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Clicker Question
_________is(are) the generation of
unregulated electrical discharges from
scar tissue in the gray matter of the brain,
which causes the muscles in the body to
contract.
A) Polyneuritis (beriberi)
B) The voltaic piles
C) Galvanism
D) Pellagra
E) Epilepsy
Pale Blue Dot
Where are we?

Last time I discussed…
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the evidence that led us to know that the nervous signal is
electrical.
biomechanical and bioelectrical devices produced by
bioengineers that interface with the nervous system.
This time I will discuss…
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the structure of neurons.
the blood-brain barrier.
how neurons generate the electrical message known as an
action potential.
multiple sclerosis (MS).
synapses and excitatory and inhibitory postsynaptic
potentials.
botulism and Botox.
Nerves Were Observed Under the
Microscope By Antony van Leeuwenhoek
in 1675
Nerves are Fibrous, Not a Cavity
through which the Animal Spirits Flow
“I…observed, that after
those Nerves had been
but a little while cut off
from the eye, the
filaments, of which they
are made up, did shrink
up….And upon this
shrinking up, a little pit
comes to appear…and ‘tis
this pit in all probability,
that Galen took for a
cavity.”
Stimulated Nerves Pass an Electrical
Current
Emil Du BoisReymond (1848), a
student of Johannes
Muller, provided
evidence that the
nervous principle is
electrical by showing
that stimulated
nerves pass an
electrical current
along their length.
Nerves are Made of Cells
Theodor Schwann
(1830s), a cofounder of
the cell theory, who was
also working with
Johannes Muller,
discovered that
nucleus-containing
cells, now known as
Schwann cells, were a
component of nerves.
Schwann Cells
Rudolf Virchow (1854), another of Johannes Muller’s
students, discovered a fatty substance in the brain that
he called myelin. Myelin is formed by the Schwann cells.
The Structure of Neurons
Otto Deiters (1865) found that
nerves were also composed of
another cell type, now known as
neurons. The neurons have two
different kinds of branching
processes attached to the cell
body: one which was tree-like,
which he called "protoplasmic
extensions", and another which
was more like a long fiber, which
he called "axis cylinder".
Wilhelm His (1889) called the
tree-like extensions, dendrites;
Rudolph von Kölliker (1896)
called the long projections axons
and the cell itself was named the
neuron by Heinrich Wilhelm von
Waldeyer (1891).
The Dendrites, Axon and Cell Body
of a Myelinated Neuron
The Brain is Composed of a Giant
Network of Neurons
Joseph von Gerlach
(1880) proposed that
the recently
discovered nerve
impulses studied by
Emil du BoisReymond propagated
from cell to cell
across the axons and
dendrites, and that
the brain was formed
by giant nets made
out of a large number
of interconnected
filaments.
The Brain is Composed of One Large
Cell

Camillo Golgi developed
a silver stain that
allowed the visualization
of the internal reticular
apparatus, now known
as the Golgi body.
 After staining the brain, it
seemed to Golgi, that all
the cells fused to form a
single cell so that the
brain consisted of a
continuous mass of
tissue that shared a
single cytoplasm.
Disagreement on the Neural
Structure of the Brain

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Using Golgi’s silver stain, Santiago
Ramón y Cajal was able to see that
the brain was not a single cell, but
composed of individual neurons.
Ramón y Cajal, with all due respect,
disagreed with Golgi’s conclusion.
Both Ramón y Cajal and Golgi won the
Nobel Prize in 1906 despite their
opposite views of the brain.
Golgi got the prize for developing the
techniques used to visualize the
nervous system and Ramón y Cajal
got the prize for describing the correct
structure of the nervous system.
The Brain is Composed of Individual
Cells (Neurons)
Ramón y Cajal concluded
that
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neurons are discrete and
autonomous cells that can
interact.
the neuron is the basic
unit of the nervous system.
there are gaps, now called
synapses, that separate
neurons.
Information is
transmitted in one
direction from dendrites to
the axon.
Ramón y Cajal Traced the Networks of Neurons
Over Small and Large Distances
Ramón y Cajal Traced the Networks of Neurons
Over Small and Large Distances
Books by Santiago Ramón y Cajal
Blood Brain Barrier

