Chapter 1

BIOELECTRICAL CONTROL OF GROWTH -

A RETROSPECTIVE LOOK
EPHF. . D. 11 ITI

A T THE
fo
PRE · E
·
T T IME, Lhere i a great deal of int
i el tri al phenomena. Exper
in a1 d nthu iasm
t · d aling \; ith the
origin nt , ontrol, biological "meani and imulat ion of
uch fi · ce in man laborat around the ,. arid.
In addi ·ng agnal fi · · hemi tr i
b ginni I world a w I g founded
and · voted lo ele of the life
pro tion and deb atur and
irre d ov r into · media,
ro · e itab l a .
Id Lo be on d e pa e
od rn cientifi t · i mo t
it might be w 11toe t of our
pr n rive at a omewhat d
f prog1 hi ti ation.
I adm th t th is wiJI not be an a Lat an xhau tive or
e Lailed r · onl a brieflook at ome of th hlight along the way
nd a hig ana l look at that. Howev r iLn ad the read r into the
older literature , whi h i remarkabl rich.
he di · bioelectri ity i lo tin the m
lfi h gatherer who tr cl up om
maz man vho jabbed an ele tri · ed th
man ti-ation of it e. t trul
ati n of the relatio1 1 and life
Galvani ( 1791 ), who u le can be
ntr h app li ati n · I · and that
e ontra ac ompanied b tr nt . Th
m ete enth cen aw an arra of ie rl ing a1 d
· n bio le tri effe at harlatan
h I a endance a w L nton Me mer 's
h anima l magne li m' anding example (in-
ly oft n th ca e in other i h theories, hi con-
n m of truth) . One ne d o ru e th ad erti ement of
3
4 Mechanisms of Growth Control
the popul a r magaz ines of the day LO find an amazing var iety of devices
offere d that purported to cure everyt hin g from micromastia to melan oma
by th e application of un spec ified "elect rical principles." eed less to say,
the reputation of electrob io logy d windled to an aby ma l nadir in th e face
of such quackery. The par k was maint ained by the neuroph ysiolog ists
and myologist , who had solid reason to cont inu e th eir studi es.
Invertebrates
The reawakening of int erest in this area see ms to have come in the ear ly
1900s (exce ptin g the neurophysiolog isLS and electromyo logists , whose
effo n s lie outs ide the scope of this meander) with the stu die s of Matt hews
( I903) on h ydro ids. He used rather nude methods by today 's sta nd ard s
but a rri ved at the corre ct conclu sio ns no neth eless - mar ine h ydro ids are
electr ically polarized. £ . J. Lund followed up o n this obse rvatio n with a n
elegan t ser ies of pap ers in the early 1920s (e.g., 192 1, 1925). He confirmed
Matthew's find ings an d di cove red th at the direct io n an d po larity (h y-
dra nth ver us ho ld fast) of growt h and rege ne ratio n in Obeliacommissuralis
could be contro lled by the appl icati on o f small dire ct curr ents. ln add ition,
he determined chat the effects on l) ou.:ur within na rr ow, paramet ric limits
- a finding that has bee n confirm ed by every invest iga to r in the field . His
pape rs are true class ics and shou ld be consult ed by an yone int ereste d in
thi s field - ind eed by an yone interested in see ing how mu ch ca n be
lear ned usin g simple techniqu es a nd an o riginal mind . Lund 's work has
been repeated many limes , by a numb er of investigators, includin g Barth
(1934) and Levin (1961). T heir results confirm Lund 's observat ions.
All o f thi s ac tivity led Burr ( 1932) a nd Burr and orlh ro p ( 1935) to
develop the ea rliest genera lized theo ries of the elect rical corre lates of
development in particular ( 1932) an d life in ge neral ( 1935). Lund came
om with his own version in 194 7. All thr ee are of co nsiderab le histo rical
interesl. .
Experiments with invertebrates have con tinu ed , shed din g mu ch light
on the ge nera l mech an isms o f electr ica l comr o l of' developme nt. Stu dies by
Marsh and Beams (e.g. , 1952) demonstrated that Platyhe lminth es are
quite susce ptibl e to electr ical contr o l of not on ly the ir regeneration , but
even of their ent ire morpho log ical orga nizatio n . Suit able fields can cause
the compl ete reversa l o f head and tail end s in a n int act an imal! 1 showed
( 1970 ) th at contro l ca n be exerc ised over t he ou tgr owth o f stolons in the
colo nial protoc hor dat e , Peropltoraviridis. T he question arises , o r cour se, as
to the mechani sms o f this comro l. The most obvious explanation lies in the
indu ced move me nt o f morp hogenet ica lly determinant molecu les from
place to p lace. Rose ( 195 7, 1962) has postu lated per hap s the most elega nt
of these th eo rie , involving contr ol loo ps of information -beari ng mo le-
cules that ca n be passed fr om ti sue to tis ue and thus determine spat ial
 A Retrospective Look 5
and t mp ral or anizati n. Re ent th · a u in Hydra
xampl ha e pro id d mathemat o ier r, 1977).
perim ntal confirmation · ontro od i not la kin . Ro ( l
ha hO\"n that m le ul ollin amh formati n in Tubularia
croce an be p1 · rentiall pa ed r da g · b , an
elect al ow d ( l 963) that p inh t rati n
in th ol vorm Clpnenell te a\ a
fro w . II Ii t th at
morphogen
dif~ r nti a
o at work.

