UNRAVELING
THE DNA MYTH
The spurious foundation of genetic
engineering
Barry Commoner / Harper's Magazine Feb02
Barry Commoner is senior scientist at the Center for the
Biology of Natural Systems at Queens College, City University of New
York, where he directs the Critical Genetics Project. Readers can
obtain a list of references used as sources for this article by
sending a request to cbns@cbns.qc.edu.
Biology once was regarded as a languid, largely descriptive
discipline, a passive science that was content, for much of its history,
merely to observe the natural world rather than change it. No longer.
Today biology, armed with the power of genetics, has replaced physics as
the activist Science of the Century, and it stands poised to assume
godlike powers of creation, calling forth artificial forms of life
rather than undiscovered elements and subatomic particles. The initial
steps toward this new Genesis have been widely touted in the press. It
wasn't so long ago that Scottish scientists stunned the world with Dolly1,
the fatherless sheep cloned directly from her mother's cells; these
techniques have now been applied, unsuccessfully, to human cells. ANDi2,
a photogenic rhesus monkey, recently was born carrying the gene of a
luminescent jellyfish. Pigs now carry a gene for bovine growth hormone
and show significant improvement in weight gain, feed efficiency, and
reduced fat.3 Most soybean plants grown in the United
States have been genetically engineered to survive the application of
powerful herbicides. Corn plants now contain a bacterial gene that
produces an insecticidal protein rendering them poisonous to earworms.4
Our leading scientists and scientific entrepreneurs (two
labels that are increasingly interchangeable) assure us that these feats
of technological prowess, though marvelous and complex, are nonetheless
safe and reliable. We are told that everything is under control.
Conveniently ignored, forgotten, or in some instances simply suppressed,
are the caveats, the fine print, the flaws and spontaneous abortions.
Most clones exhibit developmental failure before or soon after birth,
and even apparently normal clones often suffer from kidney or brain
malformations.5 ANDi, perversely, has failed to glow
like a jellyfish. Genetically modified pigs have a high incidence of
gastric ulcers, arthritis, cardiomegaly (enlarged heart), dermatitis,
and renal disease. Despite the biotechnology industry's assurances that
genetically engineered soybeans have been altered only by the presence
of the alien gene, as a matter of fact the plant's own genetic system
has been unwittingly altered as well, with potentially dangerous
consequences.6 The list of malfunctions gets little
notice; biotechnology companies are not in the habit of publicizing
studies that question the efficacy of their miraculous products or
suggest the presence of a serpent in the biotech garden.
Glossary
of terms
Alternative
splicing
Reshuffling of the RNA
transcription of a gene's nucleotide sequence that generates
multiple proteins.
Cell
The fundamental,
irreducible unit of life.
Central
dogma
A theory concerning the
relation among DNA, RNA, and protein in which the nucleotide
sequence of DNA exclusively governs its own replication and
engenders a specific genetic code trait.
Chaperone
protein
Folds new strung-out
proteins into the ball-like structure that specifies their
biochemical activity.
Gene
A term applied to
segments of DNA that encode specific proteins that give rise to
inherited traits. Human DNA contains about 30,000 genes. The
term's meaning has become increasingly uncertain.
DNA
Deoxyribonucleic acid. A
large molecule composed of a specific sequence of four kinds of
nucleotides found in the nucleus of living cells.
Nucleotide
The four kinds of
subunits of which nucleic acid is constructed.
RNA
Ribonucleic acid. Its
various forms transmit genetic information from DNA to protein.
Spliceosome
A specialized group of
proteins and ribonucleic acids that carries out alternate
splicing.
|
The mistakes might be dismissed as the necessary errors
that characterize scientific progress. But behind them lurks a more
profound failure. The wonders of genetic science are all founded on the
discovery of the DNA double helix - by Francis Crick and James Watson in
1953-and they proceed from the premise that this molecular structure is
the exclusive agent of inheritance in all living things: in the kingdom
of molecular genetics, the DNA gene is absolute monarch. Known to
molecular biologists as the "central dogma," the premise
assumes that an organism's genome-its total complement of DNA
genes---should fully account for its characteristic assemblage of
inherited traits.7 The premise, unhappily, is false.
