Volume 12, Issue No. 2

About This Issue...

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Researchers would get laughed at if they showed

up for work with a Sherlock Holmes cape and hat, but

scientists are indeed detectives, solving mysteries.

Dear Reader,Our fi rst understanding of heredity is credited to Gregor Mendel’s curiosity about how traits were passed through generations of peas.

The accumulated work of many scientists, including Rosalind Franklin’s X-ray crystallographic picture of DNA, provided the clues that led two men to write an article in the April 25, 1953, issue of Nature that humbly began, “We wish to suggest…” What did James Watson and Francis Crick suggest? That they had found the secret of life—the structure of the molecule that carries hereditary traits for all living things, deoxyribonucleic acid!

In turn, Watson and Crick’s work provided the foundation for an explosion of knowledge about DNA, obtained through many tools. This issue offers an overview of the progress made in unraveling the secrets of the human genome. We examine how proteins are made, genetic testing, DNA fi ngerprinting, personalized medicine, and the role of mathematics in genetics.

In this issue, you will also glimpse the ethical implications of this work. We hope that it will help you make informed decisions about the way these discoveries can be applied. Some of you will become the scientists of tomorrow, working on questions that we can’t even imagine today. All of you, however, can play a role in how society will use biotechnology in everyday life.

Sincerely,

Paul A. Hanle, President

Biotechnology Institute

People have asked questions about life throughout the ages: How are babies made? Why are children so similar and yet so different from their parents? Why do some people live to be 100 while others die young? Why do we get sick?

And they’ve certainly come up with ideas. For example, in 100 AD, Romans speculated that horses could be fertilized by the wind. From 1100 to 1700, “spontaneous generation” was a popular explanation for organisms springing forth from nonliving matter. Maggots, for example, supposedly arose from horsehair.

Motivated by a desire for knowledge, today’s scientists sift through physical evidence to make a case to explain “why” and “how.” A clue here. Evidence there. Sometimes building on the work done in altogether different fi elds, they develop both the ideas to be tested and the tools they need to do so.

Having the evidence, however, doesn’t always close the book on a case. People were using biotechnol-

ogy—manipulating living matter to solve problems or create useful prod-

ucts—to make beer, wine, and bread, and to breed plants and animals, before they had a clue about the “why.” Like-wise, Gregor Mendel explained in 1865 how traits are inherited, but his work was ignored for 35 years. Then three scientists, working independently, picked

up the trail in 1900.Today we understand more about how

heredity works. We’ve pieced togeth-er amazing connections, from

cell to nucleus to chromosome to gene to the double helix of DNA (deoxyribonucleic acid). Our genetic information contains the recipes for proteins. Now, some scientifi c sleuths are studying genomics (the study of genes and their function) and proteomics (the study of proteins—their locations, structure, and function).

During your lifetime, researchers have sorted out some of the genes that affect people’s ability to stay healthy, such as tendencies to gain weight, suffer heart conditions, and get cancer. They’ve also uncovered some genetic markers linked to personality traits.

Scientists can analyze your genetic profi le, but the complete picture of heredity—and how we should treat many genetic conditions—is still a mystery.

Scientifi c detectives have opened doors of understanding, but they have much more to explore. Young, creative minds are always in great demand in the sciences. Become a scien-tifi c detective and see how much more you can unravel about “the secret of how life works.”

—Lois M. Baron

The year 2003 marks the 50th anniversary of Crick and Watson solving the puzzle of DNA’s structure.

2 The Secret of How Life Works

Contents...

The Case of the Sleuthing Scientists........................ 2Cooking Up Proteins .............................................. 4Math Matters ..........................................................6Testing What We’re Made Of .................................. 8A New Kind of Fingerprint ....................................10Pharmacogenetics: Tailor-Made Medicine ..............12Profile: Forensics at Work: DNA Analyst ................14Activity: The Case of the Crown Jewels ..................15‘DNA’s Dark Lady’ ................................................ 16Resources ............................................................. 16

Biotechnology & You

Volume 12, Issue No. 2

Publisher:The Biotechnology Institute

Editor in Chief:Kathy Frame

Managing Editor:Lois M. Baron

Writing (Except Where Noted):The Writing CompanyCathryn M. Delude andKenneth W. Mirvis, Ed.D.

