The Year of Miracles Part 2
Scientists could ignore these signs largely because they seemed to be making progress. By combining new DNA-sequencing tools ith studies of inherited diseases in large families, medical geneticists identified the genetic culprits responsible for
cystic fibrosis, Huntington's disease, Duchenne muscular dystrophy and a host of other diseases. Each of these "all or none" diseases is caused by a mutation in a single protein-coding region of the DNA. Few diseases, unfortunately, work so neatly. In particular, the search for genetic bases of common diseases that affect large numbers of aging people came up empty.
During this lull, a visionary physician-scientist named Leroy Hood, now at the Institute for Systems Biology in Seattle, was growing impatient. Genetics, he recognized, was still a cottage industry of government-funded university professors, who each
directed a small group of students and technicians to study an isolated gene. At the pace research was progressing, it would have required 100,000 worker-years of concerted effort to decipher just one complete human genome.
Hood thought it was absurd that genetic scientists spent nearly all their lab time performing tedious and repetitive
mechanical and chemical procedures. At the same time, he grasped the far-reaching implications of a fundamental fact: while even the simplest organism is immensely complicated, the primary structures of its most complicated parts—DNA and proteins—are very simple. The alphabet of DNA contains only the four chemical letters (or bases) A, C, G and T, and proteins are made from just 21 amino acids. Hood saw that this simplicity would make it possible for robots and computers to read and write DNA and proteins more quickly, accurately and cheaply than human beings.
The rest of the biomedical community refused to believe that robots could analyze something as complex as a living system.
And in any case, no practicing geneticist had the capacity to design such machines. Unable to obtain government grants, Hood
secured private funding to bring together dozens of scientists, engineers and computer programmers (far larger and more
diverse than any other genetics team). They proceeded to invent the first generation of molecular-biology machines. Two read
and recorded information from DNA and proteins respectively (a process known as sequencing), and two others worked backward,
converting digital electronic information into newly written sequences of DNA or protein.
Hood completely transformed the biomedical enterprise. DNA-writing machines give genetic engineers an unlimited capacity to create novel genes that can be studied in test tubes or added to the genomes of living organisms. And protein-writing and - reading machines provided drug firms with the ability to create a new generation of protein-based drugs. The DNA-reading machines suddenly made it conceivable to crack the 3 billion-base sequence of an entire human genome. In 1990 the U.S.
government embarked on a 15-year, $3 billion project to do just that.
Eight years later, however, the project—parceled out to many U.S. scientists—was still less than 10 percent complete. Now it
was biotech entrepreneur Craig Venter who was frustrated. Convinced that government-funded workers were the problem rather than the solution, Venter enlisted private funding of $200 million to build an enormous lab filled with hundreds of automated machines, working 24/7, overseen by a handful of technicians. Within three years, the first reading of a human genome was essentially complete.
Armed with data from the genome project, scientists figured they'd surely be able to crack the really hard diseases, like
cancer and heart disease. But a funny thing happened when they began to look closely at this vast storehouse of genetic information. Geneticists Andrew Fire and Craig Melo galvanized the field by discovering a key mechanism that had been completely overlooked—the cellular process of RNA interference. (They shared a Nobel Prize in 2006 for the work.)
Finding evidence of extraterrestrial life couldn't have come as a bigger shock. Geneticists had taken for granted that the
machinery of cells involved genes directing the production of proteins, and proteins doing the work of the cell. Here was a
process that didn't involve proteins at all. Instead, tens of thousands of hitherto mysterious regions of the human genome—
part of the so-called junk DNA—directed the production of specific molecules called microRNAs (consisting of bits of RNA, a well-known component of cells). These microRNAs then oversaw a whole new process, called RNA interference (RNAi), that served to modulate the expression of DNA.
The good news was that RNAi could open up a whole new approach to biomedical therapy (more on that later). But RNAi also made
it clear that the fundamental unit of heredity and genetic function is not the gene but the position of each individual DNA letter.
To make it all harder to fathom, each bit of DNA is susceptible to mutation and variation among individuals. Of the 3 billion
DNA bases in the human genome, geneticists identified about one tenth of one percent (millions) that differ from one person
to another. Variations in these particular letters—called "snips," or SNPs, for single nucleotide polymorphisms—have replaced genes as the unit of heredity.
Many scientists responded to this devastating realization by going into a funk. "It will be difficult, if not impossible, to
find the genes involved [in common diseases] or develop useful and reliable predictive tests for them," Dr. Neil Holtzman,
director of genetics and public policy at Johns Hopkins University, said in 2001.
Fortunately, another visionary scientist, Kari Stefansson of Iceland, was already blazing a trail out of this thicket. If the genome was far more complex than scientists had thought, they would need to test for many more variables, and to do that they would need more test subjects. To find the cause of diseases would now require the participation of very large groups of genetically related people.
Like Hood and Venter, Stefansson was originally motivated by frustration with the pace of research. In the United States,
where most of the disease-gene-discovery projects were being conducted, most people cannot trace their ancestors back more
than a few generations, and the largest families consist of a few hundred living subjects at most. Subject panels of this
size failed to provide sufficient data to identify the genetic bases for complicated and variable common diseases. Stefansson
decided to solve this problem by taking aim at the largest well-documented extended family that he knew—his own.