Tested between 1990 and 2001 in one of the largest and most highly
publicized scientific undertakings of our time, the Human Genome
Project, the theory collapsed under the weight of fact. There are far
too few human genes to account for the complexity of our inherited
traits or for the vast inherited differences between plants, say, and
people. By any reasonable measure, the finding (published last February)
signaled the downfall of the central dogma; it also destroyed the
scientific foundation of genetic engineering and the validity of the
biotechnology industry's widely advertised claim that its methods of
genetically modifying food crops are "specific, precise, and
predictable"8 and therefore safe. In short, the
most dramatic achievement to date of the $3 billion Human Genome Project
is the refutation of its own scientific rationale.
Since Crick first proposed it forty-four years ago, the
central dogma has come to dominate biomedical research. Simple, elegant,
and easily summarized, it seeks to reduce inheritance, a property that
only living things possess, to molecular dimensions: The molecular agent
of inheritance is DNA, deoxyribonucleic acid, a very long, linear
molecule tightly coiled within each cell's nucleus. DNA is made up of
four different kinds of nucleotides, strung together in each gene in a
particular linear order or sequence. Segments of DNA comprise the genes
that, through a series of molecular processes, give rise to each- of our
inherited traits:
Guided by Crick's theory, the Human Genome Project was
intended to identify and enumerate all of the genes in the human body by
working out the sequence of the three billion nucleotides in human DNA.
In 1990, James Watson described the Human Genome Project as "the
ultimate description of life." It will yield, he claimed, the
information "that determines if you have life as a fly, a carrot,
or a man." Walter Gilbert, one of the project's earliest
proponents, famously observed that the 3 billion nucleotides found in
human DNA would easily fit on a compact disc, to which one could point
and say, "Here is a human being; it's me!"9
President Bill Clinton described the human genome as "the language
in which God created life."10 How could the
minute dissection of human DNA into a sequence of 3 billion nucleotides
support such hyperbolic claims? Crick's crisply stated theory attempts
to answer that question. It hypothesizes a clear-cut chain of molecular
processes that leads from a single DNA gene to the appearance of a
particular inherited trait. The explanatory power of the theory is based
on an extravagant proposition: that the DNA genes have unique, absolute,
and universal control over the totality of inheritance in all forms of
life.
In order to control inheritance, Crick reasoned, genes
would need to govern the synthesis of protein, since proteins form the
cell's internal structures and, as enzymes, catalyze the chemical events
that produce specific inherited traits. The ability of DNA to govern the
synthesis of protein is facilitated by their similar structures-both are
linear molecules composed of specific sequences of subunits. A
particular gene is distinguished from another by the precise linear
order (sequence) in which the four different nucleotides appear in its
DNA. In the same way, a particular protein is distinguished from another
by the specific sequence of the twenty different kinds of amino acids of
which it is made. The four kinds of nucleotides can be arranged in
numerous possible sequences, and the choice of any one of them in the
makeup of a particular gene represents its "genetic
information" in the same sense that, in poker, the order of a hand
of cards informs the player whether to bet high on a straight or drop
out with a meaningless set of random numbers.
Crick's "sequence hypothesis" neatly links the
gene to the protein: the sequence of the nucleotides in a gene "is
a simple code for the amino acid sequence of a particular protein."11
This is shorthand for a series of well-documented molecular processes
that transcribe the gene's DNA nucleotide sequence into a complementary
sequence of ribonucleic acid (RNA) nucleotides that, in turn, delivers
the gene's code to the site of protein formation, where it determines
the sequential order in which the different amino acids are linked to
form the protein. It follows that in each living thing there should be a
one-to-one correspondence between the total number of genes and the
total number of proteins. The entire array of human genes-that is, the
genome must therefore represent the whole of a person's inheritance,
which distinguishes a person from a fly, or Walter Gilbert from anyone
else. Finally, because DNA is made of the same four nucleotides in every
living thing, the genetic code is universal, which means that a gene
should be capable of producing its particular protein wherever it
happens to find itself, even in a different species.
