Milwaukee Journal Sentinel, April 28, 2003

Unlocking Secret of DNA Model Helix Made World Do Double Take


Apr. 27--Few discoveries have changed the course of human history, requiring people to re-evaluate their concept of nature and place within it.

The taming of fire was one, as was the Mesopotamian invention of the wheel.

Fifty years ago last Friday, another such discovery occurred. It appeared in the scientific journal Nature, and it described the physical structure of DNA: the molecular blueprint of life.

That find, by James Watson and Francis Crick, launched humankind into a whole new dimension of scientific understanding.

It has since propelled people into a world where they can pick the sex of their children, grow legs where flies' wings should develop, clean oil spills with genetically modified bacteria and realize that in terms of our molecular makeup, we aren't much different from a worm.

It also has affected the daily life of nearly every person on the planet. From the medicines we take and the court battles we fight, to the foods we eat and the clothes we wear, gene technology plays a role.

Indeed, nearly 80 percent of soybean and 70 percent of cotton plants grown in the United States were genetically modified, according to 2002 statistics from the U.S. Department of Agriculture.

For thousands of years people have understood the concept of heredity. The domestication of plants and animals were experiments in gene selection. Five thousand years ago, early Americans bred together particularly tasty, bountiful and hardy strains of a plant called teosinte. After several generations of this manipulated breeding, a new plant was created, one we call corn.

"We knew a lot about what a gene did," said Jim Crow, retired professor of genetics at the University of Wisconsin-Madison. "We just didn't know what it was."

That changed when Watson, an American biologist, and Crick, an English chemist, met at Cambridge University in 1951.

Both had read "What Is Life?" by Erwin Schrodinger, who argued that life was simply the process of storing and passing on biological information. Chromosomes were the bearers of this information, he surmised. For this system to work, all the information of life had to be packed into every cell. This required that each cell be equipped with some sort of "hereditary code-script."

The genius of what Watson and Crick did was pull from the work of others and weave it into a coherent whole; indeed, they performed no experiments of their own.

They built models out of metal and cardboard cutouts. One construction finally made sense.

It was simple in form; a double-stranded helix that coiled round and round, like a spiral staircase or piece of rotini.

Each strand is connected to its mate by rungs, which are composed of four chemicals called bases.

Each rung has two bases that can form only two combinations: adenine with thymine, or cytosine with guanine. In other words, if adenine was found at a particular location on one strand, thymine would be found at the same place on the other strand.

This is what Watson and Crick published on April 25, 1953. And the power their discovery unleashed was enormous.

It challenged our perceptions of the past and present, and paved an uncertain road for the future.

"We knew that a mouse and an elephant were different," said Crow, "but, we didn't know why two different species couldn't be mated."

"Today we take it for granted that differences between species, genera, families, even kingdoms involve changes in DNA," Crow wrote in a recent Nature article. "Yet, before molecular technology, there was considerable doubt."

Molecular analyses since have shown that modern humans arose in Africa, some 150,000 years ago; and that we share 98.5 percent of our DNA with chimpanzees -- our closest living relatives on the planet.

DNA testing has established that we are connected to all living creatures by a common molecule, and it has shed light on how we -- and all species -- evolved and differentiated.

In a sense, the history of genetics could be loosely compared to human evolutionary history.

Just as Homo erectus -- an ancestor of modern humans -- observed and captured fires caused by nearby lightning strikes, early geneticists understood, but could not harness, the power of the gene.

It took a quick-witted Neanderthal to pick up two stones, rub them together and make a fire to change Pleistocene human culture and technology.

And in that vein Watson and Crick collected chemical, physical and X-ray information to build a 3-D model of DNA; culminating in a product that had no less an effect on the world than those first Neanderthal sparks.

But DNA is not only a tool for discovering our past. We also are using it to change the future.

It has already fundamentally changed the field of medicine, and is predicted to do so even more in the future.

For instance, we now understand that some diseases are caused by tiny changes in a single gene. Cystic fibrosis is caused by a change in one of the bases, resulting in overproduction of sticky mucus in the lungs and damage to other organs.

Other diseases involve multiple genes whose identity, importance and interplay are just starting to be discovered.

We now know that all cancers are genetic -- the result of flawed genes inherited from birth or, far more commonly, damaged during life. A key area of cancer research involves exploring genes that cause or allow cancer to spread, and developing targeted tests and drugs based on that knowledge.

"People are treated today, in most cases, as they were 50 years ago," with chemicals that kill healthy cells along with cancerous ones because there's no way to distinguish the two, said Tyler Jacks, director of the Center for Cancer Research at Massachusetts Institute of Technology.

But that is changing as a new generation of designer gene drugs emerge. The first, Rituxan, was approved in 1997 for lymphoma, followed by Herceptin for breast cancer in 1998 and Gleevec for certain stomach cancers and leukemias in 2001.

DNA is reshaping medicine in other ways:

--GENE TESTS: People can find out if they have faulty genes that put them at higher risk of developing specific diseases, such as Huntington's or breast cancer, and use that information to make decisions about whether to have children or preventive treatment such as a mastectomy. They also can screen embryos for signs of these diseases before pregnancy.

