Renewing the nervous system

20 April 2016

Medical dramas on television are full of gasp-inducing accidents miraculously patched up in under an hour. Being crushed under a truck during a bridge collapse ends with a man’s arm stitched back with floss and recovering with his family while the inordinately attractive doctors turn to their personal lives. But in reality, the body’s work is just beginning. The next few weeks are of particular interest to Dr Eddie Ma, a researcher at The City University of Hong Kong focusing on the intrinsic molecular machinery of central and peripheral nervous system regeneration after injury.

The peripheral nervous system (PNS) wraps the brain and spinal cord, the cable connecting a printer to a mainframe, as it were. Peripheral nerves relay sensory information from around the body to the brain, which then sends instructions back to muscles. Damage to a peripheral nerve cripples the muscle it controls, losing mass and motor function. 

For instance, a torn brachial plexus, very common in high-contact sports, involves damage to the network of nerves in the shoulder that conducts signals from the spinal cord to the arm and hand. While it does have the ability to regenerate, there are significant limits, especially in the slow rate of 1 millimetre per day. Nerve regeneration from shoulder to fingertip would take at least two years, and only partial arm movement could be hoped for even after a year of therapy, in which time the joint and muscle would atrophy.

Nervous System Regeneration

The knowledge gained through study and research on PNS regeneration would have far-reaching impact. Reviewing how scientists look at the disease model for peripheral neuropathy, commonly known as side effects, would be especially valuable, such as in cancer cases where attacks on the PNS cause nerve damage and neuropathic pain. Accelerating axonal regeneration could also be extended to treatment of neurodegenerative diseases and autoimmune neuropathies, both of which are on the rise.

While central nervous system (CNS) regeneration also continues to be studied, the system is less conducive to recovery, and side effects are a major concern of some therapies. The PNS environment is less hostile and supports neuron growth, but the trouble here is that regeneration is still too slow over long distances. 

This problem is primarily concerned with axon growth during the critical window, the period between initial injury and irreparable muscle atrophy, which varies according to the nature of the injury. Sensory function usually returns first, but recovering motor function outside this window is nearly impossible, even if the nerves regenerate and reach the muscle, requiring better immediate care options.

While extending this critical window is a research concern, another is to further fundamental understanding by determining common biochemical pathways for intrinsic growth capacity. Using traditional Chinese medicine remedies, a few promising herbs have been identified, following the chemical pathways they activate in PNS, with a 40-50% improvement in healing time. Low-dose ionised radiation after injury also shows accelerated recovery at a rate of over 40%. Both boost axon growth, helping to bridge the gap between two broken nerves. 

“The long-term goal is to have a few targeted treatment options that act synergistically in the critical window to help the body repair itself, promoting motor function recovery,” Ma says, “In the coming years, we aim to have identified active molecules or pathways that switch on regeneration.”

Fighting Neurodegenerative Diseases

A damaged neuron

Finding common pathways will also be useful for protecting and improving neuron survival before disease onset, a crucial question for neurodegenerative diseases. However, Ma notes that this is another case of having to work backwards from treatment to preventive care. 

“The neuromuscular junction and recovery of motor function in particular yields a lot of information that we can then plug in to other questions, and impacting neuron behaviour at a moment of crisis is something we can actively engage with right now,” he says. Ma agrees that finding effective treatment for neurodegenerative disease will be the next big challenge, such as how to regenerate neurons for motor function in Parkinson’s disease patients. This will pose a multitude of challenges, though he does mention that the trend towards targeted medicine will be an advantage, because every treatment for nerve degeneration carries so many questions and side effects. 

“It was very popular at one time to claim that a single gene could activate or reverse disease,” Ma remarks, “But I think it would be a mistake to ignore the combination of factors for a good, full recovery. We need to be aware of the timing, when and how to activate different pathways, and be able to measure axons’ journey during the critical window.” That said, Ma’s team have studied growth-associated genes in relation to peripheral nerve regeneration, and his own personal goal is to find a small molecule that can activate genes of physiological conditions.

The Path to Neuroscience

Neuroscience has always been trendy, but Ma cautions that this field, like many others in science, is also evolving and becoming more interdisciplinary. “I always tell my students to have a thorough understanding of your interests, to work in different labs and figure out what you’re interested in,” he says, “With a good foundation of knowledge and technique, you need that fundamental curiosity and enthusiasm to take neuroscience to the next level.”

Ma’s own history reflects this advice. As an undergraduate student of biology, studying the receptors required for formation of neuromuscular juncture recovery triggered his interest in neuroscience. “In science, there is a slight tendency to divide up the body—neuroscientists only look at the brain, cardiologists only care about the heart—when in reality you have to have an understanding of the whole system,” he says. 

Ma pursued this interest through his graduate research in molecular endocrinology within the umbrella of neuroscience, focusing on growth hormone receptor expression in the brain. He continued his doctoral work on axonal regeneration and CNS signalling pathways at Oxford, but he was intrigued by the advances in PNS regeneration during his postdoctoral training at Harvard. 

The common thinking on CNS research is that axon regrowth studies are promising, but regaining complete motor function recovery is still a distant prospect. Ma realised that the greater flexibility of the PNS was a better match for his research interests. He was particularly drawn to the novel challenges of elucidating key molecular pathways that facilitate PNS axonal regeneration, yielding opportunities not only for PNS injury and treatment but also greater study of CNS-related neurodegenerative diseases. 

His current research lays the groundwork for more applied research to more targeted areas such as neurodegenerative diseases, and he believes this is the best way forward, giving researchers a clear picture of key mechanisms in neuronal regeneration and expanding understanding of regenerative processes. “Machines have to function, not just look complete from the outside. My lab is more translational, we create connections and look at how axons reconnect to original targets for greater functional recovery, with the added beauty of being able to see something grow,” Ma remarks.

Dr Eddie Ma obtained his BSc in Biology from The Hong Kong University of Science and Technology in 1997 and his M.Phil. in Molecular Endocrinology from the University of Hong Kong in 2000. He won a Croucher scholarship in 2001 for his doctoral studies at the University of Oxford, and was a Croucher Fellow as a postdoctoral researcher at Harvard Medical School and the Children’s Hospital Boston. In 2011, he joined The City University of Hong Kong as an Assistant Professor in the Department of Biomedical Sciences.  

To view Dr Ma’s personal Croucher profile, please click here.