Crick's theory includes a second doctrine, which he
originally called the "central dogma" (though this term is now
generally used to identify his theory as a whole). The hypothesis is
typical Crick: simple, precise, and magisterial. "Once (sequential)
information has passed into protein it cannot get out again."12
This means that genetic information originates in the DNA nucleotide
sequence and terminates, unchanged, in the protein amino acid sequence.
The pronouncement is crucial' to the explanatory power of the theory
because it endows the gene with undiluted control over the identity of
the protein and the inherited trait that the protein creates. To stress
the importance of this genetic taboo, Crick bet the future of the entire
enterprise on it, asserting that "the discovery of just one type of
present-day cell" in which genetic information passed from protein
to nucleic acid or from protein to protein "would shake the whole
intellectual basis of molecular biology."13
Crick was aware of the brashness of his bet, for it was
known that in living cells proteins come into promiscuous molecular
contact with numerous other proteins and with molecules of DNA and RNA.
His insistence that these interactions are genetically chaste was
designed to protect the DNA's genetic message-the gene's nucleotide
sequence-from molecular intruders that might change the sequence or add
new ones as it was transferred, step by step, from gene to protein and
thus destroy the theory's elegant simplicity.
Last February, Crick's gamble suffered a spectacular loss.
In the journals Nature and Science and at joint press conferences and
television appearances, the two genome research teams reported their
results. The major result was "unexpected."14
Instead of the 100,000 or more genes predicted by the estimated number
of human proteins, the gene count was only about 30,000. By this
measure, people are only about as gene-rich as a mustard-like weed
(which has 26,000 genes) and about twice as genetically endowed as a
fruit fly or a primitive worm-hardly an adequate basis for
distinguishing among "life as a fly, a carrot, or a man." In
fact, an inattentive reader of genomic CDs might easily mistake Walter
Gilbert for a mouse, 99 percent of whose genes have human counterparts.15
The surprising results contradicted the scientific premise
on which the genome project was undertaken and dethroned its guiding
theory, the central dogma. After all, if the human gene count is too low
to match the number of proteins and the numerous inherited traits that
they engender, and if it cannot explain the vast inherited difference
between a weed and a person, there must be much more to the
"ultimate description of life" than the genes, on their own,
can tell us.
Scientists and journalists somehow failed to notice what
had happened. The discovery that the human genome is not much different
from the roundworm's led Dr. Eric Lander, one of the leaders of the
project, to declare that humanity should learn "a lesson in
humility."17 In the New York Times, Nicholas
Wade merely observed that the project's surprising results will have an
"impact on human pride" and that "human self-esteem may
be in for further blows" from future genome analyses, which had
already found that the genes of mice and men are very similar.16
The project's scientific reports offered little to explain
the shortfall in the gene count. One of the possible explanations for
why the gene count is "so discordant with our predictions" was
described, in full, last February in Science as follows: "nearly
4096 of human genes are alternatively spliced."18
Properly understood, this modest, if esoteric, account fulfills Crick's
dire prophecy: it "shakes the whole intellectual basis of molecular
biology" and undermines the-scientific validity of its application
to genetic engineering.
Alternative splicing is a startling departure from the
orderly design of the central dogma, in which the distinctive nucleotide
sequence of a single gene encodes the amino acid sequence of a single
protein. According to Crick's sequence hypothesis, the gene's nucleotide
sequence (i.e., its "genetic information") is transmitted,
altered in form but not in content, through RNA intermediaries, to the
distinctive amino acid sequence of a particular protein. In alternative
splicing, however, the gene's original nucleotide sequence is split into
fragments that are then recombined in different ways to encode a
multiplicity of proteins, each of them different in their amino acid
sequence from each other and from the sequence that the original gene,
if left intact, would encode.
The molecular events that accomplish this genetic
reshuffling are focused on a particular stage in the overall
DNA-RNA-protein progression. It occurs when the DNA gene's nucleotide
sequence is transferred to the next genetic carrier—messenger
RNA. A specialized group of fifty to sixty proteins, together with five
small molecules of RNA-known as a "spliceosome"—assembles
at sites along the length of the messenger RNA, where it cuts apart
various segments of the messenger RNA. Certain of these fragments are
spliced together into a number of alternative combinations, which then
have nucleotide sequences that differ from the gene's original one.