Tissue Culture
hile all thi a tJ 1t \ ith in ert bra pla e, th ti u -
p pl were al o beginning t t f ele trical field .
( 192 d that c I oc rv in ultur ori nt
1e fi alvani n . v n wa on firm d
b Pet rfi and Wi · · b Kar nan h am ear ( 1934).
Hm e er, W i ( u their find d that their ffe t
were due to orien a rial in the pla n in u e , and that
the effect , a d guidance. I rep rt t pp d
v · g tw a perf ec pl f h w the pro of
o im wn leadi ht . far hand Beam 6)
ef u d pro re Id , gain omm n e. nt
ur labo1 and mith, J975) indi ate that e ca l
n utgrowth of neurit , but an al o parti II
t · · taining cu ltur d trig minal
ion ffe it rath · d nigra-
f al xp r· ded in a but n-
ation and minor ext apa in
,· ral la · · n lu ont rowth of
n rvou ti ue t of · e int
In ano er an Ilea 196 red what
ppear d ing ph on . t fr c t are
pp ar ntl into ca l at f ra tu r pon e
o injury if · tion pha e of ormation
ro all D. . ) in what
t h (I than one hour). Thi paper
debat contin owev r
It d nfirmed in ur labo ( 1975),
ilia (1974). In addition, owed that the effect d to be
ent upon a ++ ion and could b imulated b en ratin an
ng "front" of a ion in th cultur di h. We on firm d the role
6 M echa11· ms of rowth Control

of + + ion ing that th

blo ke m ti Is then r d or i m
ionoph ( mation n
c n · urrents in dev lopmen d
b orking with a ibraLing
bl int re
tion · I
f
ari u i o g
po ibil - n 1 ,
al mod x ha I
of + e d
th a
to ti r
an e na le trical
f e" atur xp nl i r d-

