Carl Zimmer's Blog, page 25

A Living Drug Cocktail

We know that the 100 trillion microbes in the human body are important to our health. What’s harder to know is how to use them to make us healthy.

Normally, our resident microbes–the microbiome–carry out a number of important jobs for us, from fighting off pathogens to breaking down food for us. If they get disrupted, we  suffer the consequences. Sometimes antibiotics can upset the ecological balance in our bodies so severely, for example, that rare, dangerous species can take over.

For decades, doctors and scientists have searched for microbes that can promote our health by taking up residence in our bodies. They’ve had some modest success in treating people by giving them a single species at a time. (Don’t be fooled by all the so-called probiotic foods and pills you can buy over the counter–few, if any, have ever been scientifically shown to be effective.) Part of the problem has been that scientists haven’t been terribly systematic about searching for microbes. Very often, their most important standard for a probiotic germ is not its healing power, but its ability to survive in food, or packed into a pill.

Scientists have also had some limited success at the other end of the spectrum, by exploiting much of the microbiome’s diversity at all once. For some people with deadly gut infections, for example, the only cure is to get a so-called fecal transplant from a healthy donor. Fecal transplants show a lot of promise, but scientists don’t have a clear idea of how they work. A stool sample is loaded with hundreds of different species, any one of which might be either essential for overthrowing pathogens or just along for the ride.

In Nature today, a team of scientists report taking an important step forward in microbiome-based medicine. They searched for species methodically, in the same way medicinal chemists search for new drugs. They have pinpointed a handful of species living in the human gut that collectively show signs of fighting effectively against some autoimmune diseases.

Scientists have long suspected that the immune system would benefit from microbiome-based medicine. That’s because immune systems depend on the microbiome to develop normally in the first place. As a child’s immune cells grow and divide, they pick up signals from the microbes. Those signals teach the immune system to become tolerant. They can still recognize a dangerous pathogen and kill it, but they spare the beneficial bugs. And they also become less likely to overreact to a harmless molecule or our own tissues.

One important group of immune cell involved in this tolerance are known as Tregs (short for the CD4+ FOXP3+ T regulatory cells). They are abundant in the microbe-packed gut, where they help to broker a truce between host and the germs that live there. Tregs also depend on the microbiome for their very existence. When scientists rear mice without any germs at all, the animals develop very few Tregs. And as a result their immune system becomes prone to raging out of control.

A number of experiments have hinted that abnormal levels of Tregs are behind some autoimmune gut diseases, such as colitis, which causes chronic inflammation in the large intestines and diarrhea. This raises the possibility that a treatment for colitis would be to bring Tregs back to normal levels. Perhaps among all the bacteria in the gut, scientists could find the ones that sent the signals to the Tregs.

Over the past few years, Kenya Honda of the University of Tokyo and his colleagues have been hunting for those species. They started by testing out subsets of the microbiome to find groups of species that could foster the growth of Tregs. Raising healthy mice, they collected the mouse droppings, which contained lots of bacteria. They treated the droppings with chloroform, which kills most bacteria. The only microbes that survived were species that make spores tough enough to withstand the chemical.

When the scientists gave those spore-forming bacteria to germ-free mice, the level of Tregs in the animals went up. That didn’t happen when the scientists gave the mice other kinds of bacteria instead.

This discovery didn’t pinpoint exactly which bacteria were fostering Tregs. But it certainly narrowed down the line-up of suspects dramatically. And it also prompted Honda and his colleagues to start acting more like a drug company testing promising new compounds. In fact, Honda co-founded a company called Vedanta Biosciences for that express purpose.

Their goal now became finding a species, or a group of species, that live in humans, and which promote the growth of Tregs in the gut. Rather than taking the kitchen-sink approach of fecal transplants, they would try to deliver a surgically precise germ.

They took stool samples from a healthy Japanese volunteer and doused them with chloroform, so that once more they only had to contend with spore-forming species. Then they inoculated germ-free mice with different combinations of the surviving bacteria. After letting the bacteria grow in the mice, they then inspected the animals to see if any of them had high levels of Tregs as a result. They did find some of those combinations, and they went on narrowing down the suspects until  they were left with just seventeen species, along belong to a type of bacteria called Clostridia.