These numerous, redesigned messenger RNAs govern the production of an
equal number of proteins that differ in their amino acid sequence and
hence in the inherited traits that they engender. For example, when the
word TIME is rearranged to read MITE, EMIT, and ITEM, three alternative
units of information are created from an original one. Although the
original word (the unspliced messenger RNA nucleotide sequence) is
essential to the process, so is the agent that performs the
rearrangement (the spliceosome).19
Alternative splicing can have an extraordinary impact on
the gene/protein ratio. We now know that a single gene originally
believed to encode a single protein that occurs in cells of the inner
ear of chicks (and of humans) gives rise to 576 variant proteins,
differing in their amino acid sequences.20 The current
record for the number of different proteins produced from a single gene
by alternative splicing is held by the fruit fly, in which one gene
generates up to 38,016 variant protein molecules.21
Alternative splicing thus has a devastating impact on
Crick's theory: it breaks open the hypothesized isolation of the
molecular system that transfers genetic information from a single gene
to a single protein. By rearranging the single gene's nucleotide
sequence into a multiplicity of new messenger RNA sequences, each of
them different from the unspliced original, alternative splicing can be
said to generate new genetic information. Certain of the spliceosome's
proteins and RNA components have an affinity for particular sites and,
binding to them, form an active catalyst that cuts the messenger RNA and
then rejoins the resulting fragments. The spliceosome proteins thus
contribute to the added genetic information that alternative splicing
creates. But this conclusion conflicts with Crick's second hypothesis—that
proteins cannot transmit genetic information to nucleic acid (in this
case, messenger RNA)—and
shatters the elegant logic of Crick's interlocking duo of genetic
hypotheses.22
The
Precise Duplication of
DNA is accomplished by the
living cell, not by the DNA
molecule alone
|
The discovery of alternative splicing also bluntly
contradicts the precept that motivated the genome project. It nullifies
the exclusiveness of the gene's hold on the molecular process of
inheritance and disproves the notion that by counting genes one can
specify the array of proteins that define the scope of human
inheritance. The gene's effect on inheritance thus cannot be predicted
simply from its nucleotide sequence—the
determination of which is one of the main purposes of the Human Genome
Project. Perhaps this is why the crucial role of alternative splicing
seems to have been ignored in the planning of the project and has been
obscured by the cunning manner in which its chief result has been
reported. Although the genome reports do not mention it, alternative
splicing was discovered well before the genome project was even planned—in
1978 in virus replication23, and in 1981 in human
cells.24 By 1989, when the Human
Genome Project was still being debated among molecular biologists, its
champions were surely aware that more than 200 scientific papers on
alternative splicing of human genes had already been published.25
Thus, the shortfall in the human gene count could—indeed
should—have
been predicted. It is difficult to avoid the conclusion—troublesome
as it is that the project's planners knew in advance that the mismatch
between the numbers of genes and proteins in the human genome was to be
expected, and that the $3 billion project could not be justified by the
extravagant claims that the genome—or
perhaps God speaking through it would tell us who we are.26
Alternative splicing is not the only discovery over the
last forty years that has contradicted basic precepts of the central
dogma. Other research has tended to erode the centrality of the DNA
double helix itself, the theory's ubiquitous icon. In their original
description of the discovery of DNA, Watson and Crick commented that the
helix's structure "immediately suggests a possible copying
mechanism for the genetic material." Such self-duplication is the
crucial feature of life, and in ascribing it to DNA, Watson and Crick
concluded, a bit prematurely, that they had discovered life's magic
molecular key.27
Biological replication does include the precise duplication
of DNA, but this is accomplished by the living cell, not by the DNA
molecule alone. In the development of a person from a single fertilized
egg, the egg cell and the multitude of succeeding cells divide in two.
