Carcinogens for Geniusalert92 only
22 / Regulation / Winter 2015–2016
P
resident George H. W. Bush’s loss in the 1992
general election was a setback to American agri- culture. n o longer did the nation have a White
House eager to advance the use of relatively new techniques of molecular genetic engineering—
the prototype of which was recombinant Dn A
technology, or “genetic modification” (GM).
instead, during Bill Clinton’s administration, with agricultural biotechnology (and other federal technology policy) under the
influence of Vice President Al Gore, the policy direction shifted toward the excessive and unnecessary regulation that he had
sought unsuccessfully to impose while in Congress. A prime example is the U.S. Food and Drug Administration’s
1993 decision to expand its regulatory oversight to include all
“genetically modified” animals, including insects. this move was surprising for a couple of reasons. First, the FDA’s Center for Veterinary Medicine decided to
subject genetically engineered animals and insects to the same rig- orous, burdensome pre-market research and approval procedures and regulations as new veterinary drugs such as antibiotics, pain
relievers, and anti-flea medicines. the rationale was that the new
D n A in the animal and any proteins it expresses are analogous to
drugs that have been injected or ingested—even though animals
with identical traits introduced by techniques such as natural breeding, artificial insemination, irradiation, or cloning would
not be subject to any premarket review at all. Second, the U.S. Department of Agriculture—not the FDA—
had long been the agency most experienced in dealing with farm animals. And both the USDA and ePA had regulated insect
John J. Cohr ssen formerly was counsel to the White house Biotechnology
Working Group, associate director of the President’s Council on Competitiveness,
and counsel for the house energy and Commerce Committee.
h enry I. M Iller , a
physician, is the r obert Wesson Fellow in scientific Philosophy and Public Policy at
s tanford University’s hoover Institution. he was the founding director of the office
of Biotechnology at the U.s. Food and Drug Administration.
Stunted
HarveS t
Regulatory reform for biotechnology is a tough row to hoe.
✒ By John J. Cohrssen AnD henry I. MIller
jpavlish (salmon), redstallion (apples), abadonian ( mosquito), erdemerdemli (potatoes)
biological control agents, which have been used successfully for
more than half a century.
FIsh s tory
the FDA’s long review times have virtually obliterated the once-
promising biotechnology sector of new, improved food animals.
Under its authority to regulate veterinary drugs, the FDA dith- ered for more than 20 years in reviewing the AquAdvantage
genetically engineered, faster-growing salmon. After the appli- cation had successfully fulfilled all FDA requirements, includ- ing an environmental assessment (the result of which was “no
significant impact”), the decision was hijacked by the Obama
White House, where it languished for three years before finally gaining approval this n ovember.
the poor fish that treaded water in regulatory limbo for
more than two decades is simply an Atlantic salmon with an
added Chinook salmon growth hormone gene that is turned on
all year long instead of only during the warmer months, as in
nature. this roughly halves the salmon’s time to maturity. the
genetic change confers no detectable difference in the salmon’s appearance, ultimate size, taste, or nutritional value; it just grows faster—a tremendous economic advantage in farming the fish in
a closed water system. this will benefit consumers, who will have
access to a greater supply and lower prices. the availability of the
AquAdvantage salmon will also help to alleviate the pressure on populations of wild Atlantic and Pacific salmon, many species of
which are threatened or endangered. the FDA’s exhaustive (and excessively lengthy) analysis con-
cluded that the salmon has no detectable differences and that it
“is as safe as food from conventional Atlantic salmon.” Because the farmed fish will be sterile females and farmed inland in a closed
system, they will be unable to affect the gene pool. (even if they
were to escape somehow, the fish would not adapt well in the wild because they are accustomed to being fed and coddled by humans.)
AGRICULTURE
24 / Regulation / Winter 2015–2016
agriculture
this was neither a complicated nor difficult review. the genetic
construction consisted of the addition of a gene from another salmon and a snippet of Dn A from another fish, the ocean pout,
that keeps the gene turned on continuously. there were no other
detectable compositional differences. And the farming of only sterile females in a closed system will prevent the AquAdvantage
salmon from replicating the horror of the science-gone-wrong
B-movie spoof Attack of the Killer Tomatoes. this excessively lengthy and uncertain regulation has forced
some U.S. animal genetic engineering researchers to take their
promising work to other countries such as Brazil and China,
which offer a friendlier regulatory regime. t hat means once-
highly-touted genetic modifications of animals—such as chickens and cows that produce less environmentally harmful manure, and
pigs with muscles that have a higher ratio of protein to fat—are
no longer on the horizon, at least in the United States.