One particularly interesting result of the experiment was that they couldn’t get these good results from any fewer than those seventeen species. On its own, each of the species was unable to foster the immune cells. It may be a combination of signals from all seventeen species that promotes the Tregs.

The researchers wondered if these seventeen species played a special role in autoimmune diseases in humans. To find out, they looked at the microbiomes from health people and people with colitis. The seventeen species tended to be rarer in the sick people.  Perhaps, the researchers reasoned, losing this network of microbes weakens the signals that keep Treg levels normal. The immune system spins out of control, leading to colitis.

If that were true, then giving someone a pill with all seventeen species might be an effective way to fight colitis. But Honda and his colleagues weren’t ready to start inoculating people with Clostridia. Clostridia is a huge group of species that includes some very nasty characters that cause diseases like tetanus and botulism. They would have to do some preliminary work first.

All seventeen species were new to science (something that’s pretty typical for microbiome research), so the scientists sequenced their genomes. None of the seventeen species carried genes for toxins or other disease-causing proteins. From an inspection of their DNA, at least, the microbes looked safe.

Next, the scientists tested the bacteria out on mice. They gave the microbes to animals either suffering from colitis or from allergy-triggered diarrhea. In both cases, the bacteria raised the level of Tregs dramatically in the guts of the mice. The mice also partly recovered from their diseases. The mice with colitis had less inflammation, and the mice with diarrhea had healthier stool.

From here, the Vedanta researchers eventually hope to get to clinical trials on humans. As I wrote in April, turning bugs into drugs is a big challenge on many levels. For one thing, the FDA doesn’t have a long tradition of approving such research. And while Honda and his colleagues have certainly gone a long way to pinpointing how microbes foster Tregs, they have yet to work out the precise balance of signals that really matters to the immune system.

Nevertheless, a seventeen-bug cocktail would be appealing in many ways. For one thing, the microbes are regular residents of the human gut, dwelling their for people’s entire lifetime. And they only live in the gut, and not the heart or the liver or some other organ. Both these facts suggest that such a cocktail would be unlikely to cause harmful side effects. What’s more, the microbes would be able to deliver a steady, long-running dose of the chemicals necessary to keep Treg levels healthy.

The new study also points to a way to systematically search the microbiome for treatments for other diseases. It’s possible that small teams of other species handle other jobs in the body. They may nurture other types of immune cells, for example. Or they may send signals into the body that regulate body weight. By winnowing down the microbiome, scientists may be able to deploy those elite units to fight other diseases.

The Tangled Bank 2.0, Ready For Pre-Order

In 2009, I published The Tangled Bank: An Introduction. I intended it as a textbook for non-majors, as well as a guide to evolution for people looking for a thorough but non-technical account of how life has gotten to be the way it is. The project proved to be far more work than I had reckoned, but I was happy with how it turned out, especially thanks to the talented artists and designers I had the privilege to work with. The reception has been gratifying; the Quarterly Review of Biology, for example, called it “spectacularly successful.” A number of courses have adopted The Tangled Bank both in the United States and abroad.

It’s hard to believe that four years have rushed by since the book came out. A lot has happened in the world of evolutionary biology during that time, some of which I’ve tried to document here and in my articles. And so, next month, I’ll be publishing the second edition of The Tangled Bank.

I’ve tried to improve on the first edition in several ways. For one thing, I’ve brought it up to date with recent research. In the past couple years, for example, scientists have sequenced genomes of species such as the gorilla and the coelacanth, and they’ve discovered important clues in those genomes about our own ancestry. Here at the Loom I reported on how microbiologists have observed what may be the evolution of a new species in their lab. In The Tangled Bank, I’ve delved deeper into this research, to show how evolution rewired the microbe’s DNA and produced an organism capable of living in a new way.