Each such division is preceded by a doubling of the cell's DNA; two new
DNA strands are produced by attaching the necessary nucleotides (freely
available in the cell), in the proper order, to each of the two DNA
strands entwined in the double helix. As the single fertilized egg cell
grows into an adult, the genome is replicated many billions of times,
its precise sequence of three billion nucleotides retained with
extraordinary fidelity.28 The rate of error—that
is, the insertion into the newly made DNA sequence of a nucleotide out
of its proper order—is
about one in 10 billion nucleotides. But on its own, DNA is incapable of
such faithful replication; in a test-tube experiment, a DNA strand,
provided with a mixture of its four constituent nucleotides, will line
them up with about one in a hundred of them out of its proper place. On
the other hand, when the appropriate protein enzymes are added to the
test rube, the fidelity with which nucleotides are incorporated in the
newly made DNA strand is greatly improved, reducing the error rate to
one in 10 million. These remaining errors are finally reduced to one in
10 billion by a set of "repair" enzymes (also proteins) that
detect and remove mismatched nucleotides from the newly synthesized DNA.29
GENETIC
INFORMATION ARISES NOT
FROM DNA ALONE BUT THROUGH
ITS ESSENTIAL COLLABORATION
WITH PROTEIN ENZYMES
|
Thus, in the living cell the gene's nucleotide code can be
replicated faithfully only because an array of specialized proteins
intervenes to prevent most of the errors—which
DNA by itself is prone to make—and
to repair the few remaining ones. Moreover, it has been known since the
1960s that the enzymes that synthesize DNA influence its nucleotide
sequence. In this sense, genetic information: arises not from DNA alone
but through its essential collaboration with protein enzymes—a
contradiction of the central dogma's precept that inheritance is
uniquely governed by the self-replication of the DNA double helix.
Another important divergent observation is the following:
in order to become biochemically active and actually generate the
inherited trait, the newly made protein, a strung-out ribbon of a
molecule, must be folded up into a precisely organized ball-like
structure. The biochemical events that give rise to genetic traits—for
example, enzyme action that synthesizes a particular eye-color pigment—take
place at specific locations on the outer surface of the
three-dimensional protein, which is created by the particular way in
which the molecule is folded into that structure. To preserve the
simplicity of the central dogma, Crick was required to assume, without
any supporting evidence, that the nascent protein—a
linear molecule—always
folded itself up in the right way once its amino acid sequence had been
determined. In the 1980s, however, it was discovered that some nascent
proteins are on their own likely to become misfolded—and
therefore remain biochemically inactive—unless
they come in contact with a special type of "chaperone"
protein that property folds them.
The importance of these chaperones has been underlined in
recent years by research on degenerative brain diseases that are caused
by "prions," research that has produced some of the most
disturbing evidence that the central dogma is dangerously misconceived.30
Crick's theory holds that biological replication, which is essential to
an organism's ability to infect another organism, cannot occur without
nucleic acid. Yet when scrapie, the earliest known such disease, was
analyzed biochemically, no nucleic acid—neither
DNA nor RNA—could
be found in the infectious material that transmitted the disease. In the
1980s, Stanley Prusiner confirmed that the infectious agents that cause
scrapie, mad cow disease, and similar very rare but invariably fatal
human diseases are indeed nucleic-acid-free proteins (he named them
prions), which replicate in an entirely unprecedented way. Invading the
brain, the prion encounters a normal brain protein, which it then
refolds to match the prion's distinctive three-dimensional shape. The
newly refolded protein itself becomes infectious and, acting on another
molecule of the normal protein, sets up a chain reaction that propagates
the disease to its fatal end.31
The prion's unusual behavior raises important questions
about the connection between a protein's amino acid sequence and its
biochemically active, folded-up structure. Crick assumed that the
protein's active structure is automatically determined by its amino acid
sequence (which is, after all, the sign of its genetic specificity), so
that two proteins with the same sequence ought to be identical in their
activity. The prion violates this rule. In a scrapie-infected sheep, the
prion and the brain protein that it refolds have the same amino acid
sequence, but one is a normal cellular component and the other is a
fatal infectious agent. This suggests 'that the protein's folded-up
configuration is, to some degree, independent of its amino acid sequence
and therefore determined, in part, by something other than the DNA gene
that governed the synthesis of that sequence. And since the prion
protein's three-dimensional shape is endowed with transmissible genetic
information, it violates another fundamental Crick precept as well—the
forbidden passage of genetic information from one protein to another.*
Thus, what is known about the prion is a somber warning that processes
far removed from the conceptual constraints of the central dogma are at
work in molecular genetics and can lead to fatal disease.**
* Although Crick localizes the protein's genetic
information in its amino acid sequence, it must also be found in the
protein s three-dimensional folded structure, an the surface of which
the highly specific biochemical activity that generates the inherited
trait takes place.