Paul Ehrlich (1870s) injected
various aniline dyes, produced
by the new German dye
industry, into the blood stream of
animals and found that the dye
stained everything but the brain.
 His student, Edwin Goldmann
(1913) injected the aniline dyes
into the brain fluid and found
that the brain stained, but not
the rest of the body.
 Lina Stern (1921) proposed that
there was a blood-brain barrier
that separated the brain from the
rest of the body.
Blood Brain Barrier
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Unlike the capillaries in the rest of the
body that are “leaky”, the capillaries in
the brain are tight because the
membranes of the epithelial cells that
make up the capillaries in the brain
are tightly appressed to each other.
Because of this, any chemical that
leaves the blood stream and enters
the brain must either be nonpolar and
small enough to pass through the
lipid bilayer or must have a specific
transport protein to let it enter the
intercellular milieu of the brain.
The blood brain barrier protects the
brain from viruses and toxins, but also
makes it a challenge to deliver some
drugs to the brain.
Cell Types in the Brain

The blood-brain barrier is composed of glial cells,
called astrocytes, which help prevent many
substances in the blood from entering the brain.
 Oligodendrocytes in the central nervous system
(CNS), like the Schwann cells in the peripheral
nervous system (PNS) are glial cells that surround
the axons and make up the myelin sheath.
 The glial cells, which mean “glue cells” have multiple
functions, including structurally supporting neurons
and regulating the biochemical balance of the brain.
They were discovered in 1856 by Rudolf Virchow.
 The dendrites and cell bodies of the neurons make up
the gray matter of the brain and the axons make up
the white matter.
The Cell Types in the Brain
Electrical Transmission Along Neurons
The Plasma Membrane of Neurons
The Plasma Membrane Contains Receptor
Proteins and Transport Proteins, Including Ion
Channels, and Ion Pumps Driven by the Energy
of ATP
Ion channels act as enzymes that reduce the
activation energy or thermal energy that would
be necessary to move a charged ion through a
hydrophobic lipid bilayer.
It Would Take a Lot of Heat to Move a Charged
Ion Through the Lipid Bilayer. Because of
Channels, Ions Can Move Through Aqueous
Channels at Body Temperature
The Influence of Ion Channels on the
Movement of Ions Across a Membrane
Hot Temperature→
Body Temperature→
Without the channel, the ions do not have enough
energy at body temperature to pass through the plasma
membrane.
An Unequal Distribution of Ions on the Two Sides
of a Membrane Leads to a Voltage Across the
Membrane Known as the Membrane Potential
Electrical Hyperpolarization of the
Membrane

When the inside concentration of a positive ion is
greater than the outside concentration, the ion will
tend to diffuse out of the cell using its thermal
energy.
 The electrical potential inside the cell will become
more negative and the membrane will be
hyperpolarized.
 At some point, the membrane potential will become so
negative that the outgoing positive ions will be
attracted back into the cell and the ions will be at
equilibrium at the hyperpolarized electrical potential.
That is, the concentration difference driving the ions
out of the cell will be equivalent to the voltage driving
the ions back into the cell.
Generation of an Electrical
Potential Across the Membrane
Initial
Final (At Equilibrium)
Assume inside of cell (1) and outside of cell is (2)
and membrane is only permeable to the positive ion
(K+) as a result of the ion channels present. At
equilibrium, membrane is electrically hyperpolarized.
Hyperpolarized and Depolarized
Membranes
• The electrical potential
outside the cell is
considered to be 0 volts by
definition.
• When the electrical
potential inside the cell is
more negative than 0
volts, the membrane is
said to be hyperpolarized.
• When the electrical
potential inside the cell is
less negative than the
hyperpolarized potential,
the membrane is said to
be depolarized.
Electrical Depolarization of the
Membrane