I’ve also applied some lessons that I learned while co-authoring my other textbook, for biology majors. The big challenge in explaining evolution is navigating between concepts and examples. Too much conceptual material leaves an explanation bloodless and abstract. Too many examples leave it scattershot. To find the right balance, I and my co-author, Doug Emlen, worked closely with leading experts on different aspects of evolution (John Thompson on coevolution, for example). I’ve tried to strike that balance in the new edition of The Tangled Bank as well.

The most obvious change to the book is a new chapter. I decided to include a chapter dedicated to human evolution, where I can give a focused account of our own species and look at some of the new research on human origins. But I have continued to integrate our own species into other chapters. The new edition, at 394 pages, is a bit longer than the first edition, but I’ve been careful not to let the book get bloated.

I’ve also crammed it with even more illustrations and photographs, because they help so much to drive home the wonderment of evolution. The new cover, by Carl Buell, is a portrait of Ambulocetus, an early walking whale. I write about Ambulocetus in the first chapter, which you can download for free.

The publication date is August 23, but you can pre-order it now at my publisher’s site (the best deal), Amazon, Powell’s, and Barnes & Noble’s. Instructors can contact my publisher, Roberts & Company, for a desk copy.

The Mark of Cetology (Science Ink Sunday)

Dan Weston writes, “Given your interest in Moby Dick and tattoos, I thought you might appreciate my recent tattoo, based on an illustration by Rockwell Kent from the 1930′s edition (that I inherited from my grandmother and have read so many times that I had to have it rebound).”

Clearly, Dan has read my post from last year, “Herman Melville, Science Writer.”

For years I owned a copy of Moby Dick with Rockwell Kent’s dream-like engravings. The book disappeared a while ago, but the pictures remain how I see the story. The Plattsburgh State Art Museum has an online gallery of Kent’s illustrations here; I’ve reprinted the source of Dan’s ink below.

I think I need to buy myself another copy as a birthday present.

You can see the rest of the Science Tattoo Emporium here or in my book, Science Ink: Tattoos of the Science Obsessed.

Plattsburgh State Art Museum: http://clubs.plattsburgh.edu/museum/m...

Some of My Favorite Loom Posts To Tide You Over

I’m off this week for an extended Fourth-of-July break. I won’t be writing any new posts here (except for a pointer to my “Matter” column in the New York Times on Thursday).

But with nearly ten years of archives, I can offer some old favorites to read in the meantime, from oldest to newest:

Hamilton’s Fall: Why leaves change color in the fall.

Spite in a Petri Dish: Spite and bacteria are not two words that usually go together.

Two posts on eyes: building them up and taking them apart.

An Inordinate Fondness for Beetle Horns: A post on the research of Doug Emlen, who later became my textbook co-author.

Florida, Where The Living Is Contradictory: Evolution-based biotech and creationism thrive in the same state.

The Wisdom of Parasites: On discovering the emerald jewel wasp, a sinister brain surgeon.

Behold, For I Am The Giant Flatulent Raccoon! How Ann Coulter became obsessed with my appendix.

A Dead Dog Lives On (Inside of New Dogs): More details on contagious cancers.

Cystic Fibrosis? Blame Eve. A look at Young Earth Genomics–with a creationist making a fascinating guest appearance in the comment thread.

Question of the Day: How Do You Get Crabs from a Gorilla?

Dawn of the Picasso Fish: A fossil fish halfway to being flat.

The Human Lake: Medicine as ecology

“You, My Friend, Are a Wonderland”–What’s living in my bellybutton.

Mammals Made By Viruses

Are We the Teachable Species?

Tongue Parasites to the People of Earth: Thank You For Overfishing

Fifty-seven Years of Darkness: Evolving with the lights out.

The Birth of the New, The Rewiring of the Old: An experiment with E. coli produces what may be a new species

The Norovirus: A Study in Puked Perfection

So Long, Swarmageddon. My Post-Game Analysis In Today’s New York Times

I’ve lived in central Connecticut for ten years now, and so I missed their last emergence here in 1996. I was looking forward a June deafened by the songs of lovesick male cicadas, but my month turned out to be disappointingly quiet.

And yet, when my two daughters paid a visit to friends who live just seven miles away, they came home with a shoebox full of exoskeletons.

