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The New Genetics
Contents

FOREWORD 2

CHAPTER 1: HOW GENES WORK 4

Beautiful DNA 5

Copycat 8

Let’s Call It Even 9

Getting the Message 11

Nature’s Cut-and-Paste Job 14

All Together Now 16

Genetics and You: Nursery Genetics 17

Found in Translation 18

RNA Surprises 19

An Interesting Development 20

The Tools of Genetics: Mighty Microarrays 22

CHAPTER 2: RNA AND DNA REVEALED: NEW ROLES, NEW RULES 24

RNA World 25

Molecular Editor 26

Healthy Interference 29

Dynamic DNA 30

Secret Code 30

Genetics and You: The Genetics of Anticipation 32

Battle of the Sexes 33

Starting at the End 34

The Other Human Genome 36

The Tools of Genetics: Recombinant DNA and Cloning 38

CHAPTER 3: LIFE’S GENETIC TREE 40

Everything Evolves 40

Selective Study 42

Clues from Variation 43

Living Laboratories 46
The Genome Zoo 52

Genes Meet Environment 53

Genetics and You: You’ve Got Rhythm! 56

Animals Helping People 58

My Collaborator Is a Computer 58

The Tools of Genetics: Unlimited DNA 60

CHAPTER 4: GENES ARE US 62

Individualized Prescriptions 64

The Healing Power of DNA 65

Cause and Effect 67

Us vs. Them 68

Genetics and You: Eat Less, Live Longer? 69

Gang Warfare 70

The Tools of Genetics: Mathematics and Medicine 72

CHAPTER 5 : 21ST-CENTURY GENETICS 74

No Lab? No Problem! 76

Hard Questions 78

Good Advice 80

Genetics and You: Crime-Fighting DNA 81

Genetics, Business, and the Law 82

Careers in Genetics 85

The Tools of Genetics: Informatics and Databases 86

GLOSSARY 88
Consider just three of Earth’s inhabitants:

a bright yellow daffodil that greets the

spring, the single-celled creature called

Thermococcus that lives in boiling hot

springs, and you. Even a science-fiction

writer inventing a story set on a distant

planet could hardly imagine three more different forms of life. Yet you, Thermococcus,

and the daffodil are related! Indeed, all of

the Earth’s billions of living things are kin

to each other.

And every living thing

does one thing the same

way: To make more of

itself, it first copies its

molecular instruction

manual—its genes—and then passes this information on to its offspring. This cycle has been

repeated for three and a half billion years.

But how did we and our very distant relatives come to look so different and develop so

many different ways of getting along in the 

world? A century ago, researchers began to answer

that question with the help of a science called

genetics. Get a refresher course on the basics in

Chapter 1, “How Genes Work.”

It’s likely that when you think of heredity 

you think first of DNA, but in the past few years,

researchers have made surprising findings about

Foreword
Can DNA and RNA help doctors predict

whether we’ll get diseases like cancer, diabetes, or

asthma? What other mysteries are locked within

the 6 feet of DNA inside nearly every cell in our

bodies? Chapter 4, “Genes Are Us,” explains what

researchers know, and what they are still learning,

about the role of genes in health and disease.

Finally, in Chapter 5, “21st-Century

Genetics,” see a preview of things to come. Learn

how medicine and science are changing in big

ways, and how these changes influence society.

From metabolism to medicines to agriculture,

the science of genetics affects us every day. It is

part of life ... part of your life!

another molecular actor that plays a starring role.

Check out the modern view of RNA in Chapter 2,

“RNA and DNA Revealed: New Roles, New Rules.”

When genetics first started, scientists didn’t

have the tools they have today. They could only

look at one gene, or a few genes, at a time. Now,

researchers can examine all of the genes in a living organism—its genome—at once. They are

doing this for organisms on every branch of the

tree of life and finding that the genomes of mice,

frogs, fish, and a slew of other creatures have

many genes similar to our own.

So why doesn’t your brother look like your

dog or the fish in your aquarium? It’s because of

evolution. In Chapter 3, “Life’s Genetic Tree,”

find out how evolution works and how it relates

to genetics and medical research.

The New Genetics I Foreword 3
eople have known for many years that 

living things inherit traits from their parents.

That common-sense observation led to agriculture, the purposeful breeding and cultivation of

animals and plants for desirable characteristics.

Firming up the details took quite some time,

though. Researchers did not understand exactly

how traits were passed to the next generation

until the middle of the 20th century.

Now it is clear that genes are what carry our

traits through generations and that genes are

made of deoxyribonucleic acid (DNA). But

genes themselves don’t do the actual work.

Rather, they serve as instruction books for making functional molecules such as ribonucleic

acid (RNA) and proteins, which perform the

chemical reactions in our bodies.

In 1900, three European scientists independently discovered an obscure research

paper that had been published nearly 35

years before. Written by Gregor Mendel,

an Austrian monk who was also a scientist, the report described a series of

breeding experiments performed with pea

plants growing in his abbey garden.

Mendel had studied how pea plants

inherited the two variant forms of easy-to-see

traits. These included flower color (white or purple)

and the texture of the peas (smooth or wrinkled).

Mendel counted many generations of pea plant 

offspring and learned that these characteristics

were passed on to the next generation in orderly,

predictable ratios.

When he cross-bred purple-flowered pea plants

with white-flowered ones, the next generation had

only purple flowers. But directions for making white

flowers were hidden somewhere in the peas of that

generation, because when those purple-flowered

How Genes Work

CHAPTER 1

Proteins do many other things, too. They

provide the body’s main building materials,

forming the cell’s architecture and structural

components. But one thing proteins can’t do is

make copies of themselves. When a cell needs

more proteins, it uses the manufacturing instructions coded in DNA.

The DNA code of a gene—the sequence of

its individual DNA building blocks, labeled A

(adenine), T (thymine), C (cytosine), and G

(guanine) and collectively called nucleotides—

spells out the exact order of a protein’s building

blocks, amino acids.

Occasionally, there is a kind of typographical

error in a gene’s DNA sequence. This mistake—

which can be a change, gap, or duplication—is

called a mutation.

P

Genetics in the Garden

 The monk Gregor

Mendel first described

how traits are inherited

from one generation to

the next.
The New Genetics I How Genes Work 5

plants were bred to each other, some of their offspring had white flowers. What’s more, the

second-generation plants displayed the colors in a

predictable pattern. On average, 75 percent of the

second-generation plants had purple flowers and

25 percent of the plants had white flowers. Those

same ratios persisted, and were reproduced when

the experiment was repeated many times over.

Trying to solve the mystery of the missing color

blooms, Mendel imagined that the reproductive

cells of his pea plants might contain discrete 

“factors,” each of which specified a particular trait,

such as white flowers. Mendel reasoned that the

factors, whatever they were, must be physical 

material because they passed from parent to 

offspring in a mathematically orderly way. It wasn’t

until many years later, when the other scientists

unearthed Mendel’s report, that the factors were

named genes.

Early geneticists quickly discovered that

Mendel’s mathematical rules of inheritance applied

not just to peas, but also to all plants, animals, and

people. The discovery of a quantitative rule for

inheritance was momentous. It revealed that that a

common, general principle governed the growth

and development of all life on Earth.

Beautiful DNA

Up until the 1950s, scientists knew a good deal

about heredity, but they didn’t have a clue what

DNA looked like. In order to learn more about

DNA and its structure, some scientists experimented with using X rays as a form of molecular

photography.

Rosalind Franklin, a physical chemist working with Maurice Wilkins at King’s College in

London, was among the first to use this method

to analyze genetic material. Her experiments

A mutation can cause a gene to encode a 

protein that works incorrectly or that doesn’t

work at all. Sometimes, the error means that no

protein is made.

But not all DNA changes are harmful. Some

mutations have no effect, and others produce 

new versions of proteins that may give a survival

advantage to the organisms that have them. Over

time, mutations supply the raw material from

which new life forms evolve (see Chapter 3,

“Life’s Genetic Tree”).
6 National Institute of General Medical Sciences

produced what were referred to at the time as

“the most beautiful X-ray photographs of any

substance ever taken.”

Other scientists, including zoologist James

Watson and physicist Francis Crick, both working at Cambridge University in the United

Kingdom, were trying to determine the shape

of DNA too. Ultimately, this line of research

revealed one of the most profound scientific discoveries of the 20th century: that DNA exists as

a double helix.

The 1962 Nobel Prize in physiology or medicine was awarded to Watson, Crick, and Wilkins

for this work. Although Franklin did not earn a

share of the prize due to her untimely death at age

38, she is widely recognized as having played a significant role in the discovery.

The spiral staircase-shaped double

helix has attained global status as

the symbol for DNA. But what

is so beautiful about the discovery of the twisting 

ladder structure isn’t just 

its good looks. Rather, the

structure of DNA taught

researchers a fundamental 

lesson about genetics. It taught

them that the two connected

strands—winding together like parallel

handrails—were complementary to each other,

and this unlocked the secret of how genetic

information is stored, transferred, and copied.

In genetics, complementary means that if

you know the sequence of nucleotide building

blocks on one strand, you know the sequence of

nucleotide building blocks on the other strand:

A always matches up with T and C always links

to G (see drawing, page 7).

Long strings of nucleotides form genes,

and groups of genes are packaged tightly into

structures called chromosomes. Every cell in your

body except for eggs, sperm, and red blood cells

contains a full set of chromosomes in its nucleus.

If the chromosomes in one of your cells were

uncoiled and placed end to end, the DNA would

be about 6 feet long. If all the DNA in your body

were connected in this way, it would stretch

approximately 67 billion miles! That’s nearly

150,000 round trips to the Moon.

COLD SPRING HARBOR LABORATORY ARCHIVES

In 1953, Watson and Crick created their historic

model of the shape of DNA: the double helix.

Rosalind Franklin’s 

original X-ray diffraction

photo revealed the physical

structure of DNA.

OREGON STATE UNIVERSITY LIBRARIES

SPECIAL COLLECTIONS
The New Genetics I How Genes Work 7

Cell

Chromosome

Nucleotide

SugarPhosphate

Backbone

Thymine Adenine

Guanine Cytosine

Bases

DNA

G C

C G

G C

A T

G C

A T

C G

T A

A T

G C

A T

C

S

P

C G

Gene

 The long, stringy DNA that makes up genes is

spooled within chromosomes inside the nucleus 

of a cell. (Note that a gene would actually be a much

longer stretch of DNA than what is shown here.) 

 DNA consists of two long, twisted chains made up 

of nucleotides. Each nucleotide contains one base,

one phosphate molecule, and the sugar molecule

deoxyribose. The bases in DNA nucleotides are 

adenine, thymine, cytosine, and guanine. 

Nucleus
8 National Institute of General Medical Sciences

Copycat

It’s astounding to think that

your body consists of trillions

of cells. But what’s most

amazing is that it all starts

with one cell. How does this

massive expansion take place?

As an embryo progresses

through development, its cells

must reproduce. But before

a cell divides into two new,

nearly identical cells, it must

copy its DNA so there will be a complete set of

genes to pass on to each of the new cells.

To make a copy of itself, the twisted, compacted double helix of DNA has to unwind and

separate its two strands. Each strand becomes a

pattern, or template, for making a new strand, so

the two new DNA molecules have one new strand

and one old strand.

The copy is courtesy of a cellular protein

machine called DNA polymerase, which reads

the template DNA strand and stitches together

the complementary new strand. The process,

called replication, is astonishingly fast and

accurate, although occasional mistakes, such as

deletions or duplications, occur. Fortunately, a

cellular spell-checker catches and corrects nearly

all of these errors.

Mistakes that are not corrected can lead to

diseases such as cancer and certain genetic disorders. Some of these include Fanconi anemia, early

aging diseases, and other conditions in which

people are extremely sensitive to sunlight and

some chemicals.

DNA copying is not the only time when DNA

damage can happen. Prolonged, unprotected sun

exposure can cause DNA changes that lead to

skin cancer, and toxins in cigarette smoke can

cause lung cancer.

When DNA polymerase makes an error while copying a gene’s

DNA sequence, the mistake is called a mutation. In this example,

the nucleotide G has been changed to an A.

Humans have 23 pairs of chromosomes. Male DNA (pictured here)

contains an X and a Y chromosome, whereas female DNA contains

two X chromosomes.

CYTOGENETICS LABORATORY, BRIGHAM AND WOMEN’S HOSPITAL
The New Genetics I How Genes Work 9

It may seem ironic, then, that many drugs

used to treat cancer work by attacking DNA. That’s

because these chemotherapy drugs disrupt the

DNA copying process, which goes on much faster

in rapidly dividing cancer cells than in other 

cells of the body. The trouble is that most of these

drugs do affect normal cells that grow and 

divide frequently, such as cells of the immune

system and hair cells.

Understanding DNA replication better could

be a key to limiting a drug’s action to cancer 

cells only.

Let’s Call It Even

After copying its DNA, a cell’s next challenge is

getting just the right amount of genetic material

into each of its two offspring.

Most of your cells are called diploid

(“di” means two, and “ploid” refers to sets of

chromosomes) because they have two sets of

chromosomes (23 pairs). Eggs and sperm are

different; these are known as haploid cells. Each

haploid cell has only one set of 23 chromosomes

so that at fertilization the math will work out:

A haploid egg cell will combine with a haploid

sperm cell to form a diploid cell with the right

number of chromosomes: 46.

Chromosomes are numbered 1 to 22,

according to size, with 1 being the largest

chromosome. The 23rd pair, known as the sex

chromosomes, are called X and Y. In humans,

abnormalities of chromosome number usually

occur during meiosis, the time when a cell

The New Genetics I How Genes Work 9

New Strand

C

T

A

T

G C

A T

G C

G C

A T

C G

A T

A T

G C

G

A

A T

T A

A T

C G

C G

C G

T A

G C

T A

T A

A

T

G C

T

G C

G C

A T

G C

A T

C G

A T

C

A T

G

A T

A T

A T

G C

During DNA replication, each strand of the

original molecule acts as a template for

the synthesis of a new, complementary

DNA strand.

A
10 National Institute of General Medical Sciences

 During meiosis, chromosomes

from both parents are copied

and paired to exchange portions

of DNA.

Chromosomes

replicate.

Chromosomes

from Parents

Like chromosomes

pair up.

Chromosomes swap

sections of DNA.

Chromosome pairs divide.

Chromosomes divide.

Daughter nuclei have

single chromosomes

and a new mix of

genetic material.

Nucleus divides into

daughter nuclei.

Daughter nuclei

divide again. 

Meiosis

 This creates a mix of new genetic

material in the offspring’s cells.

Cell Nucleus
Amon has made major progress in understanding the details of meiosis. Her research shows

how, in healthy cells, gluelike protein complexes

called cohesins release pairs of chromosomes at

exactly the right time. This allows the chromosomes to separate properly.

These findings have important implications

for understanding and treating infertility, birth

defects, and cancer.

Getting the Message

So, we’ve described DNA—its basic properties

and how our bodies make more of it. But how

does DNA serve as the language of life? How do

you get a protein from a gene?

reduces its chromosomes from diploid to haploid

in creating eggs or sperm.

What happens if an egg or a sperm cell gets

the wrong number of chromosomes, and how

often does this happen?

Molecular biologist Angelika Amon of

the Massachusetts Institute of Technology in

Cambridge says that mistakes in dividing DNA

between daughter cells during meiosis are the

leading cause of human birth defects and miscarriages. Current estimates are that 10 percent

of all embryos have an incorrect chromosome

number. Most of these don’t go to full term and

are miscarried.

In women, the likelihood that chromosomes

won’t be apportioned properly increases with age.

One of every 18 babies born to women over 45

has three copies of chromosome 13, 18, or 21

instead of the normal two, and this improper

balancing can cause trouble. For example, three

copies of chromosome 21 lead to Down

syndrome.

To make her work easier, Amon—like many

other basic scientists—studies yeast cells, which

separate their chromosomes almost exactly the

same way human cells do, except that yeast do it

much faster. A yeast cell copies its DNA and

produces daughter cells in about 11/2 hours,

compared to a whole day for human cells.

The yeast cells she uses are the same kind

bakeries use to make bread and breweries use

to make beer!

The New Genetics I How Genes Work 11

Trisomy, the hallmark of Down syndrome, results

when a baby is born with three copies of chromosome 21 instead of the usual two.
12 National Institute of General Medical Sciences

There are two major steps in making a protein. The first is transcription, where the

information coded in DNA is copied into RNA.

The RNA nucleotides are complementary to

those on the DNA: a C on the RNA strand

matches a G on the DNA strand.

The only difference is that RNA pairs a

nucleotide called uracil (U), instead of a T, with

an A on the DNA.

A protein machine called RNA polymerase

reads the DNA and makes the RNA copy. This

copy is called messenger RNA, or mRNA, because

it delivers the gene’s message to the proteinproducing machinery.

At this point you may be wondering why all

of the cells in the human body aren’t exactly

alike, since they all contain the same DNA. What

makes a liver cell different from a brain cell? How

do the cells in the heart make the organ contract,

but those in skin allow us to sweat?

Cells can look and act differently, and do

entirely different jobs, because each cell “turns

on,” or expresses, only the genes appropriate for

what it needs to do.

That’s because RNA polymerase does not

work alone, but rather functions with the aid of

many helper proteins. While the core part of

RNA polymerase is the same in all cells, the

helpers vary in different cell types throughout

the body.

DNA

RNA polymerase transcribes DNA to

make messenger RNA (mRNA).

A

C

A

T

T

G

T

A

You’d think that for a process so essential to

life, researchers would know a lot about how

transcription works. While it’s true that the

basics are clear—biologists have been studying

gene transcribing by RNA polymerases since

these proteins were first discovered in 1960—

some of the details are actually still murky.

1
The New Genetics I How Genes Work 13

The mRNA sequence (dark red strand) is complementary to the DNA sequence (blue strand).

Amino acids link up to

make a protein.

mRNA

Ribosome

Amino Acids

tRNA

Threonine

Tyrosine

Arginine

Threonine

A C G U A U C G U A C A

Codon 1 Codon 2 Codon 3 Codon 4

A A T

C C G

A A T

T U A

G G C

C C G

T U A

A A T

T U A

G C G

C G C

A T A

The biggest obstacle to learning more has

been a lack of tools. Until recently, researchers

were unable to get a picture at the atomic level

of the giant RNA polymerase protein assemblies

inside cells to understand how the many pieces

of this amazing, living machine do what they do,

and do it so well.

