JEB Classics 3485 TRANSLATIONAL to neurobiology by discovering and JEB Classics is an occasional NEUROSCIENCE DURING characterizing the giant fiber system of the column, featuring historic squid (Young, 1939), whose large caliber publications from The Journal of THE SECOND WORLD axon and huge synapse made possible the Experimental Biology. These WAR Nobel Prize-winning work of Alan articles, written by modern experts Hodgkin and A. F. Huxley on axonal in the field, discuss each classic conduction (Hodgkin, 1964; Huxley, 1964) paper’s impact on the field of and of Bernard Katz on synaptic biology and their own work. A transmission (Katz, 1971). PDF of the original paper is available from the JEB Archive Young, in turn, assembled a team that was, (http://jeb.biologists.org/). in his words ‘a curious mixture’ (Young, 1993). His three co-authors on the paper featured here were Ernst Gutmann, Ludwig Guttmann and Peter Medawar. Gutmann (1910–1977) was a Czech physician who, according to Young (1993), had arrived in Britain as a prisoner of war. He was sent to the group in response to their request for ‘someone to clean out the animal house’ (Young, 1993), but it soon became apparent that he was a knowledgeable and technically gifted researcher. Guttmann (1899–1980) had been a leading neurologist in Germany, who had fled to England in 1939. His refugee status prevented him from resuming his practice, so he was eager to join a group that not s A copy of Gutmann et al.’s 1942 classic only allowed him to gain a livelihood but paper ‘The Rate of Regeneration of Nerve’ also to use his skills. Medawar can be accessed from (1915–1987) was a Fellow at Oxford who http://jeb.biologists.org/cgi/content/abstract had studied under Young, then gone on to c /19/1/14 do pioneering work on the analysis of cell growth in tissue culture. Others in Young’s

i A peculiar concomitant of war is to group, but not authors of this paper, stimulate highly focused, collaborative included M. Abercrombie, D. Barker, W. scientific research endeavors that lead to Holmes and F. K. Sanders. extraordinary accomplishments. The s developments of radar and of nuclear Together, the group undertook a series of weapons (The Manhattan Project), are investigations aimed at understanding why particularly well-known examples. the regeneration of peripheral sensory and motor axons was often imperfect and how

s Likewise, groups of biomedical researchers have been assembled in wartime to aid in it could be improved. ‘The Rate of the efforts to treat the injuries that Regeneration of Nerve’ published in The inevitably occur. The paper discussed here Journal of Experimental Biology in 1942, was their first major work. It was written,

a (Gutmann et al., 1942) is a result of one such effort in Britain, during the Second as the title suggests, to re-examine a simple World War. question. The rate of regeneration had been l studied previously by several Of all the non-fatal injuries that occur in neuroscientists, beginning with Ramon y battle, the most disabling are neural, Cajal (1928), but there was little consensus because of the limited ability of the human on what the rate was, and little clarity on

C nervous system to regenerate. With this in why estimates varied so widely. Gutmann mind, the British Army and the British and colleagues were aware that the time of

Medical Research Council convened a recovery from a nerve lesion was affected group of neurologists and neurosurgeons in by several factors including a latent period 1939 to confront the special challenges of after nerve damage and the speed at which neurological injury. The group was led by nerves regrew. But the distinction between B Hugh Cairns and Herbert Seddon, the rate of growth and the separate, Professors of Surgery at Oxford University; significant interval before functional Seddon was also an expert in nerve injuries recovery was not well appreciated when

E and their repair. They recruited J. Z. Young these experiments were planned. (1903–1997), a brilliant cellular neuroscientist, to establish a unit devoted The basic protocol that the team used was J to peripheral nerve repair. Young had to damage a peripheral nerve so that its already made an unforgettable contribution axons would be severed, leading to

