In what many scientists say is a revolution in biology, a giant new project is rewriting our understanding not only of what causes diseases or what makes our eyes a certain color, but what makes us human. And it turns out scientists have been looking in the wrong place for a very long time.
The bounty of new discoveries, released in a batch of 40 research papers on Wednesday, shows the stretches of DNA that we call genes are only a very small piece of what makes the body work. Much more important is the stuff in between the genes – stuff once dismissed as “junk DNA”. It turns out that junk DNA is what is in control, they report in the series of papers in the journals Nature, Science and elsewhere.
“This has opened up whole new galaxies. It’s like having a bigger telescope,” says Dr. Bruce Stillman, president of Cold Spring Harbor Laboratory, which played a major role in the work.
Scientists already knew in 2003, as they finished the giant Human Genome Project, that they did not have the understanding they had hoped for. It turned out that humans had just a measly 22,000 genes – fewer than some animals and far fewer even than a plant such as rice. How could something as complex and advanced as a human be boiled down into something so simple?
“We understood precious little about the processes that turns genes on and off. In short we had more questions than answers about how the human genome works,” said Dr. Eric Green, director of the National Human Genome Research Institute, which conducted the study.
The next phase of work, called ENCODE for Encyclopedia of DNA Elements, shows there’s nothing simple about it. As many as 40 million different switches are controlling these genes, turning them on and off in complex and subtle ways.
“The genome is loaded with gene controlling switches. There are literally millions of these,” Dr. John Stamatoyannopoulos of the University of Washington, who worked on the studies, told reporters in a telephone briefing.
Dr. Francis Collins, director of the National Institutes of Health, calls the findings “awesome and elegant.”
“This is the first truly comprehensive view, of how the three billion letter instruction book for human biology actually carries out its work, across many tissues and over the course of development,” he told NBC News in an interview.
Stanford University genomic expert Michael Snyder says it looks like gene mutations -- the changes in DNA sequences that we associate with causing diseases -- may only affect rare diseases. Common diseases, like heart disease, cancer, and allergy, are probably controlled elsewhere. “We think that most of the changes that affect disease don’t lie in the genes themselves, but the switches,” Snyder says.
So treating these common diseases may lie in trying to affect the switches. “The pharmaceutical industry has largely given up on genomics and the genome in favor of older approaches,” said Stamatoyannopoulos. These new findings may reinvigorate new drug research, he said. “Now we have a huge amount of genetic data about human disease that we can actually put to work to find the right kind of genes and proteins to target,” he said.
This new data will also help doctors diagnose disease in the first place, predict which treatments will work best for patients, and monitor their progress. It points the way to studies to determine the causes of hundreds of diseases including all kinds of cancer, Alzheimer’s disease, schizophrenia, heart disease, type 1 and type 2 diabetes, lupus, rheumatoid arthritis and asthma. It also may lead to a better understanding of how our genetics determine such non-disease factors as height, weight and expected life span.
Not only that, it also can help explain why humans and chimpanzees share 98 percent or more of our genes, yet are so different.
"Genes occupy only a tiny fraction of the genome, and most efforts to map the genetic causes of disease were frustrated by signals that pointed away from genes. Now we know that these efforts were not in vain, and that the signals were in fact pointing to the genome's 'operating system' -- the instructions for which are hidden in millions of locations around the genome," said Stamatoyannopoulos. "The findings provide a new lens through which to view the role of genetics and genome function in disease."
Another surprising finding was that the regulatory circuitry blueprints could be used to pinpoint cell types that play a role in specific diseases -- without requiring any prior knowledge about how the disease worked. For example, DNA changes associated with Crohn's disease (a common type of inflammatory bowel disease) are concentrated in the switches controlling two types of immune cells.
Researchers can use this same method to identify cell types not previously known to play a role in a particular disease, expanding our understanding of the disease process and potentially leading to new therapies.
"We now have a parts list of what makes us human," says Mark Gerstein of Yale university, who worked on the project. "What we are doing is figuring out the wiring diagram of how it all works."
The findings rewrite biology 101 for most of us. Each gene, we were taught, provided the code for a single protein. The proteins were the building blocks of cells, and the products made by the cells, from compounds called growth factors to signal-carrying chemicals. An intermediary genetic structure called RNA carried this information. ENCODE shows this is not quite so straightforward, that RNA generates the 40 million switches that can affect how and when many things happen within the cells.
“This is another grand chapter in the ongoing and historic research story that is unraveling the details about how life works, and how disease occurs,” Collins said.
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