Vertebrate Regeneration
hi area · em to b th ti l in
r arts have er-
r I and p la ic
bi . . id n
thi 41 e
ele t vi r fr and ta d
th pattern hortl th r after (I 944)
Ro that pa Id b induced in duh
a · · ng th tump int tr ngl
h in irritation and an in-
. I na · o
tration of the
o ran earl di u -
i i up th later work i
b v k du r ner sible, that th r
a ca t er n, and that meh \ ar er
important in the pr
r · d in 1960and 19 I. In 19 0, he
r o M and on tru ted an i ·
e a e H orrelat d thi ,
current flow in ra and ,.,ith th dif · b -
tw n nd n form f amphibi I b).
Mor h d (19 ale of re ner ti b
infl in re at r b a lterin g the trength of th fi rl
B d m r ( 1964) added another link in th I ical hain b d mon trating
 A RetrospectiveLook 7
that partia l regene ration in ad ult frog s cou ld be obtai ned without irri tation
of the stu mp or augmentat ion of the nerve suppl y to the limb . He did so by
simpl y electrica lly stimu lating th e nerves of the brachia! plexus.
The logical ex tens ion of all of this see med to be simpl e- if the electr ical/
nervous behav ior of a non-rege nerator's limb could be made to simul ate
that of a rege nerator , regeneration shou ld ensue. The que stio n was, how
to do it? The a nswer tu rn ed out to be simp licity itself.Just put a batte ry in
the anima l, and ru n the leads to the wound sur face. It see med to me that
the simpl est way to do th is wou ld be to let th e animal be its own battery.
Impl ant ed in a limb , a pair of dissimilar meta l wires, if the junct ion were
insulated, sho uld ge nerate a current in the saline tissue e nviron ment.
Knowing abso lute ly nothing about the required voltages, curre nt, etc. that
would be e ffective (exce pt th at they wou ld be small), I picked a bimetall ic
pair (silver and plat inu m) that seemed like ly to do little harm, at least, if
metal ions were re lease d , as wou ld be expected fro m electrochem ical
considerat ions.
By sheer luck, the Ag- Pt couple produced current that fell with in the
effect's thresho lds, a nd I obtai ned considerab le rege neration in ad ult frog
limbs ( 1967). It wou ld be nice to be ab le to say that I had worked out all the
paramet ers in advance, and knew exactly what I was do ing, but such was
not the case. As so often has happe ned in the histor y of science, I stumb led
onto th e right proc edure . The approac h was logical enoug h, perha ps, but
the details were wor ked out on the "wrong " basis (at least in retrospect).
T he end result was th e same, however. Since then, Becker (J 972) ha s
used a modifi ed but similar devi ce to stimulat e partia l regeneratio n in
juv eni le rat limbs.
More recent ex per iments have been performed using imp lan table bat-
tery/res isto r packs that are m uch more reliab le and predictab le. In 1974, I
bowed that rege ner ates of remarkable complet e ness were obta ined in
adu lt frogs if the stimulating electrode were placed in approx imate ly the
position occupied by the a pical ectoder mal ridge dur ing ontogeny. It
eems th at in ad dition to th e stimul ator y effect of the current, its polarizing
effect on the regenerate is extreme ly importan l. It may well prove to be
true that to obtain the best possible re genera tion, a combin ation of a D.C.
polarizing stimu lus with th e sort of genera l excita tion prov ided by pu lsed
tim uli (seeChapter 8) may be req uir ed. It seems pr obab le that regenera-
tion is a severa l-step process:
A. The anima l mu st "recog nize " that a piece is missing ;
B. A blastema mu st be formed by de diff erentiat ion and/or cell repl ica-
tion ;
C. Th e cells within the blastema must "know " where they are a nd what
to become; and
D. Differe nti ation must th en ensue.
8 M.eclianismsof Growth Control
Tho ugh thi s hypot hesis see ms al least minim ally logical to me, and is based
on more evide nce than is ap pr opr iate to review in thi s brief in trodu ction ,
the 1974 paper on which it is partl y base d has aro used a great d ea l of
con trove r sy. Apparently th ere ar e so me who beli eve th al it state s that
perfe ct rege ne ratio n will sur ely ensue if one fo llows th e tec hniqu es out-
lined . Ca re ful reading of th e texl reveals no such claim. 011e anim al out of
many r egrew a perfect hand. It is a ce rt aint y th at we mu st know a g reat deal
more abo ut reg eneration befo re such a re sult is p red ictab le sta tistically.
H oweve r , I d o not think it unr easo nab le to state th at if we d o lea rn enoug h
about the co nt ro lling factors, p erf ect limb re ge ner atio n oug ht to be obta in-
able. T here see ms to be little doubt th at th e cells co ntain the informat io n
necessary to build a new arm , ha nd , leg, or liver. We ju st do no t know at
pr esent how lo make them use it in a n e ntir ely p redictab le fashio n .
In any case, wor k o n limb rege nerat io n is con tinuin g in man y laborato-