** In 1997, when Prusiner was awarded the Nobel
Prize, several scientists publicly denounced the decision because that
the prion, through infectious, is a nucleic-acid-free protein
contradicted the central dogma and was too controversial to warrant
the award. This bias impeded not only scientific progress but human
health as well. Although Prusiner's results explained why the prion's
structure resists them, conventional sterilization procedures were
nevertheless relied on to fight mad cow disease in Britain, with fatal
results.
By the mid 1980s, therefore, long before the $3 billion
Human Genome Project was funded, and long before genetically modified
crops began to appear in our fields, a series of protein-based processes
had already intruded on the DNA gene's exclusive genetic franchise. An
array of protein enzymes must repair the all-too-frequent mistakes in
gene replication and in the transmission of the genetic code to proteins
as well. Certain proteins, assembled in spliceosomes, can reshuffle the
RNA transcripts, creating hundreds and even thousands of different
proteins from a single gene. A family of chaperones, proteins that
facilitate the proper folding—
and therefore the biochemical activity—of
newly made proteins, form an essential part of the gene-toprotein
process. By any reasonable measure, these results contradict the central
dogma's cardinal maxim: that a DNA gene exclusively governs the
molecular processes that give rise to a particular inherited trait. The
DNA gene clearly exerts an important influence on inheritance, but it is
not unique in that respect and acts only in collaboration with a
multitude of protein-based processes that prevent and repair incorrect
sequences, transform the nascent protein into its folded, active form,
and provide crucial added genetic information well beyond that
originating in the gene itself. The net outcome is that no single DNA
gene is the sole source of a given protein's genetic information and
therefore of the inherited trait.
The credibility of the Human Genome Project is not the only
casualty of the scientific community's stubborn resistance to
experimental results that contradict the central dogma. Nor is it the
most significant casualty. The fact that one gene can give rise to
multiple proteins also destroys the theoretical foundation of a
multibillion-dollar industry, `the genetic engineering of food crops. In
genetic engineering it is assumed, without adequate experimental proof,
that a bacterial gene for an insecticidal protein, for example,
transferred to a corn plant, will produce precisely that protein and
nothing else. Yet in that alien genetic environment, alternative
splicing of the bacterial gene might give rise to multiple variants of
the intended protein—or
even to proteins bearing little structural relationship to the original
one, with unpredictable effects on ecosystems and human health.
The delay in dethroning the all-powerful gene led in the
1990s to a massive invasion of genetic engineering into American
agriculture, though its scientific justification had already been
compromised a decade or more earlier. Nevertheless, ignoring the
profound fact that in nature the normal exchange of genetic material
occurs exclusively within a single species, biotech-industry executives
have repeatedly boasted that, in comparison, moving a gene from one
species to another is not only normal but also more specific,
precise, and predictable. In only the last five years such transgenic
crops have taken over 68 percent of the U.S. soybean acreage, 26 percent
of the corn acreage, and more than 69 percent of the cotton acreage.32
That the industry is guided by the central dogma was made
explicit by Ralph W.F. Hardy, president of the National Agricultural
Biotechnology Council and formerly director of life sciences at DuPont,
a major producer of genetically engineered seeds. In 1999, in Senate
testimony, he succinctly described the industry's guiding theory this
way: "DNA (top management molecules) directs RNA formation (middle
management molecules) directs protein formation (worker
molecules)."33 The outcome of transferring a
bacterial gene into a corn plant is expected to be as predictable as the
result of a corporate takeover: what the workers do will be determined
precisely by what the new top management tells them to do. This
Reaganesque version of the central dogma is the scientific foundation
upon which each year billions of transgenic plants of soybeans, corn,
and cotton are grown with the expectation that the particular alien gene
in each of them will be faithfully replicated in each of the billions of
cell divisions that occur as each plant develops; that in each of the
resultant cells the alien gene will encode only a protein with precisely
the amino acid sequence that it encodes in its original organism; and
that throughout this biological saga, despite the alien presence, the
plant's natural complement of DNA will itself be properly replicated
with no abnormal changes in composition.