Design:Snavely Associates, Ltd.

Cover Art:Virginia Commonwealth University – Creative Services Photos: U.S. DOE Human Genome Program <http://www.ornl.gov/hgmis> and Photos.com

The Biotechnology Institute would like to thank the Pennsylvania Biotechnology Association, which originally developed Your World, and Jeff Alan Davidson, founding editor.

The Biotechnology Institute is an independent, national, nonprofi t organiza-tion dedicated to education and research about biotechnology. Our mission is to engage, excite, and educate the public, particularly young people, about biotechnology and its immense potential for solving human health, food, and environmental problems. Your World focuses on biotechnology issues and brings scientifi c discoveries to life for 7th- to 12th-grade students. We publish issues on different topics each fall and spring. Please contact the Biotechnology Institute for information on subscriptions (individual, teacher, or library sets). Some back issues are available.

Copyright 2003, Biotechnology Institute. All rights reserved.

The Biotechnology Institute acknowledges with deep gratitude the fi nancial support of Centocor, Inc., and

Ortho Biotech.

Advisory Board:Dena S. Davis, Ph.D., J.D., ClevelandState University Law School

Don DeRosa, Ed.D., CityLab,Director of Education, Boston University Medical College

Lori Dodson, Ph.D., North Montco Technical Career Center

Anthony Guiseppi-Elie, Sc.D., Virginia Commonwealth University

Lynn Jablonski, Ph.D., GeneData (USA), Inc.

Philip R. Reilly, M.D., J.D.,Interleukin Genetics, Inc.

Mark Temons, Williamsport High School

Sharon Terry, M.A., President, Genetic Alliance

Theodore Torphy, Ph.D., Centocor, Inc.

The issue of Your World, “The Secret of How Life Works,” complements two

programs: Our Genes/Our Choices, one of the PBS/Fred Friendly Seminars

(http://www.pbs.org/fredfriendly/ourgenes/), and the touring Pfi zer exhibit

“Genome: The Secret of How Life Works” (http://www.wl.com/subsites/

philanthropy/caring/science.education.museum.genome.html).

For more information:Biotechnology Institute1840 Wilson Boulevard, Suite 202 Arlington, VA 22201 Phone: (703) 248-8681 Fax: (703) 248-8687

info@biotechinstitute.org

Your World 3

People often compare a gene to a recipe. A recipe

contains the instructions for preparing a specifi c

dish. A gene contains the instructions for making a

specifi c protein. Let’s pretend the

genome—all the genetic information

in a cell—is a recipe book.

Imagine that the genome is a giant book with about 30,000 recipes, and each gene is one specifi c recipe. Nothing happens if the book just stays on the shelf. A cell (our kitchen chef) must open the book to a specifi c recipe and start following the instructions.

Each cell gets a complete recipe book (genome) regardless of what tissue or organ it belongs to. Likewise, just as the genome is the cookbook, the proteome is the complete selec-tion of proteins an organism can produce, much like all the dishes you can make from that cook-book. However, depending on the cell’s job, the cell activates only some of the recipes to make only some of the proteins. For example, the liver processes toxins found in our bodies. So liver cells produce different proteins than skin cells, which protect us from the outside world. ■

Revised Recipes and Diverse Dishes

Occasionally, a recipe in the genome book might have a misprint in it. Most of the time, a misprint doesn’t affect the fi nal dish at all, but sometimes it changes the way the dish will look or taste. Those changes can be

good (like adding chocolate chips to plain cookies) or bad (like substituting broccoli for sugar). Such misprints in our genome are called mutations. They are caused when some DNA bases (adenine,

cytosine, guanine, and thymine) are changed, added, or deleted. Most mutations don’t affect us at all, but some can cause a disease or disorder. Other

times, though, the variations can make for happy surprises. It is important to under-

stand that the word mutation doesn’t apply just to things that go wrong. Sci-

entists also use the word to mean all the different variations that make us so diverse and interesting. Without variations, everyone would look ex-actly the same, and our species could not evolve and adapt to new environ-ments. Every person’s genome has millions of genetic variations that make each of us unique.