But our understanding is improving fast,

thanks to spectacular technological advances.

We have new X-ray pictures that are far more

sophisticated than those that revealed the structure

of DNA. Roger Kornberg of Stanford University in

California used such methods to determine the

structure of RNA polymerase. This work earned

2 3 4

On ribosomes, transfer RNA (tRNA) helps

convert mRNA into protein.

DNA Strand

RNA Strand
14 National Institute of General Medical Sciences

him the 2006 Nobel

Prize in chemistry. In

addition, very powerful

microscopes and other

tools that allow us to

watch one molecule 

at a time provide a 

new look at RNA polymerase while it’s at work

reading DNA and producing RNA.

For example, Steven

Block, also of Stanford,

has used a physics technique called optical

trapping to track RNA

polymerase as it inches

along DNA. Block and

his team performed 

this work by designing

a specialized microscope

sensitive enough to watch the real-time motion of

a single polymerase traveling down a gene on

one chromosome.

The researchers discovered that molecules of

RNA polymerase behave like battery-powered

spiders as they crawl along the DNA ladder,

adding nucleotides one at a time to the growing

RNA strand. The enzyme works much like a

motor, Block believes, powered by energy released

during the chemical synthesis of DNA.

z RNA polymerase (green) and one end of a DNA

strand (blue) are attached to clear beads pinned

down in two optical traps. As RNA polymerase

moves along the DNA, it creates an RNA copy of

a gene, shown here as a pink strand.

STEVEN BLOCK

Nature’s Cut-and-Paste Job

Several types of RNA play key roles in making

a protein. The gene transcript (the mRNA)

transfers information from DNA in the nucleus to

the ribosomes that make protein. Ribosomal RNA

forms about 60 percent of the ribosomes. Lastly,

transfer RNA carries amino acids to the ribosomes. As you can see, all three types of cellular

RNAs come together to produce new proteins.

But the journey from gene to protein isn’t

quite as simple as we’ve just made it out to be.

After transcription, several things need to happen to mRNA before a protein can be made. For

example, the genetic material of humans and

other eukaryotes (organisms that have a

nucleus) includes a lot of DNA that doesn’t

encode proteins. Some of this DNA is stuck right

in the middle of genes.

To distinguish the two types of DNA, scientists call the coding sequences of genes exons and

the pieces in between introns (for intervening

sequences).

If RNA polymerase were to transcribe DNA

from the start of an intron-containing gene to

the end, the RNA would be complementary to

the introns as well as the exons.

To get an mRNA molecule that yields a working protein, the cell needs to trim out the intron

sections and then stitch only the exon pieces

together (see drawing, page 15). This process is

called RNA splicing.
The New Genetics I How Genes Work 15

 Arranging exons in different

patterns, called alternative

splicing, enables cells to

make different proteins

from a single gene.

Transcription

(RNA Synthesis)

RNA Splicing

DNA

Nuclear RNA

Messenger RNA

Gene

Exon 1 Exon 2 Exon 3

Exon 1 Intron 1 Exon 2 Intron 2 Exon 3

Exon 1 Intron 1 Exon 2 Intron 2 Exon 3

Protein

Translation

(Protein Synthesis)

Exon 1 Exon 2 Exon 3 Exon 4

Exon 1 Exon 2 Exon 3 Exon 1 Exon 2 Exon 4

Alternative Splicing

Protein A Protein B

Translation

Gene

DNA Exon 1 Exon 2 Exon 3 Exon 4

 Genes are often interrupted

by stretches of DNA

(introns, blue) that do not

contain instructions for

making a protein. The DNA

segments that do contain

protein-making instructions

are known as exons (green).
Splicing has to be extremely accurate. An

error in the splicing process, even one that results

in the deletion of just one nucleotide in an exon

or the addition of just one nucleotide in an

intron, will throw the whole sequence out of

alignment. The result is usually an abnormal

protein—or no protein at all. One form of

Alzheimer’s disease, for example, is caused by

this kind of splicing error.

Molecular biologist Christine Guthrie of the

University of California, San Francisco, wants

to understand more fully the mechanism for

removing intron RNA and find out how it stays

so accurate.

She uses yeast cells for these experiments.

Just like human DNA, yeast DNA has introns,

but they are fewer and simpler in structure and

are therefore easier to study. Guthrie can identify

which genes are required for splicing by finding

abnormal yeast cells that mangle splicing.

So why do introns exist, if they’re just going to

be chopped out? Without introns, cells wouldn’t

need to go through the splicing process and keep

monitoring it to be sure it’s working right.

As it turns out, splicing also makes it possible

for cells to create more proteins.

Think about all the exons in a gene. If a cell

stitches together exons 1, 2, and 4, leaving out

exon 3, the mRNA will specify the production

of a particular protein. But instead, if the cell

stitches together exons 1, 2, and 3, this time leaving out exon 4, then the mRNA will be translated

into a different protein (see drawing, page 15).

By cutting and pasting the exons in different

patterns, which scientists call alternative splicing,

a cell can create different proteins from a single

gene. Alternative splicing is one of the reasons

why human cells, which have about 25,000

genes, can make hundreds of thousands of

different proteins.

All Together Now

Until recently, researchers looked at genes, and

the proteins they encode, one at a time. Now, they

can look at how large numbers of genes and proteins act, as well as how they interact. This gives

them a much better picture of what goes on in a

living organism.

Already, scientists can identify all of the genes

that are transcribed in a cell—or in an organ, like

the heart. And although researchers can’t tell you,

right now, what’s going on in every cell of your

body while you read a book or walk down the

street, they can do this sort of “whole-body” scan

for simpler, single-celled organisms like yeast.

Using a new technique called genome-wide

location analysis, Richard Young of the

Massachusetts Institute of Technology unraveled

a “regulatory code” of living yeast cells, which

have more than 6,000 genes in their genome.

Young’s technique enabled him to determine the

exact places where RNA polymerase’s helper proteins sit on DNA and tell RNA polymerase to

begin transcribing a gene.

Since he did the experiment with the yeast

exposed to a variety of different conditions,

16 National Institute of General Medical Sciences
GENETICS AND YOU: Nursery Genetics

While most genetic research

uses lab organisms, test

tubes, and petri dishes,

the results have real consequences for

people. Your first encounter with

genetic analysis probably happened

shortly after you were born, when a

doctor or nurse took a drop of blood

from the heel of your tiny foot.

Lab tests performed with that single

drop of blood can diagnose certain rare

genetic disorders as well as metabolic

problems like phenylketonuria (PKU).

Screening newborns in this way

began in the 1960s in Massachusetts

with testing for PKU, a disease affecting

1 in 14,000 people. PKU is caused by an

enzyme that doesn’t work properly due

to a genetic mutation. Those born

with this disorder

cannot metabolize

the amino acid

phenylalanine,

which is present

in many foods. Left untreated, PKU can

lead to mental retardation and neurological damage, but a special diet can

prevent these outcomes. Testing for this

condition has made a huge difference in

many lives.

Newborn screening is governed by

individual states. That means that the

state in which a baby 

is born determines the

genetic conditions for

which he or she will be

screened. Currently,

some states test for

fewer than 10 conditions, whereas

others test for more than 30. All states

test for PKU.

Although expanded screening for

genetic diseases in newborns is advocated by some, others question the

value of screening for conditions that

are currently untreatable. Another 

issue is that some children with mild

versions of certain genetic diseases

may be treated needlessly.

Based on recommendations

released in 2005 by the American

College of Medical Genetics, government policymakers are now

considering a proposal that would

establish a standard, national set 

of newborn tests for 29 conditions,

ranging from relatively common 

hearing problems to very rare

metabolic diseases.

The New Genetics I How Genes Work 17
Young was able to figure out how transcription

patterns differ when the yeast cell is under stress

(say, in a dry environment) or thriving in a sugaryrich nutrient solution. Done one gene at a time,

using methods considered state-of-the-art just a

few years ago, this kind of analysis would have

taken hundreds of years.

After demonstrating that his technique

worked in yeast, Young then took his research

a step forward. He used a variation of the yeast

method to scan the entire human genome in

small samples of cells taken from the pancreases

and livers of people with type 2 diabetes. He

used the results to identify genes that aren’t transcribed correctly in people with the disease.

This information provides researchers with

an important tool for understanding how diabetes and other diseases are influenced by

defective genes. By building models to predict

how genes respond in diverse situations,

researchers may be able to learn how to stop or

jump-start genes on demand, change the course

of a disease, or prevent it from ever happening.

Found in Translation

After a gene has been read by RNA polymerase

and the RNA is spliced, what happens next in 

the journey from gene to protein? The next step

is reading the RNA information and fitting the

building blocks of a protein together. This is

called translation, and its principal actors are 

the ribosome and amino acids.

Ribosomes are among the biggest and most

intricate structures in the cell. The ribosomes of

bacteria contain not only huge amounts of RNA,

but also more than 50 different proteins. Human

ribosomes have even more RNA and between 70

and 80 different proteins!

Harry Noller of the University of California,

Santa Cruz, has found that a ribosome performs

several key jobs when it translates the genetic

code of mRNA. As the messenger RNA threads

through the ribosome protein machine, the

18 National Institute of General Medical Sciences

A ribosome consists of large and small

protein subunits with transfer RNAs

nestled in the middle.

RIBOSOME STRUCTURE COURTESY OF JAMIE CATE, MARAT YUSUPOV,

GULNARA YUSUPOVA, THOMAS EARNEST, AND HARRY NOLLER. GRAPHIC

COURTESY OF ALBION BAUCOM, UNIVERSITY OF CALIFORNIA, SANTA CRUZ.
ribosome reads the mRNA sequence and helps

recognize and recruit the correct amino acidcarrying transfer RNA to match the mRNA code.

The ribosome also links each additional amino

acid into a growing protein chain (see drawing,

page 13).

For many years, researchers believed that even

though RNAs formed a part of the ribosome, the

protein portion of the ribosome did all of the

work. Noller thought, instead, that maybe RNA,

not proteins, performed the ribosome’s job. His

idea was not popular at first, because at that time

it was thought that RNA could not perform such

complex functions.

Some time later, however, the consensus

changed. Sidney Altman of Yale University in

New Haven, Connecticut, and Thomas Cech,

who was then at the University of Colorado in

Boulder, each discovered that RNA can perform

work as complex as that done by protein enzymes.

Their “RNA-as-an-enzyme” discovery turned the

research world on its head and earned Cech and

Altman the 1989 Nobel Prize in chemistry.

Noller and other researchers have continued

the painstaking work of understanding ribosomes. In 1999, he showed how different parts

of a bacterial ribosome interact with one 

another and how the ribosome interacts with

molecules involved in protein synthesis.

These studies provided near proof that the 

fundamental mechanism of translation is 

performed by RNA, not by the proteins of

the ribosome.

The New Genetics I How Genes Work 19

RNA Surprises

But which ribosomal RNAs are doing the work?

Most scientists assumed that RNA nucleotides

buried deep within the ribosome complex—the

ones that have the same sequence in every species

from bacteria to people—were the important

ones for piecing the growing protein together.

However, recent research by Rachel Green,

who worked with Noller before moving 

to Johns Hopkins University in Baltimore,

Maryland, showed that this is not the case.

Green discovered that those RNA nucleotides 

are not needed for assembling a protein. Instead,

she found, the nucleotides do something else

entirely: They help the growing protein slip off

the ribosome once it’s finished.

Noller, Green, and hundreds of other scientists work with the ribosomes of bacteria. Why

should you care about how bacteria create

proteins from their genes?

Some first-aid ointments contain the antibiotic neomycin,

which treats infections by attacking ribosomes in bacteria.
One reason is that this knowledge is important for learning how to disrupt the actions of

disease-causing microorganisms. For example,

antibiotics like erythromycin and neomycin work

by attacking the ribosomes of bacteria, which are

different enough from human ribosomes that our

cells are not affected by these drugs.

As researchers gain new information about

bacterial translation, the knowledge may lead to

more antibiotics for people.

New antibiotics are urgently needed because

many bacteria have developed resistance to the

current arsenal. This resistance is sometimes the

result of changes in the bacteria’s ribosomal RNA.

It can be difficult to find those small, but critical,

changes that may lead to resistance, so it is

important to find completely new ways to block

bacterial translation.

Green is working on that problem too. Her

strategy is to make random mutations to the

genes in a bacterium that affect its ribosomes.

But what if the mutation disables the ribosome

so much that it can’t make proteins? Then the

bacterium won’t grow, and Green wouldn’t find it.

Using clever molecular tricks, Green figured

out a way to rescue some of the bacteria with

defective ribosomes so they could grow. While

some of the rescued bacteria have changes in

their ribosomal RNA that make them resistant

to certain antibiotics (and thus would not make

good antibiotic targets) other RNA changes that

don’t affect resistance may point to promising

ideas for new antibiotics.

An Interesting Development

In the human body, one of the most important

jobs for proteins is to control how embryos

develop. Scientists discovered a hugely important

set of proteins involved in development by studying mutations that cause bizarre malformations

in fruit flies.

The most famous such abnormality is a fruit

fly with a leg, rather than the usual antenna,

growing out of its head (see page 21). According

to Thomas C. Kaufman of Indiana University 

in Bloomington, the leg is perfectly normal—it’s

just growing in the wrong place.

In this type of mutation and many others,

something goes wrong with the genetic program

that directs some of the cells in an embryo to

follow developmental pathways, which are a

series of chemical reactions that occur in a specific order. In the antenna-into-leg problem, it

is as if the cells growing from the fly’s head,

which normally would become an antenna, mistakenly believe that they are in the fly’s thorax,

and therefore ought to grow into a leg. And so

they do.

Thinking about this odd situation taught scientists an important lesson—that the proteins

made by some genes can act as switches. Switch

genes are master controllers that provide each

body part with a kind of identification card. If a

protein that normally instructs cells to become

an antenna is disrupted, cells can receive new

instructions to become a leg instead.

20 National Institute of General Medical Sciences
The New Genetics I How Genes Work 21

genes of different organisms, it’s a good clue 

that these genes do something so important and

useful that evolution uses the same sequence 

over and over and permits very few changes in 

its structure as new species evolve.

Researchers quickly discovered nearly 

identical versions of homeobox DNA in almost

every non-bacterial cell they examined—from

yeast to plants, frogs, worms, beetles, chickens,

mice, and people.

Hundreds of homeobox-containing genes 

have been identified, and the proteins they 

make turn out to be involved in the early stages 

of development of many species. For example,

researchers have found that abnormalities in 

the homeobox genes can lead to extra fingers or

toes in humans.

Scientists determined that several different

genes, each with a common sequence, provide

these anatomical identification card instructions.

Kaufman isolated and described one of these

genes, which became known as Antennapedia,

a word that means “antenna feet.”

Kaufman then began looking a lot more

closely at the molecular structure of the

Antennapedia gene. In the early 1980s, he and

other researchers made a discovery that has been

fundamental to understanding evolution as well

as developmental biology.

The scientists found a short sequence of DNA,

now called the homeobox, that is present not only

in Antennapedia but in the several genes next to 

it and in genes in many other organisms. When

geneticists find very similar DNA sequences in the

Normal fruit fly head. Fruit fly head showing the effects of the Antennapedia

gene. This fly has legs where its antennae should be.

FLYBASE; R. TURNER 
We now have the ability to attach a piece of every

gene in a genome (all of an organism’s genes) to

a postage stamp-sized glass microscope slide.

This ordered series of DNA spots is called a DNA

microarray, a gene chip, or a DNA chip.

Whichever name you prefer, the chip could

also be called revolutionary. This technology has

changed the way many geneticists do their work

by making it possible to observe the activity of

thousands of genes at once.

In recent years, microarrays have become

standard equipment for modern biologists,

 The resulting pattern of fluorescence indicates

which genes are active.

 DNA fragments are attached to

glass or plastic, then fluorescently

tagged molecules are washed over

the fragments. 

 Some molecules (green) bind to their

complementary sequence. These molecules can be identified because they

glow under fluorescent light.

DNA Fragments

Complementary mRNA

The Tools of Genetics: Mighty Microarrays

but teachers and students are using them, too.

The Genome Consortium for Active Teaching

program (www.bio.davidson.edu/GCAT) provides resources and instructions for high school

and college students to do gene-chip experiments

in class.

Microarrays are used to get clues about

which genes are expressed to control cell, tissue,

or organ function. By measuring the level of RNA

production for every gene at the same time,

researchers can learn the genetic programming

that makes cell types different and diseased cells

different from healthy ones.

The chips consist of large numbers of DNA

fragments distributed in rows in a very small

space. The arrays are laid out by robots that can

22 National Institute of General Medical Sciences
position DNA fragments so precisely that

more than 20,000 of them can fit on one microscope slide.

Scientists isolate mRNA from cells grown

under two conditions and tag the two sources

of RNA with different colors of fluorescent molecules. The two colors of RNA are then placed

on the chip, where they attach to complementary

DNA fragments anchored to the chip’s surface.

Next, a scanner measures the amount of

fluorescence at each spot on the chip, revealing

how active each gene was (how much mRNA

each gene produced). A computer analyzes the

patterns of gene activity, providing a snapshot

of a genome under two conditions (e.g., healthy

or diseased).

In December 2004, the U.S. Food and

Drug Administration approved the first

gene chip for medical use. The Amplichip

CYP450TM, made by Roche Molecular Systems

Inc. of Pleasanton, California, analyzes variations in two genes that play a major role in

the body’s processing of many widely prescribed drugs. This information can help

doctors choose the proper dose of certain

medicines for an individual patient.

Why are some infections hard

to treat with antibiotics? What

are some things researchers

might do to solve this public

health problem?

How does DNA work as a form

of information storage?

How can 25,000 human genes

provide the instructions for

making hundreds of thousands

of different proteins?

What newborn tests does your

area hospital routinely do?

Got It?
or many years, when scientists thought

about heredity, DNA was the first thing

to come to mind. It’s true that DNA is the basic

ingredient of our genes and, as such, it often

steals the limelight from RNA, the other form

of genetic material inside our cells.

