Study shines new light on genome

[Al-khiyal]

June 14, 2007 -- Scientists have been forced to rethink how the human genome turns a single cell into a complex living being following the most intensive study of our genetic code ever undertaken.

The research reveals that genes make up only a tiny fraction of the role played by the 3bn letters that constitute the entirety of the human genome.

Large swaths of the genome, previously dismissed as "junk DNA" because it was thought to serve no practical purpose, have been found to be highly active inside the cells in our bodies. Other sequences of genetic code are thought to be "on standby", awaiting a time further down the evolutionary path when they will be beneficial to human beings.

The scientists claim the findings will have a dramatic impact on their ability to pinpoint how genetic defects trigger diseases. Instead of simply looking for mutations in individual genes, it is certain that defects in other parts of the genome will contribute to complex conditions, among them diabetes and coronary heart disease.

The results, published in Nature today, are the culmination of a $42m, five-year project called ENCODE (ENCyclopaedia Of DNA Elements) involving 80 different scientific teams in 11 countries.

The project set out to examine the human genome in unprecedented detail, to work out every different way in which the genetic building blocks, represented by the letters G, T, A and C, work within the body.

The scientists found that beyond genes lay a multitude of other jobs being done by sequences of DNA. Much of the genetic material is transcribed into molecules that relay information from the genome to the biological machinery of our cells.

"If you think of the letters that make up the human genome as the alphabet, then you can think of genes as the verbs. With this project we're identifying all of the other grammatical elements and the syntax of the language we need to read the genetic code completely," said Manolis Dermitzakis, a scientist on the ENCODE project at the Wellcome Trust Sanger Institute in Cambridge.

The findings highlighted how scientists had become so blinded by the importance of genes that the role of other parts of the genome had largely gone unappreciated, he said.

In the pilot study, the researchers focused on 1% of the human genome, or 3bn letters, which were chosen to represent the entire human genetic code. They aim to examine the rest of the genome over the next four years, streamlining the process to complete it for less than $100m.

By understanding how every letter of the human genome functions in the body, scientists believe they will be able to learn how complex diseases are caused by genetic glitches that build up throughout the genome.

Study shines new light on genome

[Al-khiyal]

June 14, 2007 -- The most detailed probe yet into the workings of the human genome has led scientists to conclude that a cornerstone concept about the chemical code for life is badly flawed. The ground-breaking study, published in more than two dozen papers in journals on both sides of the Atlantic, takes a small percentage of the genome to pieces to draw up a "parts list," identifying the biological role of every component.

For the international team of investigators, the four-year project was the computer-equivalent of passing a fine-toothed comb through a mountain of raw data. Reporting in the British journal Nature and the US journal Genome Research on Thursday, they suggest that an established theory about the genome should be consigned to history. Under this view, the genome is rather like a ribbon studded with some 22,000 "nuggets" in the form of genes, which make proteins, the essential stuff of life.

Genes - deemed so valuable that some discoverers of them have been prompted to file patents over them for commercial gain - amount to only around a twentieth, or even less, of the genetic code. In between the genes and the sequences known to regulate their activity are long, tedious stretches that appear to do nothing.

The term for them is "junk" DNA, reflecting the presumption that they are merely driftwood from our evolutionary past and have no biological function. But the work by the ENCODE (ENCyclopaedia of DNA Elements) consortium implies that this nuggets-and-dross concept of DNA should be, well, junked.

The genome turns out to a highly complex, interwoven machine with very few inactive stretches, the researchers report. Genes, it transpires, are just one of many types of DNA sequences that have a functional role. And "junk" DNA turns out to have an essential role in regulating the protein-making business. Previously written off as silent, it emerges as a singer with its own discreet voice, part of a vast, interacting molecular choir.

"The majority of the genome is copied, or transcribed, into RNA, which is the active molecule in our cells, relaying information from the archival DNA to the cellular machinery," said Tim Hubbard of the Wellcome Trust Sanger Institute, a British research group that was part of the team. "This is a remarkable finding, since most prior research suggested only a fraction of the genome was transcribed."

Francis Collins, director of the US National Human Genome Research Institute (NHGRI), which coralled 35 scientific groups from around the world into the ENCODE project, said the scientific community "will need to rethink some long-held views about what genes are and what they do." "(...) This could have significant implications for efforts to identify the DNA sequences involved in many human diseases," he said. Another rethink is in offing about how the genome has evolved, said Collins.

