Human Genome Effort on Verge of Next Great Step

As the behemoth, brute-force effort to decipher the structure of the human genetic code wraps up, scientists are feeling at once giddy over the accomplishment and awed by the challenge and promise it holds for future research.

Scientists are weeks--perhaps days--away from their goal of compiling a massive database containing the “sequence” of the human genome, the hugely complicated instruction manual for making a human being.

Decades of work since the landmark 1953 discovery of the structure of DNA have shed some light on what it is that makes us human--and susceptible to disease and, ultimately, death. But the real answers still lie down the road.

The genome will make it possible for scientists to travel that road. As Dr. Francis Collins, director of the National Human Genome Research Institute, likes to paraphrase a passage from a Winston Churchill speech, sequencing the genome is not the end, or the beginning of the end, but simply the end of the beginning.

Already, burgeoning banks of data, accessible at the click of a mouse, have transformed the work of scientists who know too well what it’s like to spend years at the lab bench trying to find a gene--just one--before they can start studying it.

Now, with more than 30 creatures’ genomes already sequenced (including those of crucial experimental animals, such as a small worm and a fruit fly) and the human genome on the verge of completion, scientists have tens of thousands of genes to play with.

The pace of new genetic discoveries has never been brisker. The potential for scientific understanding and for medicine is huge.

But that potential won’t be realized overnight. Exciting as the genome project is, cures do not automatically follow. Even with diseases for which scientists have already found crucial genes, such as Huntington’s disease or cystic fibrosis, the search for a cure has been laborious at best.

And to simply have the genome provides little understanding in and of itself. The rewards come from deciphering all this bounty.

That is the gigantic challenge.

“Having the instruction book is an incredible moment--all of biology and medicine is going to be divided into what we did before that and what we did after that,” says Collins, whose institute is part of the National Institutes of Health. “But it’s still just an instruction book. We don’t know how to read it. We don’t understand the language well.”

This is biomedical science’s mission to the moon, one that will eventually make a night-and-day difference in the understanding of human biology, as well as in the practice of medicine.

The 10-year effort is drawing to a close as government and private scientists race each other toward the finish line. Celera Genomics, a biotechnology company that started sequencing the human genome two years ago, announced recently that it expects to complete its first draft of the genome in June. The Human Genome Project, a publicly funded, international effort, predicts that it will finish its first draft that month as well.

More work must be done before these drafts--which will cover the bulk, but not all, of the genome--are checked and finalized.

The information is essentially there, laid out in endless strings of A’s and Cs and Ts and Gs, scientists’ shorthand for four chemical building blocks that make up the information-carrying part of DNA.

But only a fraction of the total--maybe 5%--contains the 80,000 or so genes that contain the blueprint for making each human being. Many genes have been found. But it’s no easy feat to find the rest among the huge quantities of DNA chaff.

And finding is only the starting point. Simply having a gene doesn’t mean that you know what that gene does. Or how it acts with other genes to do things--grow a kidney cell, perhaps, or mend a muscle tear.

Or why a kidney cell and a muscle cell are so different, when both have the exact same genetic material--why human beings, in other words, have skeletons and brains and fingers and the rest instead of just being unsightly blobs of identical cells.

Why do things go wrong and cause disease? How do we cure those maladies, or stop them from happening in the first place? Why is one person prone to heart disease and another prone to cancer?

After all, while in broad-brush strokes our genomes are the same, every person’s--except in the cases of identical twins--is unique, containing subtle differences in those patterns of A’s, Cs Ts and Gs. Ferreting out the differences will be crucial for understanding what makes one person different from the next.

The prospect of finally finding answers, with a decoded genome to guide them, has even seasoned researchers excited.

“Man, who had any idea this would ever happen--it’s sort of incomprehensible, isn’t it?” says Larry Zipursky, a molecular geneticist at UCLA’s Howard Hughes Medical Institute.

“It’s mind-boggling. It’s thrilling,” says Steve Kay, geneticist at the Institute of Childhood and Neglected Diseases at the Scripps Research Institute in La Jolla. “It’s like we’ve all learned to surf and we’re on the Banzai Pipeline and it couldn’t be better.”

