchers from 37 institutions in 12 countries including France, the United Kingdom, Australia, Italy, Singapore, Germany and the U.S. working as one to achieve its goal.

The IRC has as its objective the characterization of the mammalian regulome and looks even further into the future in tackling human stem cells. To do this, the IRC will map the transcriptional regulatory nodes and networks (the ‘regulome’) that control the function and lineage determination of embryonic and adult stem cells. Because the interactions between these regulatory nodes and networks govern normal and disease states, the outcomes of this project will strongly influence the medical practice and therapeutic development of the future.

It is hoped that through the new knowledge generated through this project, that it will set the stage for a powerful new paradigm of health-medicine centred on the regeneration of diseased or dysfunctional tissues that is at once personalized, predictive and preventive. In a larger context, the IRC’s gene regulation discoveries will serve as an enabling knowledge base that informs virtually the entire field of molecular biology.

Dr. Michael Rudnicki of the Ottawa Health Research Institute is responsible for spearheading the creation of the IRC. A leading expert in mouse genetics, stem cell biology and genes linked to muscle generation, Rudnicki along with several of his colleagues felt the time was right to begin a third generation genomics project to follow on the work started in uncovering the secrets of the human genome and where the binding sites are.

“It began as a workshop that I called back in December, 2003, which was followed by an even larger international workshop that had about 80 participants around the world. From that workshop we set out to pursue each of our own internal mechanisms for funding and once that was accomplished we were in a position to move forward,” he said.

The consortium was then incorporated as a non-profit organization in 2006 with Rudnicki named as its inaugural CEO and scientific director.

In addition to his role as the scientific director and CEO of the IRC, he also chairs the steering committee, reports to the IRC board of directors and is responsible for all aspects of the Canadian side of the project.

In describing what the IRC is trying to do he explains the goal as trying to find out how genes communicate to regulate cell activity and to find out why those communications sometimes go awry and cause disease. It was the IRC who grew the term coined in the 1950’s from regulom to regulome, encompassing not just the set of genes that are regulated by a certain transition factor, but adding the ‘e’ to include the transition factor itself.

Explains Rudnicki; “Our bodies are complex communities of cells, and each cell comes with a similarly complex set of rules that governs its function. These rules are encoded in the genome – the complete set of more than 25,000 genes that forms a vast library of information that resides in our cells. The genome contains the blueprints and instructions that enable our bodies to build proteins –molecules (including hormones, enzymes, antibodies and others) that are essential to the structure, function and regulation of the body. When we need a specific protein, genes are switched on and it’s created. But how do our bodies know which genes to switch on, what order to activate them, and when the genes should be switched off?”

He states the goal is to define the cells’ “circuit board” that regulates genes - turning them on and off.

“There are more than 20,000 different genes and about 10,000 are expressed in each of the over 300 cell types in the human body. The body uses 2,000 proteins to regulate genes. These proteins tell certain gene sequences to begin producing other proteins which in turn are used to build the various specialized cells we need to renew our bodies, repair damage and fight infections. Our research will help us better understand this process and how to make it work to our advantage.”

To further emphasize what it is the IRC is trying to accomplish Dr. Rudnicki uses an example of a piece of plywood with 25,000 light bulbs plugged into it with the wires or how it all works hidden behind the wood.

“Right now we know what the pattern of the light bulbs are, for example there has been extensive micro array experiments done to give us this information. What we want to do metaphorically is flip over that piece of plywood and see how all the wires are connected to different light bulbs or more specifically, how genetic circuitry controls the function of stem cells to commit and become different cell types.”

Dr. Rudnicki is certainly not the type of man to be left in the dark. On top of being a molecular biologist and a leading expert in mouse genetics he is also the holder of the Canada Research Chair in Molecular Genetics. His lab has made many discoveries concerning the function of regulatory genes that regulate myogenic stem cell proliferation and differentiation. He is certain the work of the International Regulome Consortium is going to revolutionize our understanding of how cells function at the gene level, and help researchers learn how to manipulate cell development and function thus impacting the development of new therapies including stem cell therapeutics and new treatments for diseases like cancer.

“By drawing the circuit board that regulates gene expression, we will be able to learn how to modify the behavior and function of cells. This knowledge will help researchers develop new treatments for diseases such as cancer, Parkinson’s, and diabetes to name a few,” he said. “Essentially we are trying to find out how genes communicate to regulate cell activity and to find out why those communications sometimes go awry and cause diseases.”