But, while they are both types of genetic

material, RNA and DNA are rather different.

The chemical units of RNA are like those of

DNA, except that RNA has the nucleotide uracil

(U) instead of thymine (T). Unlike doublestranded DNA, RNA usually comes as only a single

strand. And the nucleotides in RNA contain ribose

sugar molecules in place of deoxyribose.

RNA is quite flexible—unlike DNA, which is

a rigid, spiral-staircase molecule that is very stable.

RNA can twist itself into a variety of complicated,

three-dimensional shapes. RNA is also unstable in

that cells constantly break it down and must continually make it fresh, while DNA is not broken

down often. RNA’s instability lets cells change

their patterns of protein synthesis very quickly

in response to what’s going on around them.

Many textbooks still portray RNA as a passive

molecule, simply a “middle step” in the cell’s

gene-reading activities. But that view is no longer

accurate. Each year, researchers unlock new

secrets about RNA. These discoveries reveal that

it is truly a remarkable molecule and a multitalented actor in heredity.

RNA and DNA Revealed: New Roles, New Rules

CHAPTER 2

 Ribonucleic acid (RNA) has

the bases adenine (A),

cytosine (C), guanine (G),

and uracil (U).

SugarPhosphate

Backbone

Base

A

G

C

A

U

A

C

C

C

U

C

G

U

A

G

G

C

U

C

A

G

C

U

C

U

G

C

U

RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA

F
because of its ability to lead a double life: to store

information and to conduct chemical reactions.

In other words, in this world, RNA served the

functions of both DNA and proteins.

What does any of this have to do with human

health? Plenty, it turns out.

Today’s researchers are harnessing some of

RNA’s flexibility and power. For example, through

a strategy he calls directed evolution, molecular

engineer Ronald R. Breaker of Yale University is

developing ways to create entirely new forms of

RNA and DNA that both work as enzymes.

Recently, Breaker and others have also uncovered a hidden world of RNAs that play a major 

role in controlling gene activity, a job once

thought to be performed exclusively by proteins.

These RNAs, which the scientists named

riboswitches, are found in a wide variety of

bacteria and other organisms.

Today, many scientists believe that RNA

evolved on the Earth long before DNA did.

Researchers hypothesize—obviously, no one 

was around to write this down—that RNA was 

a major participant in the chemical reactions 

that ultimately spawned the first signs of life

on the planet.

RNA World

At least two basic requirements exist for making

a cell: the ability to hook molecules together and

break them apart, and the ability to replicate, or

copy itself, from existing information.

RNA probably helped to form the first cell.

The first organic molecules, meaning molecules

containing carbon, most likely arose out of random

collisions of gases in the Earth’s primitive atmosphere, energy from the Sun, and heat from naturally

occurring radioactivity. Some scientists think that

in this primitive world, RNA was a critical molecule

The New Genetics I RNA and DNA Revealed: New Roles, New Rules 25

RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA

Riboswitches are RNA

sequences that control 

gene activity. The riboswitch

shown here bends into a

special shape when it grips

tightly onto a molecule

called a metabolite (colored

balls) that bacteria need 

RONALD BREAKER

to survive.
This discovery has led Breaker to speculate

that new kinds of antibiotic medicines could be

developed to target bacterial riboswitches.

Molecular Editor

Scientists are learning of another way to customize proteins: by RNA editing. Although DNA

sequences spell out instructions for producing 

RNA and proteins, these instructions aren’t

always followed precisely. Editing 

a gene’s mRNA, even by a single 

chemical letter, can radically change

the resulting protein’s function.

Nature likely evolved the RNA

editing function as a way to get more

proteins out of the same number of

26 National Institute of General Medical Sciences

Recently, molecules called microRNAs have been

found in organisms as diverse as plants, worms,

and people. The molecules are truly “micro,” consisting of only a few dozen nucleotides, compared

to typical human mRNAs that are a few thousand

nucleotides long.

What’s particularly interesting about microRNAs

is that many of them arise from DNA that used 

to be considered merely filler material (see 

page 14).

How do these small but important RNA molecules do their work? They start out much bigger

but get trimmed by cellular enzymes, including

one aptly named Dicer. Like tiny pieces of

Small But Powerful

c Double-stranded DNA

(left) is a staircase-like 

molecule.

c The enzyme Dicer generates microRNAs by

chopping larger RNA molecules into tiny

Velcro®-like pieces. MicroRNAs stick to mRNA

molecules and prevent the mRNAs from being

made into proteins.

RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA

Larger RNA

MicroRNA

Near-perfect complementarity 

to target mRNA

Dicer

Enzyme

mRNA

v RNA comes in a variety of 

different shapes (above

and right).

No Translation

No Protein
the RNA sequence, which in turn changes the

protein that gets made.

Bass’ experiments show that RNA editing

occurs in a variety of organisms, including people. Another interesting aspect of editing is that

certain disease-causing microorganisms, such as

some forms of parasites, use RNA editing to gain

a survival edge when living in a human host.

Understanding the details of this process is an

important area of medical research.

genes. For example, researchers have found that

the mRNAs for certain proteins important for the

proper functioning of the nervous system are

particularly prone to editing. It may be that RNA

editing gives certain brain cells the capacity to

react quickly to a changing environment.

Which molecules serve as the editor and how

does this happen? Brenda Bass of the University of

Utah School of Medicine in Salt Lake City studies

one particular class of editors called adenosine

deaminases. These enzymes “retype” RNA letters

at various places within an mRNA transcript.

They do their job by searching for characteristic RNA shapes. Telltale twists and bends in folded

RNA molecules signal these enzymes to change

The New Genetics I RNA and DNA Revealed: New Roles, New Rules 27

Velcro®, microRNAs stick to certain mRNA molecules and stop them from passing on their

protein-making instructions.

First discovered in a roundworm model system

(see Living Laboratories, page 49), some microRNAs

help determine the organism’s body plan. In their

absence, very bad things can happen. For example,

worms engineered to lack a microRNA called let-7

develop so abnormally that they often rupture and

practically break in half as the worm grows.

Perhaps it is not surprising that since microRNAs

help specify the timing of an organism’s developmental plan, the appearance of the microRNAs

themselves is carefully timed inside a developing

organism. Biologists, including Amy Pasquinelli 

of the University of California, San Diego, are currently figuring out how microRNAs are made 

and cut to size, as well as how they are produced

at the proper time during development. 

z Worms with a mutated form of the microRNA let-7

(right) have severe growth problems, rupturing as

they develop.

MicroRNA molecules also have been linked to

cancer. For example, Gregory Hannon of the Cold

Spring Harbor Laboratory on Long Island, New

York, found that certain microRNAs are associated with the severity of the blood cancer B-cell

lymphoma in mice.

Since the discovery of microRNAs in the 

first years of the 21st century, scientists have

identified hundreds of them that likely exist as

part of a large family with similar nucleotide

sequences. New roles for these molecules are

still being found.

RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA

AMY PASQUINELLI
28 National Institute of General Medical Sciences

RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA

RNA Interference (RNAi) 

Dicer Enzyme

dsRNA

RISC

A U C G U A C G

U A G C A U G C

A U C G U A C G

Short Interfering

RNAs (siRNAs)

mRNA

Double-stranded RNA (dsRNA) is chopped

into short interfering RNAs (siRNAs) by the

enzyme Dicer.

 The RNA-Induced Silencing

Complex (RISC) enzyme

attaches to siRNA.

 The siRNA-RISC complex

attaches to target mRNA 

and chops the mRNA into

small pieces.

Chopped mRNA

(no longer functional)
of genes that affect cell growth and tissue

formation in roundworms, using a molecular tool

called antisense RNA.

To their surprise, Mello and Fire found 

that their antisense RNA tool wasn’t doing 

much at all. Rather, they determined, a doublestranded contaminant produced during the

synthesis of the single-stranded antisense RNA

interfered with gene expression. Mello and 

Fire named the process RNAi, and in 2006 were

awarded the Nobel Prize in physiology or 

medicine for their discovery.

Further experiments revealed that the doublestranded RNA gets chopped up inside the cell

into much smaller pieces that stick to mRNA and

block its action, much like the microRNA pieces

of Velcro discussed above (see drawing, page 28).

Today, scientists are taking a cue from nature

and using RNAi to explore biology. They have

learned, for example, that the process is not limited

to worms and plants, but operates in humans too.

Medical researchers are currently testing new

types of RNAi-based drugs for treating conditions such as macular degeneration, the leading

cause of blindness, and various infections, including those caused by HIV and herpes virus.

Healthy Interference

RNA controls genes in a way that was only discovered recently: a process called RNA interference,

or RNAi. Although scientists identified RNAi less

than 10 years ago, they now know that organisms

have been using this trick for millions of years.

Researchers believe that RNAi arose as a way to

reduce the production of a gene’s encoded protein

for purposes of fine-tuning growth or self-defense.

When viruses infect cells, for example, they command their host to produce specialized RNAs that

allow the virus to survive and make copies of itself.

Researchers believe that RNAi eliminates

unwanted viral RNA, and some speculate that it

may even play a role in human immunity.

Oddly enough, scientists discovered RNAi

from a failed experiment! Researchers investigating genes involved in plant growth noticed

something strange: When they tried to turn 

petunia flowers purple by adding an extra 

“purple” gene, the flowers bloomed white instead.

This result fascinated researchers, who could

not understand how adding genetic material

could somehow get rid of an inherited trait. The

mystery remained unsolved until, a few years

later, two geneticists studying development saw

a similar thing happening in lab animals.

The researchers, Andrew Z. Fire, then of the

Carnegie Institution of Washington in Baltimore

and now at Stanford University, and Craig Mello

of the University of Massachusetts Medical School

in Worcester, were trying to block the expression

The New Genetics I RNA and DNA Revealed: New Roles, New Rules 29

RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA RNA
Dynamic DNA

A good part of who we are is “written in our

genes,” inherited from Mom and Dad. Many

traits, like red or brown hair, body shape, and

even some personality quirks, are passed on from

parent to offspring.

But genes are not the whole story. Where we

live, how much we exercise, what we eat: These

and many other environmental factors can all

affect how our genes get expressed.

You know that changes in DNA and RNA can

produce changes in proteins. But additional control happens at the level of DNA, even though

these changes do not alter DNA directly. Inherited

factors that do not change the DNA sequence of

nucleotides are called epigenetic changes, and they

too help make each of us unique.

Epigenetic means, literally, “upon” or “over”

genetics. It describes a type of chemical reaction

that can alter the physical properties of DNA

without changing its sequence. These changes

make genes either more or less likely to be

expressed (see drawing, page 31).

Currently, scientists are following an intriguing course of discovery to identify epigenetic

factors that, along with diet and other environmental influences, affect who we are and what

type of illnesses we might get.

Secret Code

DNA is spooled up compactly inside cells in an

arrangement called chromatin. This packaging 

is critical for DNA to do its work. Chromatin

consists of long strings of DNA spooled around 

a compact assembly of proteins called histones.

One of the key functions of chromatin is to

control access to genes, since not all genes are

turned on at the same time. Improper expression

of growth-promoting genes, for example, can lead

to cancer, birth defects, or other health concerns.

30 National Institute of General Medical Sciences

DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA 

 Histone proteins loop together

with double-stranded DNA to

form a structure that resembles

beads on a string.

Histones

DNA

Chromatin
Many years after the structure of DNA

was determined, researchers used a powerful

device known as an electron microscope to

take pictures of chromatin fibers. Upon

viewing chromatin up close, the researchers

described it as “beads on a string,” an image

still used today. The beads were the histone

balls, and the string was DNA wrapped

around the histones and connecting one

bead to the next.

Decades of study eventually revealed that

histones have special chemical tags that act

like switches to control access to the DNA.

Flipping these switches, called epigenetic

markings, unwinds the spooled DNA so the

genes can be transcribed.

The observation that a cell’s gene-reading

machinery tracks epigenetic markings led

C. David Allis, who was then at the University

of Virginia Health Sciences Center in

Charlottesville and now works at the

Rockefeller University in New York City,

to coin a new phrase, the “histone code.”

He and others believe that the histone 

code plays a major role in determining 

which proteins get made in a cell.

Flaws in the histone code have been

associated with several types of cancer, and

researchers are actively pursuing the development of medicines to correct such errors.

The New Genetics I RNA and DNA Revealed: New Roles, New Rules 31

DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA 

 The “epigenetic code” controls gene activity with

chemical tags that mark DNA (purple diamonds)

and the “tails” of histone proteins (purple triangles).

These markings help determine whether genes will

be transcribed by RNA polymerase. Genes hidden

from access to RNA polymerase are not expressed.

DNA

Histone Tails

Histones

Chromosome
Occasionally, unusual factors 

influence whether or not a

child will be born with a

genetic disease.

An example is the molecular error

that causes Fragile X syndrome, a rare

condition associated with mental retardation. The mutation leading to a fragile

X chromosome is not a typical DNA typing mistake, in which nucleotides are

switched around or dropped, or one of

them is switched for

another nucleotide.

Instead, it is a kind

of stutter by the DNA

polymerase enzyme

that copies DNA.

This stutter creates a string of repeats of

a DNA sequence that is composed of

just three nucleotides, CGG.

Some people have only one repeat

of the CGG nucleotide triplet. Thus, they

have two copies of the repeat in a gene,

and the extra sequence reads CGGCGG.

Others have more than a thousand

copies of the repeat. These people are

the most severely affected.

The number of triplet repeats seems

to increase as the chromosome is

passed down through several generations. Thus, the grandsons of a man

with a fragile X chromosome, who is

not himself affected, have a 40 percent

risk of retardation if they inherit the

repeat-containing chromosome. The

risk for great-grandsons is even higher:

50 percent.

Intrigued by the evidence that triplet

repeats can cause genetic disease, scientists have searched for other examples

of disorders associated with the DNA

expansions. To date, more than a dozen

such disorders have been found, and all

of them affect the nervous system.

Analysis of the rare families in

which such diseases are common has

revealed that expansion of the triplet

repeats is linked to something called

genetic anticipation, when a disease’s

symptoms appear earlier and more

severely in each successive generation.

32 National Institute of General Medical Sciences

GENETICS AND YOU: The Genetics of Anticipation

DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA 
father’s copy of Igf2 is expressed, and the mother’s

copy remains silent (is not expressed) throughout

the life of the offspring.

Scientists have discovered that this selective

silencing of Igf2 and many other imprinted genes

occurs in all placental mammals (all except the

platypus, echidna, and marsupials) examined 

so far, but not in birds.

Why would nature tolerate a process that puts

an organism at risk because only one of two

copies of a gene is working? The likely reason,

many researchers believe, is that mothers and

fathers have competing interests, and the battlefield is DNA!

The scenario goes like this: It is in a father’s

interest for his embryos to get bigger faster,

because that will improve his offspring’s chances

of survival after birth. The better an individual’s

Battle of the Sexes

A process called imprinting, which occurs naturally in our cells, provides another example of

how epigenetics affects gene activity.

With most genes, the two copies work exactly

the same way. For some mammalian genes, however, only the mother’s or the father’s copy is

switched on regardless of the child’s gender. This

is because the genes are chemically marked, or

imprinted, during the process that generates eggs

and sperm.

As a result, the embryo that emerges from the

joining of egg and sperm can tell whether a gene

copy came from Mom or Dad, so it knows which

copy of the gene to shut off.

One example of an imprinted gene is insulinlike growth factor 2 (Igf2), a gene that helps a

mammalian fetus grow. In this case, only the

The New Genetics I RNA and DNA Revealed: New Roles, New Rules 33

DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA 

Igf2 is an imprinted gene. A

single copy of the abnormal,

or mutant, form of the Igf2

gene (red) causes growth

defects, but only if the

abnormal gene variant is

inherited from the father.

Paternal

Maternal

Paternal

Maternal

Normal Igf2 Gene Variant

(expressed)

Mutant Igf2 Gene Variant

(not expressed)

Mutant Igf2 Gene Variant

(expressed)

Normal Igf2 Gene Variant

(not expressed)

Normal Size Mouse

Dwarf Mouse
chance of surviving infancy, the better its chance

of becoming an adult, mating, and passing its

genes on to the next generation.

Of course mothers want strong babies, but

unlike fathers, mothers provide physical resources

to embryos during pregnancy. Over her lifetime,

a female is likely to be pregnant several times, so

she needs to divide her resources among a number of embryos in different pregnancies.

Researchers have discovered over 200 imprinted

genes in mammals since the first one was identified

in 1991. We now know that imprinting controls

some of the genes that have an important role in

regulating embryonic and fetal growth and allocating maternal resources. Not surprisingly, mutations

in these genes cause serious growth disorders.

Marisa Bartolomei of the University of

Pennsylvania School of Medicine in Philadelphia

is trying to figure out how Igf2 and other genes

become imprinted and stay silent throughout the

life of an individual. She has already identified

sequences within genes that are essential for

imprinting. Bartolomei and other researchers

have shown that these sequences, called insulators, serve as “landing sites” for a protein that

keeps the imprinted gene from being transcribed.

Starting at the End

When we think of DNA, we think of genes.

However, some DNA sequences are different:

They don’t encode RNAs or proteins. Introns,

described in Chapter 1, are in this category.

Another example is telomeres—the ends of

chromosomes. There are no genes in telomeres,

but they serve an essential function. Like

shoelaces without their tips, chromosomes without telomeres unravel and fray. And without

telomeres, chromosomes stick to each other and

cause cells to undergo harmful changes like dividing abnormally.

Researchers know a good deal about telomeres, dating back to experiments performed 

in the 1970s by Elizabeth Blackburn, a basic

researcher who was curious about some of the

fundamental events that take place within cells.

34 National Institute of General Medical Sciences

 Telomeres, repeated nucleotide sequences at the

tips of chromosomes, appear white in this photo.

DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA HESED PADILLA-NASH AND THOMAS RIED
The New Genetics I RNA and DNA Revealed: New Roles, New Rules 35

within a single cell over time. Blackburn reasoned

that the repeat number might vary if cells had

an enzyme that added copies of the repeated

sequence to the telomeres of some but not all

chromosomes.

With her then-graduate student Carol

Greider, now at Johns Hopkins University,

Blackburn hunted for the enzyme. The team

found it and Greider named it telomerase.

