With less than 2 weeks to go until the CPN Challenge’s Stage I grants’ deadline, we interviewed Professor Norman Saunders from the University of Melbourne, who is a member of the CPN Science Advisory Council. He shared with us his thoughts about our 10 year Challenge Program and also gave some advice for solvers.
Conquer Paralysis Now: Interview with SAC member Norman Saunders
1) What is your scientific background and how did you end up researching spinal cord injuries (SCI)?
I studied medicine and physiology at University College London from 1957-1967. This was long before the days of MD-PhD programs, but is was also long before the days of computer records, so I was able to save a bit of time by being registered in both Faculties of Medicine and Science without any of the administrators noticing. My PhD was on peripheral nerve regeneration, so I have been aware of neurotrauma problems for the whole of my career. Because of a publication reporting that nerve growth factor (NGF) could promote regeneration in the spinal cord, a pharmaceutical company asked me to test the possible effects of nerve growth factor on nerve regeneration (we could not detect any, although it had some other interesting effects). That was my first experience of a false dawn in the field of spinal cord research and perhaps the reason that I am profoundly skeptical of many of the claims made by people in the field.
In 1983 my wife, Katarzyna Dziegielewska, and I had the opportunity to visit Australia to do some blood-brain barrier experiments in the pouch young of several marsupial species. When we moved to Southampton in 1986, where I was head of the department of Physiology & Pharmacology for a few years, we set up a colony of another marsupial species, South American Opossums. Marsupials have the big advantage that they are born at a very early stage of development, roughly equivalent to a rat or mouse embryo 2/3rds of the way through gestation. We used them for some blood-brain barrier studies, which we continued on moving to Australia in 1992.
While we were still in Southampton, a good friend from University College days, John Nicholls, had recently move from Stanford University to the Biocenter in Basel. John was interested in spinal cord regeneration and wondered how a newborn marsupial spinal cord would respond to injury. We set up a culture system and found that such cords responded to injury with a profuse growth of axons across the injury. John continued culture experiments with a number of colleagues and students after we moved to Australia. A limitation of cultured spinal cord is that is a bit impractical for the study of behaviour. So once we were established in Australia (initially in Tasmania and later in Melbourne where we are now) we started to do in vivo experiments in opossums. These gave the remarkable result that flowing complete spinal cord transection in the first 2 weeks of life numerous axons grew across the injury site (some were regenerating but the majority were growing as part of normal development). When the animals grew up they could run climb and swim almost as well as uninjured animals.
2) What type of research are you currently working on and what are the potential implications?
We are currently working on recovery from spinal injuries made at different ages in newborn and postnatal South American opossums. An important part of the explanation for the remarkable recovery of these animals is that the inhibitory mechanisms described in the adult spinal cord do not develop until 3-4 weeks of age. An unexpected finding was that opossums with spinal transections made at 4 weeks of age did not grow any axons across the injury site but they could walk (although not use their hind limbs for swimming). We think that the explanation for this is that the spinal cord circuits below (caudal to) the lesion, which were isolated from their normal connections with the brain at 4 weeks of age when the spinal cord was cut, seem to be able to respond to the sensory information from their hind limbs which drives what is called the central pattern generator in the lower part of the spinal cord. This generator produces the normal alternating movements of the hind limbs. Although these opossums can walk quite well when put into a swimming tank they cannot use their hind limbs to swim. When they climb out of the tank and their feet touch the ground they are able to walk again. Placing the animals in water removes a lot of the sensory information to the hind limbs and then cannot move their hind limbs. This is restored when they are out of the water.
My group is also involved in 2 other spinal injury projects. One is to evaluate some new compounds that appear to have neuroprotective effects in adult rats with spinal cord injuries. This of course is a well-established approach to attempting to ameliorate the early effects of spinal cord injury. None of the numerous attempts to do this have so far translated to patients. It remains to be shown whether the 2 families of compounds we are testing will be effective, but I think this will be clearer by next year.
