Nessa Carey: The Value of ENCODE

The C. elegans connectome.

by Nessa Carey, author, The Epigenetics Revolution

Aren't we humans marvellous, with our trillions of cells, our long life spans, complex organs and higher cognitive functions? How lovely to look down on the lower creatures, like a humble microscopic worm called C.elegans. Poor old C.elegans, with its measly 1024 cells, pitiful little organs and limited brain power. You might as well compare a single Enid Blyton story with the complete works of Shakespeare. You'll never find a worm doing the fantastic things we can do, from creating the rules of ping-pong to sequencing the entire three billion letter alphabet of the human genome. Yet it was that very achievement, just over a decade ago, that made scientists feel a little less smug about our status as superior organisms.

It had long been assumed that we humans are top of the evolutionary tree in complexity because we possess the most complicated DNA blueprint (our genome). And it's certainly true that each of our cells contains a lot more DNA than that of poor old C.elegans. But the unexpected finding from the 2001 sequence release was that we and the little worm have almost exactly the same number, and same types of genes (a gene being defined as a stretch of DNA that codes for a protein, the business molecules in cells). We and the worm each possess around 21,000 genes. The only reason our genome is so much bigger is because we have loads of DNA that doesn't code for proteins. In fact, a whopping 98 percent of our genome is this non-coding DNA, more cruelly referred to as "junk."

But as the old Victorian expression about finding value in rubbish has it, there's brass in muck. A huge consortium of scientists has spent the last six years sifting through this supposed garbage tip of DNA and now the ENCODE (Encyclopedia of DNA Elements) project is starting to find the vast number of tiny flecks of gold and gemstone fragments that account for the overwhelming richness of the human organism.

Imagine you are standing on the top of one of the Himalayan peaks, of about 25,000 feet, on a day with cloud cover up to 20,000 feet. All you would see would be the other mountain peaks. That's the situation we were in when we first decoded the human genome and saw only the genes. Now, with ENCODE, the cloud has partially cleared and we can see not just how the mountains are linked together, but details of the valleys, the bridges, the forests, the villages and much more besides.

The junk DNA is actually crammed full of information. It's as if Shakespeare wrote fifty lines of stage direction for every line of dialogue. And what stage directions. Forget about "Exit, pursued by a bear." These would be more along the lines of "If performing Hamlet in Vancouver and The Tempest in Perth, then put the stress on the forth syllable of this line of Macbeth. Unless there's an amateur production of Richard III in Mombasa and it's raining in Quito."

Similarly, the various bits of junk DNA are saturated with such instructions. These act like volume controllers, governing how strongly individual genes are expressed in specific cells at different times, and how they respond if the environment changes. The human genome employs a huge variety of molecules and mechanisms to make the greatest use of this additional level of information. By contrast, there is very little of this extra complexity in the C.elegans genome and the tiny worm is stuck with a relatively rigid pattern of gene expression and is far more hard-wired than us. In visual terms, both we and the worm have a a palette of primary colours but the lower organisms aren't able to mix them to create hundreds of different shades.

The differences extend all the way through the kingdom of life. Humans and chimps share in the region of 99 percent of the genetic instruction book, but yet again we humans are able to use our information in a greater and more sophisticated variety of ways. This is particularly the case in the brain, and may be the explanation for why we are the smartest of all the apes.

Of course no system is perfect, and especially one that is designed to confer a lot of flexibility. Ever since the human genome was sequenced, scientists have been puzzled by really odd research findings. When they have searched the genome to find regions that are associated with risks of diseases in humans, from multiple sclerosis to type two diabetes, they were bemused to discover that the suspect regions weren't in genes. The findings from ENCODE are starting to show that many of these candidates for disease susceptibility are in parts of the junk DNA that control expression of key genes in relevant cell types.

It's not clear yet if the new data will help us treat human disease. Each individual component of the vast regulatory networks may in isolation only have a relatively minor effect. Creating a drug to target just one regulator may have as little impact as removing one small brick from a large well-designed house. But the more we understand the regulatory networks involved in health and disease, the more chance we have of identifying the key vulnerable pinch points in our organ systems, and this may drive new treatment approaches.

ENCODE has cost nearly $200 million and involved hundreds of scientists so far, and is by no means finished. Some scientists are concerned it could start to consume a disproportionate amount of funding. After all, there will always be more cell types to analyse, more details to explore and new questions to ask. To go back to the mountains analogy, do we need to see the houses in the village or the rice in the pots in the houses? But after such a spectacularly successful start, it's unlikely that the foot will come off the gas pedal just yet.

