What is (Quantitative) Systems Pharmacology?

By John Russell 

January 10, 2012 | The Russell Transcript | Just a few days apart in the middle of October, Harvard Medical School (HMS) announced a broad initiative in systems pharmacology and NIH released a like-minded white paper, Quantitative and Systems Pharmacology in the Post-genomic Era: New Approaches to Discovering Drugs and Understanding Therapeutic Mechanisms. That’s a fair amount of attention from two very big guns on a topic that may ring both familiar and unfamiliar. 

Actually systems pharmacology has been loosely percolating for some time. While not exactly a splinter from the systems biology world, systems pharmacology shares much of systems biology’s methodology and conceptual framework. Indeed, the Harvard Medical School systems pharmacology initiative is being launched from its systems biology department and one of the NIH paper’s lead authors (Peter Sorger) is a member of the department. 

Nuanced definitional wrangling aside (sure to be fun), what distinguishes systems pharmacology is its laser-like focus on compounds and how they perturb biological systems and pathways. How specifically do compounds—failed and successful drugs as well as others—work in the body? What are the detailed mechanisms? How are they influenced by various ‘omics? How do they vary by tissue? etc. This is a great idea, which is not to say such activities weren’t part of the broad the systems biology world. 

The practical implications of such a compound-centric approach are exciting: new targets, new screens, new markers, new understanding of drug failure mechanisms. Indeed sophisticated drug failure analysis may be one of SP’s most promising goals and eventually most rewarding contributions. (FDA should open its treasure trove of information for these efforts, but that’s another matter). It’s a fairly firm rule-of-thumb that the biopharmaceutical industry doesn’t spend a lot of time or resources investigating why drugs fail.  

Helping launch, promote and develop systems pharmacology as well as delivering concrete SP results are the main goals of the Harvard initiative. It is being led by William Chin, executive dean for research at HMS; Marc Kirschner, chairman of the HMS Department of Systems Biology; Peter Sorger; and Tim Mitchison, deputy chair of the department. The ambitious plan calls for adding faculty (10), tackling research, establishing new research infrastructure, and collaborative outreach to biopharma, other academia, and biomedical communities.  

SP in Practice 

According to the Harvard SP announcement, “The initiative will support both new approaches in translational science, such as failure analysis on unsuccessful drugs and use of chemical biology to develop probes of biological pathways. It will also include a new educational program, one that develops a new generation of students, postdoctoral fellows and physician-scientists, the future leaders in academic and industrial efforts in systems pharmacology and therapeutic discovery.” 

Obviously everything won’t happen at once, but Kirschner and colleagues are charting the path forward. “One project already going on in our place and at MGH (Massachusetts General Hospital) is a study of the drug Taxol,” he says. “It delivers nice understandable effects in some cell cultures but the effect on human xenograph tumors in the mouse, when viewed by intravital imaging, shows the drug acts in a very different way there. We have a lot to understand about drug action not only in cells but also in more complex environments.” 

Kirschner resists the notion that systems pharmacology is an applied science, “I’m not a big believer in distinguishing at least in the early stage applied from fundamental. People were trying to understand how to make steam engines more efficient and we ended up with thermodynamics. [Y]our goal may be to make nylon but you end up having to figure out all physics and chemistry surrounding polymers and how they assemble and interact. [That] gets to be very fundamental.” 

Biopharma’s response has been positive, Kirschner says. Industry execs he’s talked to believe SP can have practical benefits. They also agree the effort is best led by academia, given that economic pressures are prompting even the biggest drug makers to downscale research, especially basic research. It’s also more difficult for biopharma to attract the multi-discipline talent required to pursue SP properly, says Kirschner.  

One question is how to measure SP progress and impact. Broadly speaking, “[It] can be looked at in two different ways,” says Kirschner. “If the goal was to achieve some specific target for a specific disease, I think the likelihood of that happening quickly is small. On the other hand if the goal is to achieve significant information and tools useful for the development of targets in some disease, that likelihood is quite high.” 

In the end, he says, systems pharmacology is an open-ended exercise and biopharma will have access to the results. Systems pharmacology and framing it as a compound-driven exercise is great idea. Let’s see where it leads. • 

This article also appeared in the January 2012 issue of Bio-IT World magazine.