The telomerase enzyme, it turns out, consisted of a protein and an RNA component,

which the enzyme uses as a template for copying

the repeated DNA sequence.

At the time, Blackburn, now at the University

of California, San Francisco, was working with

Joseph Gall at Yale University. For her experimental system, she chose a single-celled,

pond-dwelling organism named Tetrahymena.

These tiny, pear-shaped creatures are covered 

with hairlike cilia that they use to propel themselves through the water as they devour bacteria

and fungi.

Tetrahymena was a good organism for

Blackburn’s experiments because it has a large

number of chromosomes—which means it has

a lot of telomeres!

Her research was also perfectly timed, because

methods for sequencing DNA were just being

developed. Blackburn found that Tetrahymena’s

telomeres had an unusual nucleotide sequence:

TTGGGG, repeated about 50 times per telomere.

Since then, scientists have discovered that the

telomeres of almost all organisms have repeated

sequences of DNA with lots of Ts and Gs. In

human and mouse telomeres, for example, the

repeated sequence is TTAGGG.

The number of telomere repeats varies enormously, not just from organism to organism but

in different cells of the same organism and even

 Molecular biologist Carol Greider discovered the

enzyme telomerase. This license plate, which was 

on her car when she worked at Cold Spring Harbor

Laboratory on Long Island, New York, advertises 

her research interest!

DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA CAROL GREIDER
What is the natural function of telomerase?

As cells divide again and again, their telomeres

get shorter. Most normal cells stop dividing when

their telomeres wear down to a certain point, and

eventually the cells die. Telomerase can counteract the shortening. By adding DNA to telomeres,

telomerase rebuilds the telomere and resets the

cell’s molecular clock.

The discovery of telomerase triggered new

ideas and literally thousands of new studies.

Many researchers thought that the enzyme 

might play important roles in cancer and aging.

Researchers were hoping to find ways to turn

telomerase on so that cells would continue to

divide (to grow extra cells for burn patients,

for example), or off so that cells would stop 

dividing (to stop cancer, for instance).

So far, they have been unsuccessful. Although

it is clear that telomerase and cellular aging are

related, researchers do not know whether telomerase plays a role in the normal cellular aging

process or in diseases like cancer.

Recently, however, Blackburn and a team of

other scientists discovered that chronic stress and

the perception that life is stressful affect telomere

length and telomerase activity in the cells of

healthy women. Blackburn and her coworkers

are currently conducting a long-term, follow-up

study to confirm these intriguing results.

The Other Human Genome

Before you think everything’s been said about

DNA, there’s one little thing we didn’t mention:

Some of the DNA in every cell is quite different

from the DNA that we’ve been talking about up

to this point. This special DNA isn’t in chromosomes—it isn’t even inside the cell’s nucleus

where all the chromosomes are!

So where is this special DNA? It’s inside mitochondria, the organelles in our cells that produce

the energy-rich molecule adenosine triphosphate,

or ATP. Mendel knew nothing of mitochondria,

since they weren’t discovered until late in the

19th century. And it wasn’t until the 1960s that

researchers discovered the mitochondrial genome,

which is circular like the genomes of bacteria.

In human cells, mitochondrial DNA makes

up less than 1 percent of the total DNA in each

of our cells. The mitochondrial genome is very

small—containing only about three dozen genes.

These encode a few of the proteins that are in the

mitochondrion, plus a set of ribosomal RNAs

used for synthesizing proteins for the organelle.

Mitochondria need many more proteins

though, and most of these are encoded by genes

in the nucleus. Thus, the energy-producing capabilities of human mitochondria—a vital part of

any cell’s everyday health—depend on coordinated teamwork among hundreds of genes in

two cellular neighborhoods: the nucleus and the

mitochondrion.

36 National Institute of General Medical Sciences

DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA 
Mitochondrial DNA gets transcribed and 

the RNA is translated by enzymes that are very

different from those that perform this job for

genes in our chromosomes. Mitochondrial

enzymes look and act much more like those

from bacteria, which is not surprising because

mitochondria are thought to have descended

from free-living bacteria that were engulfed by

another cell over a billion years ago.

Scientists have linked mitochondrial DNA

defects with a wide range of age-related diseases

including neurodegenerative disorders, some

forms of heart disease, diabetes, and various

cancers. It is still unclear, though, whether damaged mitochondria are a symptom or a cause of

these health conditions.

Scientists have studied mitochondrial DNA

for another reason: to understand the history of

the human race. Unlike our chromosomal DNA,

which we inherit from both parents, we get all of

our mitochondrial DNA from our mothers.

Thus, it is possible to deduce who our maternal ancestors were by tracking the inheritance of

mutations in mitochondrial DNA. For reasons

that are still not well understood, mutations

accumulate in mitochondrial DNA very slowly

compared to chromosomal DNA. So, it’s possible

to trace your maternal ancestry way back beyond

any relatives you may know by name—all the

way back to “African Eve,” the ancestor of us all! 

The New Genetics I RNA and DNA Revealed: New Roles, New Rules 37

Mitochondria (labeled

with a red dye) are 

scattered throughout 

the cytoplasm of this

human cancer cell.

DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA DNA ALISON DAVIS

The cell has also been

treated with a dye that

colors the mitochondrial

DNA green.

A computerized overlay

of these two images of

the same cell shows that

mitochondria and its

DNA appear together

(yellow regions).
38 National Institute of General Medical Sciences

Bacteria with hybrid plasmid replicate, creating

clone capable of producing human insulin

The Tools of Genetics: Recombinant DNA and Cloning

 Recombinant DNA. To splice a human

gene (in this case, the one for insulin)

into a plasmid, scientists take the plasmid out of an E. coli bacterium, cut the

plasmid with a restriction enzyme, and

splice in insulin-making human DNA.

The resulting hybrid plasmid can be

inserted into another E. coli bacterium,

where it multiplies along with the bacterium. There, it can produce large

quantities of insulin.

Strand of DNA from human cell

Nucleus Human Cell

E. coli bacteria, taken

from human intestine

Plasmid

E. coli

Chromosome

Plasmid removed

from E. coli

Plasmid cut open by

restriction enzyme at

a specific site

Human Insulin Gene

Recombinant DNA Human Insulin Gene

(hybrid plasmid)

Human plasmid

inserted into E. coli cell

Two pieces spliced together

Human DNA cut into pieces

by restriction enzyme
In the early 1970s, scientists

discovered that they could

change an organism’s genetic

traits by putting genetic

material from another organism into its cells. This discovery, which caused

quite a stir, paved the way for many extraordinary

accomplishments in medical research that have

occurred over the past 35 years.

How do scientists move genes from one

organism to another? The cutting and pasting

gets done with chemical scissors: enzymes, to be

specific. Take insulin, for example. Let’s say a scientist wants to make large quantities of this

protein to treat diabetes. She decides to transfer

the human gene for insulin into a bacterium,

Escherichia coli, or E. coli, which is commonly

used for genetic research (see Living Laboratories,

page 46). That’s because E. coli reproduces really

fast, so after one bacterium gets the human

insulin gene, it doesn’t take much time to grow

millions of bacteria that contain the gene.

The first step is to cut the insulin gene out of

a copied, or “cloned,” version of the human DNA

using a special bacterial enzyme from bacteria

called a restriction endonuclease. (The normal role

of these enzymes in bacteria is to chew up the

DNA of viruses and other invaders.) Each restriction enzyme recognizes and cuts at a different

nucleotide sequence, so it’s possible to be very precise about DNA cutting by selecting one of several

hundred of these enzymes that cuts at the desired

sequence. Most restriction endonucleases make slightly staggered

incisions, resulting in “sticky ends,”

out of which one strand protrudes.

The next step in this example is

to splice, or paste, the human insulin gene into

a circle of bacterial DNA called a plasmid.

Attaching the cut ends together is done with

a different enzyme (obtained from a virus),

called DNA ligase. The sticky ends join back

together kind of like jigsaw puzzle pieces. The

result: a cut-and-pasted mixture of human

and bacterial DNA.

The last step is putting the new, recombinant DNA back into E. coli and letting the

bacteria reproduce in a petri dish. Now, the

scientist has a great tool: a version of E. coli

that produces lots of human insulin that can

be used for treating people with diabetes.

So, what is cloning? Strictly speaking, it’s

making many copies of a gene—in the

example above, E. coli is doing the cloning.

However, the term cloning is more generally

used to refer to the entire process of isolating

and manipulating a gene. Dolly the cloned

sheep contained the identical genetic material

of another sheep. Thus, researchers refer

to Dolly as a clone.

Scientists in Scotland were the 

first to clone an animal, this sheep

named Dolly. She later gave birth 

to Bonnie, the lamb next to her.

ROSLIN INSTITUTE, EDINBURGH

Besides the sequence of

nucleotides in genes, what

are some other changes to

DNA and RNA that can

affect our health and who

we are?

Can you imagine treatments—other than

vaccines and current

medicines—crafted from

genetic information and

new molecular tools?

How is cloning a gene

different from cloning an

animal or a person? How

do researchers use gene

cloning to study health

and disease?

Do you have any recurring

illnesses in your extended

family?

Got It?
n all of biology, there is one thing that always

stays the same. That thing, believe it or not,

is change itself!

The millions of different living things on

Earth—plants, bacteria, insects, chimps, people,

and everything else—all came to be because of

a process called biological evolution, in which

organisms change over time.

Because of biological evolution, early humans

gained the ability to walk on two feet. Because of

evolution, air-breathing whales can live in the

ocean despite being mammals like us. Because of

evolution, some bacteria can live in scalding water,

others can survive in solid ice, and still others can

live deep in the Earth eating only rocks!

Evolution happens every day, and it affects

every species—including us. It changes entire

populations, not individuals. And it has a big

impact on medical research.

Everything Evolves

To understand evolution, let’s go back in time a

century and a half to 1854, when the British

naturalist Charles Darwin published The Origin 

CHAPTER 3

I

Life’s Genetic Tree

Time

First Living Species

Today
of Species, a book that

proposed an explanation for 

how evolution works.

The main concept in evolution is that all 

living things share a common ancestor. The very

earliest ancestor of all life forms on Earth lived

about 4 billion years ago. From that early organism, millions of types of creatures—some living

and some now extinct—have evolved.

Evolution requires diversity. You can tell that

living things are diverse just by walking down the

street and looking around you. Individual people

are very different from one another. Chihuahuas

are different from Great Danes, and Siamese cats

are different from tabbies.

Evolution also depends on inheritance. Many

of our unique characteristics are inherited—they

are passed from parent to offspring. This is easy

to see: Dalmatian puppies look like Dalmatians,

not Chihuahuas. Petunias grow differently from

pansies. Evolution works only on traits that are

inherited.

Finally, as you probably already know,

evolution favors the “fittest.” Through a process

called natural selection, only some offspring

within a given generation will survive long

enough to reproduce.

As an example, consider houseflies, each of

which lays thousands of eggs every year. Why

haven’t they taken over the world? Because

almost all of the baby houseflies die. The flies that

survive are the ones that can find something to

eat and drink ... the ones that avoid being eaten,

stepped on, or swatted ... and the ones that don’t

freeze, drown, or land on a bug zapper.

The flies that survive all these ways to die have

what it takes to outlive most of their brothers and

sisters. These inherited traits give an organism a

survival edge. Those who survive will mate with

each other and will pass on to the next generation

some of their DNA that encoded these advantageous traits.

Of course, not all aspects of survival are

determined by genes. Whether a fly gets swatted

The New Genetics I Life’s Genetic Tree 41

 Charles Darwin described

evolution in his classic text,

The Origin of Species.
depends on genes that affect its reflexes—whether

it’s fast enough to avoid the swatter— but also

on the environment. If there’s no human around

waving the swatter, the fly is quite likely to survive, regardless of its reflexes.

Evolution often takes a long time to make a

difference. But it can also happen very quickly,

especially in organisms with short lifespans. For

example, as you read earlier, some bacteria have

molecular features that let them survive in the

presence of antibiotics. When you take an

antibiotic medicine, antibiotic-resistant bacteria

flourish while antibiotic-sensitive bacteria die.

Because antibiotic resistance is a growing

public health threat, it’s important to take the

whole dosage of antibiotic medicine, not stop

when you feel better. And you should take antibiotics only when they’re needed, not for colds or

other viral infections, which antibiotics can’t

treat. Viruses must simply run their course.

Selective Study

Scientists doing medical research are very interested in genetic variants that have been selected

by evolution. For example, researchers recently

discovered a rare genetic variant that protects

people from getting AIDS. A genetic variant is a

different version of a gene, one that has a slightly

different sequence of nucleotides.

Scientists think that the rare variant of a gene

called CCR5 originally may have been selected

during evolution because it made people resistant

to an organism unrelated to HIV.

Montgomery Slatkin of the University of

California, Berkeley, has used mathematical

modeling techniques to show that natural selection over time could explain the frequency of the

CCR5 variant in human populations. The work

indicates that the CCR5 gene variant’s ability to

protect against AIDS may contribute to keeping it

in the human gene pool.

So, through evolution, living things change.

Sometimes, that’s good for us, as when humans

understand HIV resistance in hopes of preventing

AIDS. But sometimes the changes aren’t so great

—from a human perspective, anyway—as when

bacteria become resistant to antibiotics.

Whether the consequences of evolutionary

change are good or bad, understanding the

42 National Institute of General Medical Sciences

Different nucleotides 

(in this example, A or

G) can appear in the

DNA sequence of the

same chromosome

from two different 

individuals, creating 

a single-nucleotide

polymorphism (SNP).

T C G A T A A T G C A T G C A T A

T C G A T A G T G C A T G C A T A

One Person’s DNA

Another Person’s DNA
polymorphisms (abbreviated SNPs and pronounced “snips”).

For example, let’s say that a certain nucleotide

in one of your genes is A. In your uncle, however,

the nucleotide in the same place on the same

gene might be G. You and your uncle have slightly

different versions of that gene. Scientists call the

different gene versions alleles.

If two genes sit right next to each other on a

chromosome, the SNPs in those genes tend to be

inherited together. This set of neighboring SNPs

is called a haplotype (see drawing above).

Most chromosome regions have only a few,

common haplotypes among all humans. As it

turns out, these few haplotypes—in different

combinations in each person—appear to account

for most of the variation from person to person

in a population.

process can help us develop new strategies for

fighting disease.

Clues from Variation

Scientists know quite a bit about how cells

reshuffle genetic information to create each person’s unique genome. But many details are

missing about how this genetic variation contributes to disease, making for a very active area

of research.

What scientists do know is that most of the

human genome is the same in all of us. A little

bit of genetic variation—differences that

account for much less than 1 percent of our

DNA—gives each of us a unique personality,

appearance, and health profile.

The parts of the human genome where the

DNA sequences of many individuals vary by a

single nucleotide are known as single-nucleotide

The New Genetics I Life’s Genetic Tree 43

 Haplotypes are combinations of gene variants, or

SNPs, that are likely to be

inherited together within

the same chromosomal

region. In this example, an

original haplotype (top)

evolved over time to create

three newer haplotypes

that each differ by a few

nucleotides (red). 

Original Haplotype

on Chromosome

Haplotype 1

Haplotype 2

Haplotype 3

Haplotype 4

10,000 nucleotides

T A T C A T

C A T C A T

T A T C A A

T A T C C A

C G T C A T
Scientists can use haplotype information

to compare the genes of people affected by a

disease with those of unaffected people. For

example, this approach revealed a genetic variation that substantially increases the risk of

age-related macular degeneration, the leading

cause of severe vision loss in the elderly. Scientists

discovered that a single SNP—one nucleotide in

the 3 billion-nucleotide human genome—makes

some people more likely to get this eye disease.

The discovery paves the way for better diagnostic

tests and treatments.

What about other diseases? In October 2005,

an international scientific team published a

catalog of human haplotypes. Researchers are

looking through the catalog in an effort to identify genes that determine susceptibility to many

common diseases, including asthma, diabetes,

cancer, and heart disease.

But not all SNPs are in genes. Scientists studying genetic variation have also found SNPs in

DNA that doesn’t encode proteins. Nonetheless,

some of these SNPs appear to affect gene activity.

Some researchers suspect that the “cryptic”

(hidden) variation associated with SNPs in noncoding DNA plays an important role in

determining the physical characteristics and

behaviors of an organism.

Loren Rieseberg of Indiana University in

Bloomington is one scientist who would love to

take the mystery out of cryptic variation. He

wants to know how this non-coding genetic

variation can help organisms adapt to new

environments. He’s also curious about whether

it can create problems for some individuals.

You might be surprised to learn that

Rieseberg’s principal research subject is the sunflower. Although many plants produce only one

generation a year, plants like sunflowers can be

very useful tools for researchers asking fundamental questions about genetics. Because their

genetic material is more malleable than that of

many animals, plants are excellent models for

studying how evolution works.

Wild sunflowers appealed to Rieseberg

because there are several species that live in different habitats. Two ancient species of wild

sunflowers grow in moderate climates and are

broadly distributed throughout the central and

western United States.

Three recently evolved sunflower species live

in more specialized environments: One of the

new species grows on sand dunes, another grows

44 National Institute of General Medical Sciences
But when Rieseberg looked at the genomes

of his hybrid sunflowers, he was surprised to

find that they were just cut-and-pasted versions

of the ancient sunflower species’ genomes:

large chunks had been

moved rather than many

new SNPs created.

Rieseberg reasons

that plants stash away

unused genetic material,

giving them a ready supply of

ingredients they can use to adapt

quickly to a new environment. It may be that

human genomes can recycle unused genetic

material to confront new challenges, as well.

in dry desert soil, and the third species grows in a

salt marsh.

To see how quickly new plant species could

evolve, Rieseberg forced the two ancient sunflowers to interbreed with each other, something

plants but not other organisms can do. Among

the hybrid progeny were sunflowers that were just

like the three recently evolved species! What that

means is that Rieseberg had stimulated evolution

in his lab, similar to what actually happened in

nature some 60,000 to 200,000 years ago, when

the newer species first arose.

That Rieseberg could do this is pretty amazing, but the really interesting part is how it

happened. Scientists generally assume that, for a

new species with very different characteristics to

evolve, a lot of new mutations have to occur.

