© David Robinson

Schwab’s Life’s Work

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Martin Schwab has achieved what many researchers dream of their entire lives. Due to his discovery, science now understands why injured nerves within the spinal cord don’t re-grow. It was a quantum leap that changed everything. We sat down for a chat with the 69-year-old researcher from Switzerland and soon realised that the mastermind is both astute and approachable, with a restrained modesty that intrigues

Professor Schwab, what fascinates you about neuroscience?
The nervous system is incredibly complicated and the best machine in the world. I became very interested in its development at an early stage. I was eager to understand how this miracle occurs and works.
Why did you decide to specialise in the spinal cord?
An injury to a nerve in the finger, arm, or leg is easily repaired. An injury to the spinal cord, however, is only repaired very badly or not at all. This discrepancy made me wonder. Why is that the case? Why can one part of the nervous system make a nerve fibre grow again, while another part - in the event of an injury to the spinal cord or brain - can’t? I wanted to crack that nut.
How did you go about it?
It was already known that there are factors in the tissues that promote nerve growth. Our first hypothesis claimed that the spinal cord lacks such factors. I had assembled a small workgroup and we soon found out that the hypothesis was false. One can find such growth factors in the adult brain. I then conducted tissue culture experiments by adding such growth factors to a little piece of spinal cord and brain tissue. Not a single nerve fibre grew, however. It became clear to me that there must be factors that prevent nerve growth. That was a completely new concept at the time.
Is there a way to explain the concept in a simplified way?
On a very general level, these growth inhibitors - so-called Nogo proteins - are like a red light in traffic. If one covers the red light with a bag, one can no longer see the light and drives on. So if one covers this active site, nerve fibres continue to grow.
What happened next?
I was 35 years old and invited to Zurich to work on the topic. The Swiss National Fund supported my research generously. The condition was that I needed to prove that my approach really works within three years. That’s exactly what we did. My workgroup and I managed to prove that there are new, previously unknown proteins that block the regeneration of nerve fibres. These growth inhibitors are located in the myelin, the insulating layer around the nerve fibres in the brain and spinal cord.
So there are growth inhibitors in the spinal cord. Why did they remain undetected until then?
(laughs) Many people wondered why in retrospect. Today, textbooks and introductions to publications state: “As one generally knows…” Yes, today we know. But not at the time…
How does one feel after making such a milestone discovery?
The mood can be quite euphoric at times. But one is also very aware of the high risk. Is what I claim really true? Why has nobody spotted this yet? We rely on biochemical tests in cell cultures and later in animals. It’s a long process until one is completely sure that everything is true. It’s a constant back and forth between caution and the fear of having overlooked something important. In this particular case we came to the reinforcing realisation that we are right. There is something new.
You have been in spinal cord research for many years. Do you see a positive trend?
Yes, absolutely. I believe this is one of the most important experiences in my research career. I was able to be part of this upswing. When we started our research, the injured spinal cord was nothing more than a niche area. There were very few labs and there was very little interest. It was assumed that nothing could be done anyway. In the clinics, doctors told patients with fresh spinal cord injuries: “Get used to the idea that you will spend your life in a wheelchair. Nothing will regenerate!”
The situation is different today. We are beginning to understand the mechanisms and can stimulate the regeneration of injured nerve fibres in the spinal cord and brain by suppressing the growth inhibitor Nogo-A. With this, spinal cord research was suddenly thrust into the limelight. There are always large symposia on spinal cord injuries, regeneration, and functional recovery at neuroscience congresses. It’s a huge step forward.
How has science changed in general in recent years?
Science is often dependent on techniques. Today, we can conduct fantastic experiments that would have been unthinkable in the past. We now know a lot about biochemical mechanisms and can intervene. We have methods to visualise nerve fibres, fibre growth, and regeneration. We are capable of acutely influencing the activity of fibres, as well as deactivating or stimulating a regenerated nerve fibre. This provides us with evidence that what we do is meaningful and correct from a therapeutic point of view.
What is the long-term goal in terms of Nogo-A?
Once one blocks the Nogo protein with antibodies, small new branches grow out of the injured fibres within two to three weeks. They seek a way around the scarred area of the spinal cord. In injured rats, they grow centimetres down the spinal cord in some cases. At the same time, the animal regains its ability to move. In other words, these newly formed fibres and connections have restored meaningful circuitry that enables the brain to regain control of the spinal cord. Throughout my career, I have always maintained close contact with my medical colleagues and I know that some functions can be restored during a good rehabilitation process. Combining antibodies and rehabilitation yields excellent results. We now believe that growth comes first. It creates new hardware that needs to be trained. Training is an integral part of the process that creates new functional, meaningful interconnections. That’s what we’re promoting right now.
Does this mean there could be a breakthrough for patients within the next few years?
We certainly hope so! We were always extremely cautious in the past. The journey from an animal experiment - under heavily controlled conditions - to the clinic is very long, not least because of regulatory measures imposed by drug licensing authorities. One needs to invest years of work. But we have covered a large part of the journey. We’ve already conducted a large phase 1 study with Nogo-antibodies involving patients with fresh spinal cord injuries. The aim was to determine the antibody dosage in humans. The study was aimed at showing that no side effects occur, and was very successful. A 3-year efficacy trial in leading European clinics will start this year. It will determine whether a potent antibody against human Nogo leads to a functional improvement for patients.
What else are you currently working on?
As is often the case in research, we discovered something by accident. If one stimulates a small area in the midbrain base of a rat with a spinal cord injury that has destroyed 90% of the fibre tracts within, it can run and swim again. We sat down with clinicians to try the same procedure on patients. If we stimulate daily and train patients on a treadmill, can they walk better without stimulation at some point? Does the circuitry change in a manner that someone with so few surviving nerve fibres can regain control of his or her spinal cord and control walking? The stimulation experiment on patients who can stand, but not walk, after a spinal cord injury is about to start. Wings for Life has agreed to finance the fundamental research.
That sounds promising. Do you think we will have a cure soon?
A spinal cord injury affects millions of nerve fibres. Picture a thick fibre optic cable connecting two computer centres. A bomb explodes in that cable. We may never be able to repair all the damage. But restoring important functions such as breathing, bladder and bowel control, standing, and walking - perhaps from the bed to the bathroom - is a goal we could accomplish in the near future.
How do you work on such progress?
I work with my workgroup, which consists of 15 to 20 molecular and cell biologists. They deal with the molecular and cellular processes of nerve regeneration. Some work on animal experiments, while others handle the rehabilitation process of the rats or observe brain injuries and strokes. Everything is held together by the big question: How does the spinal cord work and how can we restore its functions after an injury? We want to improve conditions for patients.
What role does regular exchange play in this context?
Communication is enormously important. The group works together closely and is constantly in dialogue with each other. We also schedule a 2-hour lab meeting every week. In addition, I have a one-on-one talk with everyone every Friday. I’m in the lab every day and the door to my office is always open. Team spirit is very important to me. I don’t want my team to compete internally, but I want us all to work together and help each other out.

