FIRSTHAND KNOWLEDGE NEUROBIOLOGY
Neuronal extensions:
An axon (green), conducts
signals to a remote nerve
cell; a dendrite (red),
collects information from
neighbouring neurons.
Depending on where in the brain
the injured cells are located, many
different impairments can result,
most of which are permanent. Acci-
dents involving head injuries, dis-
eases such as multiple sclerosis or
Parkinson’s, and strokes are frequent
causes of cell death in the brain.
When nerves in the spinal cord are
badly crushed or severed, lifelong
paralysis can result. The closer to the
neck the injury occurs, the more se-
vere the paralysis. A study in the US
showed that, in that country alone,
there are 8,000 to 11,000 cases annu-
ally of spinal cord injuries that result
in paralysis. In 47 percent of these
patients, the legs are paralyzed, and
in 52 percent, both the arms and the
legs. Accidents are often the cause of
Growth
ET AL .
injury to the spinal cord, which is
N EUROBIOLOGY -B RADKE
why paralysis is frequent in 16- to
30-year-olds. As those affected have
a relatively normal life expectancy,
Treatments their number increases globally from
year to year.
OF
F IG .: MPI
STOP SIGNS IN
THE NEURAL NETWORK
for Nerve Cells I have always been impressed by the
body’s ability to heal itself. A cut on
your finger destroys skin cells, injures
ishing self-healing powers at its dis-
posal, why doesn’t it use them to re-
pair its most delicate systems, the
With so many people impacted in this
way, an urgent search is underway
for an answer to why nerve cells in
the central nervous system do not re-
A damaged nerve in a finger will heal, but a damaged muscles and blood vessels and severs brain and the spinal cord? grow their extensions after an injury.
nerve cell extensions. It is painful, but The nervous system is divided into For me and many of my colleagues,
nerve in the brain or spinal cord will not. FRANK BRADKE not a catastrophe. After a short time, two areas: the brain and the spinal this is one of the most fascinating
nerve cells regrow, muscles and blood cord form the central nervous sys- questions in modern neurobiology. In
and his research group at the MAX PLANCK INSTITUTE OF
vessels are reconstructed and the skin tem, while all other nerves, such as the past 10 to 15 years, intensive ba-
NEUROBIOLOGY in Martinsried want to encourage nerve closes over the cut. those in the arms and legs, make up sic research has brought about con-
Even more serious injuries usually the peripheral nervous system. One siderable progress in this area. For
cells in the spinal cord to regrow after injury. heal without leaving significant trac- important difference between these example, a number of factors have
es, although the cells occasionally two systems lies in their ability to re- been found in the nerve cell environ-
have to be persuaded to grow in the generate. Unlike those in the periph- ment that can stop the nerve cell ex-
right direction with a bandage or a eral nervous system, the cells in the tensions from growing.
splint. But what’s wrong with this central nervous system hardly ever These factors can be imagined as
picture? If the body has these aston- recover from damage. stop signs: as a responsible road user,
54 MA X P L ANCK R E SE ARCH 3/2008 3/2008 MAXPL A NCK R ESEARCH 55
FIRSTHAND KNOWLEDGE NEUROBIOLOGY
ET AL .
N EUROBIOLOGY -B RADKE
OF
F IG .: MPI
when injuries occur, which means questions are key to understanding but can precisely mark individual
that the growth of these connecting the growth brake in the central ner- cells or cell components and study
cables is particularly significant. vous system. For a long time, it was them. The discovery of GFP was also
At the tip of a growing axon, for impossible to directly observe how fortuitous for my work, as it enabled
instance from a young nerve cell, the retraction bulb formed. Our re- us to visualize what was happening
there is a growth cone where, quite search group was one of the first to in the retraction bulb.
