In the age of “Big Data”, hypothetical coding sequences and poorly characterized proteins are common. Transcriptomic and proteomic datasets regularly result in disappointment, as the top hit is often some unknown and almost certainly irrelevant protein. Let’s say you perform such an experiment and your top hit is RNF128. A quick Google search reveals that RNF128 is an ubiquitin ligase found in anergic CD4+ T cells – maybe the $20,000 experiment to identify something that resembles a license plate was not in vain! You perform silencing/targeted knockout studies in vitro, which show RNF128 is indeed important in your cells of interest.
But where do you go from here? There are virtually no reagents available to further investigate this protein, which only has 6 PubMed articles. You need to turn to Dr. Aled Edwards and his public-private partnership, the Structural Genomics Consortium (SGC). They will be able to figure out the structure of RNF128 and set you up with medicinal chemists who can rationally design an inhibitor or, with their recombinant antibody production facility, generate reliable reagents to probe for RNF128.
The SGC was established in 2003 with the goal of bridging the gap between industry and government-sponsored academia. This was an era when Big Pharma was failing to produce many first-in-class drugs despite huge increases in investment. It was also in the post-genomic era where one could examine every gene in the human genome, yet research remained focused on only a handful of well-characterized proteins. The idea was to combine the efficiency and resources of industry with the flexibility and knowledge of academia, together with the support of government funding. The catch: all research performed by the SGC would be made immediately available to the public. It would be open source; any researcher worldwide could download the structure or request the inhibitor to study new targets in a model of their favourite disease.
At a glance, such an approach is idealistic and puts the interests of the SGC stakeholders in direct conflict. For example, Big Pharma wants to obtain IP and exclusivity on research they fund. Academics want to push the research boundaries and obtain publications without restriction. Government funding agencies want translational research with the potential to stimulate the economy. So how does the SGC ensure that all parties benefit?
First and foremost, all stakeholders are equally represented on the board of directors. Target-enabling packages ensure that anyone can submit a locus or molecule of interest for research – even you can! Pharmaceutical companies who have invested in the SGC, such as Novartis, Abbvie and GlaxoSmithKline (GSK), are able to direct research by submitting a list of desired molecules to be examined. To keep the intentions of these pharma companies confidential, these lists of targets are anonymized and mixed with submissions from the public sector. All submissions are screened by the board and a hit list is assembled with preference given to uncharacterized, neglected molecules without reagents. Through indirect collaboration via the SGC board, companies develop an awareness of what other firms are pursuing, resulting in less unintended competition.
THE RESULT IS A SYNERGY BETWEEN THE PUBLIC AND PRIVATE SECTORS WITH THE POTENTIAL TO ACHIEVE RESULTS BEYOND THE CAPABILITY OF ANY SINGLE ORGANIZATION.”
Meanwhile, the aforementioned open-access policy is aligned with the ideals of the public sector. The government gets direct economic stimulation from Big Pharma investment into research with the potential to improve the health and wellbeing of citizens through the discovery of new drugs. Academics benefit through gaining resources and technical knowledge that help them better examine poorly studied targets. The result is a synergy between the public and private sectors with the potential to achieve results beyond the capability of any single organization.
A recent success story highlights the strengths of the SGC’s strategic public-private partnership. For years, GSK had been designing small molecule inhibitors for bromodomain proteins, which comprise a class of epigenetic modifiers. Although GSK developed very successful inhibitors for these proteins, they found no obvious indications in inflammatory disease, the area on which they were focusing in preclinical work. In collaboration with the SGC, the inhibitors were carefully characterized and released to the public via Sigma-Aldrich. One such molecule, GSK2801, was made commercially available in 2009. Within a couple of years, researchers had quickly examined the inhibitor in animal models of cancer, with promising results. Big Pharma was able to use this preclinical data to further develop the molecule for application in cancer treatment. Clinical trials were initiated just 3 years after the drug was made public. Without public partnership, Big Pharma would not have achieved such rapid progress and may never have considered cancer as an indication for this particular class of small molecule inhibitors.
