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NIH Publication No. 06-474

Reprinted July 2006
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National Institute of General Medical Sciences

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Medicines By Design

U.S. DEPARTMENT OF

HEALTH AND HUMAN SERVICES

National Institutes of Health

National Institute of General Medical Sciences

NIH Publication No. 06-474

Reprinted July 2006

http://www.nigms.nih.gov

Written by Alison Davis, Ph.D., under contracts

263-MD-205019 and 263-MD-212730.
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Contents

FO R E W O R D: A V I SI T T O T H E D O C T O R

C H A PTE R 1: A BC S O F P H AR MAC O LO GY

A Drugs Life

Perfect Timing

Fitting In

10

Bench to Bedside: Clinical Pharmacology

13

Pump It Up

14

C H A PTE R 2: BO DY, H E AL T H YS E LF

16

The Body Machine

16

River of Life

18

No Pain, Your Gain

20

Our Immune Army

23

A Closer Look

26

C H A PTE R 3: DR U GS F R O M N AT U R E , T H E N AN D N O W

28

Natures Medicine Cabinet

28

Ocean Medicines

30

Tweaking Nature

33

Is It Chemistry or Genetics?

34

TestingI, II, III

36

C H A PTE R 4: M O L EC U LE S T O ME D I C I N E S

38

Medicine Hunting

38

21st-Century Science

40

Rush Delivery

41

Transportation Dilemmas

43

Act Like a Membrane

44

The G Switch

46

M E DI C I NE S FO R TH E F U T U R E

48

GLO S SARY

50

Foreword: A Visit to the Doctor

May 17, 2050You wake up feeling terrible,

Thats right, your DNA. Researchers predict that

the medicines of the future may not only look and

and you know its time to see a doctor.

In the ofce, the physician looks you over,

work differently than those you take today, but

tomorrows medicines will be tailored to your
genes. In 10 to 20 years, many scientists expect

listens to your symptoms, and prescribes

that genetics the study of how genes inuence

actions, appearance, and healthwill pervade

a drug. But rst, the doctor takes a look

at your DNA.

medical treatment. Today, doctors usually give you

an average dose of a medicine based on your
body size and age. In contrast, future medicines
may match the chemical needs of your body, as
inuenced by your genes. Knowing your unique
genetic make-up could help your doctor prescribe
the right medicine in the right amount, to boost its
effectiveness and minimize possible side effects.
Along with these so-called pharmacogenetic
approaches, many other research directions will
help guide the prescribing of medicines. The
science of pharmacologyunderstanding the
basics of how our bodies react to medicines and
how medicines affect our bodiesis already a
vital part of 21st-century research. Chapter 1,
ABCs of Pharmacology, tracks a medicines
journey through the body and describes different
avenues of pharmacology research today.

Medicines By Design I Foreword 3

Stay tuned for changes in the way you take

delivery, discussed in Chapter 4, Molecules to

medicines and in how medicines are discovered

Medicines, is advancing progress by helping get

and produced. In Chapter 2, Body, Heal Thyself,

drugs to diseased sites and away from healthy cells.

learn how new knowledge about the bodys own

Medicines By Design aims to explain how

molecular machinery is pointing to new drugs. As

scientists unravel the many different ways medicines

scientists understand precisely how cells interact in

work in the body and how this information guides

the body, they can tailor medicines to patch gaps

the hunt for drugs of the future. Pharmacology

in cell communication pathways or halt signaling

is a broad discipline encompassing every aspect

circuits that are stuck on, as in cancer.

of the study of drugs, including their discovery

Scientists are developing methods to have

and development and the testing of their action

animals and plants manufacture custom-made

in the body. Much of the most promising

medicines and vaccines. Experimental chickens

pharmacological research going on at universities

are laying medicine-containing eggs. Researchers

across the country is sponsored by the National

are engineering tobacco plants to produce new

Institute of General Medical Sciences (NIGMS),

cancer treatments. Topics in Chapter 3, Drugs

a component of the National Institutes of Health

From Nature, Then and Now, will bring you up

(NIH), U.S. Department of Health and Human

to speed on how scientists are looking to nature

Services. Working at the crossroads of chemistry,

for a treasure trove of information and resources

genetics, cell biology, physiology, and engineering,

to manufacture drugs.

pharmacologists are ghting disease in the laboratory

Advances in understanding the roots of disease

are leading to new ways to package tomorrows
medicines. Along with biology and chemistry, the
engineering and computer sciences are leading us
to novel ways of getting drugs where they need
to go in the body. Cutting-edge research in drug

and at the bedside.

CHAPTER 1

ABCs of Pharmacology

now why some peoples stomachs burn after

medicines affect the body. Pharmacology is often

they swallow an aspirin tablet? Or why a

confused with pharmacy, a separate discipline in

swig of grapefruit juice with breakfast can raise

the health sciences that deals with preparing and

blood levels of some medicines in certain people?

dispensing medicines.

Understanding some of the basics of the science

For thousands of years, people have looked in

of pharmacology will help answer these questions,

nature to nd chemicals to treat their symptoms.

and many more, about your body and the medicines

Ancient healers had little understanding of how

you take.

various elixirs worked their magic, but we know

So, then, whats pharmacology?

much more today. Some pharmacologists study

Despite the elds long, rich history and impor

how our bodies work, while others study the

tance to human health, few people know much

chemical properties of medicines. Others investi

about this biomedical science. One pharmacologist

gate the physical and behavioral effects medicines

joked that when she was asked what she did for a

have on the body. Pharmacology researchers study

living, her reply prompted an unexpected question:

drugs used to treat diseases, as well as drugs of

Isnt farm ecology the study of how livestock

abuse. Since medicines work in so many different

impact the environment?

ways in so many different organs of the body,

Of course, this booklet isnt about livestock or

agriculture. Rather, its about a eld of science that

pharmacology research touches just about every

area of biomedicine.

studies how the body reacts to medicines and how

A Juicy Story
Did you know that, in some people, a single glass
of grapefruit juice can alter levels of drugs used
to treat allergies, heart disease, and infections?
Fifteen years ago, pharmacologists discovered
this grapefruit juice effect by luck, after giving
volunteers grapefruit juice to mask the taste of a
medicine. Nearly a decade later, researchers g
ured out that grapefruit juice affects
medicines by lowering levels of a
drug-metabolizing enzyme, called
CYP3A4, in the intestines.
More recently, Paul B. Watkins of
the University of North Carolina at
Chapel Hill discovered that other juices like Seville
(sour) orange juicebut not regular orange

juicehave the same effect on the bodys handling

of medicines. Each of 10 people who volunteered
for Watkins juice-medicine study took a standard
dose of Plendil (a drug used to treat high blood
pressure) diluted in grapefruit juice, sour orange
juice, or plain orange juice. The researchers meas
ured blood levels of Plendil at various times
afterward. The team observed that both grapefruit
juice and sour orange juice increased blood levels of
Plendil, as if the people had received a higher
dose. Regular orange juice had no effect. Watkins
and his coworkers have found that a chemical com
mon to grapefruit and sour oranges,
dihydroxybergamottin, is likely the molecular cul
prit. Another similar molecule in these fruits,

Medicines By Design I ABCs of Pharmacology 5

Many scientists are drawn to pharmacology

A Drugs Life

because of its direct application to the practice of

How does aspirin zap a headache? What happens

medicine. Pharmacologists study the actions of

after you rub some cortisone cream on a patch of

drugs in the intestinal tract, the brain, the muscles,

poison ivy-induced rash on your arm? How do

and the liverjust a few of the most common

decongestant medicines such as Sudafed dry up

areas where drugs travel during their stay in the

your nasal passages when you have a cold? As

body. Of course, all of our organs are constructed

medicines nd their way to their job sites in the

from cells, and inside all of our cells are genes.

body, hundreds of things happen along the way.

Many pharmacologists study how medicines

One action triggers another, and medicines work

interact with cell parts and genes, which in turn

to either mask a symptom, like a stuffy nose, or

inuences how cells behave. Because pharmacology

x a problem, like a bacterial infection.

touches on such diverse areas, pharmacologists

must be broadly trained in biology, chemistry, and
more applied areas of medicine, such as anatomy
and physiology.

A Model for Success

Turning a molecule into a good medicine is neither
easy nor cheap. The Center for the Study of Drug
Development at Tufts University in Boston esti
mates that it takes over $800 million and a dozen
years to sift a few promising drugs from about
5,000 failures. Of this small handful of candidate
drugs, only one will survive the rigors of clinical
testing and end up on pharmacy shelves.
Thats a huge investment for what may seem
a very small gain and, in part, it explains the high
cost of many prescription drugs. Sometimes, prob
lems do not show up until after a drug reaches
the market and many people begin taking the drug
routinely. These problems range from irritating side
effects, such as a dry mouth or drowsiness, to lifethreatening problems like serious bleeding or blood
clots. The outlook might be brighter if pharmaceutical
scientists could do a better job of predicting how
potential drugs will act in the body (a science called
pharmacodynamics), as well as what side effects the
drugs might cause.

One approach that can help is computer mod

eling of a drugs properties. Computer modeling
can help scientists at pharmaceutical and biotech
nology companies lter out, and abandon early
on, any candidate drugs that are likely to behave
badly in the body. This can save signicant
amounts of time and money.
Computer software can examine the atom-by
atom structure of a molecule and determine
how durable the chemical is likely to be inside
a bodys various chemical neighborhoods. Will
the molecule break down easily? How well will
the small intestines take it in? Does it dissolve
easily in the watery environment of the uids
that course through the human body? Will the
drug be able to penetrate the blood-brain barrier?
Computer tools not only drive up the success
rate for nding candidate drugs, they can also
lead to the development of better medicines
with fewer safety concerns.

National Institute of General Medical Sciences

Inhaled

Oral

Lung

Heart

Liver

Kidney

Stomach

Intravenous
Intestines

A drugs life in the body.

Medicines taken by mouth
(oral) pass through the liver
before they are absorbed
into the bloodstream. Other
forms of drug administration
bypass the liver, entering the
blood directly.

Medicines By Design I ABCs of Pharmacology 7

Intramuscular

Subcutaneous

Drugs enter different layers

of skin via intramuscular,
subcutaneous, or transdermal
delivery methods.

Transdermal

Skin

Scientists have names for the four basic stages

a large amount may be destroyed by metabolic

of a medicines life in the body: absorption, distri

enzymes in the so-called rst-pass effect. Other

bution, metabolism, and excretion. The entire

routes of drug administration bypass the liver,

process is sometimes abbreviated ADME. The rst

entering the bloodstream directly or via the skin

stage is absorption. Medicines can enter the body

or lungs.

in many different ways, and they are absorbed

Once a drug gets absorbed, the next stage is

when they travel from the site of administration

distribution. Most often, the bloodstream carries

into the bodys circulation. A few of the most

medicines throughout the body. During this step,

common ways to administer drugs are oral (swal

side effects can occur when a drug has an effect in

lowing an aspirin tablet), intramuscular (getting a

an organ other than the target organ. For a pain

u shot in an arm muscle), subcutaneous (injecting

reliever, the target organ might be a sore muscle

insulin just under the skin), intravenous (receiving

in the leg; irritation of the stomach could be a

chemotherapy through a vein), or transdermal

side effect. Many factors inuence distribution,

(wearing a skin patch). A drug faces its biggest

such as the presence of protein and fat molecules

hurdles during absorption. Medicines taken

in the blood that can put drug molecules out of

by mouth are shuttled via a special blood vessel

commission by grabbing onto them.

leading from the digestive tract to the liver, where

National Institute of General Medical Sciences

Drugs destined for the central nervous system

broken down, or metabolized. The breaking down

(the brain and spinal cord) face an enormous

of a drug molecule usually involves two steps that

hurdle: a nearly impenetrable barricade called

take place mostly in the bodys chemical process

the blood-brain barrier. This blockade is built

ing plant, the liver. The liver is a site of continuous

from a tightly woven mesh of capillaries cemented

and frenzied, yet carefully controlled, activity.

together to protect the brain from potentially

Everything that enters the bloodstreamwhether

dangerous substances such as poisons or viruses.

swallowed, injected, inhaled, absorbed through the

Yet pharmacologists have devised various ways

skin, or produced by the body itselfis carried to

to sneak some drugs past this barrier.

this largest internal organ. There, substances are

After a medicine has been distributed through

out the body and has done its job, the drug is

chemically pummeled, twisted, cut apart, stuck

together, and transformed.