4 The Secret of How Life Works

Getting the work order: Cells begin to make a cookie (protein) when they get a work order. Cells send messages (molecular signals) to themselves and to others. They can also pick up signals from the outside world. Some of those signals tell the cell it needs to produce a particular protein.Finding the right page: The cell needs an index to fi nd the right page for the recipe (gene) in the book. A special protein in the cell

called an enzyme helps out. This page-fi nder enzyme is called RNA polymerase, and it looks for information

that marks the beginning of a specifi c recipe.Reading the recipe: When the enzyme fi nds the right recipe, it starts to read it. It chugs down the long DNA chain like a train on a track. When it meets a stop sign (stop codon), it has reached the end of the recipe. This

DNA track is made of four chemical bases—adenine, cytosine, guanine,

and thymine—which are known by their initials A, C, G, and T. As the RNA polymerase

chugs along, it transcribes the important parts to a recipe card. This recipe card is known as messenger RNA (mRNA). When the mRNA leaves the nucleus, it contains an edited version of the gene’s recipe, with just the essential instructions.Going to the kitchen: The mRNA chain goes to the kitchen, the ribosome, which will combine the individual ingredients to make the cookie dough.

Making the dough: The ribosome reads the mRNA, three letters at a time. Those triplets are the ingredients list. For each triplet, the ribosome grabs the listed ingredient, which is one of 22 amino acids. It attaches each ingredient to the next, creating a chain of amino acids.Baking the cookie: With the last ingredient in place, the amino acid chain peels off. It is still an immature protein, like

raw cookie dough that needs to be shaped and baked. A chaperone protein rushes over

to show the immature protein when and how to fold into a three-dimensional shape. When the chain takes on the right shape, it is a mature protein, like a baked cookie. The protein’s shape will determine how it interacts with other

proteins and molecules. Those interactions

defi ne how the protein functions in

the body.

Here’s how a cell (chef) might go about making a particular type of protein (cookie).

© Bruce Cramer

Your World 5

Pass the Peas, PleaseAbout 200 years ago, many scientists

believed that children were a blend of their parents’ traits. Gregor Mendel (1822–1884), a monk in Central Eu-rope, put that idea to the test using peas as the model organism.

Between 1856 and 1863, Mendel cultivated and carefully observed some 28,000 pea plants. He examined this huge amount of data for patterns. For instance, when he cross-pollinated plants that produced just yellow seeds

with those that produced just green seeds, he found that the fi rst generation always had yellow seeds. But in the following generation, about three-quarters consistently had yellow seeds and one-quarter had green seeds. This 3:1 ratio also appeared for fl ower color and other traits.

Mendel concluded that each trait is determined by factors (now called alleles) that are passed on to descendants unchanged, not blended. An individual inherits one such factor from each parent for each trait. Moreover, even though a trait may not show up in an individual, it can still be passed on to the next generation.

A strong believer in Mendel’s theories, biologist Reginald C. Punnett (1875–1967) invented a handy way to work out the ratios of allele combinations and what traits show up (are expressed) with these combinations. Known as the Punnett square, this tool helps predict the outcomes of simple breeding experiments in certain genetic studies. (Of course, there are exceptions to the rules that Mendel formulated.)

Stringing Genetics AlongDiscovering DNA’s structure opened up new avenues of

exploration and new opportunities for applying mathematics.Human DNA consists of 3.2 billion base pairs—each one a

piece of data inherited from your parents. Called the genome, this information provides instructions for assembling molecules (mainly proteins) and controlling when and where cells make these parts. In recent years, scientists have sought to decipher the plans by sequencing the human genome—identifying and locating every base of the immensely long strands that make up chromosomes.