THE JOURNAL OF EXPERIMENTAL BIOLOGY JEB Classics 3486 degeneration of the distal part. They then perhaps the most important feature of the establishing a synapse. Gutmann and followed the progress of regrowth from the paper by Gutmann et al. (1942) is that it laid Young (1944) asked ‘what is the delay cut stump over time. The experimental data a solid foundation for much of the work the between the arrival of the tips of nerve in the paper consist of graphs plotting group went on to do. One main set of fibres at a muscle and the onset of the millimeters of regeneration versus days studies was aimed at elucidating the factors power of transmission of impulses from one following nerve injury. Experimental that limited the efficacy of regeneration. For to the other’? Also, following from the subjects included young and adult rabbits example, Holmes and Young (1942) asked differences in efficacy between prompt and and a few dogs; both sensory and motor whether delaying the onset of regrowth had delayed regeneration, they asked whether nerve regeneration were monitored. Injuries a deleterious effect. To this end, they ‘this delay [is] the same after short and included cuts, crushes near the spinal cord, compared regeneration under two different long periods of muscle atrophy’. crushes near the end organ, cuts followed conditions: after the two ends of the nerve Emphasizing the practical implications of by suture, and nerve cross-anastomoses, in were cut and sutured together immediately their work, they pointed to several ways in which the proximal stump of one nerve or after the two ends were kept apart for which delaying repair degraded was joined to the distal stump of another. protracted periods before being sutured to regenerative ability. Among many Regeneration was assessed in several initiate regrowth. They found that delay influential observations, they showed that different ways. By directly pinching the decreased the number of axons that the Schwann cell guides critical for nerve at various positions along its length, regenerated, but not the rate of regeneration, regeneration through the distal nerve also they could find the sensitive growing tip thus providing a novel explanation for the play critical roles in accurate reinnervation from which reflexes could most easily be deleterious effects of delay on recovery of of muscle fibres. In this regard, as with so elicited. Importantly, however, they also function. Gutmann and Sanders (1943) many others, they expanded on the seminal monitored recovery of sensory or motor pointed to some aspects of recovery that observations of Ramon y Cajal (1928) and function after muscle or skin were were incomplete even under optimal his students. Some of our own recent work reinnervated. In most cases, no conditions, such as the restoration of fiber has extended this theme still further, by regeneration was seen for 3–7 days. Axons diameter, and Sanders and Young (1944) using live imaging in transgenic mice to then appeared to grow at a constant rate of then performed experiments suggesting that document the guidance that Schwann cell 3–5 mm per day. Surprisingly, however, physical constrictions in the Schwann cell tubes provide to regenerating motor axons functional recovery was not detectable for guides through which regeneration occurred and the factors that regulate its efficacy 2–3 weeks after the ‘pinch test’ indicated were important determinants of the (Sanes and Lichtman, 1999; Nguyen et al., that the first axons had reached the end- limitation. Knowing that these constrictions 2002; Pan et al., 2003). Our ‘high-tech’ organ. increased with time after denervation, they measurement of regeneration rate, 2.7 mm stressed the importance of performing nerve day–1 (Pan et al., 2003), is remarkably It was this difference between the results repair surgery as soon as possible following similar to that obtained by Gutmann et al. obtained by the pinch test and by injury. (1942) six decades earlier. monitoring functional recovery that particularly caught the authors’ attention. A second set of follow-up studies was As the war came to an end, the members of The failure of previous workers to clearly strictly practical (see Young, 1942, and the group went their own ways. Of the four distinguish regeneration from recovery Guth, 1956 for summary and citations). For authors, Gutmann was the only one to almost certainly led to the general view example, Gutmann showed that fine white continue working on the peripheral nervous that axons grew much more slowly silk was a superior suture material to catgut system. He received a PhD from Oxford (~1·mm·day–1) than Gutmann and co- or colored silk; woman’s hair, he thought, University, UK for his work with Young, workers found. The authors noted that was better still. Young and Medawar then returned to Czechoslovakia, where he direct histological measures of axonal recommended the use of fibrin clots for eventually became Head of the Department length, such as those made by Ramon y holding nerve ends together when suturing of Physiology and Deputy Director of the Cajal (1928), might have provided further was infeasible. Gutmann, Sanders and Czechoslovakian Academy of Sciences insight; they also noted that Cajal’s Young tested various materials for their (Tucek, 1978). His work on regeneration, estimates of rate were fully consistent with ability to serve as grafts that could support neurotrophic relations and aging in the their own. On the other hand, the direct regeneration when nerves were so damaged neuromuscular system (Gutmann and behavioral assessment of functional that suturing was impossible. The work on Hanzlikova, 1973; Gutmann, 1976) was recovery by Gutmann and the team added a sutures and grafts presaged the current world-class at a time when little basic new dimension. In any event, by making interest in ‘biomaterials’ to aid nerve repair research of note was being done in Eastern the distinction, and by rigorously and regeneration by a half century Europe. Guttman, whose interests remained quantifying their results, Gutmann et al. (Schmidt and Leach, 2003). Likewise, the primarily clinical, turned to the practical (1942) provided data on which other surgeon in the group, Seddon, rapidly applications of the work he had done with scientists could rely. applied some of the conclusions derived the group. He founded the National Spinal from work on experimental animals to Injuries Centre at Stoke Mandeville near The differences between the rate humans (Seddon et al., 1943), in an early London, and remained as Director until measurements of Gutmann et al. and those example of minimizing the ‘bench to 1966. A pioneer in organized physical of some predecessors also raised new bedside’ lag. activities for the disabled (Guttmann, 1973), questions. In the 1942 paper’s Discussion, he began ‘Stoke Mandeville Games for the the authors considered possible explanations For neuroscientists, perhaps the most Paralyzed’ in 1948, and oversaw its for the unexpected delay between axon impressive of the studies building on that transformation into what is now the arrival and functional recovery; they were of Gutmann and colleagues (1942) was a international Paralympic Movement. unable at the time to decide amongst them, definitive analysis of what happens when Medawar pursued another war-time project, but the clear demonstration that regeneration regenerating motor axons have finally on the factors that limit the success of skin and recovery were very different was a completed their journey to the muscle, and grafts. His investigations on transplantation powerful impetus for further work. Indeed, are faced with the problem of re- immunity won him a Nobel Prize in 1960