This year’s cicada emergence was anticipated by many millions of people in the eastern United States, but many of them missed it. But that doesn’t mean that the brood was a bust. Instead, it tells us something about they mysterious seventeen-year cycle of the cicadas.

In today’s New York Times I take a look back at Swarmageddon 2013, and look at what scientists learned about the bugs thanks to some newly invented tools. Check it out.

And see you next year in Iowa!

The Devil’s Tumor: Video of My Talk About Cancer & The Evolution of A New Form of Life

As you can tell from my recent posts, I am a bit obsessed about cancer–or more specifically something you might call the natural history of cancer. Cancers in the animal kingdom can get very strange–even giving rise to what I would call new species. Earlier this month, I gave a public talk in San Francisco as part of the International Evolution and Cancer Conference. The video is now up. I hope you find these strange cancers as spookily fascinating as I do.

Beating Evolution: My New “Matter” Column in the New York Times on Fighting Cancer

A number of the newest cancer drugs can give a few months of extra life to people in advanced stages of the disease. The drugs attack the cancer cells with pinpoint accuracy and wipe out the tumors. And then, months later, the tumors come right back. In my “Matter” column today, I take a look at the work of cancer biologists and evolutionary biologists to understand how this rebound happens, and how doctors might stop it. Check it out.

A Note To Beginning Science Writers

From time to time, I get letters from people thinking seriously about becoming science writers. Some have no idea how to start; some have started but want to know how to get better. I usually respond with a hasty email, so that I can get back to figuring out for myself how to be a science writer. I thought it would be better for everyone—the people contacting me and myself—to sit down and write out a thorough response. (I’m also going to publish a final version of this on my web site, here.)

First a caveat: I am probably the wrong person to ask for this advice. I stumbled into this line of work without any proper planning in the early 1990s, when journalism was a very different industry. The answer to “How do I become a science writer?” is not equivalent to “How did you become a science writer?”

I was the sort of kid who wrote stories, cartoons, and failed imitations of Watership Down. By college, I was working on both fiction and nonfiction, majoring in English to learn from great writers while trying to avoid getting sucked into the self-annihilating maze of literary theory. After college, I spent a couple years at various jobs while writing short stories on my own, but I gradually realized I didn’t have enough in my brain yet to put on the page.

In 1989 I wrote to some magazines to see if they had any entry-level jobs. I got a response from a magazine called Discover, saying they needed an assistant copy editor. I got the job but turned out to be a less-than-perfect copy editor, which means that I was a terrible copy editor. Fortunately, by then my editors had let me start to fact-check stories, which is arguably the best way to learn how to write about science. I got a chance to write short pieces, and I realized this was an experience unlike any previous writing I had done. I was writing about the natural world, but in nature I discovered strangeness beyond my own imagining. And scientists were willing to help me come to understand their discoveries. I stayed at Discover for ten years, the last four of which I was a senior editor there, and then headed out on my own, to write books, features, and other pieces.

In other words, I did not know in college that I wanted to be a science writer. While I took science classes because I enjoyed them, I didn’t get a degree in science. I didn’t go to graduate school for science journalism. I only had the good sense to recognize that I had fallen into a deeply satisfying kind of work.

That’s one reason to take my advice with a grain of salt. Another is the fact that for the first five years of my career, I did not have access to the Internet. I did not have email. At the time, magazine publishers did not see the point of rigging their computers to telephone wires. So my on-the-job training in science writing started in the antediluvian age when magazines and newspapers held a near-monopolistic control over science writing. The only alternatives were crudely printed zines which attracted only a tiny fraction of the circulation of large magazines, and none of their big-ticket advertisers.

All of that has changed, of course. BoingBoing, one of those crude zines, is now a hugely successful web site. It took a very long time for many in the science writing world to realize that change was coming, and many tried to ignore it once it had arrived. Just as I had stumbled into science writing, I stumbled into its online world. In the early 2000s I began enjoying the handful of blogs about science. When Natural History decided to stop publishing my essays, I realized that the essay genre was going to be a hard sell to other editors. So I set up a blog where I didn’t have to pitch someone beside myself.