Interested in having a horse that runs faster, a

fl ower with a showier bloom, a cow that produces

more milk, a strain of wheat that resists disease,

or a dog that searches out rats?

For thousands of years, farmers, herders, and others have been selectively breeding plants and animals to create more productive or desirable hybrids. But it wasn’t easy to predict results. It took a remarkable combination of careful experiments and cleverly applied mathematics by 19th-century scientist Gregor Mendel to reveal what was going on.

Nowadays, mathematics continues to be a crucial tool as scientists strive to understand the details of the genetic molecular code that not only defi nes what happens during breeding but also guides many aspects of plant, animal, and human life.

If each parent has a dominant and a recessive gene for a single-gene trait, the chances are three to one that each child will exhibit that trait. But it is possible for all the offspring to exhibit the trait—or for none of them to show it—because the odds are calculated independently for each one (see box, p.7).

Mendel is called the father of genetics because his carefully controlled experiments revealed how traits are inherited.

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6 The Secret of How Life Works

Sequencing a genome is like assembling an enormous jigsaw puzzle. The genome is cut into tiny pieces, which are then indi-vidually sequenced. The millions of pieces must then be put back into the correct order. That’s where mathematics comes in.

Computer programs do the assembly work. They typically consist of a set of mathematical steps that sort, edit, and combinefragments. Normally, the easier steps are done fi rst, followed by the harder ones. It’s like fi rst organizing puzzle pieces

according to color, then working on the easiest-to-see patterns. It’s tricky. In the human genome, many DNA se-quences are repeated many times over, so one region can easily be mistaken for another when the sequence is assembled.

So far, researchers have sequenced the human

genome and those of some plants and

animals, including certain bacteria and viruses, mosquitoes, rice,

and mice. Trying to understand what different

parts of a sequence do, they again use

mathematics to sort through the jumble

of bases and compare genomes of different

organisms.

For example, scientists have started comparing the human genome with the mouse genome. To their surprise, they found many more shared sequences than they expected.

Mathematical tools help geneticists identify such similarities. One useful approach is to quantify how much one sequence differs from another.

Here are two sample strings of DNA lined up on top of one an-other. Each letter represents one of the four bases making up DNA.

a g c t t t c g t g a g a c g t t t c c a g a g t c

One simple measure of similarity is to count the number of changes needed to convert one string into the other. For the fi rst string, the answer is six: four substitutions of one letter for another and two insertions of additional letters to make it match the second string. Such numbers help specify how similar one sequence is to another. More complicated mathematical schemes help characterize similarities among three or more sequences.

Driving Each OtherToday, mathematicians and geneticists continue to use

their skills to expand our knowledge of genetics. Some write computer programs to locate the genes along a strand of DNA or use the sequence of a gene to predict the structure of the protein it creates. Others are developing theories to account for the way DNA twists and coils. Still others are trying to answer questions about how the genetic code evolved.

Mathematical techniques allow geneticists to expand their understanding of genetics. This new information raises questions that prompt mathematicians, in turn, to refi ne their techniques, develop theories, and embark on new research. ■

—Ivars Peterson

Your World 7

What Are Your Chances?Emilo has four brothers and no sisters. His mom is expecting another

baby. What are the chances that he will have a sister? Another brother? The key word is chance. You see the outcomes of chance every day. A coin toss

before a ballgame determines who gets the ball fi rst. What are the chances that your team will have the ball? The possibilities are heads and tails: two choices. So your chance of calling it correctly with each toss is one in two. When you toss the coin the next time, you still have the same possible outcomes: heads or tails. The outcome of the second toss has no connection to the fi rst toss. The same is true in Emilo’s case. The outcome will be independent of the previous ones, so he has an equal chance of getting a sister or another brother.

Another example is dice. What are your chances of rolling a die and getting a “1”? How many possibilities are there when you throw a die? Six. So, your chances would be . . . one in six.

—Kathy Frame