IMMpress Magazine caught up with SGC CEO and University of Toronto professor, Dr. Aled Edwards, to hear his take on the SGC and the future of open drug design.
IMMpress: What drove you to initiate the SGC?
Edwards: As an academic, I felt the way to make change was to develop ideas as a small biotech company. With this in mind, I started Affinium Pharmaceuticals in the late 1990s here in Toronto. I raised $30 million in capital before leaving the venture to my partner, Owen Roberts in 2002. Affinium was successful in developing and bringing a novel antibiotic to clinical trials, however this experience made me realize that the system for drug development was broken. For-profit drug design was flawed as it was driven by finances rather than science as a result of the undirected evolution of the pharma industry. Despite a handful of successes, the biotech industry was in no better a position owing to the enormous die-off of unsuccessful firms. At the same time, the scientific enterprise is flawed in that grant review panels are biased towards supporting the known. Grants are rarely awarded for the study of completely novel or hypothetical proteins. 70% of current research focuses on a handful of established molecules discovered in the pre-genomic era. Fine tuning the drug development system as it stands won’t work as the scientific underpinnings are lacking. I felt drug discovery needed a new ecosystem to reboot it. This led to the concept of pairing public-private enterprises in a completely open process in the form of the SGC. Essentially my vision was to draw on the strengths of all sectors to generate future drugs in a completely open fashion.
IMMpress: Was it difficult to convince other academic institutes and industry to sign on?
Edwards: Fortunately for us, we had [the] full support of UK and Canadian government funding agencies from the get-go. Good ideas supersede borders; we now have over 250 scientists in 6 academic centres led by world class scientists with pharma experience. Pharma now sees the benefit of such a partnership. GSK was the first company recruited, initially on philanthropic grounds. Once the success of the SGC philosophy became apparent, other companies signed up. We now have 9 partnered companies who have donated more than $7.5 million each. We just received an additional $5 million from the Bill & Melinda Gates Foundation for neglected tropical disease research.
IMMpress: How has the SGC changed over the years?
Edwards: We initially focused on characterizing protein structures. Our success in rapidly resolving and freely releasing structures led us to the next phase of small molecule design. To achieve this we branched into medicinal chemistry…. [E]very advance the SGC has taken is met with cautious hesitation. It is surprising how change is resisted, yet 5 years down the line once the advance is brought to fruition we have full support.
IMMpress: What do you see for the future of the SGC and the concept of open drug design?
Edwards: Our first question is always “how will this discovery have an impact?” not “how can we commercialize this target?” Reframing the drug design philosophy in such a way is essential to drive future endeavours. We now have hospitals involved and are working towards taking molecules into clinical trials. We want to push for open drug development to complement open drug design as we see this as the future. Although we have focused on cancer, we’d like to branch out to autoimmune disease. With huge advances in the genetics of autoimmune disease, new targets have been identified that are begging to be researched!
IMMpress: How much of your schedule is occupied with running the SGC and how do you balance this with your personal research, teaching, admin work etc.?
Edwards: You have to commit 150% to anything you do. With my children grown up and out of the house, and my wife a successful engineering professor, I am able to commit fully to the SGC. I don’t believe success can flourish when balancing multiple roles. My position now requires visiting sponsors and academic sites around the world on a regular basis from Brazil to Sweden. Last week I was in Cincinnati and Montreal, the week before, San Diego.
IMMpress: A final question on the mind of many who have met you: Why the shorts? Is this fashion statement really a philosophical statement?
Edwards: When it’s hot out, I wear shorts. When you go to a big pharmaceutical or medical conference, everyone wears suits. They all look the same, but dressing for the part is impractical. At these meetings you have the most innovative people on the planet just trying to fit in. It makes no sense! I judge someone by their talent, potential or business acumen, not by their clothes!