The New Genetics I Life’s Genetic Tree 45

 Plants like these sunflowers

make great models for studying how evolution works.

ALISON DAVIS
Like most people, you probably think of fruit flies

as kitchen nuisances. But did you know that scientists use these organisms for medical research?

Fruit flies and other model organisms—as

different as mice, plants, and zebrafish—permit

scientists to investigate questions that would not

be possible to study in any other way. These

living systems are, relatively speaking, simple,

inexpensive, and easy to work with.

Model organisms are indispensable to science

because creatures that appear very different from

us and from each other actually have a lot in

common when it comes to body chemistry. Even

organisms that don’t have a body—mold and

yeast, for example—can give scientists clues to 

the workings of the tissues and organs of people.

This is because all living things process the

nutrients they consume into the same chemicals,

more or less. The genes for the enzymes involved

in metabolism are similar in all organisms.

Below is a sampling of the wide variety of

living laboratories that scientists are using to

advance human health. Genome sequencing projects for all of these organisms are either already

done or well under way. This means that a

genetic process discovered in a tiny, see-through

worm can be found, and studied, in people, too.

1 Escherichia coli: Bacterium

“Once we understand the biology of Escherichia

coli, we will understand the biology of an elephant.” So said Jacques Monod, a French scientist

who won the 1965 Nobel Prize in physiology or

medicine for his work on gene regulation. Monod

was an early proponent of the value of experimenting with simple organisms like bacteria. Are

all bacteria bad? If all you’ve ever heard about E.

coli is its notorious link to tainted hamburger

meat, you may not realize that non-disease-causing

strains of the bacterium live in the intestinal tracts

of humans and other animals, helping them in a

variety of ways. For one thing, these bacteria are

a main source of vitamin K and B-complex 

Living

Laboratories

1

REX L. CHISHOLM

2

46 National Institute of General Medical Sciences
NAMBOORI B. RAJU

vitamins. They also aid digestion and protect

against infection by harmful bacteria.

Scientists all over the world have banded

together to sequence different versions of the 

E. coli genome. Among other things, these studies

will help distinguish the genetic differences

between bacteria in a healthy human gut and

those that cause food poisoning.

2 Dictyostelium discoideum: Amoeba

This microscopic amoeba—100,000 of them

form a mound as big as a grain of sand—is an

important tool for health studies. Scientists have

determined that Dictyostelium discoideum (Dicty)

has somewhere between 8,000 and 10,000 genes,

many of which are close copies of those in people

and animals but are missing in another singlecelled organism, yeast. Dicty was first discovered

in the 1930s in a North Carolina forest and has

since been found in many similar habitats around

the world.

Dicty normally grows as separate, independent

cells. However, when food is limited, neighboring

cells pile on top of each other to create a large,

multicelled structure containing up to 100,000

cells. This blob ambles along like a slug, leaving

a trail of slime behind. After migrating to a more

suitable environment, the blob firms up into a

towerlike structure that disperses spores, each

capable of generating a new amoeba. Because of

its unusual properties and ability to live alone or

in a group, Dicty intrigues researchers who study

cell division, movement, and various aspects of

organ and tissue development.

3 Neurospora crassa: Bread Mold

Chances are you don’t think of a moldy bread

crust as a potential science experiment, but 

thousands of researchers around the world do!

Neurospora crassa (Neurospora), which is

a species of mold that thrives on bread, is a widely

used model organism for genetic research.

3

The New Genetics I Life’s Genetic Tree 47
5

Biologists like to use Neurospora because 

it is simple to grow and has features that make 

it very suitable for answering questions about

how species arise and adapt, as well as how cells

and tissues change their shape in different

environments. Since Neurospora produces spores

on a 24-hour cycle, the organism is also useful 

for studying the biological clocks that govern

sleep, wakefulness, and other rhythms of life.

4 Saccharomyces cerevisiae: Yeast

There are hundreds of different kinds of yeast, but

Saccharomyces cerevisiae, the one scientists study

most often, is an important part of human life

outside the lab, too. It is the yeast that bakers use

to make bread and brewers use for beer.

Like Neurospora, yeast is actually a fungus—

not a plant, not an animal, but related to both.

It is also a eukaryote (as is Neurospora)—a

“higher” organism with an organized, protective

nucleus that holds its chromosomes. Researchers

like yeast because it grows fast, is cheap to feed

and safe to handle, and its genes are easy to work

with. We know a lot about mammalian genes

because scientists can easily insert them into yeast

and then study how they work and what happens

when they don’t work.

5 Arabidopsis thaliana: Mustard Plant

Researchers who study plant growth often use

Arabidopsis thaliana (Arabidopsis), a small,

flowering plant related to cabbage and mustard.

This organism is appealing to biologists because

Arabidopsis has almost all of the same genes as

other flowering plants and has relatively little

DNA that does not encode proteins, simplifying

the study of its genes. Like people and yeast,

plants are also eukaryotes. Arabidopsis grows

quickly, going from seed to mature plant in only

6 weeks—another plus for researchers who study

how genes affect biology.

4

ALAN WHEALS

GARY DITTA

48 National Institute of General Medical Sciences
6

What do you have in common with a mustard

plant? Plant cells, and parts of plant cells, communicate with each other in much the same way

that human cells do. For that reason, plants are

good models for genetic diseases that affect

cell communication.

6 Caenorhabditis elegans: Roundworm

Caenorhabditis elegans (C. elegans) is a creature

that is a lot smaller than its name! Several of

these harmless roundworms would fit on the

head of a pin, although their usual habitat is 

dirt. In the lab, they live in petri dishes and eat 

bacteria. C. elegans contains just 959 cells,

almost a third of them forming its nervous 

system. Researchers know the fate of every one 

of these cells!

This worm is particularly prized by biologists

because it is transparent, so what goes on in its

tiny body is in plain view under a microscope.

But for such a small, simple animal, C. elegans

has a lot of genes—more than 19,000 (humans

have about 25,000). Decoding the C. elegans

genome was a huge milestone for biology, since

it was the first animal genome to be sequenced

completely. Scientists quickly learned that a vast

number of genes in C. elegans are very similar

to genes in other organisms, including people.

7 Drosophila melanogaster: Fruit Fly

The fruit fly species most commonly used for

research is named Drosophila melanogaster

(Drosophila). A geneticist’s fruit fly is pretty

much the same as the ones that fly around your

overripe bananas. In the lab, though, some of

the flies are exposed to damaging chemicals or 

radiation, which changes the sequence of their

DNA. Researchers allow the flies to mate, then

search among the offspring for flies with 

abnormalities. The mutant flies are then mated 

to produce more offspring with the abnormality,

enabling researchers to close in on the defective

genes involved.

7

The New Genetics I Life’s Genetic Tree 49
Fruit flies have been a favorite experimental

organism among geneticists since early in the

20th century. Hundreds of them can live in a

pint-sized milk bottle or even a small vial, and

they reproduce so quickly that keeping track of a

particular gene as it passes through a couple of

Drosophila generations takes only about a

month. It’s also relatively easy to create flies with

mutations in many genes, enabling scientists to

study how the genes work together.

8 Danio rerio: Zebrafish

Zebrafish were originally found in slow streams,

rice paddies, and the Ganges River in East India

and Burma. They can also be found in most pet

stores and are a home aquarium favorite.

Although the fish have been used by some

geneticists for research since the early 1970s, in

recent years they have become an especially 

popular model organism.

Many researchers are drawn to zebrafish

because their eggs and embryos are transparent,

making it possible to watch development unfold.

In a span of 2 to 4 days, zebrafish cells split and

form different parts of the baby fish’s body: eyes,

heart, liver, stomach, and so on. Sometimes,

researchers will move a cell to another spot to see

if it will still go on to form the same part of the

body or if it will do something different. This

research has taught scientists about a range of

health-related matters in people, including birth

defects and the proper development of blood, the

heart, and the inner ear.

9 Mus musculus: Mouse

The branches of life’s genetic tree that led eventually to mice and to human beings split off from

each other 75 million years ago, back in the

dinosaur age. But we are both mammals, and we

share 85 percent of our genes. Because some

mouse diseases are very similar—sometimes

9

8

MONTE WESTERFIELD

50 National Institute of General Medical Sciences
identical—to human diseases, mice are 

exceptionally valuable for research.

Since the late 1980s, researchers have been 

able to engineer mice with missing genes.

Scientists make these “knockout” mice to learn

what goes wrong when a particular gene is

removed. This gives them valuable clues about 

the gene’s normal function. Identifying these

genes in humans has helped define the molecular

basis for many illnesses.

10 Rattus norvegicus: Rat

The Norway rat, or lab rat, was the first animal

domesticated for use in scientific research.

Currently, they make up about one-fourth of all

research animals in the United States. Lab rats have

been used for many decades for testing drugs, and

much of what we know about cancer-causing 

molecules was learned in basic research with rats.

10

Although rats are mammals just like mice,

they differ in important ways. Rats are much 

bigger than mice, making it easier for scientists 

to do experiments that involve the brain. For 

example, rats have taught scientists a lot about

substance abuse and addiction, learning, memory,

and certain neurological diseases. Rats are also

much better models than mice for studying

asthma and lung injury. And since, in people, the

disease arthritis is more common in women,

studying rats makes more sense because female

rats appear to be more susceptible to than male

rats. The opposite is true with mice.

This Living Laboratories section is 

available as a poster. To order a free copy,

visit http://www.nigms.nih.gov/classroom

The New Genetics I Life’s Genetic Tree 51
The Genome Zoo

Scientists often use an image of a tree to depict

how all organisms, living and extinct, are related

to a common ancestor. In this “tree of life,” each

branch represents a species, and the forks between

branches show when the species represented by

those branches became different from one another.

For example, researchers estimate that the common ancestor of humans and chimpanzees lived

about 6 million years ago.

While it is obvious just by looking that people

have a lot in common with our closest living relatives, chimpanzees, what about more distant

species? If you look at an evolutionary tree, you’ll

see that humans are related to mice, worms, and

even bacteria. The ancestral species that gave rise

to both humans and bacteria was alive a lot

longer ago than the ancestor of humans and

chimpanzees, yet we still share hundreds of genes

with bacteria.

Scientists use the term comparative genomics

to describe what they’re doing when they compare the genomes of different species to see how

similar (or how different!) the species’ DNA

sequences are. Sequences that the species have in

common are the molecular footprints of an

ancestor of those species.

Why are “old” DNA sequences still in our

genomes? It turns out that nature is quite economical, so DNA sequences that are responsible

for something as complicated and important as

controlling gene activity may stay intact for

millions of years.

Comparative genomic studies also have medical implications. What would you do if you

wanted to develop new methods of preventing,

diagnosing, or treating a human disease that

animals don’t get?

52 National Institute of General Medical Sciences

just what it is that gives stem cells their ability

to change into anything, upon the body’s

request, but stay in the “I can do anything” 

state until asked.

Some basic researchers are trying to figure out

how stem cells work by using a unique model

system: tiny, freshwater worms called planarians.

These worms are like stem cells in the sense that

they can regenerate. You can cut up planarians

into hundreds of pieces, and each piece will

regenerate into an intact worm that looks the

same as all the others. 

Stem cells—what embryos

are made up of just days

after an egg is fertilized by a

sperm—have the amazing

ability to grow up into any

kind of cell: skin, heart,

muscle, nerve, and everything else. How do they 

do it?

Intrigued by the potential

of these masterful cells,

researchers want to know

Starting All Over Again

PHILLIP NEWMARK
If people have a gene that influences their risk

for a disease, and mice have the gene too, you

could study some aspect of the disease in mice,

even though they don’t ever have the symptoms

of the disease. You could even study the disease

in yeast, if it has the gene, as well.

Genes Meet Environment

If toxins from the environment get into our 

bodies, they don’t always make us sick. That’s

because liver enzymes come to our rescue to

make the chemicals less harmful. The genes that

encode those enzymes are under constant evolutionary pressure to adapt quickly to new toxins.

For example, certain liver enzymes called

cytochrome P450 proteins metabolize, or break

down, hormones that our bodies make as well as

many of the foreign substances that we encounter.

These include harmful molecules like cancercausing agents as well as beneficial ones, like

medicines. In fact, just two genes within the

cytochrome P450 family, abbreviated 3A4 and

3A5, encode proteins that process more than half

of all of the medicines that are sold today.

Since the chemicals to which people are

exposed vary so widely, a scientist might

predict that there would be different variants

of cytochrome P450 genes in different human

populations. Using comparative genomics,

researchers such as Anna Di Rienzo of the

University of Chicago have shown that this is

indeed the case. Di Rienzo has found many

sequence differences within these genes in people

living throughout the world.

It turns out that one variant of the gene that

encodes the cytochrome P450 3A5 protein makes

this enzyme very efficient at breaking down

cortisol, a hormone that raises salt levels in the

kidneys and helps the body retain water. Di Rienzo

compared the DNA sequences of the 3A5 gene in

DNA samples taken from more than 1,000 people

representing over 50 populations worldwide. She

Planarians’ resemblance to stem cells isn’t just

coincidence. Scientists have discovered that

planarians can perform the amazing act of regeneration due to the presence of, yes, specialized

stem cells in their bodies.

Developmental biologist Alejandro Sánchez

Alvarado of the University of Utah School of

Medicine in Salt Lake City used the gene-silencing technique RNAi (see page 28) to search for

planarian genes that were essential for regeneration. He found 240 genes that, when silenced,

caused a physical defect in the worm’s growth

and regenerative ability. Interestingly, 16 percent of

these looked very much like genes that had been

linked to human disease!

Sánchez Alvarado and his team hope to figure

out how regeneration genes allow the specialized

stem cells within the worm to travel to a wounded

site and “turn into” any of the 30 or so cell types

needed to recreate a mature worm.

Although humans are only distantly related to

planarians, we have many of the same genes, so

these findings have the potential to reveal strategies

for regenerating injured body parts in people, too.

The New Genetics I Life’s Genetic Tree 53
54 National Institute of General Medical Sciences

was amazed to find a striking link between the

existence of the gene variant and the geographic

locale of the people who have it.

Di Rienzo discovered that African populations

living very close to the equator were more likely

than other populations to have the salt-saving

version of the 3A5 gene. She suggests that this is

because this gene variant provides a health

advantage for people living in a very hot climate,

since retaining salt helps ward off dehydration

caused by intense heat.

However, there seems to be a cost associated

with that benefit—the 3A5 gene variant raises

the risk for some types of high blood pressure.

That means that in environments in which

retaining salt is not beneficial, evolution selects

against this gene variant.

Another scientist who studies interactions

between genes and the environment is Serrine

Lau of the University of Arizona in Tucson. She

studies a class of harmful molecules called

polyphenols, present in cigarette smoke and car

exhaust, that cause kidney cancer in rats, and

perhaps, in people.

Lau discovered that rats and humans who

are more sensitive to some of the breakdown

products of polyphenols have an unusual DNA

sequence — a genetic signature—that increases

their risk of developing cancer. She suspects that

the gene that is affected encodes a tumor suppressor: a protein that prevents cancer from

developing. In people and rats with the genetic

signature, she reasons, the tumor suppressor

doesn’t work right, so tumors grow.

Taking this logic one step further, it may be

that certain people’s genetic make-up makes

them unusually susceptible to DNA damage

caused by exposure to carcinogens. If doctors

could identify those at risk, Lau says, such people

could be forewarned to avoid contact with specific chemicals to protect their health.

 Scientists have discovered that some African populations near the equator have evolved a genetic

variant that helps the body conserve water.
However, think about this scenario: Who

should make those decisions? For example,

would it be ethical for an employer to refuse to

hire somebody because the person has a genetic

signature that makes him or her more likely to

get cancer if exposed to a chemical used in the

workplace? Tough question.

Kidneys

Liver

 The liver and kidneys are 

susceptible to damage from

toxins since these body

organs process chemicals.

The New Genetics I Life’s Genetic Tree 55
GENETICS AND YOU: You’ve Got Rhythm!

What do waking, sleeping, 

eating, reproducing, and

birds flying south for the

winter have in common? These are all

examples of nature’s amazing sense of

rhythm. All living things are equipped

with molecular timepieces that set the

pulse of life. 

If you’ve ever crossed the country or

an ocean by plane, you know about the

importance of these clocks. You probably

experienced that traveler’s misery called

jet lag, where the body is forced to adapt

quickly to a new time zone.

But did you know that certain forms

of insomnia and manic-depressive illness

are associated with biological clocks

not working properly? And biological

rhythms may be the reason why some

medicines and surgical treatments

appear to work best at certain times 

of day. 

The human body keeps time with 

a master clock called the suprachiasmatic

nucleus or SCN. Situated inside the brain,

it’s a tiny sliver of tissue about the size of a

grain of rice, located behind the eyes. It sits

quite close to the optic nerve, which controls vision, and this means that the SCN

“clock” can keep track of day and night.

Given enough time, your SCN can reset

itself after you fly in an airplane from one

time zone to another.

The SCN helps control sleep by coordinating the actions of billions of miniature

“clocks” throughout the body. These aren’t

actually clocks, but rather are ensembles of

genes inside clusters of cells that switch on

and off in a regular, 24-hour cycle—our 

physiological day.

Scientists call this 24-hour oscillation 

a circadian rhythm. (“Circadian” comes from

the Latin words meaning “approximately 

a day.”) Researchers have discovered that 

all living things—plants, animals, and bacteria—have circadian rhythms. Many

researchers working with insect and other

model systems have identified genes that

are critical for keeping biological time. 

Understanding circadian rhythms will help

scientists better understand sleep disorders. 

If we have the opportunity, most of us sleep 

7 or 8 hours at night, and if we don’t get

enough rest we may have a hard time getting

things done the next day. Some people, 

Light

Suprachiasmatic

Nucleus (SCN)

Output Rhythms:

Physiology

Behavior

56 National Institute of General Medical Sciences
however, routinely get by with only 3 to

4 hours of sleep. Researchers have noted

that this trait seems to run in families,

suggesting a genetic link.

As it turns out, fruit flies need even

more sleep than people. Neuroscientist

Chiara Cirelli of the University of

Wisconsin-Madison did a genetic search

for fruit fly mutants that don’t sleep

much. She discovered that flies with a

variant of a gene called shaker sleep 

only 3 to 4 hours per night.