In an ordinary unmodified plant the reliability of this
natural genetic process results from the compatibility between its gene
system and its equally necessary protein-mediated systems. The
harmonious relation between the two systems develops during their
cohabitation, in the same species, over very long evolutionary periods,
in which natural selection eliminates incompatible variants. In other
words, within a single species the reliability of the successful outcome
of the complex molecular process that gives rise to the inheritance of
particular traits is guaranteed by many thousands of years of testing,
in nature.
In a genetically engineered transgenic plant, however, the
alien transplanted bacterial gene must properly interact with the
plant's protein-mediated systems. Higher plants, such as corn, soybeans,
and cotton, are known to possess proteins that repair DNA miscoding;34
proteins that alternatively splice messenger RNA and thereby produce a
multiplicity of different proteins from a single gene;35
and proteins that chaperone the proper folding of other, nascent
proteins.36 But the plant systems' evolutionary
history is very different from the bacterial gene's. As a result, in the
transgenic plant the harmonious interdependence of the alien gene and
the new host's protein-mediated systems is likely to be disrupted in
unspecified, imprecise, and inherently unpredictable ways. In practice,
these disruptions are revealed by the numerous experimental failures
that occur before a transgenic organism is actually produced and by
unexpected genetic changes that occur even when the gene has been
successfully transferred.37
Most alarming is the recent evidence that in a widely grown
genetically modified food crop—soybeans
containing an alien gene for herbicide resistance—the
transgenic host plant's genome has itself been unwittingly altered. The
Monsanto Company admitted in 2000 that its soybeans contained some extra
fragments of the transferred gene, but nevertheless concluded that
"no new proteins were expected or observed to be produced."38
A year later, Belgian researchers discovered that a segment of the
plant's own DNA had been scrambled. The abnormal DNA was large enough to
produce a new protein, a potentially harmful protein.39
One way that such mystery DNA might arise is suggested by a
recent study showing that in some plants carrying a bacterial gene, the
plant's enzymes that correct DNA replication errors rearrange the alien
gene's nucleotide sequence.40 The consequences of such
changes cannot be foreseen. The likelihood in genetically engineered
crops of even exceedingly rare, disruptive effects of gene transfer is
greatly amplified by the billions of individual transgenic plants
already being grown annually in the United States.
The degree to which such disruptions do occur in
genetically modified crops is not known at present, because the
biotechnology industry is not required to provide even the most basic
information about the actual composition of the transgenic plants to the
regulatory agencies. No tests, for example, are required to show that
the plant actually produces a protein with the same amino acid sequence
as the original bacterial protein. Yet this information is the only way
to confirm that the transferred gene does in fact yield the
theory-predicted product. Moreover, there are no required studies based
on detailed analysis of the molecular structure and biochemical activity
of the alien gene and its protein product in the transgenic commercial
crop. Given that some unexpected effects may develop very slowly, crop
plants should be monitored in successive generations as well. None of
these essential tests are being performed, and billions of transgenic
plants are now being grown with only the most rudimentary knowledge
about the resulting changes in their composition. Without detailed,
ongoing analyses of the transgenic crops, there is no way of knowing if
hazardous consequences might arise. Given the failure of the central
dogma, there is no assurance that they will not. The genetically
engineered crops now being grown represent a massive uncontrolled
experiment whose outcome is inherently unpredictable. The results could
be catastrophic.