Pl Ant ProBleMs
Other foods have fared little better. As part of its voluntary review
process for new genetically engineered plant varieties, the FDA has performed excruciatingly lengthy reviews instead of what should be routine, rapid evaluations. r ecent examples include
two and four years, respectively, to evaluate and approve bruise-
resistant potatoes and non-browning apples, even though the
genetic changes were minimal, well circumscribed, and did not involve the insertion of foreign or uncharacterized genetic mate-
rial. enzymatic browning is caused by the apple’s intrinsic chemi-
cal reaction to cell injury, such as when the fruit is bitten or sliced,
which ruptures the cells and triggers a chemical reaction between the enzyme polyphenol oxidase (PPO) and substances in the apple.
A family of four genes controls the majority of PPO production. By down-regulating those genes, scientists were able to turn off more than 90 percent of PPO production, giving
rise to the “Arctic Apple,” which does not
undergo enzymatic browning. the same enzyme-suppression technology has been
used to produce the non-browning, low- acrylamide (a presumptive carcinogen)
“innate” potatoes, which are expected to arrive in fast-food outlets later this year. Mercifully, those plants survived regu-
latory review, but the time spent on their
reviews was absurd. Complex new pharma-
ceuticals that can be prescribed to millions of patients and have potentially significant side effects often are
evaluated for safety and effectiveness and approved in less time.
When one of the authors of this article, Henry Miller, was the FDA medical reviewer for Humulin (human insulin), the very first bioengineered drug, it was approved in five months. in contrast to
the potato and apple reviews, the review of human insulin raised
a number of potentially vexing health and environmental issues.
the insulin is synthesized in bacteria—e. coli genetically engineered to synthesize the human protein—so there were concerns that the
bacteria could colonize the human gut and the insulin they pro-
duced could cause hypoglycemia in drug company workers. there
were also concerns about immunological side effects in patients from bacterial material in the purified, injected insulin. But those
concerns were handled satisfactorily in less than half a year. in con- trast to drugs, the vast majority of the FDA’s reviews of genetically
engineered foods are far less complex—so why do they take so long?
ProteCtIon FroM D AnGeroUs Pests
Delaying the availability of faster-growing salmon or non-brown-
ing apples is hardly the end of the world, but the FDA is also drag-
ging its feet on badly needed genetically engineered insect-control products that would prevent disease. A company called Oxitec has
designed a live mosquito product to reduce the population of mos-
quitoes that carry dengue fever and chikungunya. it was approved in Brazil in 2014 after persuasive evidence of safety and efficacy
in testing. But in the United States, the FDA has not yet granted
permission even for field testing. After protracted delay, a limited,
carefully controlled experimental study by the Florida Keys Mos-
quito Control District might finally start in the next few months. Mosquito control is a major public health concern worldwide,
with mosquito-borne diseases killing millions of people annually and causing suffering for many more. it takes only one bite from
a disease-carrying mosquito to transmit a debilitating or deadly
infection, and mosquitoes breed and multiply with astonishing
speed. Given that there are no vaccines or drug treatments for
illnesses like dengue fever, chikungunya, and West nile virus, and that treatments for diseases like malaria are difficult to access in
many at-risk areas, improved mechanisms for controlling mos-
quito populations are desperately needed to save lives. Oxitec’s approach involves the insertion of a lethal gene into
insect embryos using molecular genetic engineering techniques.