Although the shaker flies don’t

appear sleep-deprived, Cirelli found that

they have a different problem: They

don’t live as long as flies without the

mutation. She is now studying this new

connection between sleep and lifespan.

Her work may also pave the way for

improved sleep aids and effective

remedies for jet lag.

The New Genetics I Life’s Genetic Tree 57
Animals Helping People

Using technology that grew out of the Human

Genome Project, scientists have read the

sequences of the genomes of hundreds of organisms: dogs, mice, rats, chickens, honeybees, fruit

flies, sea urchins, puffer fish, sea squirts, roundworms, several fungi, and many disease-causing

bacteria. Next in line are dozens of additional

species including marmosets, skates, tree shrews,

sloths, and zebra finches!

What effect will all this gene sequence information have on medical research? We’ve already

talked about the fact that people share many of

their genes with other species. This means that

when scientists read the sequence of another

species’ genome, they’re likely to discover that the

organism has many of the genes that, in humans,

cause disease or raise disease risk when mutated.

Take fruit flies as one example. According to

biologist Ethan Bier of the University of California,

San Diego, 30 percent of the currently identified

human disease genes most likely have functional

counterparts in none other than Drosophila

58 National Institute of General Medical Sciences

melanogaster, a fruit fly species widely used 

in genetic research (see Living Laboratories,

page 49).

Currently, Bier and other scientists are using

experimental flies to investigate a wide range of

genes involved in conditions such as blindness,

deafness, mental retardation, heart disease, and

the way in which bacterial toxins cause illness.

By reading the DNA sequences of many other

species, researchers hope to find model systems

that are even better than fruit flies for studying

some aspects of human disease.

Sometimes, the genes that we don’t have in

common with other species are as important as

the genes we share. For example, consider the fact

that humans and chimpanzees have remarkably

different abilities and physical features. But the

chimpanzee genome is 99 percent identical to

our own.

And did you know that chimpanzees don’t

get malaria or AIDS?

So about 1 percent of our genome determines

whether we look and behave like a person or a

chimp, and whether we are susceptible to malaria

or AIDS.

My Collaborator Is a Computer

We’ve made the case that comparing genomes

can offer fresh insight on the basic genetic ingredients for health and the causes of disease. But

what does a scientist actually do when he or she

compares gene sequences? Does this mean staring

at thousands of pages of genetic letters, looking

for those that are the same or different?
things, the programs can figure out where in

the DNA sequences a gene starts and stops:

its “boundaries.”

Other researchers who work in the field of

bioinformatics mine genomic information hidden in the masses of data. They are looking for

scientific treasure in the form of new biological

knowledge. These experiments can zero in on previously hidden patterns and reveal links between

different fields of research.

Bioinformaticists and computational biologists are in high demand because they play a very

important role in 21st-century medical science.

These scientists must be fluent in both computer

science and biology.

Yes and no. Comparative genomics does

involve looking for similarities and differences,

but it isn’t something that scientists do by hand.

Certainly not for thousands of genes at a time.

Rather, the gigantic task of comparing the

nucleotides that make up the genomes of two or

more species is the perfect job for a computer, a

natural multitasker. If you consider that the

human genome contains 3 billion nucleotides,

you can easily see why this is work well suited to

a machine (with a human operator, of course).

Researchers called computational biologists

help analyze genomic data. These scientists

develop software programs that enable computers

to perform genome comparisons. Among other

The New Genetics I Life’s Genetic Tree 59

 Computers are 

an essential tool 

for scientists who

store and analyze

huge amounts of

genomic data.
60 National Institute of General Medical Sciences

You might be amazed to learn that a microbe that

lives in a boiling hot spring in Yellowstone

National Park is the essential ingredient for one

of the most important biological research tools

ever invented.

Thermus aquaticus is a bacterium that makes

a heat-resistant enzyme, which is why it can thrive

in hot springs. The enzyme, Taq polymerase, is

essential to a laboratory technique called the

polymerase chain reaction, or PCR. And PCR

is essential to lots of things that life scientists

do—and to many other fields, too. PCR’s inventor, Kary Mullis, won the 1993 Nobel Prize in

chemistry.

PCR is a quick, easy method for generating

unlimited copies of tiny amounts of DNA. Words

The Tools of Genetics: Unlimited DNA

 A microbe that lives in hot springs, like this one in

Yellowstone National Park, is home to the enzyme

that makes the polymerase chain reaction, or

PCR, possible.
like “revolutionary” and

“breakthrough” are

not an exaggeration of its impact.

PCR is at the heart of modern DNA sequencing methods. It is essential for pinpointing

mutations in genes, so it is the basis for much of

the research discussed in this booklet. PCR has

done for genetic material what the invention of

the printing press did for written material. It

makes copying easy, inexpensive, and widely

available.

PCR underlies many diagnostic techniques,

like testing individuals for genes that cause

breast cancer. It can also help diagnose diseases

other than cancer, such as infections by HIV

and hepatitis C.

PCR is a key element of “genetic fingerprinting,” which has helped free prisoners

who relied on it to prove that they were innocent of the crimes that got them locked up.

Conversely, it has provided scientific evidence

that helped convict criminals.

PCR has even revolutionized archaeology

by helping to analyze badly damaged ancient

DNA—sometimes thousands of years

old—which can reveal new information

about past people and cultures.

Scientists predict that future uses of PCR

technology will enhance medical treatment,

enabling better diagnosis and more accurate

subtyping of disease.

 PCR machine.

APPLIED BIOSYSTEMS

Discuss reasons why research

studies with identical twins

can provide valuable information about health and disease.

Humans and mice share over

80 percent of the same

genetic material: for chimps

and humans, it’s more than 99

percent. Why are people and

animals so different, if their

genes are so similar?

You are a scientist and you

want to learn more about how

humans age. Is there a way

you can address your

research question without

spending many decades

studying people?

Can you think of an experiment using fruit flies that

could help researchers better

understand jet lag?

Got It?
or science, the sequencing of the human

genome was a groundbreaking achievement,

one that made a lot of news. But what does it

actually mean? Will any of this information make

a difference in your life?

A genome is all of the genetic material that an

individual (or a species) has. The human genome

differs from the gorilla genome, which differs

from the rice genome, and so on. And while every

person has a “human genome,” it is not exactly

the same in all people. Sequence variations

within your genes makes your DNA different

from that of your mother, your cousin, or a 

complete stranger.

Think of the human genome as a long story

that contains roughly 25,000 words (the genes).

With few exceptions, each person has the same

number of words, but certain words have slightly

different spellings. In some cases, the spelling

changes create words with new meanings—

genes that code for different proteins. Other

spelling changes appear to have no effect

whatsoever, at least not ones that today’s scientists know how to measure.

Researchers are beginning to use knowledge

learned from genome sequencing research to

figure out how being healthy and being sick are

different at the level of molecules. And doctors

are starting to use genetic information to make

treatment choices.

For example, a diagnostic test can search for

differences in the level of expression of a particular gene in breast cancer cells and predict whether

a person will respond to a drug called Herceptin®.

The cancerous cells of some people who have

breast cancer make an abundance of “HER2”

proteins that are targeted by Herceptin. For those

people, Herceptin is a miracle drug because it

Genes Are Us

CHAPTER 4

F

In April 2003, researchers across the world celebrated a milestone and an anniversary. Almost 50

years to the day after James Watson, Francis Crick,

and Maurice Wilkins unveiled their Nobel Prizewinning description of the DNA double helix,

scientists completed the sequencing of the human

genome, a momentous achievement in biology.

The day was long in coming. In the 1980s,

geneticists realized that they had both the need

and the ability to learn the complete layout of the

human genome. They wanted to map the location

of every gene within chromosomes and decipher

the complete, letter-by-letter sequence of the

genome’s 3 billion nucleotides.

Reading the Book of Human Genes

 Many DNA sequencing centers joined efforts to

form the Human Genome Project, completed in

2003. Now the centers, like this one at the Broad

Institute of MIT and Harvard University in

Cambridge, Massachusetts, are working to better

understand the human genome and to sequence

the genomes of other organisms.

L. BARRY HETHERINGTON
reduces the risk that their breast cancer will come

back, and it also decreases their odds of dying

from the disease.

For cancer patients whose tumor genes do

not express HER2, Herceptin won’t do a thing,

The New Genetics I Genes Are Us 63

With that information in hand, scientists 

reasoned, it would eventually be possible to

learn exactly what job each gene performs as

well as how genes contribute to human health

and disease.

Soon, thousands of scientists in labs all over the

world got into the act. Critical to their success

were new tools and technologies that made the

work go faster and helped the researchers manage and analyze the flood of data.

Although the Human Genome Project is done,

related gene sequencing efforts continue. One

involves sequencing the genomes of many other

species (see page 58).

Another is the international HapMap Project,

the first stage of which

was completed in October

2005. Short for Haplotype

Map, this project’s goal is

to describe the common

patterns of genetic variation in humans. The plan

is to figure out which differences may be linked to disease risk and other

health-related traits, such as individual reactions

to medicines and environmental chemicals.

though, so it shouldn’t be prescribed. Research is

proceeding quickly to develop other genetic tests

that may help diagnose and treat a wide range of

health problems beyond cancer.
Individualized Prescriptions

One way variations in our genes make a difference in our health is by affecting how our bodies

react to medicines. The unsettling truth is that

medicines work as expected in fewer than half of

the people who take them.

While environmental and lifestyle factors

can explain some of this, a good part of the

individual variability in response to medicines

can be attributed to variants in the genes that

make cytochrome P450 proteins (see page 53).

These proteins process many of the drugs 

we take.

Because each person’s set of genes is a little

different, the proteins that the genes encode are

also slightly different. These changes can affect

how the cytochrome P450 proteins (and many

other types of proteins) work on drugs.

Doctors first realized this in the 1950s,

when some patients had bad—sometimes fatal—

reactions to an anesthetic medicine used in surgery.

Experiments revealed that those who reacted

poorly had a genetic variation in the enzyme that

breaks down and disposes of the anesthetic after

it’s been in the body for a while.

People whose genes encode the variant enzyme

had no trouble at all until they needed surgery that

required general anesthesia. In the operating room,

a normal human genetic variation suddenly led to

a medical crisis!

Fortunately, this type of serious reaction to

an anesthetic is very rare. But many reactions to

medicines aren’t so unusual. Researchers know

that genetic variations can cause some common

medicines to have dangerous side effects. For

example, some people who take the colon cancer

drug Camptosar® (also known as irinotecan) can

develop diarrhea and a life-threatening infection

if they have a variant form of the gene for the

protein that metabolizes Camptosar.

Genetic variations can also cause drugs to

have little effect at all. For example, in some people,

pain medicines containing codeine, like Tylenol®

with Codeine Elixir, offer no relief because their

bodies break it down in an unusual way.

64 National Institute of General Medical Sciences

 Did you know that medicines work like they’re

supposed to in fewer than half of the people who

take them? Genetic differences among people

are one reason.
common childhood cancer. The remaining 20

percent are at risk of the cancer coming back.

Mary Relling, a research clinical pharmacist

at St. Jude Children’s Research Hospital in

Memphis, Tennessee, discovered that variations

in two genes can predict which patients with

acute lymphoblastic leukemia are likely to be

cured by chemotherapy. Her research team also

identified more than 100 genes expressed only in

cancer cells that can be used to predict resistance

to chemotherapy drugs.

By taking patient and cancer cell genetic profiles into account, Relling says, researchers can

develop more effective treatments for the disease.

The use of genetic information to predict

how people will respond to medicines is called

pharmacogenetics. The ultimate goal of this field

of study is to customize treatments based on an

individual’s genes.

With this kind of approach, every patient

won’t be treated the same, because doctors will

have the molecular tools to know ahead of time

which drug, and how much of it, to prescribe—

or whether to prescribe it at all.

The Healing Power of DNA 

Pharmacogenetics is advancing quickly since scientists have a lot of new information from the

Human Genome Project and new computer tools

that help them analyze the information. One disease for which progress has been rapid is cancer.

Consider the fact that cancer is often treated

with a chemotherapy “cocktail,” a combination

of several different medicines. Each of the drugs

in the mixture interacts with different proteins

that control how well that particular drug works

and how quickly it is metabolized in the body.

What’s more, each drug may have its own set of

unpleasant—even potentially life-threatening—

side effects.

For these reasons, individually targeted, genebased prescriptions for chemotherapy may offer

a real benefit to people with cancer.

Currently, chemotherapy cures about 80 percent of the children who have been diagnosed

with acute lymphoblastic leukemia, the most

The New Genetics I Genes Are Us 65

 Pharmacogenetic researchers have discovered

that a gene test can predict which children with

acute lymphoblastic leukemia will be cured by

chemotherapy. 
Other pharmacogenetic scientists are

studying the effects of

gene variants on patients’ responses to drugs used

to treat AIDS, allergies, infections, asthma, heart

disorders, and many other conditions.

For example, researchers recently identified

two different genetic variants that play a central

role in determining the body’s response to

Coumadin® (also known as warfarin), a widely

prescribed medicine given to people who are at

risk for blood clots or heart attacks. Although 

2 million Americans take this blood-thinning

drug every day, it is very difficult to administer,

since its effects vary widely in different people

who are taking the same dose. Giving the right

dose is essential, because too much Coumadin

can cause excessive bleeding, while too little can

allow blood clots to form.

Allan Rettie, a medicinal chemist at the

University of Washington in Seattle, discovered

that genetic variation among people influences

the activity of a protein in the blood that is

Coumadin’s molecular target. He and other scientists are now trying to translate these findings

into a genetic test that could help doctors predict

what dose of Coumadin is appropriate based on

each patient’s DNA profile.

66 National Institute of General Medical Sciences

This characteristic makes them a perfect species

in which to study the genetics of behavior.

What’s particularly interesting about bees is

that rather than being stuck in a particular job,

they change jobs according to the hive’s needs.

Robinson has identified certain genes whose

activity changes during a job shift, suggesting

that the insects’ environment helps to shape their

gene expression.

Researchers who are beginning to understand

these connections are working in a brand-new

field of investigation named by Robinson himself:

sociogenomics.

What does all of this mean for humans, you

wonder? It underscores the fact that, far from

being set in stone, our genomes are influenced

by both heredity and environment, fine-tuned and

sculpted by our social life and the things we do

every day.

Did you know that, in addition to

traits you can see like hair color

and physique, genes also contribute to how we behave? It may

come as a surprise that many

researchers are answering basic

questions about the genetics of

behavior by studying insects.

For example, Gene Robinson,

an entomologist at the University

of Illinois at Urbana-Champaign,

works with honeybees. Robinson says that if you

look at honeybees in their natural hive environment, you’ll quickly see that they are very

outgoing. In fact, according to Robinson, honeybees can’t survive without the social structure of

their community within the hive.

Genes Can Do That?

 Honeybees are social

animals and they work

together to keep their

hive healthy. The forager

bee (on the left) is about

a month old and hunts

for food. The 14-day-old

undertaker bee (on the

right) removes dead bees

from the hive.

Genetic variation 

produces different

individual responses to

the blood-thinning drug

Coumadin®. A genetic

test could lead to more

accurate doses.

ZACHARY HUANG, HTTP://CYBERBEE.MSU.EDU 
disease, diabetes, or particular types of cancer

“run in your family,” especially if a lot of your

relatives get the condition when they are fairly

young, you may want to talk with your doctor

about your own risk for developing the disease.

In 2005, the U.S. Surgeon General developed

a Web-based tool for organizing family health

information. Called “My Family Health Portrait”

(see http://www.hhs.gov/familyhistory/), this tool

arranges information into a printout that you can

carry to the doctor’s office. The information can

help you and your doctor determine your risks

for various conditions.

If you do discover that you are at higher-thanusual risk for a disease like breast cancer or heart

disease, you may be able to prevent the disease, or

delay its onset, by altering your diet, exercising

more, or making other lifestyle changes. You may

also be able to take advantage of screening tests

like mammograms (breast X rays that detect signs

of cancer), colonoscopies (imaging tests for colon

cancer), or blood sugar tests for diabetes.

Screening tests can catch diseases early, when

treatment is most successful.

Cause and Effect

What more do we need to know about how 

genes shape who we are and what we become?

“A lot,” says Harvard’s Richard Lewontin, who

warned against oversimplifying the role of genes

in health in his 2001 book, The Triple Helix.

Lewontin’s main point is that context plays an

enormous role in determining how organisms

grow and develop, and what diseases they get.

A unique combination of genetic and environmental factors, which interact in a way that is very hard

to predict, determines what each person is like.

Very few, if any, scientists would argue with

this. Whether a gene is expressed, and even

whether the mRNA transcript gets translated

into a protein, depends on the environment.

Few diseases—most of which are very rare—are

caused completely by a mutated gene.

In most cases, getting or avoiding a disease

depends not just on genes but on things within

your control, such as diet, exercise, and whether

or not you smoke.

It will be many years before scientists clearly

understand the detailed meaning of our DNA

language and how it interacts with the environment in which we live. Still, it’s a great idea to

find out as much as you can about your family’s

health history. Did any of your relatives have diabetes? Do people in your family tree have cancer

or heart disease?

Keep in mind that diseases such as these are

relatively common, so it’s pretty likely that at least

one relative will have one of them. But if heart

The New Genetics I Genes Are Us 67

 Knowing about diseases

that run in your family can

help you guard against

illness in the future.
Us vs. Them

Many scientists focus on human genes, most of

which have counterparts in the genomes of

model organisms. However, in the case of infections caused by microorganisms, understanding

how the genomes of bacteria, viruses, and parasites differ from ours is a very important area of

health research.

Most of the medicines we take to treat infections by bacteria and viruses have come from

scientists’ search for molecular weak points in

these tiny organisms. As mentioned in Chapter 1,

for example, some antibiotics kill bacteria by

disarming their protein-making ribosomes.

So why don’t they kill human cells, too? The

answer is that human and bacterial ribosomes are

different. Genome sequencing is a powerful tool

for identifying differences that might be promising targets for new drugs.

Comparing genetic sequences in organisms

that are resistant and non-resistant to drugs can

reveal new approaches to fighting resistance.