Monk’s Work Set Off Landslide of Interest

A century and a half ago, an Austrian monk, Gregor Mendel, toiled diligently in his monastery garden. Through elegant breeding experiments with pea plants, he witnessed genes in action by studying simple traits such as flower color or the wrinkled or smooth texture of the peas.

Mendel’s work was ignored until 1900, when three scientists rediscovered his papers. What followed was an explosion of interest in genetics, with researchers investigating myriad traits in plants, fruit flies, fungi, bacteria, viruses and more.

For years scientists pondered the nature of the gene. But they didn’t see how DNA could be involved: They thought it was too simple a chemical--too “stupid”--for such a sophisticated job.

But by the early 1950s, compelling experiments had shown that DNA was anything but stupid. And then things started to snowball. In 1953, scientists James Watson and Francis Crick figured out the structure of DNA. Soon after, researchers discovered what made DNA so “smart”: They cracked the code, revealing how different genes--different arrays of those four little building blocks--adenine, cytosine, guanine and thymine--direct the manufacture of wildly different proteins.

Proteins are the key to understanding so much about life: They are the workhorses of the cell, the molecules that do the bulk of the body’s jobs, acting together to make us what we are. Mistakes in amounts or structure of proteins--caused by mistakes in the genes that encode them--lead to terrible diseases, such as cystic fibrosis and cancer. Understanding proteins, as well as genes, is crucial for understanding life.

The dawn of genetic engineering in the 1970s helped to vastly quicken the pace of discoveries. A new age began--one of cloning genes and examining their structures and the proteins they encode, one by one by one. Cloning, in this sense, means extracting and isolating a gene from the genome, enabling scientists to learn so much more about how it is controlled and what it does.

Dazzlingly exciting at first, the cloning of genes--especially human genes--proved to be slow: It took 10 arduous years, Collins estimates, for his lab, in collaboration with several others, to clone the gene responsible for cystic fibrosis, for instance. That case is not an exception. Whole scientific careers have been consumed by the cloning and examination of a handful of the genome’s tens of thousands of genes.

Despite the many insights that have emerged, this pace is hardly ideal, says Dr. Leena Peltonen, chairwoman of the new department of human genetics at UCLA. She herself has worked for 25 years on a few human disease genes. Beyond being time-consuming, she says, working with just a few genes makes it hard to understand anything well.

“It gives you a very narrow window on the whole human being,” she says. “It’s like monitoring only one actor in a play when you should monitor a whole stage of actors.”

Out of necessity, too, scientists have studied genes that they could find--mostly ones with large, in-your-face effects on the body. Genes such as those responsible for cystic fibrosis, sickle cell disease or Huntington’s disease. Ones you couldn’t miss.

“Up till now,” says Peltonen, “we have basically looked where there has been light.”

Such genes are important. But there are many others with more subtle effects that contribute to devastating diseases afflicting many more people--such as heart disease, diabetes, mental illness and cancer. Scientists have found a few such genes; finding many more would teach medicine so much. Yet the genes’ very subtlety has made them hellishly hard to track down.

But it’s suddenly gotten much easier.

A New Way of Examining Life

If studying one gene at a time was the hallmark of the pre-genome era, studying hundreds and thousands at a time is a hallmark of the genome one.

A slew of new tools and a new, “think big” mind-set are in the wind, bringing with them a new genetic lingo: “functional genomics,” “pharmacogenomics,” “proteomics”--natty names for ways that scientists are mining the rich lode of genome data.

Together, such tools will enable scientists to reap much more from the genome than the simple ease of cloning-by-catalog (or “Nordstromics,” as Scripps’ Kay likes to term it).

They now have a new way of examining life.

At places such as UCLA’s human genetics department and Caltech’s new L.K. Whittier Gene Expression Center, banks of powerful computers for number-crunching genome data and newfangled “DNA chip” facilities are now center-stage players in research.

