© 1998 by Oxford University Press
This is the second of two articles.
While genome sequencers worldwide were stunned by the announcement, William Haseltine, Ph.D., chief executive officer of Human Genome Sciences in Rockville, Md., and a former business partner of Venter, offered some perspective. On May 21, in an op-ed piece for the New York Times, Haseltine called for the Human Genome Project to step aside in favor of Venter and Hunkapiller, stating "Sometimes, it's smart not to compete."
Haseltine argued that Venter and Hunkapiller could quickly and much more cheaply locate genes, the so-called biologically relevant stuff. As for the government, Haseltine contended it was preoccupied with decoding the reams of biologically useless sequence, or junk DNA, that he said would offer no new leads in treating human disease.
Most experts say his argument does not wash. They state that Venter and Hunkapiller will no doubt decode a lot of sequence very quickly. But, as Venter's company readily states, the new sequencing project will employ a strategy that churns out sequence indiscriminately both from the genes and junk, meaning Venter and Hunkapiller will be just as knee deep in junk as the government. Experts say the real issues are whether the privatized effort can produce high quality sequence and not leave too many holes in their final product.
Out With the Junk
Junk bashing is nothing new. In the late 1980s, Robert Weinberg, Ph.D., a scientist at Whitehead Institute in Cambridge, Mass., said of the initial plans to sequence the human genome, junk and all, "I'm surprised consenting adults have been caught in public talking about it," and he later wrote that junk DNA is "a vast genetic desert."
But in 1998, as the Haseltine op-ed article indicates, the junk-versus-gene debate has taken on a new meaning. Experts say that in this age of a booming biotech industry, the human genome for better or worse has become a commodity. And in this patent-first climate, industry has a financial stake in getting its hands on interesting genes now and worrying about decoding the junk later.
As some also suggested, the New York Times piece was a first try at using junk DNA -- or any genetic term for that matter -- as a code word for government red tape.
"My response to the [op-ed piece] was junk DNA is worthless, who needs it, and the federal government is probably once again not using our money in the wisest manner," said Myrl Weinberg, president of the nonprofit National Health Council in Washington, D.C. "And that is an inappropriate conclusion."
But is junk DNA really worthless? According to most scientists, the answer depends on what one means by "junk." Like the word "boat" or "fish," "junk DNA" is a general term that encompasses many different types of DNA sequences. These sequences run the gamut from introns, the parts of genes that are edited out during protein synthesis; transposable elements, repeated DNA sequences that, like parasites, duplicate themselves, adding nothing to the genome except more redundant sequence; and pseudogenes, fossils of one-time genes.
That some of these elements are evolutionary trash is not debated by most junkologists. "I think much of the DNA sitting in the human genome is fairly worthless," said Thomas Eickbush, Ph.D., a scientist at the University of Rochester, who studies retrotransposable elements, known among many researchers as prototypical, bottom-of-the-barrel junk. "It is a thrown out reverse transcript of what at one time was an element and is no longer functioning. That sort of sounds like junk to me."
In some cases, however, scientists say that junk may not fit. As Eickbush and others noted, all of the regulatory elements -- promoters and inhibitors -- required for gene transcription are spelled out somewhere between the genes. The same is true of other elements deemed junk, such as introns and RNA genes, which clearly hold important clues to understanding alternative splicing, transcribing a gene in different ways to produce different proteins.
Wojciech Makolowski, Ph.D., a scientist with the National Library of Medicine, reminded that one can never say "never" with evolution. He said a classic example is the fetal globin gene, functional in humans but not in lower animals such as the rabbit. Scientists believe that about 40 million years ago, as humans and chimpanzees evolved from lower monkeys, an Alu repeat sequence happened to insert next to a pseudogene within the globin gene family. By chance, the Alu also carried part of a promoter sequence with it, allowing the Alu to jump-start this fossilized gene back to life.
Even if it were all junk, Eickbush said it still has biological significance. "It is important in the sense that having a junkyard next to your house has a significant impact on you," he said. "That is not to say that the junkyard is in any way benefitting your household. But you have to deal with it. You have to deal with hundreds of thousands of copies of repetitive elements sitting in the genome and not doing anything but occasionally causing an insertional mutation."
Endearing Term
Most scientists who study retrotransposons, Alu elements, and the like say they really have no problem with the term junk DNA. Far from offending them, they say the term has actually become kind of endearing over the years. However, most are quick to add that people should not take the term literally and should remember to make distinctions between the many different shades of junk.
They say other possible synonyms also fail to go far enough. These include "selfish genes" and "parasitic genes," which describe self-replicating transposable elements, but do not capture the essence of the more modest introns. Some noted that selfish and parasitic also presuppose a plan when in reality these elements act more like a copy machine stuck on automatic, churning out the same copy over and over.
Some add that "repetitive DNA" comes close, but it too falls down. "What it does not cover are the large quantities of non-repetitive stuff between the genes," said Prescott Deininger, Ph.D., associate director of the Tulane University Cancer Center in New Orleans. As Deininger noted a typical non-coding intron may have about one-third repetitive sequences, but the other two-thirds are unique sequence that may or may not become repetitive, but is still considered junk.
A few scientists have wondered whether a name change might be in order. They increasingly find themselves defending their junk against the promise of genes, a dichotomy that squeezes millions of years of genomic evolution into a concept as simple as "good" and "bad" cholesterol.
The problem is finding a term that fits. One way around this problem is simply to invent language that is neither technical nor derogatory. In 1992, Jorgen Brosius, Ph.D., then at Mt. Sinai School of Medicine in New York, and Stephen Jay Gould, Ph.D., of Harvard University, took a stab at it in an article published in the Proceedings of the National Academy of Sciences. They proposed that all nucleic acid sequences go by the root name of nuon, thus opening the door for promonuon (promoter), potonuon (an amplified gene), and so on.
The proposal fell on deaf ears. Today, searches of the medical literature yield no citations for potonuons, naptonuons, or any other form of nuon.
Another possibility is to replace junk DNA with a more dignified name. According to several scientists interviewed for this story, some possible replacements include: non-exonic DNA, non-protein-coding DNA, non-gene DNA, dispensable DNA, intergenic sequences, and extraneous DNA.
"I think the term junk DNA will eventually die out," said Makalowski. "It is very general, provocative, and useful to have at one time. But now it is not useful anymore in meaning."
But for the time being, junk DNA is still considered junk. In the future, scientists who study these dispensable elements will continue to face an uphill semantic battle in explaining to those outside their field why the junk's not junk. Moreover, as genetics takes on a greater role in healthcare during the 21st century, they could one day find themselves fending off the unintended associations that the term has with the public.
"Genes are genes and junk is junk," said Janet Sawyer, a musician from Beaufort, S.C. "It is worthless -- like junk bonds."
-- Bob Kuska
Bring in Da Noise, Bring in Da Junk--the Semantics of Junk DNA
Last May brought one of the biggest bombshells of the year in biomedical research. J. Craig Venter, Ph.D., president of The Institute of Genome Research, and Michael Hunkapiller, Ph.D., president of PE Applied Biosystems, Foster City, Calif., announced that they would join forces to decode all 3 billion bases of the human genome in just 3 years. What's more, they said they would do so independently of the government-led Human Genome Project, going so far as to suggest that the government might want to focus on sequencing the mouse genome instead.
But, as so often happens with newfangled genetic terms, the term junk DNA is frequently used incorrectly. Numerous articles in the medical literature use junk and non-coding DNA interchangeably, a use that scientists say is wrong because introns and promoters -- which play roles in gene transcription -- are also junk.
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