When the outside concentration of a positive ion is
greater than the inside concentration, the ion will tend
to diffuse into the cell using its thermal energy.
 If the membrane is already electrically hyperpolarized,
the electrical potential inside the cell will become
less negative and the membrane will be depolarized.
 At some point, the membrane potential will not be
negative enough to attract any more positive ions into
the cell and the ions will be at equilibrium at the
depolarized electrical potential. That is, the
concentration difference driving the ions into the cell is
equivalent to the depolarized voltage driving the ions
out of the cell.
Generation of an Electrical
Potential Across the Membrane
Initial
Final (At Equilibrium)
High [NaCl]
High [NaCl]
Low [NaCl]
Low [NaCl]
Na+
Na+
Assume outside of cell (1) and inside of cell is (2)
and membrane is only permeable to the positive ion
(Na+) as a result of the ion channels present. At
equilibrium, membrane is electrically depolarized.
Walther Nernst Derived an Equation
that Predicts the Equilibrium Potential
Nernst Equation
Equilibrium Potential = (kT/ze) ln ([ion]out/[ion]in)
k = Boltzmann’s constant (1.38 x 10-23 J/K)
T = Absolute Temperature (in K) = 310 K for humans
e = elementary charge (1.6 x 10-19 C/charge)
z = valence of ion (+1 for K+ and Na+)
(kT/ze) ln ([ion]out/[ion]in) is the voltage equivalent of the
concentration difference
1 Volt = 1 J/C = 1 Joule/Coulomb
ln 10 = 2.3
The Nernst Equation
(kT/ze) is always positive and equal for both K+
and Na+
 ln ([ion]out/[ion]in) is positive when the outside
concentration is greater than the inside
concentration of an ion.
 ln ([ion]out/[ion]in) is negative when the outside
concentration is less than the inside
concentration of an ion.
 ln ([ion]out/[ion]in) is zero when the outside
concentration is equal to the inside
concentration of an ion (= death).

Natural Logs Are Easy
 Ln
1000 = 6.9
 Ln 100 = 4.6
 Ln 10 = 2.3
 Ln 1 = 0
 Ln 0.1 = -2.3
 Ln 0.01 = -4.6
 Ln 0.001 = -6.9
Because the K+
concentration is greater
inside the cell than outside
the cell, K+ moving out of
the cell tends to
hyperpolarize the
membrane.
 The Na+ concentration is
greater outside the cell than
inside the cell, but since the
membrane at rest is
relatively impermeable to
Na+, Na+ has little effect on
the electrical potential of
the membrane at rest.
 Consequently, the resting
membrane potential is
given by the equilibrium
potential for K+.

Resting
Potential
Concentrations (in mol/m3) and
Equilibrium Potentials (in V) of Cations
Outside
Inside
Equilibrium
Potential
K+
20
400
Na+
440
50
-0.08 V
+0.06V
Measuring Membrane Potentials In
Neurons With Microelectrodes
Edgar Adrian (1928)
placed small glass
electrodes into many
kinds of neurons and
measured the single
cell electrical variation
that contributed to the
whole nerve electrical
changes that had been
measured by Emil Du
Bois-Reymond.
The Action Potential: A Variation in
Electrical Potential
The Nervous Signal is like the Morse Code
“If these records give a true
measure of the activity in the
sensory nerve fibres it is clear
that they transmit their
messages to the central
nervous system in a very
simple way. The message
consists merely of a series of
brief impulses….In any one
fibre the waves are all of the
same form….In fact, the
sensory messages are
scarcely more complex than
a succession of dots in the __ __ . . . . . . .
Morse Code.”
ADRIAN'S LAWS
 Neurons
communicate with each other by
sending a short episode of electrical
pulses, known as action potentials,
along their fibers.
 A stimulus either induces an action
potential in a neuron or it does not. It is an
all-or-none response.
 The pulses do not vary in amplitude but
vary in the frequency of the pulses.
 The frequency can be as high as 1000
impulses per second.
Resting State
Initiation of an Action Potential
A stimulus
causes Na+
channels to
open and the
influx of Na+
causes the
membrane
potential to
depolarize
(become less
negative)
beyond a
threshold.
Action Potential: Positive Feedback
The membrane
depolarization
activates additional
Na+ channels,
whose
conductance is
voltagedependent. This
causes a lot more
Na+ to enter the cell
and the membrane
potential
depolarizes further
(and even becomes
positive).
Action Potential: Negative Feedback
The Na+ channels do not remain open forever, but
become inactivated. This causes the membrane to
become repolarized (hyperpolarized again).
Action Potential: K+ ions
Once the membrane
potential is depolarized by
the Na+, the membrane
potential is no longer
negative enough to hold in
the high concentration of K+
ions and the K+ ions begin to
move out of the cell through
the K+ channels. This
enhanced K+ efflux,
combined with the
inactivation of the Na+
channels results in a return
to the resting membrane
potential and the action
potential is over.
Voltage Clamp Experiments