Until now, researchers had thought that the pressure to survive would relentlessly sculpt the human genome, leaving it with a slim, efficient core of genes that are essential for biological function. But the ENCODE consortium were surprised to find that the genome appears to be stuffed with functional elements that offer no identifiable benefits in terms of survival or reproduction.

The researchers speculate that there is a point behind this survival of the evolutionary cull. Humans could share with other animals a large pool of functional elements - a "warehouse" stuffed with a variety of tools on which each species can draw, enabling it to adapt according to its environmental niche.

The ENCODE endeavour flows from the Human Genome Project, which concluded in April 2003 with the publication of a polished draft of the human genetic code. But having the draft is not the same as knowing what is in it or how it works. And this is essential for unlocking knowledge about our evolutionary odyssey, just as it is needed for engineering new treatments for inherited disease.

The collaborative study focussed on 44 strategically chosen targets which together account for about one percent of the genome, or about 30 million of the three billion "rungs" in the DNA double-helix ladder. The data is being placed in the public domain to help medical and other research.

Landmark study prompts rethink of genetic code

[Al-khiyal]

June 26, 2007 -- In Douglas Adams's science fiction classic, "The Hitchhiker's Guide to the Galaxy," there is a character by the name of Slartibartfast, who designed the fjords of Norway and left his signature in a glacier.

I was reminded of Slartibartfast recently as I was trying to grasp the implications of the feat of a team of Japanese geneticists who announced that they had taught relativity to a bacterium, sort of.

Using the same code that computer keyboards use, the Japanese group, led by Masaru Tomita of Keio University, wrote four copies of Albert Einstein's famous formula, E=mc2, along with "1905," the date that the young Einstein derived it, into the bacterium's genome, the 400-million-long string of A's, G's, T's and C's that determine everything the little bug is and everything it's ever going to be.

The point was not to celebrate Einstein. The feat, they said in a paper published in the journal Biotechnology Progress, was a demonstration of DNA as the ultimate information storage material, able to withstand floods, terrorism, time and the changing fashions in technology, not to mention the ability to be imprinted with little unobtrusive trademark labels — little "Made by Monsanto" tags, say.

In so doing they have accomplished at least a part of the dream that Jaron Lanier, a computer scientist and musician, and David Sulzer, a biologist at Columbia, enunciated in 1999. To create the ultimate time capsule as part of the millennium festivities at this newspaper, they proposed to encode a year's worth of the New York Times magazine into the junk DNA of a cockroach. "The archival cockroach will be a robust repository," Lanier wrote, "able to survive almost all conceivable scenarios."

If cockroaches can be archives, why not us? The human genome, for example, consists of some 2.9 billion of those letters — the equivalent of about 750 megabytes of data — but only about 3 percent of it goes into composing the 22,000 or so genes that make us what we are.

The remaining 97 percent, so-called junk DNA, looks like gibberish. It's the dark matter of inner space. We don't know what it is saying to or about us, but within that sea of megabytes there is plenty of room for the imagination to roam, for trademark labels and much more. The King James Bible, to pick one obvious example, only amounts to about five megabytes.

Inevitably, if you are me, you begin to wonder if there is already something written in the warm wet archive, whether or not some Slartibartfast has already been here and we ourselves are walking around with little trademark tags or more wriggling and squiggling and folded inside us. Gill Bejerano, a geneticist at the University of California, Santa Cruz, who mentioned Slartibartfast to me, pointed out that the problem with raising this question is that people who look will see messages in the genome even if they aren't there — the way people have claimed in recent years to have found secret codes in the Bible.

Nevertheless, no less a personage than Francis Crick, the co-discoverer of the double helix, writing with the chemist Leslie Orgel, now at the Salk Institute in San Diego, suggested in 1973 that the primitive Earth was infected with DNA broadcast through space by an alien species.

As a result, it has been suggested that the search for extraterrestrial intelligence, or SETI, should look inward as well as outward. In an article in New Scientist, Paul Davies, a cosmologist at Arizona State University, wrote, "So might ET have inserted a message into the genomes of terrestrial organisms, perhaps by delivering carefully crafted viruses in tiny space probes to infect host cells with message-laden DNA?"

I should say right now that I am not talking about theology or the near theology known as intelligent design. The ability to stick a message in a cockroach does not make us the designers or creators of the cockroach — only evolution could be so kind or clever.