Medicines and Your Genes

How you respond to a drug may be quite different
from how your neighbor does. Why is that? Despite
the fact that you might be about the same age and
size, you probably eat different foods, get different
amounts of exercise, and have different medical
histories. But your genes, which are different from
those of anyone else in the world, are really what
make you unique. In part, your genes give you
many obvious things, such as your looks, your
mannerisms, and other characteristics that make
you who you are. Your genes can also affect how
you respond to the medicines you take. Your
genetic code instructs your body how to make
hundreds of thousands of different molecules
called proteins. Some proteins determine hair
color, and some of them are enzymes that process,
or metabolize, food or medicines. Slightly different,
but normal, variations in the human genetic code
can yield proteins that work better or worse when
they are metabolizing many different types of
drugs and other substances. Scientists use the
term pharmacogenetics to describe research on
the link between genes and drug response.
One important group of proteins whose genetic
code varies widely among people are sulfation

enzymes, which perform chemical reactions in

your body to make molecules more water-soluble,
so they can be quickly excreted in the urine.
Sulfation enzymes metabolize many drugs, but
they also work on natural body molecules, such
as estrogen. Differences in the genetic code for
sulfation enzymes can signicantly alter blood
levels of the many different kinds of substances
metabolized by these enzymes. The same genetic
differences may also put some people at risk
for developing certain types of cancers whose
growth is fueled by hormones like estrogen.
Pharmacogeneticist Rebecca Blanchard of Fox
Chase Cancer Center in Philadelphia has discovered
that people of different ethnic backgrounds have
slightly different spellings of the genes that make
sulfation enzymes. Lab tests revealed that sulfation
enzymes manufactured from genes with different
spellings metabolize drugs and estrogens at differ
ent rates. Blanchard and her coworkers are planning
to work with scientists developing new drugs to
include pharmacogenetic testing in the early phases
of screening new medicines.

Medicines By Design I ABCs of Pharmacology 9

The biotransformations that take place in the

methods can help track

liver are performed by the bodys busiest proteins,

medicines as they travel

its enzymes. Every one of your cells has a variety

through the body,

of enzymes, drawn from a repertoire of hundreds

scientists usually cannot

of thousands. Each enzyme specializes in a partic

actually see where a drug

ular job. Some break molecules apart, while others

is going. To compensate,

link small molecules into long chains. With drugs,

they often use mathe

the rst step is usually to make the substance

matical models and

easier to get rid of in urine.

precise measures of

Many of the products of enzymatic break

body uids, such as

down, which are called metabolites, are less

blood and urine, to

chemically active than the original molecule.

determine where a drug

For this reason, scientists refer to the liver as a

goes and how much

detoxifying organ. Occasionally, however, drug

of the drug or a break

metabolites can have chemical activities of their

down product remains

ownsometimes as powerful as those of the

after the body processes it. Other sentinels, such

original drug. When prescribing certain drugs,

as blood levels of liver enzymes, can help predict

doctors must take into account these added effects.

how much of a drug is going to be absorbed.

Once liver enzymes are nished working on a

Studying pharmacokinetics also uses chem

medicine, the now-inactive drug undergoes the

istry, since the interactions between drug and

nal stage of its time in the body, excretion, as

body molecules are really just a series of chemical

it exits via the urine or feces.

reactions. Understanding the chemical encounters

between drugs and biological environments, such

Perfect Timing
Pharmacokinetics is an aspect of pharmacology
that deals with the absorption, distribution, and
excretion of drugs. Because they are following drug
actions in the body, researchers who specialize in
pharmacokinetics must also pay attention to an
additional dimension: time.
Pharmacokinetics research uses the tools of
mathematics. Although sophisticated imaging

as the bloodstream and the oily surfaces of cells,

is necessary to predict how much of a drug will
be taken in by the body. This concept, broadly
termed bioavailability, is a critical feature that
chemists and pharmaceutical scientists keep in
mind when designing and packaging medicines.
No matter how well a drug works in a laboratory
simulation, the drug is not useful if it cant make
it to its site of action.

10

National Institute of General Medical Sciences

Fitting In

of arrows. Bernard discovered that curare causes

While it may seem obvious now, scientists did not

paralysis by blocking chemical signals between

always know that drugs have specic molecular

nerve and muscle cells. His ndings demonstrated

targets in the body. In the mid-1880s, the French

that chemicals can carry messages between nerve

physiologist Claude Bernard made a crucial

cells and other types of cells.

discovery that steered researchers toward under

Since Bernards experiments with curare,

standing this principle. By guring out how a

researchers have discovered many nervous system

chemical called curare works, Bernard pointed

messengers, now called neurotransmitters. These

to the nervous system as a new focus for pharma-

chemical messengers are called agonists, a generic

cology. Curare a plant extract that paralyzes

term pharmacologists use to indicate that a molecule

muscleshad been used for centuries by Native

triggers some sort of response when encountering a

Americans in South America to poison the tips

cell (such as muscle contraction or hormone release).

Nerve cells use a chemical

Nerve Cell

Acetylcholine
Curare

Receptor

Muscle Cell

messenger called acetyl

choline (balls) to tell muscle
cells to contract. Curare (half
circles) paralyzes muscles
by blocking acetylcholine
from attaching to its muscle
cell receptors.

Medicines By Design I ABCs of Pharmacology 11

The Right Dose

One of the most important principles of pharma
cology, and of much of research in general, is a
concept called dose-response. Just as the term
implies, this notion refers to the relationship
between some effectlets say, lowering of
blood pressureand the amount of a drug.
Scientists care a lot about dose-response data
because these mathematical relationships signify
that a medicine is working according to a specic
interaction between different molecules in the body.
Sometimes, it takes years to gure out exactly
which molecules are working together, but when
testing a potential medicine, researchers must
rst show that three things are true in an experi
ment. First, if the drug isnt there, you dont get
any effect. In our example, that means no change
in blood pressure. Second, adding more of the
drug (up to a certain point) causes an incremental
change in effect (lower blood pressure with more
drug). Third, taking the drug away (or masking
its action with a molecule that blocks the drug)

means there is no effect. Scientists most often

plot data from dose-response experiments on a
graph. A typical dose-response curve demon
strates the effects of what happens (the vertical
Y-axis) when more and more drug is added to
the experiment (the horizontal X-axis).

One of the rst neurotransmitters identied

in a communication between the outside of the

was acetylcholine, which causes muscle contrac

cell and the inside, which contains all the mini-

tion. Curare works by tricking a cell into thinking

machines that make the cell run. Scientists have

it is acetylcholine. By tting not quite as well,

identied thousands of receptors. Because receptors

but nevertheless ttinginto receiving molecules

have a critical role in controlling the activity of cells,

called receptors on a muscle cell, curare prevents

they are common targets for researchers designing

acetylcholine from attaching and delivering its

new medicines.

message. No acetylcholine means no contraction,

and muscles become paralyzed.

Effect on Body
Y-axis

Response

Desired
Effect

Dose-response curves
determine how much of
a drug (X-axis) causes
a particular effect, or a
side effect, in the body
(Y-axis).

Side
Effect

Dose
1

10

100

Amount of Drug
X-axis

Curare is one example of a molecule called

an antagonist. Drugs that act as antagonists

Most medicines exert their effects by making

compete with natural agonists for receptors but

physical contact with receptors on the surface of

act only as decoys, freezing up the receptor and

a cell. Think of an agonist-receptor interaction

preventing agonists use of it. Researchers often

like a key tting into a lock. Inserting a key into

want to block cell responses, such as a rise in

a door lock permits the doorknob to be turned

blood pressure or an increase in heart rate. For

and allows the door to be opened. Agonists open

that reason, many drugs are antagonists, designed

cellular locks (receptors), and this is the rst step

to blunt overactive cellular responses.

National Institute of General Medical Sciences

12

The key to agonists tting snugly into their

major goals is to reduce these side effects by

receptors is shape. Researchers who study how

developing drugs that attach only to receptors

drugs and other chemicals exert their effects in

on the target cells.

particular organs the heart, the lungs, the

That is much easier said than done. While

kidneys, and so on are very interested in the

agonists may t nearly perfectly into a receptors

shapes of molecules. Some drugs have very broad

shape, other molecules may also brush up to

effects because they t into receptors on many

receptors and sometimes set them off. These

different kinds of cells. Some side effects, such as

types of unintended, nonspecic interactions

dry mouth or a drop in blood pressure, can result

can cause side effects. They can also affect how

from a drug encountering receptors in places other

much drug is available in the body.

than the target site. One of a pharmacologists

Steroids for Surgery

In todays culture, the word steroid conjures up
notions of drugs taken by athletes to boost strength
and physical performance. But steroid is actually
just a chemical name for any substance that has
a characteristic chemical structure consisting of
multiple rings of connected atoms. Some examples

A steroid is a molecule
with a particular chemical
structure consisting of
multiple rings (hexagons
and pentagon, below).

CH3

CH3

OH

of steroids include vitamin D, cholesterol, estrogen,

and cortisonemolecules that are critical for
keeping the body running smoothly. Various
steroids have important roles in the bodys repro
ductive system and the structure and function of
membranes. Researchers have also discovered
that steroids can be active in the brain, where they
affect the nervous system. Some steroids may
thus nd use as anesthetics, medicines that sedate
people before surgery by temporarily slowing
down brain function.
Douglas Covey of Washington University in
St. Louis, Missouri, has uncovered new roles
for several of these neurosteroids, which alter
electrical activity in the brain. Coveys research
shows that neurosteroids can either activate
or tone down receptors that communicate the
message of a neurotransmitter called gamma
aminobutyrate, or GABA. The main job of this
neurotransmitter is to dampen electrical activity
throughout the brain. Covey and other scientists
have found that steroids that activate the receptors
for GABA decrease brain activity even more,
making these steroids good candidates for anes
thetic medicines. Covey is also investigating
the potential of neuroprotective steroids in
preventing the nerve-wasting effects of certain
neurodegenerative disorders.

Medicines By Design I ABCs of Pharmacology 13

Bench to Bedside:
Clinical Pharmacology
Prescribing drugs is a tricky science, requiring
physicians to carefully consider many factors.
Your doctor can measure or otherwise determine
many of these factors, such as weight and diet.
But another key factor is drug interactions. You
already know that every time you go to the doctor,
he or she will ask whether you are taking any other
drugs and whether you have any drug allergies or
unusual reactions to any medicines.
Interactions between different drugs in the
body, and between drugs and foods or dietary
supplements, can have a signicant inuence,
sometimes fooling your body into thinking
you have taken more or less of a drug than you
actually have taken.

how a person is processing a drug. Usually, this

important analysis involves mathematical equa
tions, which take into account many different
variables. Some of the variables include the physi
cal and chemical properties of the drug, the total
amount of blood in a persons body, the individ
uals age and body mass, the health of the persons
liver and kidneys, and what other medicines the
person is taking. Clinical pharmacologists also
measure drug metabolites to gauge how much
drug is in a persons body. Sometimes, doctors
give patients a loading dose (a large amount)
rst, followed by smaller doses at later times. This
approach works by getting enough drug into the
body before it is metabolized (broken down) into
inactive parts, giving the drug the best chance to
do its job.

By measuring the amounts of a drug in blood

or urine, clinical pharmacologists can calculate

Natures Drugs
Feverfew for migraines, garlic for heart disease,
St. Johns wort for depression. These are just a
few of the many natural substances ingested by
millions of Americans to treat a variety of health
conditions. The use of so-called alternative medi
cines is widespread, but you may be surprised to
learn that researchers do not know in most cases
how herbs workor if they work at allinside
the human body.
Herbs are not regulated by the Food and Drug
Administration, and scientists have not performed
careful studies to evaluate their safety and effec
tiveness. Unlike many prescription (or even
over-the-counter) medicines, herbs contain many
sometimes thousandsof ingredients. While some

small studies have

conrmed the useful
ness of certain herbs,
like feverfew, other
herbal products have
proved ineffective or
harmful. For example,
recent studies suggest
that St. Johns wort is of no benet in treating
major depression. Whats more, because herbs are
complicated concoctions containing many active
components, they can interfere with the bodys
metabolism of other drugs, such as certain HIV
treatments and birth control pills.