At the time, blogs seemed like odd distractions. Along with everyone else, I had no idea that they would end up at the heart of science journalism. I also didn’t realize that traditional science journalism—and journalism in general—was undergoing a drastic change. Depending on who you talk to, a better word might be metamorphosis. Or collapse.

That’s why, as I write this note in 2013, I personally feel very lucky to have ended up making a living as a science writer, but I am very cautious in recommending it to others as a line of work. If you have decided that you want to become a science writer, make sure that your impression of the field is accurate. If you have a hazy sense of journalism as it was circa 1990, then you have to update your perceptions.

American newspapers enjoyed a great boom after the end of World War II, but that boom crested around 1990, and newspapers now employ fewer people than they did in 1950. During the boom years, newspapers hired lots of science writers for weekly science sections. At their peak, in 1989, there were 95 in the United States. Now there are 19. When newspapers try to stay profitable through cuts (never a wise strategy, but one that makes the books look good in the short term), the science section is often the first to go.

The same goes for magazines: if your image of science journalism in magazine dates back to the Reagan administration, it’s time to take stock. During the 1980s, there was an amazing boom of magazines dedicated solely to science–Discover, Omni, Science Digest, and on and on. The big magazines like Time and Newsweek had full-time staffers who wrote only about science. Yes, that’s right–I just called Newsweek a big magazine. Today they may be imploding, but once they had a building in Manhattan with their name on it. Like newspapers before them, magazines are now sliding. Many of the science magazines of yore have shut down altogether.

All that being said, some venues for science writing are thriving. They include traditional publications that are working out new ways to stay in business. And they include new publications that are not burdened by the bruising history of journalism. These old and new outlets will probably never support the same number of science writers there were the 1980s, for the simple reason that an article in the Los Angeles Times and an article in the Boston Globe are no longer separated by the 3000 miles that divide the two cities. They can sit side by side in two tabs on the same browser. On the other hand, it would be absurd to extend the trend in science journalism in a straight line from the past decline until it reaches zero.

If you have developed a clear-eyed view of science journalism, the next question to ask yourself is, “Is this a field I want to enter?” Once you set off into science writing, you do not automatically receive a staff job, a retirement package, and a list of great stories to write for the next fifty years. You enter a fierce competition, either for an entry level job or freelance assignments. Pay can be lean, even at high-profile publications. Find in yourself the strength to cope in this environment. Rejection is not a career-ending catastrophe in the world of science writing; it is a regular part of experience.

If you remain determined to go into the field, you may now be asking, “How do I start writing about science?” The answer is you start writing. It’s a bit like playing the trombone. If you walked up to a jazz band and announce that, after much thought, you think being a trombonist would be fun, they probably won’t hire you on the spot. They want to hear you play. A trombone teacher can help you become a better player, as can performing in school bands. But what matters most of all is those hours, day in and day out, that you spend alone practicing the trombone.

I direct this advice in particular at those graduate students in science who think that writing about science is more fun than doing it. I share your view. But that doesn’t mean that your hard work in graduate school has prepared you very well to write about science for a popular audience. The kind of writing that gets a paper published in the American Journal of Botany is not the kind that will get a story published in the Atlantic. Learning how to write about science takes work. To embark on that work, you should begin doing research for stories and writing several hundred words every day. Don’t be discouraged if, after several months, you still feel like you’re just getting the hang of writing about physics for a wide audience. It’s not easy.

It helps to read good science writers, too. If you want to write like John McPhee, charge through Annals of the Former World and figure out how he is doing the sort of thing that won him a Pulitzer. If you want to be a scientist who can speak in the public arena, reverse engineer the work of talented scientist-writers, like Siddartha Mukherjee or Steven Pinker. There are reams of excellent science writing to explore. A few years back, Loom readers crowd-sourced this list, which is pretty great.