But I'm a sucker for secret messages. Once, long ago, I stayed up all night with my friends playing the Beatles' "White Album" backward hoping to hear the words "Turn me on dead man," referring to the rumored death of Paul McCartney. I'm ready to find Slartibartfast's signature and rediscover my cosmic heritage.

The sad truth is, as others will tell you, this is a bit like writing love letters in the sand. "I don't buy it," said Seth Shostak, an astronomer at the SETI Institute in Mountain View, California, pointing out that DNA is famously mutable. "Just ask Chuck Darwin," he added in an e-mail message.

It is the relentless shifting and mutating, the probing and testing of every possibility on the part of DNA, after all, that generates the raw material for evolution to act on and ensures the success of life on Earth (and perhaps beyond). Dr. Davies said that he had been encouraged by the discovery a few years ago that some sections of junk DNA seem to be markedly resistant to change, and have remained identical in humans, rats, mice, chickens and dogs for at least 300 million years.

But Dr. Bejerano, one of the discoverers of these "ultraconserved" strings of the genome, said that many of them had turned out to be playing important command and control functions.

"Why they need to be so conserved remains a mystery," he said, noting that even regular genes that do something undergo more change over time. Most junk bits of DNA that neither help nor annoy an organism mutate even more rapidly.

The Japanese team proposed to sidestep the mutation problem by inserting redundant copies of their message into the genome. By comparing the readouts, they said, they would be able to recover Einstein's formula even when up to 15 percent of the original letters in the string had changed, or mutated. "This is the major point of our work," Nozomu Yachie said in an e-mail message. At the rate of one mutation per generation, Dr. Yachie estimated it could take at least millions of years for the bacteria's genome to change by 15 percent — a huge change. Only 1 percent separates us from chimps. But other experts say that a stretch of DNA that is at best useless, and perhaps annoying to the little bug could disappear much more rapidly.

Calling the idea of storing information in living DNA "a nifty idea," Dr. Bejerano said: "The bottom line is if you want something to perpetuate forever, you can't just come in and type what you want. It would get washed away."

That dream, he said, "is hopeless with our current knowledge."

If we want to leave a message that would last for eons, it seems, we have to be clever enough to make sure that the message would remain beneficial to its host pretty much forever.

The challenge for an erstwhile interstellar Johnny Appleseed is to make the message part of the basic nature of its host.

If that ever turns out to be us, if we find that we are the medium, to paraphrase the late Marshall McLuhan, then, in some sense, we are also the message. Never mind who or what are the intended readers.

But if we find, say, the digits of the number pi encoded in a cockroach, I want to have a talk with old Startibartfast.

Human DNA, the ultimate spot for secret messages (are some there now?)

[Al-khiyal]

July 3, 2007 -- The $73.5 billion global biotech business may soon have to grapple with a discovery that calls into question the scientific principles on which it was founded.

Last month, a consortium of scientists published findings that challenge the traditional view of the way genes function. The exhaustive, four-year effort was organized by the United States National Human Genome Research Institute and carried out by 35 groups from 80 organizations around the world. To their surprise, researchers found that the human genome might not be a "tidy collection of independent genes" after all, with each sequence of DNA linked to a single function, like a predisposition to diabetes or heart disease.

Instead, genes appear to operate in a complex network, and interact and overlap with one another and with other components in ways not yet fully understood. According to the institute, these findings will challenge scientists "to rethink some long-held views about what genes are and what they do."

Biologists have recorded these network effects for many years in other organisms. But in the world of science, discoveries often do not become part of mainstream thought until they are linked to humans.

With that link now in place, the report is likely to have repercussions far beyond the laboratory. The presumption that genes operate independently has been institutionalized since 1976, when the first biotech company was founded. In fact, it is the economic and regulatory foundation on which the entire biotechnology industry is built.

Innovation begets risk, almost by definition. When something is truly new, only so much can be predicted about how it will play out. Proponents of a discovery often see and believe only in the benefits that it will deliver. But when it comes to innovations in food and medicine, belief can be a dangerous thing. Often, new information is discovered that invalidates the principles - thus the claims of benefit and, sometimes, safety - on which proponents have built their products.

For example, antibiotics were once considered miracle drugs that, for the first time in history, greatly reduced the probability that people would die from common bacterial infections. But doctors did not yet know that the genetic material responsible for conferring antibiotic resistance moves easily between different species of bacteria. Overprescribing antibiotics for virtually every ailment has given rise to "superbugs" that are now virtually unkillable.