The activation and inactivation of the
Na+ channel was studied by Alan
Hodgkin and Andrew Fielding Huxley
using a voltage clamp.
 The properties of the channel were
determined by holding the axon
membrane at a depolarized potential
(V).
 When the membrane is held at a
depolarizing potential, the Na+ channel
is activated and a current (I) carried
by Na+ passes. The current is
proportional to the membrane
conductance (G). After a millisecond
or so, the current stops, indicating that
the channel becomes inactivated.
Voltage Clamp Experiments
Ohm’s Law
V = IR
R = V/I
G = I/V
Equivalent Circuit of Axon Membrane
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Membrane and
channel conductance
can be determined
using Ohm’s Law.
Equilibrium potentials
act as batteries.
Channels act as
variable resistors.
Lipid bilayer acts as
insulator in a
capacitor.
Neurons are really
miniature electrical
devices!!!!!
The Neuron Acts as if it is Composed of
Electronic Parts
http://artisresistors.co.uk/gallery.html
Some Evidence for the Ionic Theory of
Action Potentials

An action potential can not be
generated unless there are
Na+ in the external medium.
 Radioactive Na+ are taken
up by the neuron during an
action potential.
 Pharmacological agents
that inhibit Na+ channels,
like tetrodotoxin, which is
isolated from the puffer fish,
prevent the action potential.
Refractory Period and Unidirectionality
The Na+ channel remains inactivated for slightly
longer than it takes to bring the membrane back
to the resting potential.
 Thus, the section of membrane that just finished
an action potential is not able to produce
another one until the Na+ channel is no longer
inactivated.
 The period of time necessary for the Na+
channel to become sensitive to a stimulus is
known as the refractory period.
 The refractory period makes it possible for
an action potential to move down a neuron in
only one direction.

Due to the
refractory
period, the
action potential
moves along
the axon
unidirectionally.
Nodes of Ranvier
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The membranes of the glial cells that form the myelin sheath
around the axon are almost purely lipid.
Since ions cannot pass through lipids, the myelin sheath acts
as a insulator around the conducting axon.
Each Schwann cell is separated from the next by a node of
Ranvier, where the sodium and potassium channels are.
The combination of the glial cells and the nodes of Ranvier
make an electrical capacitor that causes the voltage to
“jump” from node to node.
Myelin Sheath Results in a High Conduction
Velocity
Action potentials move down the axon jumping from node to
node at a rate of 150 m/s (= 330 mph). Without the myelin
sheath, the action potential would travel about 5 m/s.
Multiple Sclerosis

Multiple sclerosis is an
autoimmune disease in which
the white blood cells of the
body consider the
oligodendrocytes that form the
myelin sheath around the
neurons of the central nervous
system to be foreign invaders
and destroy them.
 The degeneration of the myelin
sheath results in a slower
conduction velocity of action
potentials and a loss of control
of neural processes.
What Happens to the Electrical Impulse When it
Gets to the End of the Cell?
How Can an Electrical Signal Stimulate Some
Cells and Inhibit Others?
Stimulatory and Inhibitory Actions of
Neurons

When one provokes a a reflex
movement, a contraction of one
muscle is accompanied by a
relaxation of an opposing muscle.
 Since all muscles are stimulated by a
depolarizing voltage shock and all
action potentials involve the
transmission of a membrane
depolarization, Charles Sherrington
suggested that action potentials must
be capable of doing at least two
different things at synapses, one
stimulatory and one inhibitory.
Excitatory and Inhibitory Synapses

While working on reflexes,
Sherrington discovered
that the there are two
types of synapses:
excitatory and
inhibitory.
 The same concepts of
excitation and inhibition
appeared again in the
sympathetic and the
parasympathetic
nervous systems.
Sympathetic and Parasympathetic
Nervous System

Since the sympathetic and the parasympathetic
nerve systems have opposite effects on cardiac
muscle, there must be two different actions at
their synapses: one excitatory, another one
inhibitory.
 No one could figure out how an electrical
message, in the form of an action potential going
to the same postsynaptic element would achieve
totally opposite effects, so some turned to the
idea that excitatory and inhibitory chemical
messengers may be involved.
Chemical Synapses?