Each budding science writer has to decide which path to take. I took the blind, twisted path I described earlier, but I’ve watched others take very different ones that led to solid careers. Some have started their own blogs, where they’ve taught themselves how to write in public. Others have simply boostrapped themselves as freelancers, starting with small publications and using those clips to get into bigger ones. Some have gone to graduate school for science journalism, where they’ve been trained by seasoned veterans and have been placed at leading publications as interns. Some scientists-in-training have become AAAS Mass Media Fellows. And other people veer off in unexpected directions. They started out in science writing and became radio producers, for example, or made animations, or built apps. These days, it’s vital to be prepared to go in a direction you couldn’t have predicted at the outset.

Along with strong writing in articles themselves, another important skill that often goes unappreciated is learning how to write a good proposal. You have to entice editors to get them to give you an assignment. And that requires a few things. First, you have to understand the story you want to write clearly enough that you can describe it in miniature in a pitch. You also have to understand the spirit of each publication you approach. Some magazines pride themselves in their intense nerdiness, while others see themselves as magazines for people who are curious but lack expertise. Some care most about a gripping narrative, while others put scientific detail above all else. Know the difference. And find stories that the editors can’t find themselves, the stories that they crave on their pages.

I could go on, but others have already done so and I shouldn’t replicate their fine efforts. Here are a few places to continue reading and learning:

On the Origin of Science Writers. Fellow Phenom Ed Yong crowd-sourced hundreds of stories of how people got into the business.

Pitch Publish Prosper: This site is the online home of an excellent book, The Science Writers’ Handbook.

Advice for Aspiring Science Writers: Kristen Delevich, one of the students who took my workshop at Yale, distilled some of my remarks about the craft of science writing (such as choosing your words carefully and building paragraphs like cathedral arches) in this blog post.

New To Science Writing? The National Association of Science Writers has a collection of articles for people starting out.

If you like audio, I have also spoken to audiences about my own experiences in science writing. Here’s a talk I gave at the University of British Columbia. And here’s a talk I gave at Story Collider, which was later aired on Radiolab.

So…this is about all I can think of as a response to the letters I get. I’m not sure if that covers everything, or if I’ve left something huge unaddressed. Feel free to leave a comment below, and I’ll update this post accordingly.

Listening to the Genome, Updated

I’ve updated yesterday’s post on the “dark matter” of the genome with replies from a co-author of the paper I wrote about.

Listening to the Genome: Music or Noise?

One of the great triumphs of twentieth-century biology was the discovery of how genes make proteins. Genes are encoded in DNA. To turn the sequence of a gene into a protein, a number of molecules gather around it. Reading its sequence, they produce a single-stranded version of it made of RNA, called a transcript. The transcript gets shipped to a cluster of other molecules, the ribosome, which picks out building blocks to construct a protein that corresponds to the gene. The protein floats off to do its job, whether that job is to catch light, digest food, or help generate a thought.

We have about 20,000 protein-coding genes. If you tally up the amount of DNA they constitute, you get less than 3 percent of the human genome. Which naturally raises the question of what’s in the other 97 percent.

This question is hardly new, and the answers have earned scientists scads of Nobel prizes over the years.

Some of them found pieces of non-protein coding DNA that are essential to our survival. Over fifty years ago, Francois Jacob and his colleagues realized that the non-protein-coding DNA contains stretches, called regulatory elements, that act like switches for genes. When proteins and RNA molecules grab onto those switches, the genes become active.

Scientists have also known for decades that sometimes when a cell makes an RNA transcript, it can use that transcript for an important job without bothering to translate it into a protein. The ribosome, for example, is an assembly of proteins and RNA molecules. George Palade published this discovery in 1955.

Since then, scientists have plunged ever deeper into the workings of regulatory elements and functional RNAs. Many of our genes are controlled not just by a single switch, but by a veritable combination lock of different regulatory elements. RNAs can carry out many more jobs than just working in the ribosome. They can silence other genes, for example, by locking onto their transcripts.

Understanding the other 97 percent of the genome is a challenge at once profound and medically practical. Earlier this year, for example, scientists identified a gene for a long piece of RNA called PTCSC3 that suppresses cancer in the thyroid.