14

National Institute of General Medical Sciences

Pump It Up
Bacteria have an uncanny ability to defend

the bacteria themselves. Microorganisms have

themselves against antibiotics. In trying to

ejection systems called multidrug-resistance

gure out why this is so, scientists have noted

(MDR) pumpslarge proteins that weave

that antibiotic medicines that kill bacteria in

through cell-surface membranes. Researchers

a variety of different ways can be thwarted

believe that microbes have MDR pumps

by the bacteria they are designed to destroy.

mainly for self-defense. The pumps are used

One reason, says Kim Lewis of Northeastern

to monitor incoming chemicals and to spit out

University in Boston, Massachusetts, may be

the ones that might endanger the bacteria.

LINDA S. NYE

Lewis suggests that plants, which produce

example, are often kicked out of cancer cells

many natural bacteria-killing molecules, have

by MDR pumps residing in the cells mem

gotten smart over time, developing ways to

branes. MDR pumps in membranes all over

outwit bacteria. He suspects that evolution has

the bodyin the brain, digestive tract, liver,

driven plants to produce natural chemicals that

and kidneysperform important jobs in

block bacterial MDR pumps, bypassing this

moving natural body molecules like hormones

bacterial protection system. Lewis tested his idea

into and out of cells.

Got It?

Explain the difference

between an agonist and

by rst genetically knocking out the gene for

Pharmacologist Mary Vore of the

the MDR pump from the common bacterium

University of Kentucky in Lexington has

Staphylococcus aureus (S. aureus). He and his

discovered that certain types of MDR pumps

coworkers then exposed the altered bacteria to

do not work properly during pregnancy,

How does grapefruit juice

a very weak antibiotic called berberine that had

and she suspects that estrogen and other

affect blood levels of

been chemically extracted from barberry plants.

pregnancy hormones may be partially respon

certain medicines?

Berberine is usually woefully ineffective against

sible. Vore has recently focused efforts on

S. aureus, but it proved lethal for bacteria missing

determining if the MDR pump is malformed

the MDR pump. Whats more, Lewis found

in pregnant women who have intrahepatic

that berberine also killed unaltered bacteria

cholestasis of pregnancy (ICP). A relatively

given another barberry chemical that inhibited

rare condition, ICP often strikes during the

the MDR pumps. Lewis suggests that by

third trimester and can cause signicant

co-administering inhibitors of MDR pumps

discomfort such as severe itching and nausea,

along with antibiotics, physicians may be able

while also endangering the growing fetus.

to outsmart disease-causing microorganisms.

Vores research on MDR pump function may

MDR pumps arent just for microbes.

Virtually all living things have MDR pumps,

also lead to improvements in drug therapy

an antagonist.

What does a pharmacologist plot on the vertical

and horizontal axes of a
dose-response curve?

Name one of the potential

risks associated with
taking herbal products.

for pregnant women.

including people. In the human body, MDR

pumps serve all sorts of purposes, and they can

What are the four

sometimes frustrate efforts to get drugs where

stages of a drugs life

they need to go. Chemotherapy medicines, for

in the body?

Many body molecules and drugs (yellow balls)

encounter multidrug-resistance pumps (blue)
after passing through a cell membrane.

CHAPTER 2

Body, Heal Thyself

cientists became interested in the workings

of the human body during the scientic

The Body Machine

Scientists still think about the body as a well-oiled

revolution of the 15th and 16th centuries. These

machine, or set of machines, powered by a control

early studies led to descriptions of the circulatory,

system called metabolism. The conversion of food

digestive, respiratory, nervous, and excretory

into energy integrates chemical reactions taking

systems. In time, scientists came to think of the

place simultaneously throughout the body to

body as a kind of machine that uses a series of

assure that each organ has enough nutrients and

chemical reactions to convert food into energy.

is performing its job properly. An important prin

ciple central to metabolism is that the bodys basic
unit is the cell. Like a miniature body, each cell is
surrounded by a skin, called a membrane. In turn,
each cell contains tiny organs, called organelles,
that perform specic metabolic tasks.

Discovery By Accident
The work of a scientist is often likened to locking
together the pieces of a jigsaw puzzle. Slowly and
methodically, one by one, the pieces t together to
make a pretty picture. Research is a puzzle, but the
jigsaw analogy is awed. The truth is, scientists
dont have a puzzle box to know what the nished
picture is supposed to look like. If you know the
result of an experiment ahead of time, its not really
an experiment.
Being a scientist is hard work, but most researchers
love the freedom to explore their curiosities. They test
ideas methodically, nding answers to new problems,
and every day brings a new challenge. But researchers
must keep their eyes and ears open for surprises. On
occasion, luck wins out and breakthroughs happen
by accident. The discovery of vaccines, X rays, and
penicillin each came about when a scientist was willing
to say, Hmmm, I wonder why and followed up on
an unexpected nding.

Medicines By Design I Body, Heal Thyself 17

The cell is directed by a command center, the

One important type of metabolism that occurs

nucleus, where the genes you inherited from your

constantly in our bodies is the reading and inter

parents reside. Your genesyour bodys own

preting of genes to make proteins. These proteins

personalized instruction manualare kept safe

underlie the millions of chemical reactions that

in packages called chromosomes. Each of your

run our bodies. Proteins perform structural roles,

cells has an identical set of 46 chromosomes,

keeping cells shaped properly. Proteins also work

23 inherited from your mother and 23 from

as enzymes that speed along chemical reactions

your father.

without an enzymes assistance, many reactions

would take years to happen.

Want a CYP?
Your body is a model of economy. Metabolism
your bodys way of making energy and body
parts from food and water takes place in every
cell in every organ. Complex, interlocking path
ways of cellular signals make up metabolism,
linking together all the systems that make
your body run. For this reason, researchers
have a tough time understanding the
process, because they are often faced
with studying parts one by one or a
few at a time. Nevertheless, scientists
have learned a lot by focusing on
individual metabolic pathways,
such as the one that manufactures
important regulatory
molecules called
prostaglandins
(see page 21).
Important enzymes called cytochrome
P450s (CYP, pronounced sip, 450s) process
essential molecules such as some hormones
and vitamins. The CYP 450 enzymes are
a major focus for pharmacologists because

they metabolize either break

down or activatehundreds of
prescribed medicines and natural
substances. Scientists who specialize
in pharmacogenetics (see page 8) have dis
covered that the human genetic code contains
many different spellings for CYP 450 genes, resulting
in CYP 450 proteins with widely variable levels of
activity. Some CYP 450 enzymes also metabolize
carcinogens, making these chemicals active and
more prone to causing cancer.
Toxicologist Linda Quattrochi of the University
of Colorado at Denver and Health Sciences Center
is studying the roles played by certain CYP 450
enzymes in the metabolism of carcinogens. Her
research has revealed that natural components
of certain foods, including horseradish, oranges,
mustard, and green tea, appear
to protect the body by
blocking CYP
450 enzymatic
activation of
carcinogens.

18

National Institute of General Medical Sciences

Red blood cells carry oxygen

throughout the body.

River of Life
Since blood is the bodys primary internal trans
portation system, most drugs travel via this route.
Medicines can nd their way to the bloodstream
in several ways, including the rich supply of blood

magical molecules that can make a clot form

vessels in the skin. You may remember, as a young

within minutes after your tumble. Blood is a rich

child, the horror of seeing blood escaping your

concoction containing oxygen-carrying red blood

body through a skinned knee. You now know that

cells and infection-ghting white blood cells.

the simplistic notion of skin literally holding

Blood cells are suspended in a watery liquid

everything inside isnt quite right. You survived

called plasma that contains clotting proteins,

the scrape just ne because blood contains

electrolytes, and many other important molecules.

Burns: More Than Skin Deep

More than simply a protective covering, skin is a
highly dynamic network of cells, nerves, and blood
vessels. Skin plays an important role in preserving
uid balance and in regulating body temperature
and sensation. Immune cells in skin help the body
prevent and ght disease. When you get burned, all
of these protections are in jeopardy. Burn-induced
skin loss can give bacteria and other microorgan
isms easy access to the nutrient-rich uids that
course through the body, while at the same time
allowing these uids to leak out rapidly. Enough
uid loss can thrust a burn or trauma patient into
shock, so doctors must replenish skin lost to severe
burns as quickly as possible.
In the case of burns covering a signicant
portion of the body, surgeons must do two things

fast: strip off the burned skin, then cover the

unprotected underlying tissue. These important
steps in the immediate care of a burn patient
took scientists decades to gure out, as they
performed carefully conducted experiments on
how the body responds to burn injury. In the early
1980s, researchers doing this work developed
the rst version of an articial skin covering called
Integra Dermal Regeneration Template, which
doctors use to drape over the area where the
burned skin has been removed. Today, Integra
Dermal Regeneration Template is used to treat
burn patients throughout the world.

Medicines By Design I Body, Heal Thyself 19

Blood also ferries proteins and hormones such as

Scientists called physiologists originally came

insulin and estrogen, nutrient molecules of vari

up with the idea that all internal processes work

ous kinds, and carbon dioxide and other waste

together to keep the body in a balanced state. The

products destined to exit the body.

bloodstream links all our organs together, enabling

While the bloodstream would seem like a

them to work in a coordinated way. Two organ

quick way to get a needed medicine to a diseased

systems are particularly interesting to pharma

organ, one of the biggest problems is getting the

cologists: the nervous system (which transmits

medicine to the correct organ. In many cases,

electrical signals over wide distances) and the

drugs end up where they are not needed and cause

endocrine system (which communicates messages

side effects, as weve already noted. Whats more,

via traveling hormones). These two systems are

drugs may encounter many different obstacles

key targets for medicines.

while journeying through the bloodstream. Some

medicines get lost when they stick tightly to
certain proteins in the blood, effectively putting
the drugs out of business.

Skin consists of three layers, making up

a dynamic network of cells, nerves, and
blood vessels.

Blood Vessel

Nerve

Hair Follicle
Sweat Gland
Fat

20

National Institute of General Medical Sciences

No Pain, Your Gain

Like curares effects on acetylcholine, the inter
actions between another drugaspirin and
metabolism shed light on how the body works.
This little white pill has been one of the most
widely used drugs in history, and many say that
it launched the entire pharmaceutical industry.
As a prescribed drug, aspirin is 100 years old.
However, in its most primitive form, aspirin is
much older. The bark of the willow tree contains
a substance called salicin, a known antidote to
headache and fever since the time of the Greek
physician Hippocrates, around 400 B.C. The body
converts salicin to an acidic substance called salicylate.
Despite its usefulness dating back to ancient times,
early records indicate that salicylate wreaked havoc
on the stomachs of people who ingested this
natural chemical. In the late 1800s, a scientic

Salicylate

Acetylsalicylate is the aspirin

of today. Adding a chemical tag
called an acetyl group (shaded
yellow box, right) to a molecule
derived from willow bark (salicy
late, above) makes the molecule
less acidic (and easier on the
lining of the digestive tract), but
still effective at relieving pain.

Acetylsalicylate
(Aspirin)

Medicines By Design I Body, Heal Thyself 21

breakthrough turned willow-derived salicylate

into a medicine friendlier to the body. Bayer
scientist Felix Hoffman discovered that adding
a chemical tag called an acetyl group (see gure,
page 20) to salicylate made the molecule less acidic
and a little gentler on the stomach, but the chemical
change did not seem to lessen the drugs ability to
relieve his fathers rheumatism. This molecule,
acetylsalicylate, is the aspirin of today.
Aspirin works by blocking the production
of messenger molecules called prostaglandins.
Because of the many important roles they play
in metabolism, prostaglandins are important
targets for drugs and are very interesting to pharma
cologists. Prostaglandins can help muscles relax and
open up blood vessels, they give you a fever when
youre infected with bacteria, and they also marshal
the immune system by stimulating the process called
inammation. Sunburn, bee stings, tendinitis,
and arthritis are just a few examples of painful
inammation caused by the bodys release of certain
types of prostaglandins in response to an injury.