the modified mosquitoes can only be raised in a laboratory while kept alive by supplementing their diet with the antibiotic tet-racycline. these modified mosquitoes, which are all male (and therefore don’t bite people), are then released to mate with female
mosquitoes in the wild. the males impart the lethal gene to their
offspring, which, in the absence of the tetracycline supplement to
keep them alive, die before adulthood. Continued releases of the
Once-highly-touted genetic modifications of animals—
such as chickens and cows that produce less manure, and
pigs that have a higher ratio of protein to fat—are no
longer on the horizon, at least in the United States. Winter 2015–2016 / Regulation / 25
engineered mosquitoes cause precipitous declines in wild mosquito
populations and a corresponding drop in the diseases they cause. the Oxitec insect-control technology has important applica-
tions for agriculture as well as public health. Last summer, the
company announced successful early studies with a genetically modified diamondback moth that could control this destructive
pest, which attacks cruciferous vegetables such as broccoli, cab- bage, cauliflower, Brussels sprouts, and radishes. Given the impaired evolutionary fitness of the Oxitec mos-
quitoes, the FDA’s long delays in approving limited field trials are inexplicable. the reason that governments, industries, and
academic sponsors perform field trials is to determine safety
and efficacy, yet FDA regulators continue to stand in the way of
obtaining these essential data. in contrast to the interminable reviews by the FDA Center for
Veterinary Medicine of the faster-maturing salmon and the Oxitec insect-control technology, those same FDA regulators have chosen to exercise “regulatory discretion” to forgo any review at all of the
huge numbers of genetically engineered animals used extensively in biomedical research. they also exempted from regulation the
widely available GloFish, a genetically engineered fluorescent zebra danio fish for aquariums.
revIsIn G the FrAMe Work
the Obama administration recently announced an ambitious
White House initiative to update the 30-year-old Coordinated Framework for the regulation of Biotechnology. (Disclosure: the
coauthor of this article, John Cohrssen, was legal counsel to the
White House working group that developed and implemented the 1986 Coordinated Framework.) the White House has directed
the three regulatory agencies with biotechnology oversight—the
ePA, FDA, and USDA—to update the Framework and develop a long-term strategy to ensure that the regulatory system is prepared for the future products of biotechnology, using a newly commis-
sioned expert analysis of the biotechnology landscape. By creating an environment that is friendly to biotechnology
and the commercialization of products, the Obama White House
has a unique opportunity to reduce the regulatory obstacles to
continued U.S. advances in agriculture. thirty years of experi- ence with the molecular techniques and products of genetic
engineering have proven their versatility, shown that new vari-
eties of plants, animals, and microorganisms genetically engi- neered with molecular techniques have not
posed any incremental risks compared to other techniques for genetic modification, and found that once-hypothesized risks
have not materialized. Clearly, reforms are
needed to make regulation scientifically
defensible and risk-based, and to ensure that it provides acceptable cost-benefit. the White House should adhere to the
fundamental principles of the 1986 Coor-
dinated Framework, which remain valid today for the oversight of research and development:
■■n ew laws specifically for biotechnology are unnecessary and
should be avoided. Biotechnology products can be regulated effectively under the mosaic of existing product-specific laws.
■■Biotechnology regulation should avoid using a process- based scope, which by definition subjects all products within
a defined process-based category to regulation, regardless of
whether they are of high, moderate, low, or trivial risk. Such over-regulation not only retards innovation, but also feeds the self-perpetuating, incorrect perception that these prod-
ucts must pose a high risk because they are highly regulated.
■■the degree (intrusiveness) of regulation should be commen- surate with the risk of the product.
What sorts of regulatory changes are needed? the United States should return to the basic tenets of regulation prescribed more than two decades ago in the 1992 White House “scope” docu-
ment, which supplemented the 1986 Coordinated Framework:
■■the scope of regulation should be based on the risk-related characteristics of new products, not on the particular tech-nology that enabled them.
■■the scope of regulation should be based on evidence that the risk of a particular use of an organism for a particular
application is unreasonable.
■■A genetically engineered organism with new traits posing no greater risk than the unmodified organism should be subject to no greater scope of regulation.
As a practical matter, this means that to the extent appropri- ate, products of biotechnology should be regulated no more
stringently than products developed by older and less precise manufacturing processes. twenty years of continuing White House and regulatory agen-
cies’ disregard of the Coordinated Framework and “scope” policies have led to the unnecessary, anti-competitive obstacles to U.S. agricultural applications of biotechnology that the Obama White
House now supposedly seeks to address. in order to rationalize regulation, we need to return to a scope of regulation that is based on scientific evidence of an unreasonable risk—the overarching
principle adopted by the White House to prevent unnecessary regulatory burdens in the first place.
By creating an environment that is friendly to biotech-
nology and the commercialization of products, the Obama
White House has an opportunity to reduce the regulatory
obstacles to continued U.S. advances in agriculture. Copyright
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