This mini‐symposium focuses on the role of neurotrophins and other neurotrophic factors in human neurological disease processes. There have been many recent reviews, and even a few review series, on biological effects of the neurotrophins. Here, we try to look at these growth (or neurotrophic) factors from a pathological perspective, focusing on diseases that neuropathologists continue to see in clinical practice. Rather than delineate an exhaustive review of neurotrophin biology, our intent is to provide the reader with a perspective on the potential for future treatments based on neurotrophic factors and directions for research that are relevant to human disease. Consequently, each of the reviews in this series refers the reader to more detailed works on basic neurotrophin and neurotrophic factor biology.
When one takes a perspective of several months or a few years, the progress in getting neurotrophins and neurotrophic factors into the clinic appears to be extremely slow. It is a bit like the fabled race of the tortoise and the hare. Fitting with the analogy of the hare, early attempts at clinical trials with neurotrophic factors were disappointing, oftentimes being ineffectual or plagued with side effects from systemic exposure to these factors. In retrospect, one could argue that neither the state of knowledge nor scientific technology was then in place to get the right neurotrophic factor to the right site at the right time in order to provide robust therapeutic benefit. Over decades, the tortoise has continued to progress forward with a slow but steady pace, providing a wealth of knowledge and new technology. As presented in the reviews by Blesch and Sahenk in this mini‐symposium, this arduous task of scientific discovery that the tortoise “undertook” has now achieved a level of success for treating human neurodegenerative disease and neuropathy with directed neurotrophic factor therapy.
The first neurotrophic factor, nerve growth factor (NGF), was initially hinted at over half a century ago. This was the beginning of a remarkable series of discoveries that led to the “neurotrophic hypothesis,” a premise that continues to fuel scientific discovery. Although the functions of NGF were first considered to be limited to the developing peripheral nervous system (PNS), NGF’s expression in the adult central nervous system (CNS) was detected after technical advances in molecular and cellular biology. This, along with the discovery that NGF belongs to a family of related neurotrophic factors, the “neurotrophins,” has generated a wave of research into the basic and applied biology of the neurotrophins in neuronal development and degeneration. This wave continues to build. The review by Twiss et al in this mini‐symposium presents a short historical perspective of the neurotrophins and discusses their role in neurodevelopmental disorders, neuroplasticity and regeneration.
Along with the slow but steady pace of the tortoise, surprises have crept into the neurotrophin field. As mentioned in several of the reviews here, neurotrophins do have a dark side and have been shown to kill neurons and glial cells under some circumstances. These apoptotic events are often generated by one of the neurotrophin receptors, p75NTR, that was thought to not have any signal‐transducing capacity. Rosenberg et al review another surprise from the neurotrophins. Although NGF and the other neurotrophins were largely considered as only neurotrophic in their activities, it is now clear that they act as growth or tropic factors for a number of different cell types outside the nervous system. The observations that neurotrophins play a role in myelination, and potentially remyelination, open up an entirely new course for future therapeutic intervention. In their review, Rosenberg et al review the current knowledge of neurotrophin‐mediated myelination. This has important implications for both PNS and CNS demyelinating and dysmyelinating disorders.
The review by Krüttgen et al highlights the real dark side of the neurotrophins. NGF and the other neurotrophins now have a clear role in neoplasia. Their effects can be good, inducing differentiation or halting growth, or bad, inducing cell division and invasion. With the increasing recognition of neurotrophin effects outside the nervous system, it is not surprising that some epithelial cancers also respond to these molecules.
Considering the diverse roles of neurotrophins in cell function and the surprises that have popped up along the course to discovery, the “tortoise and hare” analogy is not really a good one. Indeed, “slow and steady” may win a foot race, but the tortoise would never have had the luxury of following the tangents that led to the discovery that neurotrophins can regulate myelination. The hare is wise to stop, not to rest, but to inspect his surroundings and modify his course. Given the increasingly recognized effects of neurotrophic factors outside of the nervous system and the myriad of their good and bad effects within the nervous system, we will need to carefully consider the best course in planning future neurotrophic‐based therapies. Still, this is an exciting era for clinical applications of neurotrophic factors. There are bound to be more surprises and tangents—we will need a bit of the tortoise’s and the hare’s philosophies to make the best use of scientific discoveries for the benefit of human health.