Inammation leads to pain in arthritis.

22

National Institute of General Medical Sciences

Aspirin belongs to a diverse group of

To understand how enzymes like COX work,

medicines called NSAIDs, a nickname for

some pharmacologists use special biophysical

the tongue-twisting title nonsteroidal anti-

techniques and X rays to determine the three-

inammatory drugs. Other drugs that belong

dimensional shapes of the enzymes. These kinds

to this large class of medicines include Advil,

of experiments teach scientists about molecular

Aleve, and many other popular pain relievers

function by providing clear pictures of how all the

available without a doctors prescription. All these

folds and bends of an enzymeusually a protein

drugs share aspirins ability to knock back the

or group of interacting proteins help it do its

production of prostaglandins by blocking an

job. In drug development, one successful approach

enzyme called cyclooxygenase. Known as COX,

has been to use this information to design decoys

this enzyme is a critical driver of the bodys

to jam up the working parts of enzymes like COX.

metabolism and immune function.

Structural studies unveiling the shapes of COX

COX makes prostaglandins and other similar

enzymes led to a new class of drugs used to treat

molecules collectively known as eicosanoids from

arthritis. Researchers designed these drugs to selec

a molecule called arachidonic acid. Named for

tively home in on one particular type of COX

the Greek word eikos, meaning twenty, each

enzyme called COX-2.

eicosanoid contains 20 atoms of carbon.

By designing drugs that target only one form

Youve also heard of the popular pain reliever

of an enzyme like COX, pharmacologists may be

acetaminophen (Tylenol), which is famous for

able to create medicines that are great at stopping

reducing fever and relieving headaches. However,

inammation but have fewer side effects. For

scientists do not consider Tylenol an NSAID,

example, stomach upset is a common side effect

because it does little to halt inammation

caused by NSAIDs that block COX enzymes. This

(remember that part of NSAID stands for

side effect results from the fact that NSAIDs bind

anti-inammatory). If your joints are aching

to different types of COX enzymeseach of

from a long hike you werent exactly in shape

which has a slightly different shape. One of these

for, aspirin or Aleve may be better than Tylenol

enzymes is called COX-1. While both COX-1 and

because inammation is the thing making your

COX-2 enzymes make prostaglandins, COX-2

joints hurt.

beefs up the production of prostaglandins in sore,

Medicines By Design I Body, Heal Thyself 23

inamed tissue, such as arthritic joints. In con

Our Immune Army

trast, COX-1 makes prostaglandins that protect

Scientists know a lot about the bodys organ

the digestive tract, and blocking the production

systems, but much more remains to be discovered.

of these protective prostaglandins can lead to

To design smart drugs that will seek out

stomach upset, and even bleeding and ulcers.

diseased cells and not healthy ones, researchers

Very recently, scientists have added a new

need to understand the body inside and out.

chapter to the COX story by identifying COX-3,

One system in particular still puzzles scientists:

which may be Tylenols long-sought molecular

the immune system.

target. Further research will help pharmacologists

Even though researchers have accumulated

understand more precisely how Tylenol and

vast amounts of knowledge about how our bodies

NSAIDs act in the body.

ght disease using white blood cells and thousands

of natural chemical weapons, a basic dilemma
persistshow does the body know what to ght?
The immune system constantly watches for foreign

The Anti Establishment

Common over-the-counter medicines used to treat
pain, fever, and inammation have many uses.
Here are some of the terms used to describe the
particular effects of these drugs:

ANTIPYRETICthis term means fever-reducing;

it comes from the Greek word pyresis, which
means re.
ANTI-INFLAMMATORYthis word describes a
drugs ability to reduce inammation, which can
cause soreness and swelling; it comes from the
Latin word amma, which means ame.
ANALGESICthis description refers to a medicines
ability to treat pain; it comes from the Greek word
algos, which means pain.

24

National Institute of General Medical Sciences

Antibodies are Y-shaped

molecules of the immune
system.

Antibodies are spectacularly specic pro

teins that seek out and mark for destruction
anything they do not recognize as
belonging to the body. Scientists have
learned how to join antibody-making
cells with cells that grow and divide continuously.
invaders and is exquisitely

This strategy creates cellular factories that work

sensitive to any intrusion perceived

around the clock to produce large quantities of

as non-self, like a

specialized molecules, called monoclonal antibodies,

transplanted organ from

that attach to and destroy single kinds of targets.

another person. This pro

Recently, researchers have also gured out how to

tection, however, can run afoul if the body

produce monoclonal antibodies in the egg whites

slips up and views its own tissue as foreign.

of chickens. This may reduce production costs of

Autoimmune disease, in which the immune system

these increasingly important drugs.

mistakenly attacks and destroys body tissue that it

believes to be foreign, can be the terrible consequence.
The powerful immune army presents signi

Doctors are already using therapeutic mono

clonal antibodies to attack tumors. A drug called
Rituxan was the rst therapeutic antibody

cant roadblocks for pharmacologists trying to

approved by the Food and Drug Administration

create new drugs. But some scientists have looked

to treat cancer. This monoclonal antibody targets

at the immune system through a different lens.

a unique tumor ngerprint on the surface of

Why not teach the body to launch an attack

immune cells, called B cells, in a blood cancer

on its own diseased cells? Many researchers are

called non-Hodgkins lymphoma. Another thera

pursuing immunotherapy as a way to treat a

peutic antibody for cancer, Herceptin, latches

wide range of health problems, especially cancer.

onto breast cancer cell receptors that signal growth

With advances in biotechnology, researchers are

to either mask the receptors from view or lure

now able to tailor-produce in the lab modied

immune cells to kill the cancer cells. Herceptins

forms of antibodiesour immune systems

actions prevent breast cancer from spreading to

front-line agents.

other organs.
Researchers are also investigating a new kind of
vaccine as therapy for diseases such as cancer.
The vaccines are not designed to prevent cancer,

Medicines By Design I Body, Heal Thyself 25

but rather to treat the disease when it has already

research will point the way toward getting a

taken hold in the body. Unlike the targeted-attack

sick body to heal itself, it is likely that there

approach of antibody therapy, vaccines aim to

will always be a need for medicines to speed

recruit the entire immune system to ght off a

recovery from the many illnesses that

tumor. Scientists are conducting clinical trials of

plague humankind.

vaccines against cancer to evaluate the effectiveness

of this treatment approach.
The body machine has a tremendously com
plex collection of chemical signals that are relayed
back and forth through the blood and into and
out of cells. While scientists are hopeful that future

A Shock to the System

A body-wide syndrome caused by an infection

called sepsis is a leading cause of death in hospital
intensive care units, striking 750,000 people every
year and killing more than 215,000. Sepsis is a
serious public health problem, causing more deaths
annually than heart disease. The most severe form
of sepsis occurs when bacteria leak into the blood
stream, spilling their poisons and leading to a
dangerous condition called septic shock. Blood
pressure plunges dangerously low, the heart has

difculty pumping enough blood, and body temper

ature climbs or falls rapidly. In many cases, multiple
organs fail and the patient dies.
Despite the obvious public health importance of
nding effective ways to treat sepsis, researchers
have been frustratingly unsuccessful. Kevin Tracey
of the North Shore-Long Island Jewish Research
Institute in Manhasset, New York, has identied an
unusual suspect in the deadly crime of sepsis: the
nervous system. Tracey and his coworkers have
discovered an unexpected link between cytokines,
the chemical weapons released by the immune
system during sepsis, and a major nerve that con
trols critical body functions such as heart rate and
digestion. In animal studies, Tracey found that
electrically stimulating this nerve, called the vagus
nerve, signicantly lowered blood levels of TNF, a
cytokine that is produced when the body senses
the presence of bacteria in the blood. Further
research has led Tracey to conclude that produc
tion of the neurotransmitter acetylcholine underlies
the inammation-blocking response. Tracey is
investigating whether stimulating the vagus nerve
can be used as a component of therapy for sepsis
and as a treatment for other immune disorders.

26

National Institute of General Medical Sciences

A Closer Look

Seeing is believing. The clich could not

be more apt for biologists trying to
understand how a complicated
enzyme works. For decades,
researchers have isolated and
puried individual enzymes
from cells, performing experi
ments with these proteins to
nd out how they do their job
of speeding up chemical reac
tions. But to thoroughly understand a
molecules function, scientists have to take a
very, very close look at how all the atoms t
together and enable the molecular machine
to work properly.
Researchers called structural biologists are
fanatical about such detail, because it can
deliver valuable information for designing
drugseven for proteins that scientists have

One protruding end (green) of the MAO B enzyme

anchors the protein inside the cell. Body mole
cules or drugs rst come into contact with MAO B
(in the hatched blue region) and are worked on
within the enzymes active site, a cavity nestled
inside the protein (the hatched red region). To get
its job done, MAO B uses a helper molecule (yel
low), which ts right next to the active site where
the reaction takes place.
REPRINTED WITH PERMISSION FROM J. BIOL. CHEM. (2002) 277:23973-6.
HTTP://WWW.JBC.ORG

studied in the lab for a long time. For example,

Dale Edmondson of Emory University in

biologists have known for 40 years that an

Atlanta, Georgia, has recently uncovered new

enzyme called monoamine oxidase B (MAO B)

knowledge that may help researchers design

works in the brain to help recycle communica

better, more specic drugs to interfere with

tion molecules called neurotransmitters. MAO

these critical brain enzymes. Edmonson and

B and its cousin MAO A work by removing

his coworkers Andrea Mattevi and Claudia

molecular pieces from neurotransmitters, part

Binda of the University of Pavia in Italy got a

of the process of inactivating them. Scientists

crystal-clear glimpse of MAO B by determin

have developed drugs to block the actions

ing its three-dimensional structure. The

of MAO enzymes, and by doing so, help

researchers also saw how one MAO inhibitor,

preserve the levels of neurotransmitters in

Eldepryl, attaches to the MAO B enzyme,

people with such disorders as Parkinsons

and the scientists predict that their results

Name three functions

disease and depression.

will help in the design of more specic drugs

of blood.

However, MAO inhibitors have many

Got It?

Dene metabolism.

How does aspirin work?

with fewer side effects.

undesirable side effects. Tremors, increased

heart rate, and problems with sexual function
are some of the mild side effects of MAO

Give two examples of

immunotherapy.

inhibitors, but more serious problems include

seizures, large dips in blood pressure, and
difculty breathing. People taking MAO
inhibitors cannot eat foods containing the
substance tyramine, which is found in wine,
cheese, dried fruits, and many other foods.
Most of the side effects occur because drugs
that attach to MAO enzymes do not have a
perfect t for either MAO A or MAO B.

What is a technique
scientists use to study
a proteins threedimensional structure?

CHAPTER 3

Drugs From Nature, Then and Now

ong before the rst towns were built, before

written language was invented, and even

Natures Medicine Cabinet

Times have changed, but more than half of the

before plants were cultivated for food, the basic

worlds population still relies entirely on plants for

human desires to relieve pain and prolong life

medicines, and plants supply the active ingredients

fueled the search for medicines. No one knows

of most traditional medical products. Plants have

for sure what the earliest humans did to treat

also served as the starting point for countless drugs

their ailments, but they probably sought cures in

on the market today. Researchers generally agree that

the plants, animals, and minerals around them.

natural products from plants and other organisms

have been the most consistently successful source for
ideas for new drugs, since nature is a master chemist.
Drug discovery scientists often refer to these ideas as
leads, and chemicals that have desirable properties
in lab tests are called lead compounds.

Natural Cholesterol-Buster
Having high cholesterol is a signicant risk factor
for heart disease, a leading cause of death in the
industrialized world. Pharmacology research has
made major strides in helping people deal with
this problem. Scientists Michael Brown and
Joseph Goldstein, both of the University of Texas
Southwestern Medical Center at Dallas, won the
1985 Nobel Prize in physiology or medicine for
their fundamental work determining how the
body metabolizes cholesterol. This research, part
of which rst identied cholesterol receptors, led to
the development of the popular cholesterol-lowering
statin drugs such as Mevacor and Lipitor.
New research from pharmacologist David
Mangelsdorf, also at the University of Texas
Southwestern Medical Center at Dallas, is pointing
to another potential treatment for high cholesterol.
The new substance has the tongue-twisting
name guggulsterone, and it isnt really new at all.
Guggulsterone comes from the sap of the guggul
tree, a species native to India, and has been used
in Indias Ayurvedic medicine since at least 600
B.C. to treat a wide variety of ailments, including
obesity and cholesterol disorders. Mangelsdorf

and his coworker David Moore of Baylor College

of Medicine in Houston, Texas, found that guggul
sterone blocks a protein called the FXR receptor
that plays a role in cholesterol metabolism,
converting cholesterol in the blood to bile acids.
According to Mangelsdorf, since elevated levels of
bile acids can actually boost cholesterol, blocking
FXR helps to bring cholesterol counts down.