The principle that gave rise to the biotech industry promised benefits that were equally compelling. Known as the Central Dogma of molecular biology, it stated that each gene in living organisms, from humans to bacteria, carries the information needed to construct one protein.

The scientists who invented recombinant DNA in 1973 built their innovation on this mechanistic, "one gene, one protein" principle.

Because donor genes could be associated with specific functions, with discrete properties and clear boundaries, scientists then believed that a gene from any organism could fit neatly and predictably into a larger design - one that products and companies could be built around, and that could be protected by intellectual-property laws.

This presumption, now disputed, is what one molecular biologist calls "the industrial gene."

"The industrial gene is one that can be defined, owned, tracked, proven acceptably safe, proven to have uniform effect, sold and recalled," said Jack Heinemann, a professor of molecular biology in the School of Biological Sciences at the University of Canterbury in New Zealand and director of its Center for Integrated Research in Biosafety.

In the United States, the Patent and Trademark Office allows genes to be patented on the basis of this uniform effect or function. In fact, it defines a gene in these terms, as an ordered sequence of DNA "that encodes a specific functional product."

In 2005, a study showed that more than 4,000 human genes had already been patented in the United States alone. And this is but a small fraction of the total number of patented plant, animal and microbial genes.

In the context of the consortium's findings, this definition now raises some fundamental questions about the defensibility of those patents.

If genes are only one component of how a genome functions, for example, will infringement claims be subject to dispute when another crucial component of the network is claimed by someone else?

Might owners of gene patents also find themselves liable for unintended collateral damage caused by the network effects of the genes they own?

And, just as important, will these not-yet-understood components of gene function tarnish the appeal of the market for biotech investors, who prefer their intellectual property claims to be unambiguous and indisputable?

While no one has yet challenged the legal basis for gene patents, the biotech industry itself has long since acknowledged the science behind the question.

"The genome is enormously complex, and the only thing we can say about it with certainty is how much more we have left to learn," wrote Barbara Caulfield, executive vice president and general counsel at the biotech pioneer Affymetrix, in a 2002 article on Law.com called "Why We Hate Gene Patents."

"We're learning that many diseases are caused not by the action of single genes, but by the interplay among multiple genes," Caulfield said. She noted that just before she wrote her article, "scientists announced that they had decoded the genetic structures of one of the most virulent forms of malaria and that it may involve interactions among as many as 500 genes."

Even more important than patent laws are safety issues raised by the consortium's findings. Evidence of a networked genome shatters the scientific basis for virtually every official risk assessment of today's commercial biotech products, from genetically engineered crops to pharmaceuticals.

"The real worry for us has always been that the commercial agenda for biotech may be premature, based on what we have long known was an incomplete understanding of genetics," said Heinemann, who writes and teaches extensively on biosafety issues.

"Because gene patents and the genetic engineering process itself are both defined in terms of genes acting independently," he said, "regulators may be unaware of the potential impacts arising from these network effects."

Yet to date, every attempt to challenge safety claims for biotech products has been categorically dismissed, or derided as unscientific.

A 2004 round table on the safety of biotech food, sponsored by the Pew Initiative on Food and Biotechnology, provided a typical example:

"Both theory and experience confirm the extraordinary predictability and safety of gene-splicing technology and its products," said Dr. Henry Miller, a fellow at the Hoover Institution who represented the pro-biotech position.

Miller was the founding director of the Office of Biotechnology at the Food and Drug Administration, and presided over the approval of the first biotech food in 1992.

Now that the consortium's findings have cast the validity of that theory into question, it may be time for the biotech industry to re-examine the more subtle effects of its products, and to share what it knows about them with regulators and other scientists.

This is not the first time it has been asked to do so. A 2004 editorial in the journal Nature Genetics beseeched academic and corporate researchers to start releasing their proprietary data to reviewers, so it might receive the kind of scrutiny required of credible science.

According to Heinemann, many biotech companies already conduct detailed genetic studies of their products that profile the expression of proteins and other elements. But they are not required to report most of this data to regulators, so they do not. That means that vast stores of important research information sit idle.

"Something that is front and center in the biosafety community in New Zealand now is whether companies should be required to submit their gene-profiling data for hazard identification," Heinemann said. With no such reporting requirements, companies and regulators alike will continue to "blind themselves to network effects," he said.

The Nature Genetics editorial, titled "Good Citizenship, or Good Business?," presented its argument as a choice for the industry to make. Given the significance of these new findings, it is a distinction without a difference.

Change to gene theory raises new challenges for biotech