CHDI recently appointed Keith Elliston, PhD, to the newly created position of Vice President for Systems Biology. Per the announcement from CHDI, this scientist brings the right mix of computer and biology skills to advance drug development in Huntington's disease (HD) by bringing a systems biology approach.

Systems Biology approach? What is this? And how can it advance drug development in HD?

Systems Biology is a scientific approach that starts with the big picture, analogous to looking at an overview of the forest. This contrasts with the present target approach to drug discovery which first looks at, and is limited to the details of a single (target) tree.

Why do we need Systems Biology? The simple answer: Adding this approach will likely improve our chances for finding drug treatments for HD. In the past 30 years or so, scientists in the drug industry have been able to develop drugs using a process that first identifies a molecular target, which in most cases is a particular chemical reaction that is thought to cause disease. Chemists then synthesize, or build a drug aimed at that target. This works pretty well if the disease mechanism is relatively simple, such as that for most infectious diseases. However, as the last decade of slow new-drug development has shown, it is much harder to find drug treatments for more complex diseases like cancer and diabetes which have many causes and therefore many targets.

Huntington's falls into the complex-disease category. Though due to a single gene abnormality, from the biologic perspective HD is a very complex disease because the abnormal huntingtin protein affects many different cell systems. Indeed hardly a month goes by without identification of new problems -- and new drug targets - for HD. Already there are literally hundreds of cellular chemical reactions that are known to be abnormal in HD. And because many of these abnormal chemical reactions in turn affect many others, the abnormal reactions that are known is probably just the tip of the iceberg.

How Complex? Scientific laboratory study shows that normal cell function (depicted below) is complex. Just imagine how much more complex it becomes when hundreds of these pathways are affected by the mutant huntingtin protein.

Complex network diagram

Certainly stopping HD at its source by preventing the action of the mutant protein (as in RNA interference strategies) would be effective. However this therapy would require delivery of drug directly into brain, a relatively high risk type of treatment. What are the best alternative strategies when there are so many different cell problems and targets? Systems biology may be able to help.

Complex network whiteboard

Using systems biology technology, computer scientists can capitalize on the large knowledge base of HD biology (gained through lab experiments) to create computer models. When there is sufficient laboratory research information available, systems biology methods can make data-based predictions about the success of drug development programs. This kind of systems biology "big picture" analysis has potential to:

  • Identify specific cell systems (metabolism-energy for instance) that are more likely to be critical to Huntington's disease -- so that greater effort can be concentrated in those areas.
  • Predict potential importance of different drug targets within a system (how likely is the the major energy problem of HD due to mitochondria energy systems, or does it happen in cell systems before mitochondria). For instance, even if a drug is found to work at a particular target (mitochondrial target), this drug will have a low likelihood of success in clinical trials if the target (mitochondrial) doesn't play an early (upstream) significant role in the disease process.
  • Inform lab scientists on the types of experiments needed to answer drug target questions.
  • Predict new drug side effects. Even if effective at an important target in HD, unwanted "off-target" side effects can cause a new drug to fail. If off-target effects can be predicted, scientists can attempt to change the structure of the new drug so that fewer side effects are likely to occur before it goes to clinical trial.

Author comments: Systems biology adds an important perspective to efficient drug development for HD. The basic research community of scientists have provided a large base of information on many individual targets in HD, such as caspase inhibitors, KMO inhibitors, etc. for which many drug programs are progressing based on target information alone. Since realistically we can't take them all to clinical trial, we hope that systems biology techniques will help predict programs more likely to be successful. It is important to remember that systems biology is a tool, and by itself won't be the answer. However coming at the problem from both perspectives, target identification and systems biology should improve the chances for finding HD drugs.

Welcome aboard Dr. Elliston. We look forward to learning more about this CHDI program.