Magazine Article | September 28, 2012

The Only Path To True Innovation In Drug Discovery

Source: Life Science Leader

By Philip Haydon, Ph.D., chair of neuroscience at Tufts University and president and cofounder, GliaCure, Inc.

Going against established thinking can be an uphill battle, but the payoffs can be huge in both academia and business. To achieve such payoffs, a scientific leader needs conviction, tenacity, and perhaps a slightly stubborn streak.

When I took my first faculty appointment in neuroscience in 1986 my work focused on neuronal signaling. In 1992 we had an experimental result that seemed to make no sense — in a dish of cells in which we had killed all of the neurons, we could still measure chemical signals. How could this be? I could draw only one conclusion: glia cells, the only cells left in the dish, must be releasing the same chemical transmitters as those released from neurons.

Glia. Even the name — Greek for “glue” — suggested that these were merely support cells. But why had no one questioned this assumption? As is so often the case, scientific inquiry was limited both by established thinking and by the tools and techniques available to ask the novel question. Electrical recording and stimulation techniques had allowed great insights to be made into neuronal function and the development of the field of “neurosciences.” Glia, by contrast, are electrically mute. Their signals could not be picked up using these techniques.

Not A Popular Conclusion
Our suggestion that glia not only release chemical transmitters but also play a key role in the modulation of synaptic transmission was not well accepted for a long time by neurocentric scientists. Fortunately we were confident in our glial hypothesis and ignored this advice. Along with other groups, we went on to identify how glia can play an active role in the brain and how different subtypes of glia serve different functions. Astrocytes, for example, which are the most plentiful glial cell in the brain, modulate synaptic transmission, plasticity, learning, and memory and play pivotal roles in the control of sleep. Microglia, another glial cell type, hold promise as therapeutic targets for Alzheimer’s disease.

In the past 20 years skepticism has turned into success. The study of glia is now recognized as vital in understanding brain function. Our research has been so successful that we have formed a company — GliaCure, Inc. — to identify and target glial-based signaling pathways for the development of new drugs. As we gain an understanding about the biology and put this in the perspective of translationally relevant disease models, we have then been able to ask whether such targets have the potential to offer therapeutic opportunities. This strategy has already led to the synthesis of novel chemical entities targeting Alzheimer’s disease that we will soon take into IND (Investigational New Drug)-enabling studies. Further down our development pipeline, we have identified new targets for sleep disorders and fastacting antidepressive therapies.

We identify those new targets by looking for glial-enriched receptors that are preferentially expressed in this cell type. For example, it is known that the pressure to sleep is controlled by the accumulation of the extracellular signal adenosine. Through our basic investigations of glia and the use of molecular genetics, we have discovered that a subtype of glial cell called astrocytes is the cell that is responsible for the regulation of the amount of adenosine in the extracellular space and, as a consequence, homeostatic sleep responses. Due to these insights, we are now identifying the signaling pathways which control the release of adenosine from astrocytes with the long-term idea of specifically activating these pathways to control adenosine release and consequently sleep.

A Frustrating Approach
Our approach to drug discovery — going against the literature — has at times been very frustrating. However, we believe that, while a healthy respect for the past has its place, innovators have to have the courage to break away from the crowd. It is essential to take risks away from the common focus so you can make quantal jumps forward. However, one of the difficulties of going against dogma is to find backers who will invest in this approach. Thus, it becomes important to recognize that there is a need to invest outside of the mainstream in high-risk high-payoff areas.

Our approach doesn’t guarantee success, but the success it does lead to is truly rewarding.