Thomas Elliot (1904) could mimic the excitatory
effects of the sympathetic nervous system on
cardiac muscle with an extract of the adrenal
medulla known as adrenaline.
 Henry Dale (1920s) could mimic the inhibitory
effects of the parasympathetic nervous system
on cardiac muscle with an extract from ergot of
rye, known as acetylcholine.
 Dale coined the terms "adrenergic" and
"cholinergic" synapses to describe the
chemicals that may couple the neural stimulus to
the cardiac muscular response.
Henry Dale
By 1936, Henry Dale
concluded that, "According
to this relatively new
evidence, a chemical
mechanism of transmission
is concerned, not only with
the effects of autonomic
nerves, but with the whole
of the efferent activities of
the peripheral nervous
system, whether voluntary
or involuntary in function."
Occam’s Razor Sliced a Little Too
Close
 Electrophysiologists
did not want
to believe in chemical signals.
 They invoked Occam’s Razor,
claiming that there is no need for
two kinds of signals.
 In general, as scientists, we are
reductionists and try to simplify
things as much as possible. But
biological systems are never as
simple as reductionists postulate.
Graded Potential Responses
John Eccles (1952) began to
insert microelectrodes into
the cell bodies of postsynaptic neurons of the
CNS. After stimulating either
excitatory or inhibitory presynaptic nerves, he
discovered that there were
two kinds of graded
potential responses in the
post-synaptic cell.
The Excitatory Graded Potential

The excitatory response
depolarized the post-synaptic
nerve cell, bringing the
membrane potential closer to
the threshold.
 This would increase the
probability of activating
voltage-dependent Na+
channels and initiating an action
potential in the post-synaptic
cell.
The Inhibitory Graded Potential

The inhibitory response
hyperpolarized the postsynaptic nerve cell, bringing
the membrane potential further
from the threshold.
 This would decrease the
probability of activating
voltage-dependent Na+
channels and initiating an action
potential in the post-synaptic
cell.
The Excitatory (EPSP) Graded
Potential Results from the Activation of
Voltage-Independent Na+ Channels
The Inhibitory (IPSP) Graded Potential Results
from the Activation of Voltage-Independent K+
Channels or Voltage-Independent Cl- Channels
Integration by the Post-Synaptic
Neuron
The sum of all the
excitatory (+) post
synaptic potentials
(EPSP) and the
inhibitory (-) post
synaptic potentials
(IPSP) determine the
probability of
initiating an action
potential in the postsynaptic cell.
Integration by the Post-Synaptic
Neuron: The Basis of Decision Making?

When a large number of excitatory postsynaptic potentials (EPSP) and a small number
of inhibitory post-synaptic potentials (IPSP) are
evoked, the post-synaptic membrane is
depolarized and the post synaptic neuron
becomes likely to initiate an action potential.
 If a small number of excitatory post-synaptic
potentials (EPSP) and a large number of
inhibitory post-synaptic potentials (IPSP) are
evoked, the post-synaptic membrane becomes
hyperpolarized and the post synaptic neuron is
unlikely to initiate an action potential.
The Post-Synaptic Cell is an Analog to
Digital Converter
The Post-Synaptic Cell is also an
Integrator
In the Post-Synaptic Cell,
the Majority Rules
Integration Can Take Place Over Time (from a
single Pre-synaptic Neuron) or Over Space (from
Many Pre-synaptic Neurons)
Excitatory and Inhibitory
Neurotransmitters

Whether a pre-synaptic neuron is excitatory or
inhibitory depends on the neurotransmitter that
is released.
 Excitatory neurotransmitters include:




acetylcholine (neuromuscular junction of skeletal
muscle)
noradrenaline
glutamate (an amino acid)
Inhibitory neurotransmitters include:



acetylcholine (neuromuscular junction of cardiac
muscle)
glycine (an amino acid)
GABA
How does an action potential trigger
neurotransmitter release in a neuromuscular
junction?
The membrane depolarization at the pre-synaptic
membrane due to the action potential opens calcium
channels. The calcium entering the cell acts as a
second messenger to trigger the secretion of
acetylcholine by exocytosis into the neuromuscular
synapse.
Stimulus-Response in Neurons
Stimulus: Action
potential (membrane
depolarization)
Receptor: Voltagedependent Ca2+
channels
Second Messenger:
Ca2+
Response: Secretion
of neurotransmitters
Neuromuscular Junction of Skeletal Muscle



