Research surrounding drug discovery has historically been highly competitive and expensive. Unfortunately, many late-stage drug failures have occurred over recent years, often due to lack of efficacy. These failures have left the industry searching for new means by which to improve early drug discovery efforts aimed at understanding the drug target and its role in disease. One idea that is gaining traction is partnerships to openly share information at the early, precompetitive stages of drug discovery.
I used to think of open access only in terms of publishing data and information—online sites where you could freely access data without a subscription or membership, and without payment.
Meet the Structural Genomics Consortium (SGC), the international partnership that’s taking open access to a new level in order to advance scientific research for scientists working in a variety of disciplines—structural genomics and beyond. The SGC might just become your new, best laboratory research partner.
The SGC Vision
The SGC focuses on biology pertinent to drug discovery, in particular the lesser-studied areas such as developing chemical probes, characterizing drug discovery targets, solving protein structures and developing recombinant antibodies. Their goal is to lay important research groundwork that can be used by researchers worldwide.
All of the work of the SGC is open access, meaning that there are no restrictions on the sharing of knowledge, data or reagents. SGC scientists do not file patents on their research; their aim is simply to advance the research.
A Global Consortium
The SGC was founded in 2004 as a not-for-profit public-private partnership focused on precompetitive research relevant to drug discovery. SGC labs are now based at six universities around the globe: University of Oxford‐U.K.; University of Toronto‐Canada; Unicamp‐Brazil; Karolinska Institute‐Sweden; UNC‐Chapel Hill, NC (US); and Goethe University-Frankfurt, Germany. The work done in SGC labs is chosen from a target list developed in collaboration with their partners and the SGC Scientific Committee. In addition to intellectual contributions, the partners provide funding to support the research undertaken in SGC labs. Current partners are from both private industry and the public sector, and are listed on the SGC web page. In addition to their partners, SGC scientists have hundreds of collaborators worldwide.
I recently chatted with Susanne Müller-Knapp at SGC via email and thought you would enjoy learning more about the consortium from an SGC insider. Here are some questions and her responses:
Q: Open access research is beneficial to scientists worldwide—not only discovering new information, but also making it publically available for anyone to use. Have you done research at places other than SGC, and does working at SGC feel more rewarding to you because of the potential benefit of immediately sharing results with everyone?
Dr. Müller-Knapp: I would like to stress that the SGC not only makes research data available, as the term ‘open access’ usually describes, but also does ‘open science’. This means we also share our reagents and methods and actively look for possibilities to enable this. Truly open science is costly as you have to find the means to share the reagents and even open access requires usually additional payments to the journal.
I have worked in many labs in different countries: at the University of Marburg in Germany, the Karolinska Institute in Sweden and at San Raffaele Research Institute in Italy before joining the SGC at Oxford and now at Frankfurt University. Before joining the SGC my work was mainly lab‐based. This was a very exciting time as well, and I enjoyed doing research. However, you usually communicate only with a relatively small number of peers working in the same area. Working at the SGC in an open science way has opened many more possibilities of interaction, both with other academics and also with many industrial partners and partners in Biotechs, such as Promega. Because you do not have to think about potential IP constrains, we can concentrate on the project and on collaborating which is much more exiting. Also within the SGC we are of course sharing results e.g., via electronic lab notebooks. It really is like a big family where you progress together.
Q: What do you do at SGC? Do you work in the laboratory? If so, can you tell us what you’re currently working on or about a favorite project/target of yours and why you enjoyed working on it?
Dr. Müller-Knapp: I am no longer working in the lab myself, but am supervising a small group of researchers who work on cellular assays. My main role is the management of the chemical probe project i.e., working together with a team of diverse scientists across different SGC sites (Frankfurt, UNC, Campinas and Oxford) to generate specific kinase probes.
A very exciting project we started recently is called the ‘pharma donated project’. SGC-associated pharma partners have agreed to donate probes (highly selective inhibitors) that they generated in the course of their own research and that are no longer pursued clinically. In June we had a face‐to‐face meeting with all SGC pharma partners as well as Anton Simeonov from NCATS here in Frankfurt, looking at the probe proposals from the other companies. This was a truly historic event as all these representatives from otherwise competing organizations sat together at one table showing openly the data they generated for these probes and agreeing to make the compounds and the data available to the scientific community via the SGC. To be involved in such a ‘game changing’ project is very exciting. We are currently in the process to generate a database to make the information associated with these highly characterized probes more easily accessible to the research community.
Q: Would you explain what a chemical probe is and why they are important?
Dr. Müller-Knapp: Chemical probes are potent, selective and cell‐permeable inhibitors or agonists of protein function. They are very powerful reagents and are valued reagents in both fundamental and applied biological research. Chemical probes allow the interrogation of a specific protein domain and the biological effect inhibition/activation this domain has. This insight is important for basic biology to understand the function of the protein/‐domain and also critical for target validation for the pharmaceutical industry. Chemical probes may moreover provide the starting point for a potential future drug.
The important feature of a chemical probe is its characterization and associated profiling data. Only if you know the potential off‐target effects, you can interpret a phenotypic result correctly. We therefore screen all chemical probes extensively, not only against the target and closely related family members, but also against a selection of pharmacologically-relevant off‐targets. We also aim to provide a negative control compound, with a similar chemical structure, but lacking activity on the target. Important features of a chemical probe are well described in the literature, including the article, “The promise and peril of chemical probes“.
Q: What can you learn about a protein from its structure?
Dr. Müller-Knapp: The structure provides a description of the shape of the protein. It is used to identify ‘pockets’ or similar areas to which chemical compounds can bind. By knowing the shape of the pocket you can look for chemicals that fit snugly into this pocket and interact with parts of the protein through chemical bonds.
Q: Is there an example of a structure that SGC has identified or worked on that is now being studied in clinical trials?
Dr. Müller-Knapp: The structure of the 2 bromodomains of BRD4 has been solved by the SGC. Several inhibitors against BRD4 are now in clinical trials, mostly in oncology.
Q: Is there anything else that people should know about SGC and the work that is done there?
Dr. Müller-Knapp: The SGC has several other projects besides the chemical probes project, including TEPs (Target Enabling Packages), structures, human tissue platform and an antibody project. Some are more difficult to explain (e.g., TEP) than others (learn more under the Science tab at SGC.org ). A project that is tightly connected with the chemical probe program is the patient tissue platform. The probes are being profiled in patient cell‐derived assays and thus may provide biomarker and phenotypic read‐outs that should more accurately mimic the disease itself compared to the often used cell line models. The focus is on autoimmune diseases, fibrosis, inflammation, neurodegenerative diseases and oncology.
Conclusion
Thanks to Dr. Susanne Müller-Knapp for her insights and explanation of how the Structural Genomics Consortium works, who is involved and some of the exciting research going on at this open access research institute.
Has your work benefited from information you’ve found on the Structural Genomics Consortium website? We’d love to hear about what you’re studying and if you’ve collaborated with SGC or used their open access information in your studies.
Reference
- The promise and peril of chemical probes. (2015) Nature Chemical Biology 11, 536–41. PMID: 26196764.
Kari Kenefick