But for just as long, scientists have known that some of the genome does not carry out such vital functions. Barbara McClintock discovered in the 1940s that parts of the genome can make copies of themselves which can then insert themselves elsewhere in our DNA. It turns out our genomes are a veritable zoo of these so-called “mobile elements,” including ancient viruses. In some cases, evolution harnesses these mobile elements for useful purposes. But a lot of them have mutated to the point that they do nothing at all. About eight percent of our genome is made up the littered remains of dead viruses, for example.

While the basics of the human genome have been clear for decades, the particulars have remained murky. Scientists today are using better tools to explore the genome. They can now gain some clues about any particular chunk of DNA by looking at its sequence. It’s possible to recognize a protein-coding gene, for example–and it’s also possible to see if it has mutations that have rendered it functionally dead (a pseudogene).

But there’s no getting around the hard work of old-fashioned biology–of peering into cells to see what’s going on. And when scientists look in there, things get contentious.

In 2008, I wrote in the New York Times about a then-new project called ENCODE, in which a small army of scientists would create an encyclopedia of information about the entire genome, not just the protein-coding bits. Last year, the ENCODE team unveiled their analysis of this encyclopedia. It traveled through the high-profile-paper-becomes-a-press-release-and-inspires-breathless-articles-with-misleading-headlines sausage machine and ended up giving the impression that until now, scientists thought everything in the genome besides protein-coding genes was “junk,” and that the ENCODE project proved–without a doubt–that about eighty percent of the genome has a function.

What the scientists actually demonstrated was that cells produce RNA transcripts from a huge portion of the genome, not just for the protein-coding parts. They also observed that proteins were able to grab onto those regions–a suggest that they were switching on genes for RNA. They concluded that this kind of evidence demonstrated that eighty percent of the genome has “biochemical function.” (John Timmer wrote a good analysis of the ENCODE saga at Ars Technica.)

The ENCODE team incurred a remarkably high tide of criticism from other researchers. One long-running complaint is that the mere existence of an RNA transcript does not mean it serves any function at all. Cells can be sloppy, shooting off RNA transcripts from useless DNA. Those accidentally transcribed pieces of RNA promptly get destroyed.

To get a feel for its intensity, check out this piece that Dan Graur and colleagues published this February in the journal Molecular Biology and Evolution:

Here, we detail the many logical and methodological transgressions involved in assigning functionality to almost every nucleotide in the human genome. The ENCODE results were predicted by one of its authors to necessitate the rewriting of textbooks. We agree, many textbooks dealing with marketing, mass-media hype, and public relations may well have to be rewritten.

I’ve been very curious about how scientists would move on from here, and how the debate over the genome would evolve. Now a team of scientists at the University of California at San Francisco has published an interesting paper on the issue in the journal PLOS Genetics.

The UCSF researchers come to a conclusion much like that of ENCODE. They analyzed newly compiled databases of the RNA produced in cells from different tissues. They then pinpointed which segments of DNA encoded that RNA. They found about 85% of the genome produced at least one copy of RNA in one of the databases. The UCSF researchers argued that these results support ENCODE’s work.

The scientists then probed those transcripts to see whether they were just sloppy mistakes or served a function. They focused on one class of transcripts, known as long intergenic noncoding RNAs, or lincRNAs for short. A number of scientists have been cataloging lincRNAs for a few years now, but they’ve only identified a few thousand that appear to have a function. The UCSF searched their new databases for more lincRNAs. They first identified long transcripts, and then they winnowed down their list to get rid of false positives. They filtered out sequences that might be fragments of protein-coding genes that managed to slip into the database, for example. They also combined segments of DNA that overlapped in a way that suggested they both came from a single lincRNA gene.

Counting previously discovered lincRNAs, the researchers ended up with a total 55,000 potential non-protein coding genes. The scientists then looked at each of the candidate genes to look for clues to whether they serve a function. One clue was that the transcripts tend to show up just in one kind of tissue. That’s the rule for many proteins–hemoglobin is very useful in your blood but not very helpful in your eye.