literally, everything goes on. This is attempt to get to the bottom of these My colleague Ali Ertürk discov-
home to special proteins that allow fascinating questions. This was pos- ered that a retraction bulb can be
the axon to find its way to the cor- sible thanks to the great progress identified less than an hour after an
rect partner cell among thousands of
nerve cells. CENTRAL NERVOUS SYSTEM PERIPHERAL NERVOUS SYSTEM
In addition, the growth cone con-
tains many mitochondria, the cellu-
lar powerhouses, and parallel bundles
of microtubules without which the
axon could not extend. Microtubules
Growth stop: Retraction bulbs, seen here as small green bulges, form An injured axon with microtubules in an orderly arrangement continues are tiny protein tubes that lengthen Severance Stabilization
ET AL .
where the nerve cells have been severed. to grow (top), unlike one with its microtubules in disarray (bottom). the axon by means of a coordinated of the nerve of the microtubules
N EUROBIOLOGY -B RADKE
extension
push forward. Thus, in our search for Destabilization
a cell extension stops growing when side the cells that are responsible for sions of the cells do not regrow. the brake in the cell, the microtubules of the microtubules
it reaches one of these stop signs. stopping cell growth in the central However, when the same cell is dam- seemed to be a very promising place
And this is precisely the problem: as nervous system. We have set out to aged first in the peripheral section to start our research. Perhaps it would
FOR
soon as the nervous system is fully look for the brake, so to speak, that and then in the central section, it will be possible to use the microtubules to
F IG .: MPI
developed, these stop signs are put brings the cells to a halt in front of also be able to regrow in the central make a damaged axon grow past the A few days after the injury
up throughout the central area. When the stop signs. We are hoping that we nervous system. These observations stop signs.
the nerve cell extensions in an adult will be able to release this brake for show that nerve cells in the central
THE SEARCH FOR
organism are severed, they are faced long periods, or even deactivate it nervous system can, in principle, re-
THE GROWTH BRAKE
with a forest of stop signs. As long as completely. cover from an injury.
these signs are present, the cell ex- What actually happens in the ex- In order to understand why the When an axon in the peripheral ner-
tensions can grow no further. This tension of a central nervous system cells nevertheless do not grow after vous system is severed, a growth
Vesicles
also means that once contact with cell when it stops growing after an being damaged, it is helpful to recall cone forms at its tip – exactly in the A few weeks later
Mitochondria
partner cells has been broken off, it injury? It could be assumed that these the structure of nerve cells and how same way as in a young cell – and Microtubules
cannot be re-established. The conse- nerve cells are unable to regrow at all they develop. A typical nerve cell the axon grows anew. The tip of a
quence is paralysis. after an injury. Fortunately, though, consists of a cell body and a series of damaged axon in the central ner- Class divisions in medicine: Peripheral nerve cells heal after an injury;
But what would happen if the there are nerve cells whose exten- extensions. Depending on the cell vous system also thickens. However, nerves in the central nervous system do not, as the microtubules in them are destabilized.
nerve cells could be turned into more sions project into both the central type, they can develop into axons unlike the growth cone, this axonal
daring road users that would simply and the peripheral nervous systems. and/or dendrites. Like a long cable, bulb shows no inclination to grow. made in genetics in recent years, injury. While it slowly swells during
ignore the signs and grow right past If these cells are damaged in the pe- an axon propagates incoming infor- On the contrary: we observed that, which has brought increasing num- the ensuing hours, mitochondria
them, more or less the way it is in ripheral section, they regrow after a mation to remote nerve cells; den- in the weeks following the injury, bers of new methods and analyses. accumulate inside it, which is simi-
everyday traffic situations? This short time – as in our example with drites collect information from many the axonal retraction bulb continued For example, it recently became lar to what happens in a growth
question has not only occupied my the cut finger. different nerve cells with their fine to swell, but stopped moving for- possible to mark individual nerve cone. With these cellular power-
thoughts while driving, it is also the branches. The separate pieces of in- ward to extend the axon for an in- cells with green fluorescent protein houses on the job, it is rather un-
AN INSIDER’S VIEW
main subject of my work at the Max formation coming from the dendrites definite period. (GFP). This has revolutionized neu- likely that the growth stop is caused
OF THE GROWTH CONE
Planck Institute of Neurobiology. are computed and the result passed What happens in this retraction robiology: scientists are no longer by a lack of energy. Things became
This is where my research group and When an injury occurs in the central on to other cells via an axon. It is bulb, and what prevents the axon faced with a confusing array of really interesting, however, when
I are examining the mechanisms in- nervous system, the damaged exten- often the long axons that are severed from continuing to grow? These thousands of identical nerve cells, we looked at the microtubules. Nor-
56 MA X P L ANCK R E SE ARCH 3/2008 3/2008 MAXPL A NCK R ESEARCH 57
FIRSTHAND KNOWLEDGE
short time, we have found out a
great deal about what happens in
the axonal retraction bulb. We also
now know one of the reasons why
N EUROBIOLOGY
damaged axons in the central ner-
vous system do not continue to
grow. The next steps are to find out
OF
whether Taxol works in the same
P HOTO : MPI
way in living organisms. We also
need to find the correct dosage and
They want to release the neuronal growth brake: Farida Hellal,
a way of administering it. Too much
Frank Bradke, Ali Ertürk and Harald Witte (from left)
Taxol suppresses the dynamics of
the microtubules so that axons can-
mally they are in a very regular axon. The addition of Taxol stabi- not grow properly. These problems
parallel arrangement, like a set of lized the microtubules of any ran- need to be resolved, first in the labo-
railroad tracks; in the retraction domly chosen extension and allowed ratory and then in clinical studies.