ries , includin g o ur s, with pr om isin g a nd in fo rmativ e resu lts. Th e trend, at
least , is to mo re and bett er und ersta ndin g of the pro cesses involved.
Even in the best of a!J possible world s, rou tine indu ctio n of limb a nd
orga n regeneration see ms a fairl y di ta n t prospect. Of mu ch more im-
mediate scientific and clinica l int e 1·est is the indu ction of tissue rege nera-
tio n/repair. The tissue whose prop e rti es are best und er stood, a nd which is
being mo re or less routinel y repa ired by electri cal mea ns in clinical set-
tin gs, is bone. I t wou ld requir e the res t of th is volum e to re view the
literature o n bone , but it may be of intere st to look at so me o f the hig h-
lig hts. Some o f th e ea rli esl work o n the elec trical prop e rties of bone was
d o n e by Fuka da and Yasud a in 195 7. Fuka d a had in vest iga ted Lhe
piezoe lectric prop ert ies of wood in 1955 , and the work was ex ten d ed to
bo ne in coo peratio n with Yasuda in 1957. In 1962. Bassett an d Becke r
repo rted that str esse d bone prndu ces stead y sta te pote ntia ls as well. Not ing
that bone is depos ited in areas of nega ti\'e charge when stresse d, Bassett ,
Pawluk , and Bec ker ( 1974) impl an ted electr ode s into th e medull ar y ca nals
of do g femur s. I nde ed , bone fo rm ed in r espo nse LO th e timu lu , nea rly
fillin g the ca na l near the ca thod e.
Bec ke r pr ese n ted a th eo r y for th e e lectr ical stimul at ion of bone forma-
tion in l 967, base d o n its known electr ical properti es. Ma care nh as d em-
o n trated that bon e may also act as a table electret ( 1974), and Er iksson
add ed th e po ibility of st rea min g pote ntial ( 1974) to th e mix of possible
ele ct rical e ffects in str essed bon e.
Prior LOthe e last two pape rs, however, int erve n tion in fr actur e hea ling
had alread y been und e rt a ke n in a numb e r o fl abor a to ries using a variety of
direct-c u rrent techniqu es. Indu ctively co upl ed cur rents d e rived by pul s-
ing e lec tro ma g netic fie ld were added by Bassell, Pawluk , a nd Pilla in
1974. Since then , th e use of elec tri cal curr e m s Lohea l fract ur es ha beco me
wide pread, a nd th e rea d er mig ht well refer to o ne of the num ero us
 A RetrospectiveLook 9
modern volumes (e.g., Br igh ton et al., 1979) for a comprehen ive look. As
a genera l sta tement , three type of treat me nt technique see m to be in use
at the present:
A. Low-leve l (ca. l µ A/mm 2 ) D.C., as exemp lified by Becker and h is
colleagues;
B. Hig h-level (> lµ A/mm 2 ) D.C., as exem plified by Brig hton 's col-
leagues; an d
C. Ind uctively coup led pu lsed fields, as exe mpli fied by Pilla a nd Bas-
sett's studies.
ft seems pr obable that the low-leve l D.C. and indu ctively coupled method s
operate by prod ucing stimu lation at the cell or its surfaces. T he indu ctively
cou pled metho d appare ntl y works by a d iffe rent mechanism than the
low-leve l D.C., pro du cing little callus as opposed to much. In contrast, the
high-leve l D.C. met hod prob ab ly operates electroche mically by re leasing
quanti ties o f e lect rode p rod ucts (0 2 molecu les, Ch, etc.) that eit her stimu -
late or irritate the tissues into a response. Th e net effec t of all treat ment
eems similar, howe ver: the bones hea l.
Widesp re ad use of e lect ,; cal tissue stimulation seems t0 be immi nent, in
any case, and is beginning to include man y tissues other than bone (see
Brighto n et al., 1979 , for some examples). One of the more interesting is
periph era l nerve. If 1.h e regeneration of severed axon could be acceler-
ated across a gap, and cou ld be di rected prefe1·ent iallr to the ir or igina l site
of ter min at io n , a knotty clinical pr ob le m wou ld be solved. Some progress
i.n this dire ctio n is being made in man y laboratories, inclu di ng ours, an d I
believe that the nea r fu tu re will pr ove to be very im erest ing in the area of
ind uced peri ph era l nerve regeneration, as well as in many ot her fields
relating to e lectrica l effects i.n a variety of othe r biologica l systems.
Perhaps no t the least of the question s aris ing fro m much of the mode rn
work re late lo e nvironmenta l exposure to small fields. It is not inconce iv-
able, given lhe large effects see n in response to very small curre nts and
field , that mode rn techno logy exposes u s daily to biologica lly signifi cant
do e of electricity abo u l wh ich we know pr actically not hing at all. On this
rnodes lly sobering note, I will end th is evidentl y pe rsona l re miniscence,
J nd co mm end Lhe symp osium that follows to th e reader 's attentio n. It
p re ents a pleth o ra of in for matio n on a wide var iety of subject systems and ,
i usua l for suc h volume s, ra ises far more que stions than it answers.

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 Mechanismsof Growth Control
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