Nearly all the 300,000 citizens of Iceland can trace their ancestors back, through detailed, public genealogical records, to the Vikings who settled this desolate European island more than 1,000 years ago. Stefansson gave up his faculty position at Harvard Medical School to return to Iceland, where he founded the company deCODE Genetics in 1996. He persuaded the Icelandic government to provide deCODE with exclusive access to the health records of its citizens in return for bringing investment capital and high-tech jobs to the capital, Reykjavik. So far, more than 100,000 Icelandic volunteers have donated their DNA to deCODE.
Stefansson's project was roundly criticized by international bioethicists and other geneticists for violating the privacy of
Icelanders (even though 90 percent of the population approved). Nevertheless, he persevered, placing "the genealogy of the
entire nation on a computer database," together with the health and DNA records of still-living individuals. The power of
large numbers was soon apparent. In a study of obesity, he directed his software to look for SNPs associated with subsets of the population who were either extremely overweight or very thin. Within just a few hours, it began finding evidence that
variations among particular DNA letters indeed played a causative role, confirming SNPs as the new unit of inheritance.
As of September, deCODE has made progress in identifying SNPs that may play a role in 28 common diseases, including glaucoma,
schizophrenia, diabetes, heart disease, prostate cancer, hypertension and stroke. In some cases, such as glaucoma and
prostate cancer, deCODE's findings could lead to diagnostic tests for identifying people at risk of developing the disease.
In other instances, such as schizophrenia, links to particular proteins have led to insight about the cause of the disease,
which could lead to therapies. Buoyed by Stefansson's success, other geneticists were eager to perform large-scale family studies, yet few had similar access to ancient genealogical records. But serendipity would deliver an epiphany: it's possible to study the entire human population as a single extended family, provided scientists collect enormous amounts of data. Eric Lander, an MIT professor and the intellectual leader of the U.S. government effort to sequence the first human genome, realized scaling up would require a new approach. In 2004, Lander persuaded MIT and Harvard to combine their enormous resources toward the creation of the Broad Institute. Backed by $200 million from billionaire philanthropists Eli and Edythe Broad, the institute is driving the development of ever more advanced genetic technologies. One technology, based on computer-chip fabrication, can identify
DNA base letters present at 500,000 SNPs in the genomes of 40,000 or more people. Think of this as a spreadsheet with 500,000 columns (each representing a specific SNP) and 40,000 rows (one for each person). To hunt for a genetic basis for, say, bipolar disease, the computer searches rows of people who have the disorder, checking column by column for an unusually high frequency of particular letters in comparison with people without the disease. As it turns out, a collaboration of American and German researchers has done this work—and found that variations of DNA letters in 20 different positions are influential in bipolar disease.
Incredibly, most disease-causing variants are the most common ones present in the human population: the strongest-acting one,
for instance, exists in 80 percent of people without bipolar disease and 85 percent of people with the disease. The
implication is that these variants are beneficial in some way, and cause problems only when their number exceeds a threshold.
To make sense of this complexity, scientists would like ultimately to build a vast international database that contains the complete sequence of DNA bases in the genomes of hundreds of millions of people. Ideally, such a database would be available for analysis by all biomedical researchers and would provide the foundation for understanding the genetic components of all human traits. That sounds like a lot of data—think of a spreadsheet with 3 billion columns and 100 million rows—but computing power is getting cheaper by the year. Within a decade, the cost of obtaining a sequence of all 3 billion DNA letters in an individual's genome will drop from $2 million now to $1,000. It will be a routine part of a person's health record, enabling physicians to prescribe genome-specific preventions and treatments.
The discovery of RNAi, meanwhile, suggests a completely new personalized form of disease therapy. Whereas drugs act on
proteins, RNAi therapy would act on the expression of DNA itself, potentially preventing or reversing diseases such as
Alzheimer's, Parkinson's, Huntington's, bipolar disorder, schizophrenia and others. Old-school pharmaceutical firms have
taken notice. The largest ones are betting heavily on the gene-targeted RNAi therapeutic approach to fill product pipelines,
as the discovery of traditional chemical drugs becomes more elusive. Novartis and Roche have both signed nonexclusive
licensing deals with the biotech firm Alnylam (founded by Phillip Sharp) for new therapeutic techniques that are valued at up to $700 million and $1 billion respectively; Merck paid $1.1 billion to buy another biotech company outright, solely to
obtain its contested portfolio of RNAi intellectual property, and the London-based drug firm AstraZeneca has a $405 million
licensing deal with Alnylam's competitor Silence Therapeutics.
The explosion of genetic discoveries shows no sign of letting up any time soon. New diseases are being added to the list
every month, and biologists are rapidly parlaying gene- and SNP-disease links into a deeper understanding of how proteins and
other molecules can misbehave to cause different medical problems in different people. And other scientists are working to advance the biology revolution (accompanying interviews). As a result of their efforts, many children born this year could
very well be alive and healthy at the dawn of the next century, when they may look back in awe at the annus mirabilis of biomedical genetics in 2007.