THE JOURNAL OF EXPERIMENTAL BIOLOGY JEB Classics 3487 (Medawar, 1991). Young moved to References precise projection patterns. Nat. Neurosci. 5, University College London, where he was Boycott, B. B. (1998). John Zachary Young. 861-867. Chair of Anatomy from 1945 until 1974 Biographical Memoirs of Fellows of the Royal Pan, Y. A., Misgeld, T., Lichtman, J. W. and (Boycott, 1998). He turned to cellular Society 44, 486-509. Sanes, J. R. (2003). Effects of neurotoxic and studies of memory in the octopus, an animal Guth, L. (1956). Regeneration in the neuroprotective agents on peripheral nerve mammalian peripheral nervous system. Physiol. regeneration assayed by time-lapse imaging in whose prodigious feats of learning he was Rev. 36, 441-478. vivo. J. Neurosci. 23, 11479-11488. among the first to appreciate (Young, 1965). Gutmann, E. (1976). Neurotrophic relations. Ramon y Cajal, S. (1928). Degeneration and His interests shifted gradually to more Annu. Rev. Physiol. 38, 177-216. Regeneration of the Nervous System. Oxford: cognitive levels, and eventually beyond Gutmann, E and Hanzlikova, V. (1973). Basic Oxford University Press; reprinted, 1991. laboratory science to the philosophy of brain mechanisms of aging in the neuromuscular Sanders, F. K. and Young, J. Z. (1944). The and mind (Young, 1988). system. Mech. Ageing Dev. 1, 327-349. role of the peripheral stump in the control of Gutmann, E. and Sanders, F. K. (1943). fiber diameter in regeneration nerve. J. Physiol. In conclusion, the Second World War Recovery of fibre numbers and diameters in the 103, 119-136. stimulated intensive, focussed research on regeneration of peripheral nerves. J. Physiol. Sanes, J. R. and Lichtman, J. W. (1999). 101, 489-518. Development of the vertebrate neuromuscular nerve regeneration. It is hard to imagine Gutmann, E. and Young, J. Z. (1944). The re- junction. Annu. Rev. Neurosci. 22, 389-442. any other motivation for the painstaking innervation of muscle after various periods of Schmidt, C. E. and Leach, J. B. (2003). Neural experiments that Gutmann et al. (1942) atrophy. J. Anat. 78, 15-42. tissue engineering: strategies for repair and undertook. These studies, which were more Gutmann, E., Guttmann, L., Medawar, P. B. regeneration. Annu. Rev. Biomed. Eng. 5, 293- descriptive than experimental, provided a and Young, J. Z. (1942). The rate of 347. lasting, reliable data set upon which to regeneration of nerve. J. Exp. Biol. 19, 14-44. Seddon, H. J., Medawar, P. B. and Smith, H. compare the effects of various interventions Guttmann, L. (1973). Sport and recreation for (1943). Rate of regeneration of peripheral nerves on nerve regrowth. This paper has been the mentally and physically handicapped. R. Soc. in man. J. Physiol. 102, 191. cited more than 270 times over the years, Health J. 93, 208-212. Tucek, S. and Gutmann, E. (1978). J. Neurol. Hodgkin, A. L. (1964). The ionic basis of Sci. 35, 399-400. with 10% of those in the 21st century, nervous conduction. Science 145, 1148-1154. Young, J. Z. (1939). Fused neurons and synaptic provide ample testimony to its value. The Holmes, W. and Young, J. Z. (1942). Nerve contacts in the giant nerve fibres of cephalopods. eminent individuals involved and the regeneration after immediate and delayed suture. Phil. Trans. R. Soc. Lond. B. Biol. Sci. 229, 465- brilliant careers that each had are also a J. Anat. 77, 63. 503. testament to the power of a pressing Huxley, A. F. (1964). Excitation and conduction Young, J. Z. (1942). The functional repair of societal need that drove these independent- in nerve: quantitative analysis. Science 145, nervous tissue. Physiol. Rev. 22, 318-374. minded individuals to work together for the 1154-1159. Young, J. Z. (1965). Croonian Lecture: The greater common good. Katz, B. (1971). Quantal mechanism of neural organization of a memory system. Proc. R. Soc. transmitter release. Science 173, 123-126. Lond. B. Biol. Sci. 163, 285-320. 10.1242/jeb.02458 Medawar, P. B. (1991). The Nobel Lectures in Young, J. Z. (1988). Philosophy and the Brain. Immunology. The Nobel Prize for Physiology or Oxford University Press. Jeff W. Lichtman and Joshua R. Sanes Medicine, 1960. Immunological tolerance. Young, J. Z. (1993). Introduction. In: Peripheral Harvard University Scand. J. Immunol. 33, 337-344. Neuropathy, Third Edition (ed. P. J. Dyck and P. [email protected], Nguyen, Q. T., Sanes, J. R. and Lichtman, J. K. Thomas), pp. 2-5. Philadelphia: W. B. [email protected] W. (2002). Pre-existing pathways promote Saunders.

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