Drug resistance is a worldwide problem for a

number of diseases, including malaria.

Although researchers have developed several

different types of medicines to treat this

disease—caused by parasites carried by mosquitoes, not by a bacterium or a virus—malaria is

rampant, especially in the developing world.

68 National Institute of General Medical Sciences

Resistance to antimalarial

drugs like chloroquine is

widespread throughout

much of Africa and other

parts of the developing

world where malaria

transmission is high.

WHO/UNICEF. WORLD MALARIA 

REPORT 2005, GENEVA, MAY 3, 2005 

Areas where malaria transmission occurs (high/low)

Chloroquine resistance
GENETICS AND YOU: Eat Less, Live Longer?

Would you consume an extremely low-calorie diet if itmeant you would live longer?

The kind of diet we’re talking about

isn’t just cutting back here and there. It

involves severely reducing calorie intake

to about 60 percent of what we normally eat, enough to make most people

ravenously hungry.

A 19th-century French doctor,

Maurice Gueniot, thought the tradeoff

would be worth it. Throughout his adult

life, he ate very little. He died at the ripe

old age of 102!

Later, in the 1930s, researchers

followed up on this observation by

showing that rats on a diet containing

20 percent indigestible fiber—calories

that can’t be used—lived much longer

than their normally fed peers.

Intrigued by the health connection,

scientists are continuing to investigate

potential links between diet and aging,

and genetic studies are starting to turn

up some clues.

For example, geneticist David Sinclair

of Harvard Medical School has found that

proteins known as sirtuins may be able to

stall aging. As yeast cells age, they accumulate extra DNA, which eventually kills

them. Sinclair discovered that sirtuins

become more active in yeast cells that

are on a low-nutrient “diet.” He reasons

that by restricting the 

formation of extra DNA,

sirtuins keep the yeast

young.

Not so fast, say other

scientists like geneticist

Stanley Fields of the

University of Washington. His experiments

have turned up other, unrelated genes

linked to lifespan in yeast. He argues that

while calorie restriction is the only intervention that has been shown to extend

lifespan in a wide range of organisms,

including mammals, the accumulation of

extra DNA does not always appear to play

a role in this process.

What’s the final answer, you ask? It’s

probably a bit of both.

Molecules like sirtuins, which are

involved in cellular metabolism, may protect cells against the harmful effects of

stress, extending lifespan. Other molecules that affect different aspects of cell

health may be just as important.

Lifespan in complex, multicellular

organisms like people is affected by many

different factors, most of which we know

very little about. For sure, understanding

more about these mystery molecules

could have a considerable benefit—

perhaps providing you a chance to add

years to your life without starving!

The New Genetics I Genes Are Us 69
This is partly

because not all people

have access to treatment, or to simple

preventive measures like

bed nets, which protect

sleeping people from

mosquito bites. But

another problem is the

malaria parasite itself, which has rapidly evolved

ways to avoid the effects of antimalarial drugs.

Scientists are trying to counter this process by

studying microbial genetic information. In the

case of malaria, geneticists like Dyann Wirth of

the Harvard School of Public Health compare the

genomes of drug-resistant parasites and those

that can still be killed by antimalarial medicines.

Wirth’s research suggests that it should be

possible to develop a simple, inexpensive genetic

test that could be given to people with malaria,

anywhere in the world. This test would identify

drugs that are likely to be most effective

and help decrease the rate at which 

parasites become resistant to the antimalarial medicines we already have.

Gang Warfare

Did you know that scientists are using genetics to

break up gangs ... of microbes, that is? These

gangs, known as biofilms, are layers of slime that

develop naturally when bacteria congregate on

surfaces like stone, metal, and wood. Or on your

teeth: yuck!

Biofilms grow in all sorts of conditions. For

example, one biofilm known as “desert varnish”

thrives on rocks, canyon walls, or, sometimes,

entire mountain ranges, leaving a reddish or

other-colored stain. It is thought that petroglyphs

left on boulders and cave walls by early desert

dwellers were often formed by scraping through

the coating of desert varnish formations with a

hard object.

Sometimes, biofilms perform helpful functions. One of the best examples of the use of

biofilms to solve an important problem is in the

cleaning of wastewater.

70 National Institute of General Medical Sciences

Biofilms, like the one shown in this 

fluorescent microscopic photo, are 

bacterial communities. 

P. SINGH AND E. PETER GREENBERG

 Mosquitoes spread

malaria by picking up

parasites from blood and

spreading them to the

next person they bite.

Resistance spreads this

way, too.

CDC/ JAMES GATHANY
goal of being able to use this knowledge to break

up bacterial “gang meetings.”

Bassler’s research subjects have a definite

visual appeal. They glow in the dark, but only

when they are part of a group. The bioluminescence, as the glow is called, arises from chemical

reactions taking place within the biofilm. It provides a way for the bacteria to talk to each other,

estimate the population size of their community,

and distinguish themselves from other types of

microorganisms.

Through her studies, Bassler has identified a

set of molecules that biofilm-forming microorganisms use to pass messages to each other. By

devising genetically based methods to cut off

the chatter, Bassler reasons, she may be able to

cause bacterial communities to fall apart. This

approach would provide a whole new way to treat

health problems linked to harmful biofilms.

But biofilms can be quite harmful, contributing to a wide range of serious health

problems including cholera, tuberculosis, cystic

fibrosis, and food poisoning. They also underlie

many conditions that are not life-threatening

but are nonetheless troublesome, like tooth

decay and ear infections.

Bacteria form biofilms as a survival measure.

By living in big groups rather than in isolation,

the organisms are able to share nutrients and

conserve energy. How do they do it?

A biofilm is not just a loose clump of cells—

it’s a highly sophisticated structure. As in any

community, the individuals in biofilms communicate with each other.

Beyond that, many aspects of biofilms are

poorly understood. Bacterial geneticist Bonnie

Bassler of Princeton University in New Jersey is

working to understand biofilms better, with the

The New Genetics I Genes Are Us 71

 Bonnie Bassler (right)

uses glow-in-the dark 

bacteria to study

the genetics of biofilms.

DENISE APPLEWHITE
What if public health officials had a script for

what to do in the face of an infectious disease

outbreak that had never been seen before? One

thing that would help them prepare for this sort

of scenario is the ability to know, ahead of time,

how an epidemic develops and spreads.

Toward this goal, some scientists are using

mathematical tools to create simulations, or

models, of infectious disease outbreaks. They

can then use the models to test the effects of

various intervention strategies. Part of the work

involves plugging in genetic information about

how infectious organisms evolve over time and

how fast they change as they interact with human

populations.

In 2005, the Models of Infectious Disease

Agent Study (MIDAS), a team of biologists,

computer scientists, statisticians, mathematicians,

social scientists, and others, set out to model an

epidemic of avian influenza, or “bird flu.” This

disease occurs naturally among wild birds, which

carry the viruses in their intestines but don’t

always get sick from them.

However, health experts worldwide became

worried as cases of human infection with bird

flu viruses began to appear. While the bird virus

isn’t transmitted easily from one person to

another, there’s a risk that the virus’ genetic material could mutate inside the body of an infected

person. These changes could make it much easier

for the virus to pass between humans, a key

ingredient for an influenza pandemic—a huge,

global epidemic.

The MIDAS team, whose leaders include

computational biologist Neil M. Ferguson of

Imperial College in London and biostatistician

Ira M. Longini, Jr., of the University of

Washington, simulated what might happen if the

original, deadly strain of bird flu virus mutated

and started to spread from person to person.

The Tools of Genetics: Mathematics and Medicine

72 National Institute of General Medical Sciences

 Computer simulations are helping scientists understand how infectious

diseases spread. 
The scientists first created hypothetical

communities in Southeast Asia, where human

cases of bird flu first appeared, and then wrote

computer programs that took into account the

potential infectiousness of the bird flu virus, population densities, and the locations of schools,

hospitals, and other community structures. The

models indicated that to successfully contain an

epidemic, health officials would need to find the

first flu cases early and implement a combination

of public health measures very fast.

Next, using data from the 2000 U.S. Census

and the U.S. Department of Transportation,

the researchers developed a model of pandemic

flu spread based on the demographics and travel

patterns of 281 million people living in the

United States.

The U.S. models showed that outcomes

varied depending on the contagiousness of

the virus. When the simulated virus was less

contagious, three effective single measures

included antiviral treatment, school closures,

and vaccinating 10 million people per week

with one dose of a poorly matched vaccine.

When the virus was highly contagious, however, the models predicted that all singleintervention strategies would leave nearly half

the population infected, but that combination

approaches could slow the spread.

Discuss how mathematics

can help scientists ask questions about human health.

Would you contribute a

sample of your DNA for

genetic research on common

diseases like heart disease,

depression, or cancer—

even if you didn’t have any

of these health problems?

Why or why not?

Drugs work like they’re

supposed to in only half the

people who take them, so

scientists are trying to make

“personalized medicines” that

work very well in an individual because they match his

or her genetic make-up. Are

there economic, social, or

other issues that the development of such medicines

might raise?

Got It?
edicine has evolved tremendously since

the earliest human civilizations, when

the diagnosis and treatment of disease were far

from scientific. Medieval medicine, for example,

relied heavily on supernatural beliefs. Limited 

scientific knowledge led to seemingly bizarre

21st-Century Genetics

CHAPTER 5

practices like opening the vein of a sick person

and draining off quarts of precious blood!

Later, in the Renaissance period of the 15th

and 16th centuries, scholars centered on anatomy.

One of them, the Italian artist-inventor Leonardo

da Vinci, created beautiful and accurate

M

 By the end of the 16th 

century, anatomy was a

common focus for scientific scholars.

RARE BOOK AND SPECIAL COLLECTIONS DIVISION, LIBRARY OF CONGRESS
The New Genetics I 21st-Century Genetics 75

One of today’s challenges is to map the

actions and interactions of all these molecules,

a focus of the new field called systems

biology. Genetic and genomic

research is helping scientists tackle many

questions in this

area. By building

models of cells,

tissues, and

organs in action,

scientists hope to

learn how these

complex systems work.

Researchers need to

know these basics in order to

understand how the systems fail, when

disease strikes. An essential tool in this research

is the computer.

illustrations of the human body. His work

and that of other scientists of his day

focused on the practice of dissection,

providing never-before-seen details of

the body’s architecture of limbs, joints,

muscles, nerves, and vessels.

Modern medicine got its real start

during the 19th century, after the microscope was invented. Medical school subjects like

physiology, pathology, and microbiology were

born. During this time, scientists discovered that

bacteria—not evil spirits or other imaginary

entities—caused human diseases like cholera,

anthrax, and tuberculosis.

The birth of modern genetics, which

occurred in the 20th century, accelerated the

study of all these areas of science. Now, at 

the start of the 21st century, opportunities

have never been greater for turning scientific 

knowledge into better health for all.

We often take for granted the amazing

complexity of the human body. Without even

thinking, we sweat to maintain body temperature, get hungry when we need energy, and feel

tired when we need to sleep.

These seemingly simple actions require a

sophisticated coordination of many different

organs and the millions of molecules that work

together inside them. Thousands of networks

of interacting genes underlie these actions in

our bodies.

19th-century scientists

discovered that bacteria 

can cause disease. Bacillus

anthracis (left) causes anthrax

and Vibrio cholerae (below)

causes cholera.

PAUL KEIM (ANTHRAX), 

CDC/ WILLIAM A. CLARK (CHOLERA)
76 National Institute of General Medical Sciences

No Lab? No Problem!

Those who work at the intersection

of computer science and biology

often combine and analyze data

from many different sources, looking for informative patterns.

Andrey Rzhetsky of Columbia

University in New York City is 

one of these people. Through an

approach known as knowledge

engineering, Rzhetsky and his team

write computer programs that scan the contents

of thousands of published scientific papers.

The “knowledge mining” tool they use, called

GeneWays, focuses mainly on research literature

about changes in genes and proteins.

The program first scans scientific papers

using pre-set search terms, much like a GoogleTM

search of the Web. Next, it evaluates the search

results and makes sure they don’t overlap. For

example, if a molecule has 16 different names 

in different papers, the program simplifies it to

just one.

Here’s an interesting

news flash: “Glowin-the-dark jellyfish

revolutionizes genetic

research!”

Although it may

sound bizarre, the claim

is true. A jellyfish protein is essential to

modern cell biology

experiments that track

the movements, quantities, and interactions of

the millions of proteins inside cells.

Called green fluorescent protein, or GFP, this

natural protein is found in specific parts of the

jellyfish. Those parts glow because the protein

absorbs energy from light in the environment

and then produces a different color of light.

Scientists don’t really know how and why jellyfish use their glow. They do know that jellyfish

don’t flash at each other in the dark, nor do they

glow continuously. And the glow is rarely seen in

undisturbed animals.

Taken out of the jellyfish, GFP has played a

major role in advancing the study of genes and

Green Fluorescent Protein

 Fruit fly sperm cells glow bright green when they

express the gene for green fluorescent protein.

CATHERINE FERNANDEZ AND JERRY COYNE
Finally, after applying specific rules, sort of

like “biological grammar,” the computer program

identifies associations, which are possible links

between molecules. The information then goes to

a database that Rzhetsky and other scientists use

to build large networks of molecular interactions.

Rzhetsky and his team used GeneWays to identify risk genes for Alzheimer’s disease, a complex

condition thought to be caused by many factors.

In analyzing the data, Rzhetsky found important

“nodes,” molecules that play key roles in the disease gene network that GeneWays modeled.

These predicted molecular interactions were

later confirmed by other researchers working in a

lab, underscoring the value of computer modeling as a way to learn more about the molecular

basis of disease.

The New Genetics I 21st-Century Genetics 77

the proteins they encode. The story of how GFP

became a research tool began in 1992, when

Martin Chalfie of Columbia University showed

that the gene that makes GFP produced a fluorescent protein when it was removed from the

jellyfish genome and transferred to the cells of

other organisms (see page 38). Chalfie, a developmental biologist, first put the gene into

bacteria and roundworms, creating glowing

versions of these animals.

Since then, researchers have transferred the

GFP gene into many other organisms, including

fruit flies, mice, and rabbits—and even human

cells growing in a lab dish. Recently, scientists

used the GFP gene to create green-glowing

zebrafish. Although the fish were created for

the purpose of scientific research, they’ve

also become an “exotic” species for home

aquariums.

Thanks to GFP and related technologies,

scientists can now view living cells and their

constantly moving contents. GFP is also used

in diagnostic tests for drugs, foods, herbicides,

and hazardous chemicals. 

 Andrey Rzhetsky uses the computer program

GeneWays to locate important “hubs” of activity

(large spheres) within massive gene networks.

This particular network represents embryonic

developmental pathways in a fruit fly.

ANDREY RZHETSKY AND KEVIN P. WHITE

 Scientists engineered

this experimental worm

to express green fluorescent protein in two

of its nerve cells (bright

green spots).

MARTIN CHALFIE
78 National Institute of General Medical Sciences

Hard Questions

While the task of sorting through large volumes

of genomic data remains a central challenge in

modern biology and medicine, one of the knottiest dilemmas to emerge from this research is a

social and ethical one. That is, how should people

make use of information about their own genes?

Because genetic information is both powerful

and incredibly personal, there are deep societal

concerns regarding its use. These concerns

include the potential for discrimination from

health insurance companies or employers who

learn about a person’s risk of disease, or susceptibility to toxicity from an environmental chemical.

Some laws are already in place to protect

individuals from the misuse of their genetic

information. When you visit a new doctor, nurse

practitioner, or dentist, you’ll be asked to read

and sign a form that outlines your medical 

privacy rights under the Health Insurance

Portability and Accountability Act, or HIPAA.

This law protects your genetic and other personal

health information from being used or shared

without your knowledge.

It’s important to realize that, in most cases,

genetic information cannot offer definitive proof

that a disease will occur. But if you have a very

strong family history of breast cancer, for example, there may be a faulty gene in your family that

increases your risk of getting the disease.

Doctors can now test for two known gene

variants associated with inherited forms of breast

cancer, BRCA1 and BRCA2. If you carry either of

these gene variants, your lifetime risk of getting

breast cancer is significantly higher than it would

be for someone without either variant. But some

people who have BRCA gene variants never get

breast cancer.

Only about 5 percent of all breast cancer 

can be traced to a known, inherited gene 

variant. Since so many breast cancers are not

linked to BRCA1 or BRCA2, genetic testing for

these variants is irrelevant for the vast majority 

of people who do not have a family history of

breast cancer.

But let’s say you do have a relative who tested

positive for BRCA1 or 2. Should you get tested, too?

A difficult question, for sure, but consider

this: Knowing about this risk ahead of time

might save your life. For example, you might

want to begin getting mammograms or other
this gene can cause the disease, and those are

just the ones researchers know about!

How can there be 30 different variants of

one gene? Remember that a gene is a long

DNA sequence, consisting of hundreds of

nucleotides. A change in one of those

nucleotides produces one variant, a change in

another produces another variant, and so on.

Because there are so many possibilities, it’s

hard to tell whether a person has a variant

form of the cystic fibrosis gene. So the standard

genetic screening test for this disease scans for 

all of the more than 30 variants known to cause 

cystic fibrosis.

The New Genetics I 21st-Century Genetics 79

screening tests at an early age. If cancer is found

very early, it is usually more treatable, and the

odds for a cure are much higher.

Currently, diagnostic laboratories across the

United States offer genetic tests for more than

1,000 disorders. Some of these tests detect

problems with entire chromosomes, not just

individual genes. Perhaps the most well-known

example of a chromosome problem is Down

syndrome, in which cells have an extra copy of

chromosome 21 (see page 11).

Most genetic diseases aren’t caused by a

chromosome abnormality, or even by one gene

variant. Cystic fibrosis, for example, is due to a

faulty gene, but more than 30 different variants of

 Scientists are developing genetic tests that will

help doctors diagnose and treat diseases.
Doctors usually order a genetic test only if a

person has a strong family history of a disease.

But even so, deciding to have such a test is not a

simple choice. Think about what you would do

with the information.

One thing you might consider is whether you

could do something with what you learn from a

genetic test.

You’ve already read about what you could

do if you discovered that you were at high risk

for developing breast cancer. But what about a

condition that shows up in middle-aged or older

people—or one for which there is currently

no cure?