Martin Schwab at the Wings for Life Scientific Meeting (David Robinson )
Martin Schwab at the Wings for Life Scientific Meeting  © David Robinson

Do you ever tire of asking new questions?
(laughs) That’s just how we researchers are. It is fantastic to work in this group of young people. They are all 100% motivated. 10 to 12 hour days are commonplace and it isn’t unusual for someone to visit my office with a question in the evening. We then spend hours together at the microscope, endeavouring to understand new observations. The intellectual challenge is wonderful.
One can say that you have dedicated your life to research, right?
That’s probably true. This also means that one has very little free time. It’s a real problem for families. My wife and I don’t have children. Children deserve time, so one really shouldn’t come home as late as 9pm every day.
Were you forced to decide between child and career?
You have been married to an artist for 33 years. Are there any professional parallels?
There are to a certain extent, yes. As a researcher, one also needs to take a step back when considering a new idea. One needs to put aside what is seen as established knowledge today and think in other directions. This creative step isn’t easy. It helps me to sit in my wife’s studio in the evening and watch her paint. Her completely different way of working allows me to gain some distance to my everyday life.
What helps you to switch off properly?
We have a very beautiful garden. I enjoy working in it on the weekends. I don’t really have a hobby in that sense. After all, a part of my job is my hobby.
What would you like people to say in 200 years when they read your name?
We are a large community of researchers and everyone contributes. Of course it would be nice if people still remember that I made an important step after such a long time. But I didn’t achieve that alone. It was always with my team.
What do you expect from the future?
My immediate goal is to really push ahead with these clinical Nogo antibody trials and hopefully get a good result. Then we need to create structures that ensure that this new therapy can be implemented on a grand scale. I hope I can stay in good shape myself - not least in my head - to be able to continue working within the given framework. Naturally, one gets older and one needs one’s health to play along too. But as I said before, interacting with brilliant young people every day keeps you young. I would like to experience this as long as possible, which is why it doesn’t bother me to forego holidays.

Neurobiologist Martin Schwab studied biology with a focus on neuroanatomy at the University of Basel. He subsequently conducted research at Harvard and at the Max Planck Institute for Psychiatry in Munich. From an early stage in his career, he was a pioneer in detecting nerve growth inhibitors and contributed numerous publications to renowned scientific journals. He has been working at the Institute of Brain Research of the University of Zurich and the ETH Zurich for 33 years.