At Caltech, Brian Williams, a postdoctoral researcher in the lab of Barbara Wold, the center’s director, picks up a DNA “chip” in a carefully gloved hand. At first glance, what he’s holding looks like an old-fashioned microscope slide.

Peering more closely, though, one sees not a fusty anatomy specimen but 10,000 tiny dots of DNA, arranged in an orderly pattern. Each dot comes from a different mouse gene. A robot placed them there in a neat, precise grid.

Now Williams pops a chip--one that’s been experimentally treated--into a scanning machine. Up on his computer screen, something that looks like a nighttime city skyline blazes into view, in red, green, yellow and orange.

It’s a very precise (and very pretty) description of which genes--out of all those 10,000 on the chip--are active (being copied into proteins) or inactive in a muscle cell. There to see on just one small slide.

Using such chips, scientists hope they can answer one of biology’s most pressing questions: why cells in our bodies can be so different when they all contain the same genetic material. The answer, clearly, must lie in the turning on and off of different sets of genes in different tissues--one pattern for a muscle cell, a different one for a kidney cell. But which genes? In which tissues? Chips will shed much light on such questions.

They will also shed new light on disease, says Dr. Patrick Brown, a researcher with the Howard Hughes Medical Institute at Stanford University and a pioneer in this technology. That holds great promise for more sophisticated, fine-tuned treatments for killers such as cancer.

For instance, he says, “we’ve known for a long time that we can have 100 patients with a cancer that we would give the same name to--prostate cancer, perhaps, or breast cancer--and yet their whole response to treatment and their whole clinical course can vary widely.” The reason, medical researchers suspect, is that the cancers--however similar they may look--are actually different.

Brown and colleagues recently showed this for one cancer, non-Hodgkin’s lymphoma. Examining samples from patients, the team showed that aggressive, hard-to-treat lymphomas did indeed have different patterns of active genes than ones that had been easier to fight.

The implications for this and other cancers are obvious: If doctors could analyze patients’ cancers with chips, they’d have a much better idea of how to treat those patients.

Plethora of Diagnostic Tests Is Foreseen

So many changes, predict scientists, will come as fallout from cloning the genome: dizzying numbers of diagnostic tests for anything from one’s chances of getting colon cancer or one’s need to avoid demon drink to whether one needs to take a folate supplement; drugs, down the road, tailor-made for patients with particular genetic profiles--ones to better treat them without dangerous side effects.

Meanwhile, companies and research labs around the world are scaling up so they can study proteins in exquisite detail, offering even deeper insights. Bioinformatics--number-crunching all that genome data to make sense of things too complex for the human brain to fathom--is growing ever more important.

“People in white robes will definitely exist in the future, doing brilliant research,” predicts Pavel Pevzner, professor of mathematics, computer science and molecular biology at USC. “But it wouldn’t be crazy to think that, 10 years from now, 50% of biologists will be essentially working on computers.”

And the data just keep coming. Genomes of scores more creatures, it’s estimated, will be sequenced in years to come--including that of the mouse, an animal crucial for biomedical discovery because its biology is so similar to our own.

The ethical issues will be enormous. The splashiest applications may be a long time coming.

But no one doubts the impact that the genome will ultimately have--on not just medicine but on understanding practically every part of our biology, from how our nerves wire up to what makes a girl a girl and a boy a boy. From the perspective of the future, the efforts of molecular biologists up till now may well seem like ineffectual tinkering.

“When you look at the big picture, it trivializes these skirmishes about who’s going to get the genome finished first and when it’s going to happen,” says Melvin Simon, chairman of the division of biology at Caltech. “All that stuff I think will go down as a landmark.

“But the stuff that comes after is going to be unbelievable.”

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Active and Inactive Genes

Nearly every cell in the body contains the same set of genes. Yet a skin cell is different from a bone cell, which is different from a blood cell. Scientists know that in each cell, some genes are active and others are inactive, giving each cell its unique properties. But they don’t know which genes are responsible among cells. New technology allows them to study which genes are active and inactive in different cells and at different times.

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Source: laboratory of Dr. Patrick Brown, Stanford University