The other project is quite different and in my life-time is probably the only one that will contribute to the well-being of people with spinal cord injuries (and many other disabilities), and involves the use of real-time sailing simulators. These are used to teach people with a whole range of severity of spinal cord injuries (and other causes of disability) to sail on dry land. After about half a dozen sessions of about 45 minutes., all of the people we have taught so far have been able to sail on their own. Some compete including a woman from New Zealand who represented her country in the last Paralympics. There are simulators in Auckland, Baltimore and Melbourne, which between them have been used to teach over 100 people with disabilities (including tetrapelegics) to sail. We are currently running trials to measure the effects on physiology and well-being.
3) What is the most challenging aspect of SCI research right now? The most promising?
I think the general challenge is that in spite of 30 years of intensive and expensive research we still do not have much that is helping people with spinal cord injuries.
Some of the reasons for this were highlighted at a workshop organized by NIH in 2012, a summary of which was published in Nature (Landis et al., 2012, doi:10.1038/nature11556). This included a report from Shai Silberberg (NINDS) showing that papers describing attempts to treat a wide range of neurological disorders in animals were seriously flawed in basic elements of experimental design (power, randomization, blinding and choice of appropriate end points). At the same NIH workshop Ossie Steward presented a report of attempts to replicate about 12 of the apparently most promising preclinical papers describing attempts to treat spinal cord injuries. None could be successfully replicated (Steward et al., 2011; doi:10.1016/j.expneurol.2011.06.017).
The spinal injury field, with strong encouragement from NIH and some journals is now trying to improve standards. It remains to be seen how successful this will be, particularly given that the Stroke field recognised these problems more than 10 years ago and has gone to considerable efforts to promote high standards in basic science. But so far not much new has translated to stroke patients.
Preventing the effects of secondary injury would seem a good way to go, since much of the disability following injury seems to be attributable to the progressive destructive changes in the hours and days after injury. The processes involved have been extensively studied, but so far none of the proposed treatments have been effective, perhaps for reasons highlighted in the NIH workshop.
4) Why did you decide to collaborate with Conquer Paralysis Now?
I was attracted by the approach. The field needs new ideas and new people. Without wishing to cause offence, my observation is that the field is too wedded to a limited range of experimental methods (some of which are not very good) and approaches and the peer review system discourages innovation. I can vouch for this from personal experience. I think the opossum project has gone to our Medical Research Council (NHMRC, Australia) about 20 times in various forms and but has never been supported. The response from various charitable funds has been similar in some case with the question ”why are you not working on rats?”
5) The Conquer Paralysis Now Challenge will award nearly $20 million in grants and prizes over the next 10 years. What is different about this Challenge compared to traditional sources of funding?
The criteria are clearly different from the traditional ones: “out of the box” promotion of collaboration which is often poor in the field because a lot of people seem be to wanting to be the one to ’cure’ spinal cord injury. Medicine can do a good job of patching people up so that they can lead a tolerable life. Cures in the sense taking people back to where they were before their accident or illness occurred are not so common. Also bringing new people into the field. It often seems not to be realised that major advances occur when new people come into a field, perhaps they are not blinkered by the prevailing ideas in the field and come with fresh approaches.
6) How would you respond to those who believe it is too ambitious to think we can restore functions of people suffering from chronic paralysis?
Spinal cord injury is undoubtedly a difficult problem to deal with. But I think with a gradual approach of trying to improve function and well-being with less overoptimistic interpretation of what prove to be unrepeatable experiments then I do think that progress will be made.
7) Any final words of advice or guidance for people looking to enter the Challenge?
Think imaginatively and don’t take too much notice of what is already happening in the field (it isn’t working!). Try to do the best experiments you can. A negative result is not a failure. Providing the experiments were well done it shows that a particular approach in the context of how it was tested did not work and is therefore not worth following up or fro others to repeat. A negative result from some really well conducted experiments is worth more than poorly conducted experiments with an apparently positive outcome. Although of course I hope that your experiments do work!
You can enter and find out more about the CPN Challenge here