Stroke: Treatment Development

Associate Professor David Howells discusses the integration of basic and clinical science in the development of treatments for stroke.

Hello, I’m associate professor David Howells, Associate Director of the National Stroke Research Institute and Head of the University of Melbourne Neuro Regeneration Research Laboratories at the Austin Hospital. I joined the Editorial Advisory Board of the Virtual Neuro Centre 2 years ago and today I would like to share with you my insights on the integration of basic and clinical science.

The main interests of the lab are stroke and spinal cord injury. Our goal is to stop brain cells dying after these injuries and get them to regenerate so the patients regain function. Much of our effort is devoted to moving promising areas from the laboratory to the clinic. In this respect we’re very fortunate in having clinicians, such as Geoff Donnan and Peter Batchelor, as integral members of the team. Although stroke is as common as heart attack, it’s a poor cousin in terms of the financial investment and our ability to treat the disease. This is largely a reflection of history. It’s only really in the last decade that we’ve had treatment that works. Before this time, you just had to be one of the lucky patients who did well. This made it hard to recruit laboratory researchers and to generate the money needed to do the research. This all changed with the advent of tissue plasminogen activator or TPA for short, a drug that helps break up the clot that makes part of the brain die. All of a sudden we had something to work with and a new excitement for making even better drugs that would work in more people.

An important concept in stroke is that you have to break up the clot, which obstructs blood flow to all other major arteries of the brain. The longer it takes you to do this the worse the outcome is. TPA can do this but unfortunately it’s only useful in the small group of patients who get to the hospital quickly. Sadly, stroke victims and their relatives often don’t realise this need for speed.

My research team’s interest is to help develop a drug that could be given to a broader range of patients and stop the stroke growing while the sophisticated assessments that are needed for safe use of TPA can be performed. This is a concept known as neuro protection. Around the world there are now many laboratories that can make this work in animal models of stroke. But despite the success, our attempts to get the same drugs to work in people have failed.

With other researchers, and in particular Malcolm Macleod in Edinburgh and Bart van der Worp in Utrecht, we’re consolidating the data from around the world to see if we can identify a common theme that will explain why we have failed so far and what we need to do to make sure the next drug tested has a better chance of success when given to stroke patients. As we learn more about how strokes happen and the biology behind how drugs work in the laboratory, the prospect of getting a drug to work in people increases.

The key to this is ensuring that scientists like me work closely with stroke doctors. We need to make sure our enthusiasm doesn’t make us push drugs forward for use in patients before they are ready and we need to make sure that the clinical trials take into account any limitations that might have been revealed in the laboratory. For example, hypothermia or chilling the body is perhaps the most effective way of limiting the size of strokes in animals. It also works in other disease models such as traumatic brain injury, which attempts to mimic injuries like those sustained after car accidents, suggesting it has broad applicability. Importantly, we already know that it provides an effective way of protecting other tissues such as the heart during surgery. However, mice and rats are very easy to cool because they’re small. It takes much longer to chill the human body by 3 or 4 degrees. We also still need to ask many questions: do we need to cool the whole body or just the head? With further research, could we identify the switches of the body that trigger the protective effects we see? While the latter might seem a little farfetched, you should remember that other mammals have strong diving reflexes that allow them to go without high oxygen concentrations for considerable periods of time. Other mammals can hibernate, switching off most of their metabolic processes. The brains of fish such as the carp and some turtles can survive on virtually no oxygen for extended periods of time. Another major difference is that when we apply hypothermia to animals they are usually deeply anaesthetised because of the community’s quite appropriate concerns about the ethics of animal research. We can’t readily do this in old frail people so they would have to suffer the extreme discomfort that cold imposes and also the risk of quite significant secondary complications, such as pneumonia.

So you see, even for a fairly simple approach like chilling we still have a lot of very practical issues to work through. This requires team work, a tuning and flowing of the ideas and experiments between the lab and the clinic.

Above all we must not let past disappointments slow our drive to examine new possibilities and work through the practicalities of taking them from the bench to the bedside. After all, if our colleagues in cancer or transplant research hadn’t pushed on we still wouldn’t have effective treatments for childhood leukaemias or the wide range of life saving transplants that are in routine use today.

Thank you for watching. Have a great day.

More information on stroke