Sap from the guggul tree, a species native

to India, contains a substance that may help
ght heart disease.

Medicines By Design I Drugs From Nature, Then and Now 29

Relatively speaking, very few species of living

things on Earth have actually been seen and

only a few of these organisms to see whether they

harbor some sort of medically useful substance.

named by scientists. Many of these unidentied

Pharmaceutical chemists seek ideas for new

organisms arent necessarily lurking in uninhab

drugs not only in plants, but in any part of nature

ited places. A few years ago, for instance, scientists

where they may nd valuable clues. This includes

identied a brand-new species of millipede in a

searching for organisms from what has been called

rotting leaf pile in New York Citys Central Park,

the last unexplored frontier: the seawater that

an area visited by thousands of people every day.

blankets nearly three-quarters of Earth.

Scientists estimate that Earth is home to at least

250,000 different species of plants, and that up to
30 million species of insects crawl or y some
where around the globe. Equal numbers of species
of fungi, algae, and bacteria probably also exist.
Despite these vast numbers, chemists have tested

Cancer Therapy Sees the Light

Some forms of cancer

can be treated with
photodynamic therapy,
in which a cancer-killing
molecule is activated
by certain wavelengths
of light.
JOSEPH FRIEDBERG

A novel drug delivery system called photodynamic

therapy combines an ancient plant remedy,
modern blood transfusion techniques, and light.
Photodynamic therapy has been approved by the
Food and Drug Administration to treat several
cancers and certain types of age-related macular
degeneration, a devastating eye disease that is the
leading cause of blindness in North America and
Europe. Photodynamic therapy is also being tested
as a treatment for some skin and immune disorders.
The key ingredient in this therapy is psoralen,
a plant-derived chemical that has a peculiar prop
erty: It is inactive until exposed to light. Psoralen
is the active ingredient in a Nile-dwelling weed
called ammi. This remedy was used by ancient
Egyptians, who noticed that people became
prone to sunburn after eating the weed. Modern
researchers explained this phenomenon by discov
ering that psoralen, after being digested, goes
to the skins surface, where it is activated by the

suns ultraviolet rays. Activated psoralen attaches

tenaciously to the DNA of rapidly dividing cancer
cells and kills them. Photopheresis, a method
that exposes a psoralen-like drug to certain wave
lengths of light, is approved for the treatment
of some forms of lymphoma, a cancer of white
blood cells.

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National Institute of General Medical Sciences

Ocean Medicines

More commonly known as sea squirts, tunicates

Marine animals ght daily for both food and

are a group of marine organisms that spend most

survival, and this underwater warfare is waged

of their lives attached to docks, rocks, or the

with chemicals. As with plants, researchers have

undersides of boats. To an untrained eye they look

recognized the potential use of this chemical

like nothing more than small, colorful blobs, but

weaponry to kill bacteria or raging cancer cells.

tunicates are evolutionarily more closely related

Scientists isolated the rst marine-derived cancer

to vertebrates like ourselves than to most other

drug, now known as Cytosar-U, decades ago.

invertebrate animals.

They found this chemical, a staple for treating

One tunicate living in the crystal waters of

leukemia and lymphoma, in a Caribbean sea

West Indies coral reefs and mangrove swamps

sponge. In recent years, scientists have discovered

turned out to be the source of an experimental

dozens of similar ocean-derived chemicals

cancer drug called ecteinascidin. Ken Rinehart, a

that appear to be powerful cancer cell killers.

chemist who was then at the University of Illinois

Researchers are testing these natural products

at Urbana-Champaign discovered this natural

for their therapeutic properties.

substance. PharmaMar, a pharmaceutical company

For example, scientists have unearthed several

promising drugs from sea creatures called tunicates.

based in Spain, now holds the licenses for

ecteinascidin, which it calls Yondelis, and is

Miracle Cures

CHRISTINE L. CASE

Led by the German scientist Paul

Ehrlich, a new era in pharmacology
began in the late 19th century.
Although Ehrlichs original idea
seems perfectly obvious now,
it was considered very strange
at the time. He proposed that
every disease should be treated
with a chemical specic for that
disease, and that the pharma
cologists task was to nd these
treatments by systematically
testing potential drugs.

A penicillin-secreting Penicillium
mold colony inhibits the growth
of bacteria (zig-zag smear growing
on culture dish).

The approach worked: Ehrlichs greatest triumph

was his discovery of salvarsan, the rst effective
treatment for the sexually transmitted disease
syphilis. Ehrlich discovered salvarsan after screening
605 different arsenic-containing compounds. Later,
researchers around the world had great success in
developing new drugs by following Ehrlichs meth
ods. For example, testing of sulfur-containing dyes
led to the 20th centurys rst miracle drugsthe
sulfa drugs, used to treat bacterial infections. During
the 1940s, sulfa drugs were rapidly replaced by a
new, more powerful, and safer antibacterial drug,
penicillinoriginally extracted from the soil-dwelling
fungus Penicillium.

Medicines By Design I Drugs From Nature, Then and Now 31

Yondelis is an experimental
cancer drug isolated from
the marine organism
Ecteinascidia turbinata.

PHARMAMAR

conducting clinical trials on this drug. Lab tests

species of snail found in the reefs surrounding

indicate that Yondelis can kill cancer cells, and

Australia, Indonesia, and the Philippines. The

the rst set of clinical studies has shown that the

animals, called cone snails, have a unique venom

drug is safe for use in humans. Further phases of

containing dozens of nerve toxins. Some of these

clinical testingto evaluate whether Yondelis

venoms instantly shock prey, like the sting of an

effectively treats soft-tissue sarcomas (tumors of

electric eel or the poisons of scorpions and sea

the muscles, tendons, and supportive tissues)

anemones. Others cause paralysis, like the venoms

and other types of cancerare under way.

of cobras and puffer sh.

Animals that live in coral reefs almost always

Pharmacologist Baldomero Olivera of the

rely on chemistry to ward off hungry predators.

University of Utah in Salt Lake City, a native of

Because getting away quickly isnt an option in

the Philippines whose boyhood fascination with

this environment, lethal chemical brews are the

cone snails matured into a career studying them,

weaponry of choice for these slow-moving or

has discovered one cone snail poison that has

even sedentary animals. A powerful potion comes

become a potent new pain medicine. Oliveras

from one of these animals, a stunningly gorgeous

experiments have shown that the snail toxin is

32

National Institute of General Medical Sciences

1,000 times more powerful than morphine in

treating certain kinds of chronic pain. The snailderived drug, named Prialt by the company (Elan
Corporation, plc in Dublin, Ireland) that developed
and markets it, jams up nerve transmission in the
spinal cord and blocks certain pain signals from
K.S. MATZ

reaching the brain. Scientists predict that many

more cone snail toxins will be drug leads, since 500

A poison produced by the cone snail C. geographus

has become a powerful new pain medicine.

different species of this animal populate Earth.

Prospecting Biology?

The cancer drug Taxol

originally came from
the bark and needles
of yew trees.

Are researchers taking advantage of nature

when it comes to hunting for new medicines?
Public concern has been raised about
scientists scouring the worlds tropical rain
forests and coral reefs to look for potential
natural chemicals that may end up being
useful drugs. While it is true that rainforests
in particular are home to an extraordinarily
rich array of species of animals and plants,
many life-saving medicines derived from
natural products have been discovered in temper
ate climates not much different from our kitchens
and backyards.
Many wonder drugs have arisen from nonendangered species, such as the bark of the willow
tree, which was the original source of aspirin.

The antibiotic penicillin, from an ordinary mold, is

another example. Although scientists rst found
the chemical that became the widely prescribed
cancer drug Taxol in the bark of an endangered
species of tree called the Pacic yew, researchers
have since found a way to manufacture Taxol in
the lab, starting with an extract from pine needles
of the much more abundant European yew. In
many cases, chemists have also gured out ways
to make large quantities of rainforest- and reefderived chemicals in the lab (see main text).

Medicines By Design I Drugs From Nature, Then and Now 33

Tweaking Nature

deciphered natures instructions on how to make

Searching natures treasure trove for potential

this powerful medicinal molecule. Thats impor

medicines is often only the rst step. Having tapped

tant, because researchers must harvest more than a

natural resources to hunt for new medicines, pharma

ton of Caribbean sea squirts to produce just 1 gram

ceutical scientists then work to gure out ways to

of the drug. By synthesizing drugs in a lab, scien

cultivate natural products or to make them from

tists can produce thousands more units of a drug,

scratch in the lab. Chemists play an essential role

plenty to use in patients if it proves effective

in turning marine and other natural products,

against disease.

which are often found in minute quantities, into

useful medicines.
In the case of Yondelis, chemist Elias J. Corey of
Harvard University in Boston, Massachusetts,

Scientists are also beginning to use a relatively

new procedure called combinatorial genetics
to custom-make products that dont even exist
in nature. Researchers have discovered ways to

Toxicogenetics: Poisons and Your Genes

Just as your genes help determine how you respond
to certain medicines, your genetic code can also
affect your susceptibility to illness. Why is it that
two people with a similar lifestyle and a nearly
identical environment can have such different
propensities to getting sick? Lots of factors con
tribute, including diet, but scientists believe that
an important component of disease risk is the
genetic variability of peoples reactions to chemicals
in the environment.
On hearing the word chemical, many people
think of smokestacks and pollution. Indeed, our
world is littered with toxic chemicals, some natural
and some synthetic. For example, nearly all of us
would succumb quickly to the poisonous bite of a
cobra, but it is harder to predict which of us will
develop cancer from exposure to carcinogens like
cigarette smoke.
Toxicologists are researchers who study
the effects of poisonous substances on living
organisms. One toxicologist, Serrine Lau of the
University of Texas at Austin, is trying to unravel
the genetic mystery of why people are more or
less susceptible to kidney damage after coming

into contact with some types of poisons. Lau and

her coworkers study the effects of a substance
called hydroquinone (HQ), an industrial pollutant
and a contaminant in cigarette smoke and diesel
engine exhaust. Lau is searching for genes that
play a role in triggering cancer in response to
HQ exposure. Her research and the work of other
so-called toxicogeneticists should help scientists
nd genetic signatures that can predict risk of
developing cancer in people exposed to harmful
carcinogens.

34

National Institute of General Medical Sciences

remove the genetic instructions for entire metabolic

effects at lower doses. The researchers found, to

pathways from certain microorganisms, alter the

their great surprise, that cyclosporine and FK506

instructions, and then put them back. This method

were chemically very different. To try to explain

can generate new and different natural products.

this puzzling result, Harvard University organic

chemist Stuart Schreiber (then at Yale University

Is It Chemistry or Genetics?
Regardless of the way researchers nd new
medicines, drug discovery often takes many unex
pected twists and turns. Scientists must train their
eyes to look for new opportunities lurking in the
outcomes of their experiments. Sometimes, side
trips in the lab can open up entirely new avenues
of discovery.
Take the case of cyclosporine, a drug
discovered three decades ago that suppresses the
immune system and thereby prevents the body from
rejecting transplanted organs. Still a best-selling
medicine, cyclosporine was a research breakthrough.
The drug made it possible for surgeons to save the
lives of many critically ill patients by transplanting
organs. But its not hard to imagine that the very
properties that make cyclosporine so powerful in
putting a lid on the immune system can cause
serious side effects, by damping immune function
too much.
Years after the discovery of cyclosporine,
researchers looking for less toxic versions of this
drug found a natural molecule called FK506 that
seemed to produce the same immune-suppressing

in New Haven, Connecticut) decided to take

on the challenge of guring out how to make
FK506 in his lab, beginning with simple chemical
building blocks.
Schreiber succeeded, and he and scientists
at Merck & Co., Inc. (Whitehouse Station, New
Jersey) used the synthetic FK506 as a tool to
unravel the molecular structure of the receptor
for FK506 found on immune cells. According
to Schreiber, information about the receptors
structure from these experiments opened his
eyes to consider an entirely new line of research.
Schreiber reasoned that by custom-making
small molecules in the lab, scientists could probe
the function of the FK506 receptor to systemati
cally study how the immune system works. Since
then, he and his group have continued to use
synthetic small molecules to explore biology.
Although Schreibers strategy is not truly genetics,
he calls the approach chemical genetics, because
the method resembles the way researchers go
about their studies to understand the functions
of genes.