bulb, however, they were complete- it to grow into an axon. However, I believe that, in the long
ly jumbled. No wonder they weren’t term, microtubule stabilization is a
A BARRIER OF
making any headway! promising approach to improving re-
SCAR TISSUE
But is it really the disarranged mi- generation of axons in the central
crotubules that prevent the axon Untreated extensions developed into nervous system. Nevertheless, there
from continuing to grow? We used a dendrites. When we injected Taxol are still many open questions, and it
substance called nocodazole to test directly into a CNS lesion in the liv- will take years before medicine will
this. Nocodazole is frequently used ing organism, the formation of re- be able to heal paraplegia. The im-
in cell biology to destabilize micro- traction bulbs was suppressed and pact of other factors, such as nerve
tubules. And indeed, when we added the cut axon did not retract from the scar tissue, is still unknown. This
nocodazole to growth cones, they lesion. Furthermore, my colleague nerve tissue initially protects the cells
became retraction bulbs, and the Farida Hellal showed in cell culture from further injury, but it also forms
axons ceased to grow. This was experiments that Taxol enables dam- a barrier that prevents the regrowth
proof that the disordered microtu- aged nerve cells in the central ner- of the cells. How to reduce this scar
bules in the bulb are one of the main vous system to grow again, even tissue and how to make the nerve
reasons why the axon stops grow- when we surrounded the nerve cells cells not only ignore the growth stop
ing. This result was quickly followed with “stop sign” molecules! signs but also break through the scar
by the next question. What if we re- The results of these studies are barrier are some of the questions we
placed the nocodazole with a sub- quite encouraging. In a relatively will be looking at next. ■
stance that would stabilize the mi-
crotubules?
P HOTO : P RIVATE
P HOTO : P RIVATE
DR. FRANK BRADKE, 38, DR. STEFANIE MERKER,
Taxol suggested itself for these in- studies the intrinsic 35, studied biology
vestigations. In cancer therapy, the cellular mechanisms that and researched the
microtubule stabilizing action of govern axonal growth. life of army ants and
Together with his group, their insect guests
Taxol stops cancer cells from divid-
he characterizes the for her doctoral thesis.
ing. In our experiments, Taxol exhib- growth and the growth- While working with
ited similarly encouraging effects: inhibitory mechanisms in various museums, she
My colleague Harald Witte was able axons during nerve cell development, in discovered her enthusiasm for public
to help a young cell decide which of the hope of being able to stimulate relations work. As an “interpreter of
damaged nerve cells in the spinal cord into science for the rest of the world,”
its extensions should become an
regrowth. He has headed the Independent she has been helping the public since
Junior Research Group “Axonal Growth and 2007 to understand and appreciate
Regeneration” at the Max Planck Institute the research undertaken at the Max
of Neurobiology since 2003. Planck Institute of Neurobiology.
58 MA X P L ANCK R E SE ARCH 3/2008