Michael White: A Genome-Sized Media Failure

Visualizations of networked linkages between genetic components broadly across the human genome (right) and in a smaller, hierarchically arranged subset (left). Image: Gerstein et al./Nature

Last week, the large genome sciences consortium ENCODE (ENCyclopedia of DNA Elements) made a big splash by presenting its long-awaited results in a publishing extravaganza. This was a fantastic opportunity for scientists and science journalists to explain to the public some of the exciting and important research findings in genome biology that are changing how we think about health, disease, and our evolutionary past. But we blew it, in a big way.

If you read anything that emerged from the ENCODE media blitz, you were probably told some version of the "junk DNA is debunked" story. It goes like this: When scientists realized that classical, protein-encoding genes make up less than 2% of the human genome, they simply assumed, in a fit of hubris, that the rest of our DNA was useless junk. (You might have also heard this from your high school or college teacher. Your teacher was wrong.) Along came the ENCODE consortium, which found that, far from being useless, junk DNA is packed with functionality. And so everything scientists thought they knew about the genome was wrong, wrong wrong.

The Washington Post headline read, "'Junk DNA' concept debunked by new analysis of human genome." The New York Times wrote that "The human genome is packed with at least four million gene switches that reside in bits of DNA that once were dismissed as 'junk' but that turn out to play critical roles in controlling how cells, organs and other tissues behave."

Influenced by misleading press releases and statements by scientists, story after story suggested that debunking junk DNA was the main result of the ENCODE studies. These stories failed us all in three major ways: they distorted the science done before ENCODE, they obscured the real significance of the ENCODE project, and most crucially, they mislead the public on how science really works.

What you should really know about the concept of junk DNA is that, first, it was not based on what scientists didn't know, but rather on what they did know about the genome; and second, that concept has held up quite well, even in light of the ENCODE results. Among the reasons that scientists in the 1970s and '80s began to believe that much of the genome is non-functional was the observation that very similar species could have very different genome sizes. There is no reason to believe that similar species require dramatically different amounts of functional DNA, and thus something other than functional requirements must explain differences in genome size. Scientists also discovered that our genomes contain parasitic, virus-like elements called "transposons" that have the ability copy themselves within our cells. This DNA ecosystem makes our genomes more like a jungle than a precision machine. At the latest count, transposon-derived DNA makes up at least half of our genome. The transposon-derived sequences in our genomes do not have to be explained by invoking some useful function for it. There is no mystery here: this DNA is there because it can replicate.

The primary scientific task of the ENCODE group was to scope out the biochemical landscape of the genome, and put the resulting data out as a resource. The Human Genome Project gave us the text of our genome, but this text is essentially impossible to read without an interpretive guide of key biochemical landmarks. ENCODE, in what was a genuine, technological tour-de-force, measured dozens of different kinds of biochemical landmarks, which can be suggestive of important functions, but do not by themselves demonstrate that a region of the genome is doing something useful for us. This distinction was obscured by the press releases put out by ENCODE, and largely lost on most of the reporters who covered the story. Missing from press releases and news reports was a description of what non-functional DNA looks like: it carries many of the same biochemical landmarks as functional DNA. The widely reported claim of debunked junk DNA is simply wrong.

The media reports on ENCODE used the word 'breakthrough,' but it is too early to fully measure the success of ENCODE, despite the high quality of the data. Ten years out, the reference human genome sequence is a must-have tool for nearly all biomedical researchers. Will the ENCODE results become equally indispensable to our efforts to understand the connection between our genomes and our health? ENCODE's results are very big, but not comprehensive: they don't include every type of cell or class or regulatory protein that we're interested in. As our genome technology improves (which it is doing at a rate that might put the iPhone to shame), we may decide that we need to re-do much of the work done by ENCODE.

And many are worried that our funding agencies have become addicted to Big Science,
prioritizing massive data generation efforts over the more idea-driven work of smaller, individual labs.

The most damaging aspect of our massive failure to get the ENCODE story right was that readers were served up a terrible distortion of the scientific process. A rule of thumb you should apply whenever reading about supposed breakthroughs is this: past scientists weren't as dumb or credulous as they're made out to be. Scientists tend to be a cautious and skeptical lot, not given to cooking up new theories based on a blithe and arrogant dismissal of what they don't understand. They work hard to base their ideas on the best data available at the time, and then they work hard to come up with even better data.

Dr. Michael White is a systems biologist studying genes and their regulation, in the Department of Genetics and the Center for Genome Sciences and Systems Biology at the Washington University School of Medicine in St. Louis. He is co-founder of the online science pub The Finch and Pea.

In the News: New DNA project shows us living beyond our genes

Well, once again, one man's junk is another man's treasure!

New DNA project shows us living beyond our genes

by Robert Bazell and Maggie Fox, NBC News
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 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.