Acetylcholine is the
neurotransmitter released
in the neuromuscular
junction.
The acetylcholine
receptor is a Na+
channel.
The activation of which
causes a depolarization
of the muscle cell
membrane, which causes
voltage-dependent Ca2+
channels to open, which
causes the muscle to
contract.
Food Poisoning: Botulism
(Clostridium botulinum)
Botulinum Toxin Causes Paralysis by Blocking
Acetylcholine Release
Every Cloud Has a Silver Lining

Weight for weight,
botulinum toxin
is the most toxic of
toxins.
 However, it can be
used for cosmetic
reasons—where it
is sold under the
name botox.
Botox: Botulinum Toxin Injections Prevent
Contraction of the Muscles that Result in
Frowning
Cosmetic Botox Injection
Cosmetic Botox Injections
Botox Scam: Priscilla Presley Got Low
Grade Silicone Instead of a “Superior
Grade of Botox”
The Chemical Basis of the Individual’s
Mind

As I will discuss in the next lecture, there are
many different neurotransmitters, especially
in the brain, that can induce either excitation or
inhibition of the post-synaptic membrane.
 Due to differential transcription and
alternative splicing, there is a variety of
receptors for each neurotransmitter in different
post-synaptic neurons. Moreover, allelic
differences between individuals lead to
genetically-determined differences in receptors.
 The near-limitless combinations allow for near
infinite individual variations in the chemical basis
of mind.
The Mind-Body Problem: Original
Thoughts
Is the mind an emergent property of
hundreds of billions of material brain cells?
If so,


One day it will be possible to electrically
stimulate the brain with a number of
electrodes in such a way as to create an
original thought.
One day it will be possible to introduce a
combination of chemicals into the brain and
create an original thought.
The Mind-Body Problem: Original
Thoughts
Does the mind have its own energy that is
capable of influencing the physicochemical processes in the brain and
induce action potentials?

According to Wilder Penfield (1975) “…there
is no good evidence . . . that the brain alone
can carry out the work that the mind does. . . .
I believe that one should not pretend to draw
a final scientific conclusion, in man's study of
man, until the nature of the energy
responsible for mind action is discovered, as
in my own opinion, it will be."
Free Will
“Between stimulus
and response there
is a space. In that
space is our power
to choose our
response. In our
response lies our
growth and our
freedom.”
Viktor Frankl
Free Will
“The very serious and difficult
question arises of
whether…free will is
compatible with our scientific
knowledge, which plainly says
that the concept of a breach in
causal continuity is not
acceptable. From the point of
view of science, the reality of
free will cannot be conceded.
On the other hand, as human
beings, we depend on the
belief that…our actions are
preceded by deliberation and
choice….”
Hans Mohr
Free Will
“All I have to say is that
free will is a fact of
experience….Free will is
often denied on the
grounds that you can’t
explain it, that it involved
happenings inexplicable
by present-day physics
and physiology. To that I
reply that our inability may
stem from the fact that
physics and physiology
are still not adequately
developed.…”
John Eccles
Science and Free Will

I believe that we can exercise
and develop our neurons to
transform food energy into
“free will energy”, which acts
locally (100 nm range) and at
levels of about 10-20 - 10-19 J.
 Perhaps “free will energy”
could modify a calcium
channel in the presynaptic
neuron or modify a receptor
in the postsynaptic neuron
and cause us to do or not do
something (e.g. something
that takes courage).
Zorba the Greek
It may be that we can choose to convert our
food into fat, work, or spirit.
Profiles in Courage Award
In whatever arena of life
one may meet the
challenge of courage…
each…must decide for
himself the course he
will follow….
—John F. Kennedy
Profiles in Courage
A Profile in Courage
Plant and animal cell biologist
Werner Franke exposed illegal
East German steroid research and
the illegal doping of athletes.
Another Profile in Courage
Dr. Ignacio Chapela
is courageous in
“disentangling reality
from corporate
advertising” in his
ecological studies at
UC Berkeley.
www.nature.com