The scientists also found that theses stretches bear some hallmarks of being switched on and off. DNA is wound around spools called histones, and the candidate lincRNA genes had proteins latched onto them that can unwind DNA so that it can be transcribed.

Another clue came from comparing the candidate lincRNA genes in humans to other species. If a piece of DNA serves no function, it will be prone to picking up mutations.  Since the  DNA encodes nothing of importance, mutations to it can do no harm.

Mutations that strike functional pieces of DNA, on the other hand, can be devastating. In these cases, natural selection should eradicate them over millions of years. The lincRNA gene candidates that the UCSF scientists found are fairly similar to versions in other mammal. That suggests that evolution is conserving them–and that they serve a function.

If these 55,000 candidates do turn out to be true genes for lincRNAs, then they will outnumber traditional protein-coding genes by a factor of five or more. The scientists don’t claim that they’ve definitively proved that these are genes, however; they look at their catalog as a collection of candidates that deserve to be tested with experiments. “The time is ripe for this dark matter of the human genome to step further into the spotlight,” they write.

I asked a few of ENCODE’s outspoken critics about the new paper, to see whether it changes their view on the genome’s other 97 percent.

Sean Eddy, a biologist at Janelia Farm Research Campus, is very skeptical of all such large-scale catalogs. When he’s looked closely at such catalogs, he’s found plenty of false positives. Rather than just compile a list of possible genes, he thinks scientists should do some careful quality control. They should be like inspectors at a factory, and pick out a random set of candidates to test. Only if careful experiments show that really do behave the way a functional gene behaves can they have confidence in their catalog.

While he was filling up his coffee this morning, Eddy thought up an analogy for this kind of research–one, he wrote to me, “that might be clarifying rather than dumb.”

If you took a big chunk of English text and screened it for novel “dark matter” (the birth of new words!) by eliminating all words that appear in the dictionary, you would indeed find a lot of “novel” words in your “high throughput screen”, and maybe get excited. But the moment you actually looked at a sample of what you’d found, you’d see it was almost all stuff that was obvious in retrospect. You’d say, “Oh yeah, numbers. Oh yeah, abbreviations. Oh yeah, foreign words. Oh yeah, proper names. Oh yeah, misspellings.” And you’d have five new null hypotheses, alternative explanations for your “novel words”; then you’d go back and revise your screen to eliminate those. To my mind, a lot of the lincRNA papers fail to do the part where they look carefully (manually) at what their screen produced, so they fail to develop their intuition for the various failure modes of the high-throughput computational screen.

Larry Moran, a biochemist at the University of Toronto and fierce critic of ENCODE, had a similar response. “Let’s assume that these 55,000 RNAs have a function of some sort,” he wrote to me. “If true, that would require rewriting the textbooks because none of the thousands of labs studying gene expression over the past five decades has seen any hint of such a massive amount of control and regulation by RNAs.”

Moran also pointed out that in many cases, the supposed genes produced just one lincRNA per cell. It strains his imagination to picture a way for a single lincRNA to have any important role in a cell’s existence. Far more likely, it’s just a segment of DNA that the cell accidentally transcribed. “If there have to be more than 10 transcripts per cell then the number of transcripts is reduced to 4,000,” Moran wrote. “If you need more than 30 transcripts per cell then that leaves only 950 putative functional RNAs.”

Moran and Eddy both point out that even if the UCSF researchers are right and all 55,000 DNA segments are real genes for important lincRNAs, that discovery would not, in fact, clear up all that much about the genome as a whole. Here’s how Eddy put it:

Even supposing that all 55,000 were truly functional and important RNAs; 55,000 * 2000nt average lincRNA transcript length = 110MB, less than 4% of the human genome. So I think the questions about these transcripts have to be separated from the concept of junk DNA – if someone did show that an additional 4% of the genome was functional, that would be super cool, but it wouldn’t bear on the questions around junk DNA, which have to do with the majority of the genome.

I contacted two of the UCSF co-authors to respond to these critiques but haven’t yet heard back from them. As soon as I do, I will add their response and post a notice on the blog that I’ve updated this piece. I’d also love to hear from both sides of this debate in the comments below.