Medicines By Design I Drugs From Nature, Then and Now 35

In one traditional genetic approach, scientists

alter the spelling (nucleotide components) of
a gene and put the altered gene into a model
organism for example, a mouse, a plant, or
a yeast cellto see what effect the gene change
has on the biology of that organism. Chemical
genetics harnesses the power of chemistry to
custom-produce any molecule and introduce it
into cells, then look for biological changes that
result. Starting with chemicals instead of genes
gives drug development a step up. If the substance
being tested produces a desired effect, such as
stalling the growth of cancer cells, then the molecule
can be chemically manipulated in short order since
the chemist already knows how to make it.

Blending Science
These days, its hard for scientists to know what
to call themselves. As research worlds collide in
wondrous and productive ways, the lines get blurry
when it comes to describing your expertise. Craig
Crews of Yale University, for example, mixes a com
bination of molecular pharmacology, chemistry, and
genetics. In fact, because of his multiple scientic
curiosities, Crews is a faculty member in three
different Yale departments: molecular, cellular, and
developmental biology; chemistry; and pharma
cology. You might wonder how he has time to get
anything done.
Hes getting plenty doneCrews is among a
new breed of researchers delving into a growing
scientic area called chemical genetics (see main
text). Taking this approach, scientists use chemistry
to attack biological problems that traditionally have
been solved through genetic experiments such as
the genetic engineering of bacteria, yeast, and mice.
Crews goal is to explore how natural products
work in living systems and to identify new targets
for designing drugs. He has discovered how an

The herb feverfew (bachelors button) contains

a substance called parthenolide that appears to
block inammation.

inammation-ghting ingredient in the medicinal

herb feverfew may work inside cells. He found that the
ingredient, called parthenolide, appears to disable a
key process that gets inammation going. In the case
of feverfew, a handful of controlled scientic studies
in people have hinted that the herb, also known by
its plant name bachelors button, is effective in com
bating migraine headaches, but further studies are
needed to confirm these preliminary ndings.

36

National Institute of General Medical Sciences

TestingI, II, III

To translate pharmacology research into

Scientists conduct clinical trials in three

patient care, potential drugs ultimately have

phases (I, II, and III), each providing the

to be tested in people. This multistage process

answer to a different fundamental question

is known as clinical trials, and it has led

about a potential new drug: Is it safe? Does it

researchers to validate life-saving treatments

work? Is it better than the standard treatment?

for many diseases, such as childhood leukemia

Typically, researchers do years of basic work in

and Hodgkins disease. Clinical trials, though

the lab and in animal models before they can

costly and very time-consuming, are the only

even consider testing an experimental treat

way researchers can know for sure whether

ment in people. Importantly, scientists who

experimental treatments work in humans.

wish to test drugs in people must follow strict

rules that are designed to protect those who

the effectiveness of a drug as well as whether

volunteer to participate in clinical trials.

the drug is better than current treatments.

Special groups called Institutional Review

Phase III studies involve hundreds to thou

Boards, or IRBs, evaluate all proposed research

sands of patients, and these advanced trials

involving humans to determine the potential

typically last several years. Many phase II

risks and anticipated benets. The goal of an

and phase III studies are randomized,

IRB is to make sure that the risks are mini

meaning that one group of patients gets

Scientists are currently

mized and that they are reasonable compared

the experimental drug being tested while a

testing cone snail toxins

to the knowledge expected to be gained by

second, control group gets either a standard

for the treatment of which

performing the study. Clinical studies cannot

treatment or placebo (that is, no treatment,

health problem?

go forward without IRB approval. In addition,

often masked as a dummy pill or injection).

people in clinical studies must agree to the

Also, usually phase II and phase III studies are

terms of a trial by participating in a process

blindedthe patients and the researchers

called informed consent and signing a form,

do not know who is getting the experimental

required by law, that says they understand the

drug. Finally, once a new drug has completed

risks and benets involved in the study.

phase III testing, a pharmaceutical company

Phase I studies test a drugs safety in a few

dozen to a hundred people and are designed
to gure out what happens to a drug in the
bodyhow it is absorbed, metabolized, and

can request approval from the Food and Drug

Administration to market the drug.

Got It?

How are people protected

when they volunteer to participate in a clinical trial?

Why do plants and marine

organisms have chemicals
that could be used as
medicines?

excreted. Phase I studies usually take several

months. Phase II trials test whether or not a
drug produces a desired effect. These studies

What is a drug lead?

take longerfrom several months to a few

yearsand can involve up to several hundred
patients. A phase III study further examines

Name the rst marinederived cancer medicine.

CHAPTER 4

Molecules to Medicines

s youve read so far, the most important

goals of modern pharmacology are also

Medicine Hunting
While sometimes the discovery of potential medi

the most obvious. Pharmacologists want to design,

cines falls to researchers good luck, most often

and be able to produce in sufcient quantity,

pharmacologists, chemists, and other scientists

drugs that will act in a specic way without too

looking for new drugs plod along methodically

many side effects. They also want to deliver the

for years, taking suggestions from nature or clues

correct amount of a drug to the proper place in

from knowledge about how the body works.

the body. But turning molecules into medicines

Finding chemicals cellular targets can educate

is more easily said than done. Scientists struggle

scientists about how drugs work. Aspirins molecular

to fulll the twin challenges of drug design and

target, the enzyme cyclooxygenase, or COX

drug delivery.

(see page 22), was discovered this way in the early

1970s in Nobel Prize-winning work by pharma
cologist John Vane, then at the Royal College of
Surgeons in London, England. Another example is
colchicine, a relatively old drug that is still widely
used to treat gout, an excruciatingly painful type
of arthritis in which needle-like crystals of uric
acid clog joints, leading to swelling, heat, pain, and

WHO/TDR/STAMMERS

A Drug By Another Name

Drugs used to treat bone

ailments may be useful
for treating infectious
diseases like malaria.

As pet owners know, you can teach some

old dogs new tricks. In a similar vein, scientists
have in some cases found new uses for old
drugs. Remarkably, the potential new uses often
have little in common with a drugs product label
(its old use). For example, chemist Eric Oldeld
of the University of Illinois at Urbana-Champaign
discovered that one class of drugs called bisphos
phonates, which are currently approved to treat
osteoporosis and other bone disorders, may also
be useful for treating malaria, Chagas disease,
leishmaniasis, and AIDS-related infections like
toxoplasmosis.
Previous research by Oldeld and his coworkers
had hinted that the active ingredient in the
bisphosphonate medicines Fosamax , Actonel ,

and Aredia blocks a critical step in the metabo

lism of parasites, the microorganisms that cause
these diseases. To test whether this was true,
Oldeld gave the medicines to ve different types
of parasites, each grown along with human cells
in a plastic lab dish. The scientists found that small
amounts of the osteoporosis drugs killed the para
sites while sparing human cells. The researchers
are now testing the drugs in animal models of the
parasitic diseases and so far have obtained cures
in miceof certain types of leishmaniasis. If these
studies prove that bisphosphonate drugs work in
larger animal models, the next step will be to nd
out if the medicines can thwart these parasitic
diseases in humans.

Medicines By Design I Molecules to Medicines 39

stiffness. Lab experiments with colchicine led

scientists to this drugs molecular target, a cellscaffolding protein called tubulin. Colchicine
works by attaching itself to tubulin, causing
certain parts of a cells architecture to crumble,
and this action can interfere with a cells ability
to move around. Researchers suspect that in
the case of gout, colchicine works by halting
the migration of immune cells called granulo
cytes that are responsible for the inammation
NATIONAL AGRICULTURE LIBRARY, ARS, USDA

characteristic of gout.
Current estimates indicate that scientists
have identied roughly 500 to 600 molecular
targets where medicines may have effects in
the body. Medicine hunters can strategically
discover drugs by designing molecules to hit
these targets. That has already happened in some

Colchicine, a treatment for gout, was originally

derived from the stem and seeds of the meadow
saffron (autumn crocus).

cases. Researchers knew just what they were

looking for when they designed the successful
AIDS drugs called HIV protease inhibitors.
Previous knowledge of the three-dimensional

make blood clot and molecular signals that

structure of certain HIV proteins (the target)

instruct blood vessels to relax. What the scientists

guided researchers to develop drugs shaped to

did not know was how their candidate drug

block their action. Protease inhibitors have

would fare in clinical trials.

extended the lives of many people with AIDS.

However, sometimes even the most targeted

Sildenal (Viagras chemical name) did not

work very well as a heart medicine, but many

approaches can end up in big surprises. The New

men who participated in the clinical testing phase

York City pharmaceutical rm Pzer had a blood

of the drug noted one side effect in particular:

pressure-lowering drug in mind, when instead its

erections. Viagra works by boosting levels of a

scientists discovered Viagra, a best-selling drug

natural molecule called cyclic GMP that plays a

approved to treat erectile dysfunction. Initially,

key role in cell signaling in many body tissues.

researchers had planned to create a heart drug,

This molecule does a good job of opening blood

using knowledge they had about molecules that

vessels in the penis, leading to an erection.

40

National Institute of General Medical Sciences

21st-Century Science

biomedicine stems from biologys gradual transi

While strategies such as chemical genetics

tion from a gathering, descriptive enterprise to a

can quicken the pace of drug discovery, other

science that will someday be able to model and

approaches may help expand the number of

predict biology. If you think 25,000 genes is a lot

molecular targets from several hundred to several

(the number of genes in the human genome), realize

thousand. Many of these new avenues of research

that each gene can give rise to different variations

hinge on biology.

of the same protein, each with a different molecular

Relatively new brands of research that are

job. Scientists estimate that humans have hundreds

stepping onto center stage in 21st-century science

of thousands of protein variants. Clearly, theres lots

include genomics (the study of all of an organisms

of work to be done, which will undoubtedly keep

genetic material), proteomics (the study of all

researchers busy for years to come.

of an organisms proteins), and bioinformatics

(using computers to sift through large amounts
of biological data). The omics revolution in

A Chink in Cancers Armor

Doctors use the drug

Gleevec to treat a form
of leukemia, a disease in
which abnormally high
numbers of immune cells
(larger, purple circles in
photo) populate the blood.

Recently, researchers made an exciting step forward

in the treatment of cancer. Years of basic research
investigating circuits of cellular communication led
scientists to tailor-make a new kind of cancer medicine.
In May 2001, the drug Gleevec was approved to treat
a rare cancer of the blood called chronic myelogenous
leukemia (CML). The Food and Drug Administration
described Gleevecs approval as a testament to
the groundbreaking scientic research taking place
in labs throughout America.
Researchers designed this drug to halt a cellcommunication pathway that is always on in CML.
Their success was founded on years of experiments
in the basic biology of how cancer cells grow. The
discovery of Gleevec is an example of the success

of so-called molecular targeting: understanding how

diseases arise at the level of cells, then guring out
ways to treat them. Scores of drugs, some to treat
cancer but also many other health conditions, are
in the research pipeline as a result of scientists
eavesdropping on how cells communicate.

Medicines By Design I Molecules to Medicines 41

Rush Delivery

skin, nose, and lungs. Each of these methods

Finding new medicines and cost-effective ways to

bypasses the intestinal tract and can increase the

manufacture them is only half the battle. An enor

amount of drug getting to the desired site of

mous challenge for pharmacologists is guring out

action in the body. Slow, steady drug delivery

how to get drugs to the right place, a task known

directly to the bloodstreamwithout stopping

as drug delivery.

at the liver rstis the primary benet of skin

Ideally, a drug should enter the body, go

patches, which makes this form of drug delivery

directly to the diseased site while bypassing

particularly useful when a chemical must be

healthy tissue, do its job, and then disappear.

administered over a long period.