--GENE THERAPY: Although it's still extremely experimental, scientists are trying to cure some diseases by giving patients healthy genes they lack. About 200 such experiments are under way in the United States; more than half are to treat cancer.

But the field has been plagued by setbacks and concerns that some of these therapies may cause serious side effects, including cancer and death. In 2000, the National Institutes of Health set up a hotline for gene therapy patients; officials counted 652 cases of serious side effects and six unexplained deaths.

--BIOENGINEERED DRUGS: Genetic manipulation has created new kinds of drugs and vaccines, starting with Humulin: a human insulin produced by genetically engineered bacteria, in 1982.

--PERSONALIZED TREATMENTS: DNA computer chips, called microarrays, can analyze thousands of genes -- or the proteins they make -- in a single tissue sample, and reveal which are fueling a patient's disease. They're still experimental, but scientists hope to use them soon to detect diseases, monitor how treatments are working and even predict whether a drug will help someone before the first dose is given.

"We treat diseases through proteins," and having a tool to show which ones can help a patient could revolutionize treatment, said Josh LaBaer, a leading microarray researcher at Harvard Medical School.

Gene tests already are shaping some treatment decisions. For instance, at Memorial Sloan-Kettering Cancer Center in New York, doctors test bladder cancer patients for a particular gene. If they have it, chemotherapy is tried; if they don't, surgery is the only option.

--RESEARCH TOOLS: Mice can be engineered to lack or to possess a specific gene so that they model a particular human disease. These mice then are used to test drugs and treatments before they're tried on people.

UW scientists recently figured out how to do this in human embryonic stem cells -- master cells that can form any tissue in the body -- offering another potential tool for testing drugs without putting people at risk.

--CELL THERAPIES: For roughly 30 years, doctors have given transplants of adult stem cells from bone marrow or the bloodstream to treat a variety of cancers. But other cell treatments, such as fetal tissue transplants for Parkinson's disease, have produced mixed and often disappointing results.

Madison scientist James Thomson's isolation of embryonic stem cells in '98 has led to a revolution in thinking about the capabilities of cell therapy and led to a resurgence of research on all types of stem cells for many diseases besides cancer.

--TISSUE ENGINEERING: Researchers are engineering cells to form structures such as ears and noses on cellular scaffolds in the lab. In one case, a plastic surgeon at Brigham and Women's Hospital in Boston made an ear for a child born without one, and another New England scientist made a chest bone for a boy to cover and protect his heart, said Robert Langer, a tissue engineer at MIT.

He recently showed that genetically engineered cells have "shape memory" that can take a desired form, such as a nose.

But biological and medical studies don't have exclusive rights to DNA. Indeed, other fields, such as law and agriculture, have picked up the molecule and used it for their own needs.

Genetic analysis: Since the late 1980s, when ways to analyze an individual's DNA became cheap and easy, lawyers, forensic experts and detectives started using it as a tool for defense and prosecution.

"It is so exact," said Norm Gahn, Milwaukee County assistant district attorney and a nationally recognized advocate of DNA fingerprinting.

Scientific courtroom evidence used to consist of just fingerprints, handwriting and blood type. But with those techniques, the chance for error was still one in 1,000.

DNA testing has improved those odds to one in a sextillion; that's a one followed by 21 zeros.

"That provided really compelling evidence," said Gahn. "You'd just watch the jurors as they were presented with this stuff -- all those bands matching up. And you could see how effective it was."

New databases that catalog the DNA of every convicted felon make matching even easier.

But with such a powerful tool come some formidable questions and concerns about privacy and abuse.

"You worry that information will end up in the wrong hands. In the hands of somebody with the wrong philosophies," said Gahn.

Other concerns about DNA include privacy and ownership. For instance, who has rights to someone's genetic material after his or her death, and what are the ramifications of giant gene-banking efforts under way around the U.S. and in many other countries.

"We're not really prepared to understand all the implications of having genomic information out there," said Bruce Birren, assistant director of the sequencing center at the Whitehead Institute, a genome research center in Cambridge, Mass.

So, as these topics are debated at bioethics forums, in legislative halls, on talk radio shows and in the pages of books, the science of gene technology pushes forward.

And we're only 50 years into it.


DID YOU KNOW?

--Orchids have 10 times the amount of DNA as humans.

--Gophers have 88 chromosomes, compared with humans' 46, but their genome is 95 percent the same as ours.

--In 1999, an artist named Eduardo Kac persuaded a laboratory to design a genetically engineered rabbit whose DNA contains genes from a phosphorescent jellyfish. If you hold the animal to a black light, it glows green.

--In 1993, a March of Dimes poll found that 43 percent of Americans would engage in genetic engineering to enhance their child's looks or intelligence.


By Susanne Quick and Marilynn Marchione



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Copyright © 2003 Milwaukee Journal Sentinel. Distributed by Knight Ridder/Tribune Business News.

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