As a teen or young adult, would you want to

know that you’d get a serious, perhaps incurable,

disease later in life?

Patients and doctors face these tough issues

every day. Even years from now, when

researchers know more about the molecular

roots of disease, genetic tests will rarely provide

easy answers. In most cases, they won’t even provide “yes” or “no” answers.

Rather, much like a cholesterol test, they will

predict whether a person’s risk of getting a disease

is relatively high, low, or somewhere in between.

This is because many factors besides genes, including lifestyle choices such as diet and exercise, also

play a role in determining your health.

Good Advice

Since the story of genes and health is so 

complicated and is likely to stay that way 

for a while, it is very important to consider

genetic information in context. Health care

professionals known as genetic counselors

can be a big help to people who are thinking

about getting a genetic test.

As a profession, genetic counseling has

been around since the mid-1900s. However,

only a few specialty clinics offered counseling

at that time. Now, genetic counseling is much

more widely available.

80 National Institute of General Medical Sciences
L

ike your thumbprint, your genes

are unique, unless you have an 

identical twin. As such, DNA

“fingerprinting” has become a powerful

crime-fighting tool. DNA forensics is

a fast-growing specialty that has applications beyond putting criminals

behind bars.

In addition to identifying suspects

who leave traces at the scene of a crime

(for example, strands of hair, drops of

blood, or skin cells), DNA forensic technology can identify victims in a natural

disaster, such as the December 2004

tsunami that ravaged Indonesia and

other Asian countries. DNA fingerprinting can also match a transplant patient

to an organ donor or establish paternity

and other family relationships. 

Genetic fingerprinting is not limited

to people. It can find small but potentially deadly traces of disease-causing

bacteria in food or water, determine

whether an expensive horse was sired

by a Kentucky Derby winner, or figure

out whether a puppy’s parents were

first cousins.

DNA fingerprinting techniques work

by looking for differences among gene

sequences that are known to vary

between people (or between individuals

from any species). Scientists read the

sequence in a dozen or so places to 

create a molecular profile. The chances

of a molecular fingerprint being the

same in two people or two organisms

are vanishingly small.

GENETICS AND YOU: Crime-Fighting DNA

The New Genetics I 21st-Century Genetics 81
Today’s genetic counselors have gone through

a rigorous training process in which they earn

a master’s degree and learn genetics, medicine,

laboratory procedures, counseling, social work,

and ethics. Genetic counselors do their work

in many different settings, including hospitals,

private clinics, government agencies, and university laboratories.

An interesting aspect of the job is that genetic

counselors address the needs of entire families,

rather than just individual patients. To evaluate

genetic risk and its potential consequences, these

professionals gather a family medical history

covering generations.

Genetics, Business, and the Law

Can a scientist claim rights to a gene that he discovered in worms and that has a nearly identical

counterpart in humans?

Is a person who gave a blood or tissue sample

entitled to profits from a company that develops

a drug based on genetic information in her sample, or to a lifetime supply of the drug?

Can a blood or tissue sample that was donated

for one purpose be used for an entirely different

study several years later, without asking the donor

if that’s OK?

These and other issues are hotly debated 

in ethics and legal circles. Many of the most 

82 National Institute of General Medical Sciences

The word most often used to refer to

applications of genetic research, especially those leading to products for

human use, is biotechnology. It

involves techniques that use living

organisms—or substances derived

from those organisms—for various

practical purposes, such as making a

biological product.

One major application of biotechnology is in agriculture. Actually, this is

hardly new: Humanity has engaged in

agricultural biotechnology for 10,000

years or more. Many traditional farming

practices, from plant breeding to animal

husbandry, are really forms of biotechnology.

But in today’s agricultural industry,

biotechnology generally means the use

of molecular biology, recombinant DNA

technology, cloning, and other recent

scientific approaches to produce plants

and animals with new traits.

This usually involves transferring genetic material from one kind of organism into another. Using

the same techniques that were developed for putting genes into animals for research purposes,

scientists can create crop plants with desirable

traits, such as improved flavor or better resistance

to insect pests. Transferring specific genes is

faster and more efficient than traditional breeding

approaches. 

The United States is home to far more genetically modified crops than anywhere else in the

world. In 2005, 52 percent of the country’s corn,

79 percent of its cotton, and 87 percent of its soybeans were cultivated from seeds genetically

modified to resist viruses and other plant pests.

Many believe that agricultural biotechnology is

an important driver for improving world health.

They say that genetic modifications may be the

only hope for pest-ravaged crops, such as

bananas, that are essential to the economies of

poor countries. The creation of edible plants that

contain medicine, serve as a form of vaccination,

or deliver extra nutrients—such as the recently

Field Study
controversial topics have to do with the idea of

patenting life forms.

Traditionally, when an inventor comes up

with a new idea and wants to sell it—whether

it’s a radio-controlled toy boat or a customized

laboratory chemical—he or she submits an application to the U.S. Patent and Trademark Office.

By issuing patents, the Federal Government

gives an inventor ownership of his or her creation. Patents give inventors time to optimize

their products and control how their inventions

are used, allowing them to make money from

their creativity.

The New Genetics I 21st-Century Genetics 83

developed rice that makes vitamin A—could also

contribute in major ways to global health.

But opposition from farmers and consumers

within and outside the United States has clouded

agricultural biotechnology’s future. Some object

to the development of plants that are naturally

resistant to herbicides, partly out of concern that

the trait might jump to weeds, making them

impossible to destroy.

Environmental advocacy groups worry that

genetically modified plants may impact the future

biodiversity of our planet by harming beneficial

insects and possibly other organisms. However,

the U.S. Environmental Protection Agency has

stated that there is no evidence to date that

indicates that biotech crops have any adverse

effects on non-targeted wildlife, plants, or beneficial insects.

Of course, careful field tests of newly created,

genetically modified plants and animals are

essential to be sure that they cause no harm to

other organisms or to the environment.

z Biotechnology helps agricultural scientists create

crops with desired traits. The majority of cotton

and soybeans in the United States are grown with

genetically modified seeds that resist viruses and

other plant pests.
However, nobody invented a gene, a naturally

occurring chemical, or a protein, so why should a

person or a company be able to own it and control its destiny in the marketplace?

Patent laws in the United States and Europe

prohibit anyone from patenting a gene as it exists

in the human body. But for many years, scientists,

universities, and companies have earned patents

for methods of isolating genes or for specific

medical uses of genetic information. The breast

cancer gene test is one example.

84 National Institute of General Medical Sciences

Patents are great for business, but they have

the potential to slow research because patentholders control how information related to the

patent is used. For example, researchers who wish

to study patented genetic information may need

to acquire a license first. This can be timeconsuming and expensive.

Concerned about possible negative effects of

patenting genes, the U.S. National Institutes of

Health has worked with the U.S. Patent and

Trademark Office to establish guidelines for what

kind of genetic information can be patented.

Since this area of medical research is an evermoving target, government scientists and

policymakers continue to clarify patent and

licensing issues in the hope of keeping data that

is valuable for research in the public domain.
generated by life scientists, is especially short

of qualified workers. As a result, bioinformatics

scientists are in high demand.

Many careers in genetics and genomics

require advanced degrees such as a Ph.D. or M.D.

But people with master’s or bachelor’s degrees are

also needed to fill thousands of rewarding jobs as

genetic counselors, research assistants, and lab

technicians.

For more career information, see

http://www.ornl.gov/sci/techresources/

Human_genome/education/careers.shtml or

http://science.education.nih.gov/LifeWorks.

Careers in Genetics

Opportunities to be part of genetic and

genomic research have never been greater or

more exciting. In addition to studying human

genes, scientists are gathering information

about the genes of many other living things,

from microbes that cause disease to model

organisms like mice and Drosophila, livestock,

and crop plants.

Although computers do some of the work,

this avalanche of information has to be analyzed

by thousands and thousands of human brains.

In addition to identifying genes, scientists must

figure out what the genes do and—even more

complicated—how they do it.

We need laboratory scientists, doctors to do

clinical research and treat patients, genetic counselors to help people understand the information

in their genes, and lawyers and ethical specialists

who can address legal and policy concerns about

the use of genetic information.

In especially high demand are people with

expertise in mathematics, engineering, computer

science, and physics. The field of bioinformatics,

which develops hardware and software to store

and analyze the huge amounts of data being

The New Genetics I 21st-Century Genetics 85
For most of its history, biology managed to

amass its data mostly with the help of plain old

arithmetic. Gregor Mendel did genetic analysis

by simply counting the different kinds of offspring produced by his peas. By contrast, today’s

genetic research creates too much data for one

person, or even a scientific team, to understand.

New technologies are needed to manage this

huge amount of data.

Consider this: Gene-sequencing machines

can read hundreds of thousands of nucleotides a

day. Gene chips are even faster. The information

in GenBank®, a widely used database of DNA

sequences, nearly doubles every year. It is said

that a laboratory doing 

genetic research can generate hundreds of gigabytes

of data a day, every day—

more than 20,000 times 

the contents of the complete works of Shakespeare

or J.S. Bach.

How can anyone make

sense of all this information? The only way is to

enlist the aid of computers

and software that can store

the data and make it possible

for researchers to organize,

search, and analyze it. In fact, many

of today’s challenges in biology, from gene 

analysis to drug discovery, are really challenges 

in information technology. This is not surprising

The Tools of Genetics: Informatics and Databases

when you remember that DNA is itself a form of

information storage.

Where are genetic and genomic data stored?

One of the first biological databases was created

to store the huge volume of data from experiments with the fruit fly Drosophila melanogaster.

Called FlyBase, it has grown into a huge,

comprehensive, international electronic repository for information on Drosophila genetics and

molecular biology, run by scientists for scientists.

The information includes nearly a century’s

worth of published scientific literature on fruit

flies and data on the fruit fly’s genome sequence

IMAGE ON COMPUTER SCREEN COURTESY OF TOM SLEZAK,

LAWRENCE LIVERMORE NATIONAL LABORATORY

86 National Institute of General Medical Sciences
as well as information about DNA sequences of

some of Drosophila’s fly relatives.

Databases like FlyBase are also useful to scientists working with other organisms, like mice

or humans. A researcher who discovers a new

mammalian gene may consult FlyBase to see if

fruit flies have a similar gene and if the database

contains hints about what the gene does. Since

the functions of many genes are retained during

evolution, knowing what a gene does in one

organism often provides valuable clues about

what it does in another organism, even if the

two species are only distantly related.

Several other communities of researchers

have created their own databases, including

WormBase and DictyBase, dedicated to the

investigation of the roundworm Caenorhabditis

elegans and the soil-dwelling amoeba

Dictyostelium discoideum.

A key goal is to make sure that all of these

databases can “talk” to each other. That way,

similar discoveries in different organisms—

the important, common threads of all

biology—can be identified quickly and

analyzed further.

For this database communication to

work, researchers in different fields must

use the same terms to describe biological

processes. The development and use of

such a universal “ontology”—a common

language—is helping scientists analyze the

complex network of biology that underlies

our health.

Do you think modern research

tools derived from genomics and

bioinformatics will change the

practice of medicine? How?

If a genetic test revealed that you

had a 1 in 100 chance of developing a disease like type 2 diabetes,

which can be prevented with

lifestyle changes like eating a

healthier diet and exercising more,

would you change your behavior?

What if the risk were 1 in 10?

How is genetic engineering similar

to traditional farming? How is it

different?

A biotechnology company uses

genetic information from a patient

volunteer and develops an effective, profitable medicine. Should

the patient know that he or she

was part of this process? Why or

why not? What if the research did

not lead to any medical advance?

Got It?
Amino acid | A building block of proteins.

There are 20 amino acids, each of which is

coded for by three adjacent nucleotides in a

DNA sequence.

Anticipation | The disease process in which

symptoms show up earlier and are increasingly

severe in each generation.

Biofilm | A slime layer that develops naturally

when bacteria congregate on surfaces.

Bioinformatics | The field of biology specializing in developing hardware and software to store

and analyze the huge amounts of data being

generated by life scientists.

Biotechnology | The industrial use of living

organisms or biological methods derived through

basic research; examples range from genetic engineering to making cheese or bread.

Chromatin | The organization and dense packaging of DNA in the nucleus of cells.

Chromosome | A cellular structure containing

genes. Chromosomes are composed of DNA and

proteins. Humans have 23 pairs of chromosomes

in each body cell, one of each pair from the

mother and the other from the father.

Circadian | Pertaining to a period of about

24 hours; applied especially to rhythmic biological repetition like the sleep-wake cycle.

Clone | In genetics, the process of making many

copies of a gene. The term also refers to the isolation and manipulation of a gene.

Comparative Genomics | The study

of human genetics by comparisons with the

genetics of other organisms.

Diploid | Having two copies of each

chromosome.

DNA | Abbreviation for deoxyribonucleic acid,

the molecule that contains the genetic code for all

life forms except for a few viruses. It consists of

two long, twisted chains made up of nucleotides.

Each nucleotide contains one base, one phosphate

molecule, and the sugar molecule deoxyribose.

The bases in DNA nucleotides are adenine,

thymine, guanine, and cytosine.

DNA chip | See microarray.

DNA polymerase | An enzyme that copies

DNA.

Enzyme | A substance (often a protein) that

speeds up, or catalyzes, a chemical reaction without being permanently altered or consumed.

Epigenetics | The study of heritable changes in

gene function that occur without a change in the

DNA sequence.

Eukaryote | An organism whose cells have

a membrane-bound nucleus.

Exon | A DNA sequence in a gene that codes

for a gene product.

Gene | A segment of a DNA molecule that

contains information for making a protein or,

sometimes, an RNA molecule.

National Institute of General Medical Sciences

Glossary

88
Meiosis | The type of cell division that creates

egg and sperm cells.

Microarray | Sometimes called a gene chip or

a DNA chip. Microarrays consist of large numbers of molecules (often, but not always, DNA)

distributed in rows in a very small space.

Microarrays permit scientists to study gene

expression by providing a snapshot of all the

genes that are active in a cell at a particular time.

MicroRNA | A short piece of single-stranded

RNA that does not encode a protein and controls

the expression of genes.

Mitochondrion | The cell’s power plant,

supplying the energy to carry out all of the cell’s

jobs. Each cell contains up to 1,000 mitochondria. The structures contain their own small

genomes, called mitochondrial DNA.

Mutation | A change in a DNA sequence.

Nucleotide | A building block of DNA or

RNA. It includes one base, one phosphate molecule, and one sugar molecule (deoxyribose in

DNA, ribose in RNA).

Nucleus | The structure in the eukaryotic cell

containing most of its genetic material.

Pharmacogenetics | The study of how people’s genetic make-up affects their responses

to medicines.

Gene chip | See microarray.

Gene expression | The process by which

genes are first converted to messenger RNA and

then to proteins.

Genetics | The scientific study of genes and

heredity— of how particular qualities or traits

are transmitted from parents to offspring.

Genome | All of an organism’s genetic material.

Genomics | A “scaled-up” version of genetic

research in which scientists can look at large

numbers or all of the genes in an organism at

the same time.

Haploid | Having one copy of each chromosome, as in a sperm or egg.

Haplotype | A set of closely linked genes or

DNA polymorphisms inherited as a unit.

Histone | A type of protein found in chromosomes; histones attached to DNA resemble

“beads on a string.”

Homeobox | A DNA sequence found in genes

involved in the regulation of the development

of animals, fungi, and plants.

Imprinting | The phenomenon in which a gene

may be expressed differently in an offspring

depending on whether it was inherited from

the father or the mother.

Intron | A DNA sequence, or the RNA sequence

transcribed from it, that interrupts the sequences

coding for a gene product (exon).

The New Genetics I Glossary 89
Protein | A molecule or complex of molecules

consisting of subunits called amino acids.

Proteins are the cell’s main building materials

and do most of a cell’s work.

Recombinant DNA | Hybrid DNA produced

in the laboratory by joining pieces of DNA from

different sources.

Replication | The process by which DNA

copies itself in order to make a new genome to

pass on to a daughter cell.

Ribosome | The cell structure in which proteins are manufactured. Most cells contain

thousands of ribosomes.

RNA | Abbreviation for ribonucleic acid, the

molecule that carries out DNA’s instructions for

making proteins. It consists of one long chain

made up of nucleotides. Each nucleotide contains

one base, one phosphate molecule, and the sugar

molecule ribose. The bases in RNA nucleotides

are adenine, uracil, guanine, and cytosine.

RNA interference (RNAi) | A gene-silencing

process in which double-stranded RNAs trigger

the destruction of specific RNAs.

RNA polymerase | An enzyme that transcribes

a DNA sequence, creating mRNA.

RNA splicing | The process by which introns

are removed and exons are joined together

from an RNA transcript to produce an mRNA

molecule.

Sequencing | Sometimes called DNA sequencing or gene sequencing. Discovering the exact

order of the building blocks (see nucleotides) of

a particular piece of DNA.

Systems biology | A field that seeks to study

the relationships and interactions between various parts of a biological system (metabolic

pathways, organelles, cells, and organisms) and

to integrate this information to understand how

biological systems function.

Telomere | A repeated DNA sequence that caps

the ends of chromosomes.

Transcription | The first major step in gene

expression, in which the information coded in

DNA is copied into a molecule of RNA.

Translation | The second major step in gene

expression, in which the instructions encoded in

RNA are carried out by making a protein or starting or stopping protein synthesis.

Variant | A different version of a gene, one that

has a slightly different sequence of nucleotides.

90 National Institute of General Medical Sciences
What Is NIGMS?

The National Institute of General Medical Sciences

(NIGMS) supports basic biomedical research on

genes, proteins, and cells. It also funds studies on

fundamental processes such as how cells communicate, how our bodies use energy, and how we

respond to medicines. The results of this research

increase our understanding of life and lay the

foundation for advances in the diagnosis, treatment,

and prevention of disease. The Institute’s research

training programs produce the next generation of

biomedical scientists, and NIGMS has programs to

encourage minorities underrepresented in biomedical

and behavioral science to pursue research careers.

NIGMS supported the research of most of the 

scientists mentioned in this booklet.

Produced by the Office of Communications and Public Liaison

National Institute of General Medical Sciences

National Institutes of Health

U.S. Department of Health and Human Services
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