Unfortunately, this rarely happens with the typical

Hormones such as testosterone, progesterone,

methods of delivering drugs: swallowing and

and estrogen are available as skin patches. These

injection. When swallowed, many medicines made

forms of medicines enter the blood via a mesh

of protein are never absorbed into the blood

work of small arteries, veins, and capillaries in the

stream because they are quickly chewed up by

skin. Researchers also have developed skin patches

enzymes as they pass through the digestive system.

for a wide variety of other drugs. Some of these

If the drug does get to the blood from the intes

include Duragesic (a prescription-only pain

tines, it falls prey to liver enzymes. For doctors

medicine), Transderm Scop (a motion-sickness

prescribing such drugs, this rst-pass effect (see

drug), and Transderm Nitro (a blood vessel-

page 7) means that several doses of an oral drug

widening drug used to treat chest pain associated

are needed before enough makes it to the blood.

with heart disease). Despite their advantages,

Drug injections also cause problems, because they

however, skin patches have a signicant drawback.

are expensive, difcult for patients to self-administer,

Only very small drug molecules can get into the

and are unwieldy if the drug must be taken daily.

body through the skin.

Both methods of administration also result in

Inhaling drugs through the nose or mouth is

uctuating levels of the drug in the blood, which

another way to rapidly deliver drugs and bypass

is inefcient and can be dangerous.

the liver. Inhalers have been a mainstay of asthma

What to do? Pharmacologists can work around

therapy for years, and doctors prescribe nasal

the rst-pass effect by delivering medicines via the

steroid drugs for allergy and sinus problems.

42

National Institute of General Medical Sciences

Researchers are investigating insulin powders that

too small, and the particles will be exhaled. If

can be inhaled by people with diabetes who rely

clinical trials with inhaled insulin prove that it is

on insulin to control their blood sugar daily. This

safe and effective, then this therapy could make

still-experimental technology stems from novel

life much easier for people with diabetes.

uses of chemistry and engineering to manufacture

insulin particles of just the right size. Too large,
and the insulin particles could lodge in the lungs;

Reading a Cell MAP

Scientists try hard to listen to the noisy, garbled
discussions that take place inside and between
cells. Less than a decade ago, scientists identied
one very important cellular communication stream
called MAP (mitogen-activated protein) kinase
signaling. Today, molecular pharmacologists such
as Melanie H. Cobb of the University of Texas
Southwestern Medical Center at Dallas are studying
how MAP kinase signaling pathways malfunction
in unhealthy cells.

Protein

Phosphorylated Protein
Protein Kinase

Kinases are enzymes that

add phosphate groups
(red-yellow structures) to
proteins (green), assigning
the proteins a code. In this
reaction, an intermediate
molecule called ATP
(adenosine triphosphate)
donates a phosphate group
from itself, becoming ADP
(adenosine diphosphate).

ATP

ADP

Some of the interactions between proteins in

these pathways involve adding and taking away
tiny molecular labels called phosphate groups.
Kinases are the enzymes that add phosphate
groups to proteins, and this process is called phos
phorylation. Marking proteins in this way assigns
the proteins a code, instructing the cell to do some
thing, such as divide or grow. The body employs
many, many signaling pathways involving hun
dreds of different kinase enzymes. Some of the
important functions performed by MAP kinase
pathways include instructing immature cells how
to grow up to be specialized cell types like mus
cle cells, helping cells in the pancreas respond to
the hormone insulin, and even telling cells how to
die.
Since MAP kinase pathways are key to so many
important cell processes, researchers consider
them good targets for drugs. Clinical trials are
under way to test various molecules that, in animal
studies, can effectively lock up MAP kinase signal
ing when its not wanted, for example, in cancer
and in diseases involving an overactive immune
system, such as arthritis. Researchers predict
that if drugs to block MAP kinase signaling prove
effective in people, they will likely be used in com
bination with other medicines that treat a variety
of health conditions, since many diseases are
probably caused by simultaneous errors in multiple
signaling pathways.

Medicines By Design I Molecules to Medicines 43

by learning how to hijack molecular transporters

to shuttle drugs into cells. Gordon Amidon,
a pharmaceutical chemist at the University of
Michigan-Ann Arbor, has been studying one
particular transporter in mucosal membranes
lining the digestive tract. The transporter, called
hPEPT1, normally serves the body by ferrying
small, electrically charged particles and small
protein pieces called peptides into and out of
Proteins that snake through membranes help
transport molecules into cells.
HTTP://WWW.PHARMACOLOGY.UCLA.EDU

the intestines.
Amidon and other researchers discovered that
certain medicines, such as the antibiotic penicillin
and certain types of drugs used to treat high blood

Transportation Dilemmas
Scientists are solving the dilemma of drug delivery

pressure and heart failure, also travel into the

intestines via hPEPT1. Recent experiments

with a variety of other clever techniques. Many

revealed that the herpes drug Valtrex and the

of the techniques are geared toward sneaking

AIDS drug Retrovir also hitch a ride into intes

through the cellular gate-keeping systems

membranes. The challenge is a chemistry
problem most drugs are water-soluble, but
membranes are oily. Water and oil dont mix, and
thus many drugs cant enter the cell. To make
matters worse, size matters too. Membranes are
usually constructed to permit the entry of only
small nutrients and hormones, often through
private cellular alleyways called transporters.
Many pharmacologists are working hard to
devise ways to work not against, but with nature,

tinal cells using the hPEPT1 transporter. Amidon

wants to extend this list by synthesizing hundreds
of different molecules and testing them for their
ability to use hPEPT1 and other similar trans
porters. Recent advances in molecular biology,
genomics, and bioinformatics have sped the search
for molecules that Amidon and other researchers
can test.

44

National Institute of General Medical Sciences

Scientists are also trying to slip molecules

Act Like a Membrane

through membranes by cloaking them in disguise.

Researchers know that high concentrations of

Steven Regen of Lehigh University in Bethlehem,

chemotherapy drugs will kill every single cancer

Pennsylvania, has manufactured miniature

cell growing in a lab dish, but getting enough of

chemical umbrellas that close around and shield

these powerful drugs to a tumor in the body with

a molecule when it encounters a fatty membrane

out killing too many healthy cells along the way

and then spread open in the watery environment

has been exceedingly difcult. These powerful

inside a cell. So far, Regen has only used test mole

drugs can do more harm than good by severely

cules, not actual drugs, but he has succeeded in

sickening a patient during treatment.

getting molecules that resemble small segments

Some researchers are using membrane-like

of DNA across membranes. The ability to do this

particles called liposomes to package and deliver

in humans could be a crucial step in successfully

drugs to tumors. Liposomes are oily, microscopic

delivering therapeutic molecules to cells via

capsules that can be lled with biological cargo,

gene therapy.

such as a drug. They are very, very small only

Anesthesia Dissected
Scientists who study anesthetic medicines
have a daunting task for the most part,
they are shooting in the dark when
it comes to identifying the molecular
targets of these drugs. Researchers do
know that anesthetics share one common
ingredient: Nearly all of them somehow
target membranes, the oily wrappings
surrounding cells. However, despite the
fact that anesthesia is a routine part of
surgery, exactly how anesthetic medicines
work in the body has remained a mystery for more
than 150 years. Its an important problem, since
anesthetics have multiple effects on key body func
tions, including critical processes such as breathing.
Scientists dene anesthesia as a state in which
no movement occurs in response to what should
be painful. The problem is, even though a patient
loses a pain response, the anesthesiologist cant
tell what is happening inside the persons organs
and cells. Further complicating the issue, scientists
know that many different types of drugswith

little physical resemblance to each other can all

produce anesthesia. This makes it difcult to track
down causes and effects.
Anesthesiologist Robert Veselis of the Memorial
Sloan-Kettering Institute for Cancer Research in New
York City claried how certain types of these mys
terious medicines work. Veselis and his coworkers
measured electrical activity in the brains of healthy
volunteers receiving anesthetics while they listened
to different sounds. To determine how sedated the
people were, the researchers measured reaction
time to the sounds the people heard. To measure
memory effects, they quizzed the volunteers at the
end of the study about word lists they had heard
before and during anesthesia. Veselis experiments
show that the anesthetics they studied affect sepa
rate brain areas to produce the two different effects
of sedation and memory loss. The ndings may help
doctors give anesthetic medicines more effectively
and safely and prevent reactions with other drugs
a patient may be taking.

Medicines By Design I Molecules to Medicines 45

one one-thousandth the width of a single human

hair. Researchers have known about liposomes
for many years, but getting them to the right place
in the body hasnt been easy. Once in the blood
LAWRENCE MAYER, LUDGER ICKENSTEIN, KATRINA EDWARDS

stream, these foreign particles are immediately

shipped to the liver and spleen, where they
are destroyed.
Materials engineer David Needham of Duke
University in Durham, North Carolina, is investi
gating the physics and chemistry of liposomes to
better understand how the liposomes and their
cancer-ghting cargo can travel through the body.
Needham worked for 10 years to create a special

David Needham designed liposomes resembling tiny molecular soccer

balls made from two different oils that wrap around a drug.

kind of liposome that melts at just a few degrees

above body temperature. The end result is a tiny

dogs revealed that, when heated, the drug-laden

molecular soccer ball made from two different

capsules ooded tumors with a chemotherapy

oils that wrap around a drug. At room tempera

drug and killed the cancer cells inside. Researchers

ture, the liposomes are solid and they stay solid at

hope to soon begin the rst stage of human studies

body temperature, so they can be injected into the

testing the heat-triggered liposome treatment in

bloodstream. The liposomes are designed to spill

patients with prostate and breast cancer. The results

their drug cargo into a tumor when heat is applied

of these and later clinical trials will determine

to the cancerous tissue. Heat is known to perturb

whether liposome therapy can be a useful weapon

tumors, making the blood vessels surrounding

for treating breast and prostate cancer and other

cancer cells extra-leaky. As the liposomes approach

hard-to-treat solid tumors.

the warmed tumor tissue, the stitches of the

miniature soccer balls begin to dissolve, rapidly
leaking the liposomes contents.
Needham and Duke oncologist Mark Dewhirst
teamed up to do animal studies with the heatactivated liposomes. Experiments in mice and

46

National Institute of General Medical Sciences

The G Switch

(b)

(a)

(c)

Hormone

Plasma Membrane
Receptor

Active Cell Enzyme

Inactive Cell Enzyme

Inactive G Protein

Active G Protein

Cell Response

G proteins act like relay batons to pass

messages from circulating hormones
into cells.
(a) A hormone (red) encounters a receptor
(blue) in the membrane of a cell.
(b) A G protein (green) becomes activated
and makes contact with the receptor
to which the hormone is attached.
(c) The G protein passes the hormones
message to the cell by switching on
a cell enzyme (purple) that triggers
a response.

Imagine yourself sitting on a cell, looking

outward to the bloodstream rushing by.
Suddenly, a huge glob of something hurls
toward you, slowing down just as it settles
into a perfect dock on the surface of your
cell perch. You dont realize it, but your own
body sent this substancea hormone called
epinephrineto protect you, telling you to
get out of the way of a car that just about side
swiped yours while drifting out of its lane.
Your body reacts, whipping up the familiar,
spine-tingling, ght-or-ight response that
gears you to respond quickly to potentially
threatening situations such as this one.
How does it all happen so fast?
Getting into a cell is a challenge, a strictly
guarded process kept in control by a protective
gate called the plasma membrane. Figuring
out how molecular triggers like epinephrine
communicate important messages to the
inner parts of cells earned two scientists the
Nobel Prize in physiology or medicine in
1994. Getting a cellular message across the

membrane is called signal transduction, and it

the world have focused on these signaling

occurs in three steps. First, a message (such as

molecules. Research on G proteins and on all

epinephrine) encounters the outside of a cell

aspects of cell signaling has prospered, and as

and makes contact with a molecule on the

a result scientists now have an avalanche of

surface called a receptor. Next, a connecting

data. In the fall of 2000, Gilman embarked on

transducer, or switch molecule, passes the

a groundbreaking effort to begin to untangle

message inward, sort of like a relay baton.

and reconstruct some of this information to

Finally, in the third step, the signal gets ampli

guide the way toward creating a virtual cell.

ed, prompting the cell to do something:

Gilman leads the Alliance for Cellular

move, produce new proteins, even send out

Signaling, a large, interactive research network.

more signals.

