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http://www.nytimes.com/2007/07/01/business/yourmoney/01frame.html?...
July 1, 2007

RE:FRAMING
A Challenge to Gene Theory, a Tougher Look at Biotech
By DENISE CARUSO

	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 how 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, such as 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 it will deliver.
	But when it comes to innovations in food and medicine, belief 
can be dangerous.  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.
	[correction: that title denotes a different dogma  -  Crick's 
slogan that the info flows only one-way from DNA to RNA to protein. 
The other 1960s slogan'one gene/one protein' might be attributed to 
Ch. Anfinsen, but has not generally been, nor has it been deemed a 
dogma; anyhow it is not the "central dogma" - RM]
	Proteins are the cogs and the motors that drive the function 
of cells and, ultimately, organisms. In the 1960s, scientists 
discovered that a gene that produces one type of protein in one 
organism would produce a remarkably similar protein in another.  The 
similarity between the insulin produced by humans and by pigs is what 
once made pig insulin a life-saving treatment for diabetics.
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 A. 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," 
Ms. 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 Professor 
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 I. Miller, a fellow at the Hoover Institution who represented 
the pro-biotech position.  Dr. 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 Professor 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. Thus 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," Professor 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.

Denise Caruso is executive director of the Hybrid Vigor Institute, 
which studies collaborative
problem-solving. E-mail: [log in to unmask]