The challenges are enormous, but the reward promises to be great. This may come from the knowledge of what regulates stem cell functions and how they control the switch from one steady state of gene expression of stem cell to another steady state of gene expression that is different. Dr. Rudnicki states: “I think that the approach that we’re taking is that many targets that can be developed for drug exploitation or development so finding out where the key regulatory nodes are, that will be exploited by pharma, others and hopefully by ourselves as well as to exploit it for transitional purposes.”

In the first phase of the project, mice stem cells will garner much of the attention because researchers can readily do gene targeting with these cells and they can grow enough cells to do the chemistry according to Rudnicki. Computational approaches are also being used to select targets for an experimental pipeline of high-throughput analysis. States Rudnicki, in order for the IRC to move entirely into this next phase, human embryonic stem cells, the technology needed will have to continue to improve.

However he adds there are already a number of IRC partners that are currently working with human stem cells.

To achieve its goals, the IRC applies the latest genetic, genomic, proteomic and GE3LS. GE3LS or Genomic 3 means ethics, economics and environmental law and society.

The goal is not just to make the linear genome, but also really to understand the regulatory nodes and the parts that control stem cell function. The IRC has a more ambitious goal as well and that is to integrate all this information and eventually do this systematically for all stem cell factors and to understand how these intersect without the regulatory elements like RNA to define the cellular state.

There is no denying that challenges exist on the science side of the ledger, but they are no less difficult on the organizational side of things. Among the challenges the IRC is facing is that fact that it is a coalition of self-funded entities and it is not centrally funded. Similarly, funding, legislative, ethical and other considerations are compounded exponentially when working across many international jurisdictions. Networking also becomes a much more arduous task when the information is found in 37 institutions globally, across 12 different countries.

To help solve these issues, the IRC recently held a workshop in Europe to discuss the logistics of the integration and developing a database of standards, as well as helping to smooth the way to even higher levels of partnership and co-operation. The first step will see the IRC build a warehouse that will co-house Canadian data and track all the data of its partners, following a federated system model. Additionally, Ottawa is at the centre of this global effort with the Ottawa Health Research Institute (OHRI) operating as its secretariat.

The goal of adding new members to a consortium and maintaining a certain intimacy or close collaboration has a lot to do with why Dr. Rudnicki believes having the secretariat in Ottawa was the right choice.

““Really it requires people to be interested and willing; and that requires a lot work managing those relationships, and we have no shortage of that here. I think another one of the advantages we have being Canadian is that we’re not viewed as a threat, moreover we’ve developed quite the reputation in terms of organizing and running large international consortiums. We’ve seen it in the past with the 3G run by Tom Hudson and Barbara Toppers, as well as with Aled Edwards and the Structural Genomics Consortium and we are starting to see here again with this consortium. ”

Canadian involvement in the project isn’t restricted to Ottawa either, as the Toronto cluster is also heavily involved in the project. The Toronto cluster includes Dr. Jack Greenblatt at the University of Toronto, a world leader in high-throughput mass spectrometric analysis of proteins and their complexes, and Dr. Janet Rossant, Chief of Research at the Hospital for Sick Children, a leading mouse geneticist and stem cell development biologist.

Additionally, Ontario’s involvement includes a partnership with California that brings scientists from there to work within the consortium, including Dr. Robert Tijan who joined the IRC Steering Committee and leads a team from the Berkeley Stem Cell Center who will translate the findings of the IRC by working with human embryonic stem cells. Other experts around the world participating in the IRC include Dr. Frank Grosveld, Dr. Bill Skarnes, Dr. Irwin Davidson, Dr. Bing Lim, Dr. Ihor Lemischka, Dr. Mahendra Rao and Dr. Francis Steward.

The consortium also took a major step forward with its recent announcement at the annual Biotechnology Industry Organization meeting that it was partnering with Invitrogen Corporation to develop tools that will aid the consortium in its research.
On this partnership, Rudnicki has nothing but good things to say.

“It really speaks to the importance of the consortium and from our point of view it’s a huge development. We are doing some really outstanding work in the core research laboratories and their participation I believe will allow us to reach our goals in a much quicker way. With industry now involved, I hate to use this term, but it really has become a coalition of the willing. We’re no longer asking ourselves if we can do this, we already know the answer, and it yes we can.”