The group has a big dream: to understand

One of the Nobel Prize winners, pharma

Got It?

What is a liposome?

Name three drug

delivery methods.

everything there is to know about signaling

cologist Alfred G. Gilman of the University of

inside cells. According to Gilman, Alliance

Describe how

Texas Southwestern Medical Center at Dallas,

researchers focus lots of attention on G

G proteins work.

uncovered the identity of the switch molecule,

proteins and also on other signaling systems

called a G protein. Gilman named the switch,

in selected cell types. Ultimately, the scientists

which is actually a huge family of switch mol

hope to test drugs and learn about disease

ecules, not after himself but after the type of

through computer modeling experiments

cellular fuel it uses: an energy currency called

with the virtual cell system.

GTP. As with any switch, G proteins must be

turned on only when needed, then shut off.
Some illnesses, including fatal diseases like
cholera, occur when a G protein is errantly
left on. In the case of cholera, the poisonous
weaponry of the cholera bacterium freezes
in place one particular type of G protein that
controls water balance. The effect is constant
uid leakage, causing life-threatening diarrhea.
In the few decades since Gilman and the
other Nobel Prize winner, the late National
Institutes of Health scientist Martin Rodbell,
made their fundamental discovery about
G protein switches, pharmacologists all over

What do kinases do?

Discuss the omics

revolution in biomedical
research.

48

National Institute of General Medical Sciences

Medicines for the Future

he advances in drug development and

delivery described in this booklet reect

scientists growing knowledge about human

biology. This knowledge has allowed them to
develop medicines targeted to specic molecules
or cells. In the future, doctors may be able to treat
or prevent diseases with drugs that actually repair
cells or protect them from attack. No one knows
which of the techniques now being developed will
yield valuable future medicines, but it is clear that
thanks to pharmacology research, tomorrows
doctors will have an unprecedented array of
weapons to ght disease.

Medicines By Design I Medicines for the Future 49

Careers in Pharmacology
Wanna be a pharmacologist? If you choose pharma
cology as a career, here are some of the places you
might nd yourself working:
College or University. Most basic biomedical
research across the country is done by scientists
at colleges and universities. Academic pharma
cologists perform research to determine how
medicines interact with living systems. They also
teach pharmacology to graduate, medical, pharmacy,
veterinary, dental, or undergraduate students.
Pharmaceutical Company. Pharmacologists
who work in industry participate in drug develop
ment as part of a team of scientists. A key aspect
of pharmaceutical industry research is making
sure new medicines are effective and safe for use
in people.
Hospital or Medical Center. Most clinical pharma
cologists are physicians who have specialized
training in the use of drugs and combinations of

drugs to treat various health conditions. These

scientists often work with patients and spend a
lot of time trying to understand issues relating
to drug dosage, including side effects and
drug interactions.
Government Agency. Pharmacologists and
toxicologists play key roles in formulating drug
laws and chemical regulations. Federal agencies
such as the National Institutes of Health and the
Food and Drug Administration hire many pharma
cologists for their expertise in how drugs work.
These scientists help develop policies about the
safe use of medicines.
You can learn more about careers in pharmacology
by contacting professional organizations such
as the American Society for Pharmacology and
Experimental Therapeutics (http://www.aspet.org/)
or the American Society for Clinical Pharmacology
and Therapeutics (http://www.ascpt.org/).

50

National Institute of General Medical Sciences

Glossary
ADME | Abbreviation for the four steps in a

Bioavailability | The ability of a drug or other

medicines journey through the body: absorption,

chemical to be taken up by the body and made

distribution, metabolism, and excretion.

available in the tissue where it is needed.

Agonist | A molecule that triggers a cellular

Bioinformatics | A eld of research that relies

response by interacting with a receptor.

on computers to store and analyze large amounts

Analgesic | A medicines ability to relieve pain,

of biological data.

or a drug that alleviates pain; the term comes from

Biotechnology | The industrial use of living

the Greek word algos, which means pain.

organisms or biological methods derived through

Antagonist | A molecule that prevents the

basic research.

action of other molecules, often by competing

Biotransformation | The conversion of a

for a cellular receptor; opposite of agonist.

substance from one form to another by the

Antibiotic | A substance that can kill or inhibit

the growth of certain microorganisms.
Antibody | A protein of the immune system,
produced in response to an antigen (a foreign,
often disease-causing, substance).
Anti-inammatory | A drugs ability to
reduce inammation, which can cause soreness
and swelling.
Antipyretic | Fever-reducing; the term comes
from the Greek word pyresis, which means re.
Arachidonic acid | A molecule that synthesizes
regulatory molecules such as prostaglandins; it is

actions of organisms or enzymes.

Blood-brain barrier | A blockade consisting
of cells and small blood vessels that limits the
movement of substances from the bloodstream
into the brain.
Carcinogen | Any substance that, when exposed
to living tissue, may cause cancer.
Cell | The basic subunit of any living organism;
the simplest unit that can exist as an independent
living system.
Central nervous system | The brain and
spinal cord.

found in fatty animal tissue and foods such as egg

Chemical bond | Physical force holding atoms

yolk and liver.

together to form a molecule.

Bacterium | One-celled organism without

Chemical genetics | A research approach

a nucleus that reproduces by cell division; can

resembling genetics in which scientists custom-

infect humans, plants, or animals.

produce synthetic, protein-binding small

molecules to explore biology.

Medicines By Design I Glossary 51

Cholesterol | A lipid unique to animal cells that

Dose-response curve | A graph drawn to

is used in the construction of cell membranes and

show the relationship between the dose of a drug

as a building block for some hormones.

or other chemical and the effect it produces.

Chromosome | A structure in the cell nucleus

Enzyme | A molecule (usually a protein) that

that contains hereditary material (genes); humans

speeds up, or catalyzes, a chemical reaction with

have 23 pairs of chromosomes in each body cell,

out being permanently altered or consumed.

one of each pair from the mother and the other

from the father.

Essential fatty acid | A long, fat-containing

molecule involved in human body processes that

Clinical trial | A scientic study to determine

is synthesized by plants but not by the human

the effects of potential medicines in people;

body and is therefore a dietary requirement.

usually conducted in three phases (I, II, III), to

determine whether the drug is safe, effective,

First-pass effect | The breakdown of orally

administered drugs in the liver and intestines.

and better than current therapies, respectively.

G protein | One of a group of switch proteins
Combinatorial genetics | A research process
in which scientists remove the genetic instructions

involved in a signaling system that passes incoming

messages across cell membranes and within cells.

for entire metabolic pathways from certain

microorganisms, alter the instructions, and
then put them back.

Gene | A unit of heredity; a segment of a DNA

molecule containing the code for making a protein
or, sometimes, an RNA molecule.

Cyclooxygenase | An enzyme, also known as

COX, that makes prostaglandins from a molecule
called arachidonic acid; the molecular target of
nonsteroidal anti-inammatory drugs.
Cytochrome P450 | A family of enzymes
found in animals, plants, and bacteria that have
an important role in drug metabolism.
DNA (deoxyribonucleic acid) | A doublestranded, helical molecule that encodes genetic
information.

Genetics | The scientic study of genes and

heredity, of how particular qualities or traits are
transmitted from parents to offspring.
Genomics | The study of all of an organisms
genetic material.
Hormone | A messenger molecule that helps
coordinate the actions of various tissues; made
in one part of the body and transported, via the
bloodstream, to tissues and organs elsewhere in
the body.

Dose | The amount of medicine to be taken

at one time.

52

National Institute of General Medical Sciences

Immunotherapy | A medical treatment to

Model organism | A bacterium, animal, or

stimulate a patients immune system to attack

plant used by scientists to study basic research

and destroy disease-causing cells.

questions; common model organisms include

Inammation | The bodys characteristic

yeast, ies, worms, frogs, and sh.

reaction to infection or injury, resulting in

Monoclonal antibody | An antibody that rec

redness, swelling, heat, and pain.

ognizes only one type of antigen; sometimes used

Informed consent | The agreement of a person

as immunotherapy to treat diseases such as cancer.

(or his or her legally authorized representative) to

NSAID (nonsteroidal anti-inammatory

serve as a research subject, with full knowledge of

drug) | Any of a class of drugs that reduces pain,

all anticipated risks and benets of the experiment.

fever, or inammation by interfering with the

Kinase | An enzyme that adds phosphate groups

to proteins.
Lipid | A fatty, waxy, or oily molecule that
will not dissolve in water; it contains hydrogen,
carbon, and oxygen.
Liposome | Oily, microscopic capsules designed
to package and deliver biological cargo, such as
drugs, to cells in the body.
Membrane | A thin covering surrounding a cell
and separating it from the environment; consists
of a double layer of molecules called phospholipids
and has proteins embedded in it.
Metabolism | All enzyme-catalyzed reactions
in a living organism that builds and breaks down
organic molecules, producing or consuming

synthesis of prostaglandins.
Neurotransmitter | A chemical messenger that
allows neurons (nerve cells) to communicate with
each other and with other cells.
Nucleus | The membrane-bound structure
within a cell that contains most of the cells
genetic material.
Organelle | A specialized, membrane-bound
structure that has a dened cellular function;
for example, the nucleus.
Peptide | A small protein fragment.
Pharmacodynamics | The study of how drugs
act at target sites of action in the body.
Pharmacogenetics | The study of how peoples
genes affect their response to medicines.

energy in the process.

Pharmacokinetics | The study of how the
Metabolite | A chemical intermediate in
metabolic reactions; a product of metabolism.

body absorbs, distributes, breaks down, and

eliminates drugs.

Medicines By Design I Glossary 53

Pharmacologist | A scientist focusing

Recombinant DNA technology | Modern

on pharmacology.

techniques in molecular biology to manipulate an

Pharmacology | The study of how drugs

interact with living systems.
Pharmacy | An area in the health sciences
that deals with the preparation, dispensing,
and appropriate use of medicines.

organisms genes by introducing, eliminating, or

changing genes.
RNA (ribonucleic acid) | A molecule that
serves as an intermediate step in the synthesis of
proteins from instructions coded in DNA; some
RNA molecules also perform regulatory functions

Physiology | The study of how living

in cells and viruses.

organisms function.
Sepsis | A clinical condition in which infectious
Prostaglandins | Any of a class of hormonelike, fat-soluble, regulatory molecules made from
fatty acids such as arachidonic acid; prostaglandins

agents (bacteria, fungi) or products of infection

(bacterial toxins) enter the blood and profoundly
affect body systems.

participate in diverse body functions, and their

production is blocked by NSAIDs.

Side effect | The effect of a drug, other than

the desired effect, sometimes in an organ other

Protein | A large molecule composed of one or

than the target organ.

more chains of amino acids (the building blocks

of proteins) in a specic order and a folded
shape determined by the sequence of nucleotides
in the gene encoding the protein; essential for all
life processes.
Proteomics | The systematic, large-scale study
of all proteins in an organism.
Receptor | A specialized molecule that receives
information from the environment and conveys

Signal transduction | The process by which

a hormone or growth factor outside the cell
transmits a message into the cell.
Site of action | The place in the body where a
drug exerts its effects.
Steroid | A type of molecule that has a multiple
ring structure, with the rings sharing molecules
of carbon.

it to other parts of the cell; the information is

Structural biology | A eld of study dedicated

transmitted by a specic chemical that must t

to determining the three-dimensional structures

the receptor, like a key in a lock.

of biological molecules to better understand the

function of these molecules.

54

National Institute of General Medical Sciences

Therapeutic drug | A drug used to treat a

disease or condition; contrast with drug of abuse.
Toxicology | The study of how poisonous
substances interact with living organisms.
Virus | An infectious agent composed of a
protein coat around a DNA or RNA core; to
reproduce, viruses depend on living cells.
X-ray crystallography | A technique used
to determine the detailed, three-dimensional
structure of molecules based on the scattering
of X rays through a crystal of the molecule.

What Is NIGMS?

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