Crick's central dogma has played a powerful role in
creating both the Human Genome Project and the unregulated spread of
genetically engineered food crops. Yet as evidence that contradicts this
governing theory has accumulated, it has had no effect on the decisions
that brought both of these monumental undertakings into being. It is
true that most of the experimental results generated by the theory
confirmed the concept that genetic information, in the form of DNA
nucleotide sequences, is transmitted from DNA via RNA to protein. But
other observations have contradicted the one-to-one correspondence of
gene to protein and have broken the DNA gene's exclusive franchise on
the molecular explanation of heredity. In the ordinary course of
science, such new facts would be woven into the theory, adding to its
complexity, redefining its meaning, or, as necessary, challenging its
basic premise. Scientific theories are meant to be falsifiable; this is
precisely what makes them scientific theories. The central dogma has
been immune to this process. Divergent evidence is duly reported and,
often enough, generates intense research, but its clash with the
governing theory is almost never noted.
Because of their commitment to an obsolete theory, most
molecular biologists operate under the assumption that DNA is the secret
of life, whereas the careful observation of the hierarchy of living
processes strongly suggests that it is the other way around: DNA did not
create life; life created DNA.41 When life was first
formed on the earth, proteins must have appeared before DNA because,
unlike DNA, proteins have the catalytic ability to generate the chemical
energy needed to assemble small ambient molecules into larger ones such
as DNA. DNA is a mechanism created by the cell to store information
produced by the cell. Early life survived because it grew, building up
its characteristic array of complex molecules. It must have been a
sloppy kind of growth; what was newly made did not exactly replicate
what was already there. But once produced by the primitive cell, DNA
could become a stable place to store structural information about the
cell's chaotic chemistry, something like the minutes taken by a
secretary at a noisy committee meeting. There can be no doubt that the
emergence of DNA was a crucial stage in the development of life, but we
must avoid the mistake of reducing life to a master molecule in order to
satisfy our emotional need for unambiguous simplicity. The experimental
data, shorn of dogmatic theories, points to the irreducibility of the
living cell, the inherent complexity of which suggests that any
artificially altered genetic system, given the magnitude of our
ignorance, must sooner or later give rise to unintended, potentially
disastrous, consequences. We must be willing to recognize how little we
truly understand about the secrets of the cell, the fundamental unit of
life.
DNA did
not create life;
life created
DNA
|
Why, then, has the central dogma continued to stand? To
some degree die theory has been protected from criticism by a device
more common to religion than science: dissent, or merely the discovery
of a discordant fact, is a punishable offense, a heresy that might
easily lead to professional ostracism. Much of this bias can be
attributed to institutional inertia, a failure of rigor, but there are
other, more insidious, reasons why molecular geneticists might be
satisfied with the status quo; the central dogma has given them such a
satisfying, seductively simplistic explanation of heredity that it
seemed sacrilegious to entertain doubts. The central dogma was simply
too good not to be true.
As a result, funding for molecular genetics has rapidly
increased over the last twenty years; new academic institutions, many of
them "genomic" variants of more mundane professions, such as
public health, have proliferated. At Harvard and other universities, the
biology curriculum has become centered on the genome. But beyond the
traditional scientific economy of prestige and the generous funding that
follows it as night follows day, money has distorted the scientific
process as a once purely academic pursuit has been commercialized to an
astonishing degree by the researchers themselves. Biology has become a
glittering target for venture capital; each new discovery brings new
patents, new partnerships, new corporate affiliations. But as the
growing opposition to transgenic crops clearly shows, there is
persistent public concern not only with the safety of genetically
engineered foods but also) with the inherent dangers in arbitrarily
overriding patterns of inheritance that are embedded in the natural
world. through long evolutionary experience. Too often those concerns
have been derided by industry scientists as the "irrational"
fears of an uneducated public. The irony, of course, is that the
biotechnology industry is based on science that is forty years old and
conveniently devoid of more recent results, which show that there are
strong reasons to fear the potential consequences of transferring a DNA
gene between species. What the public fears is not the experimental
science but the fundamentally irrational decision to let it out
of the laboratory into the real world before we truly understand it.
References
1: Dolly.
Wilmut I, Schnieke AE, McWhir J, Kind AJ, Campbell KH. Viable
offspring derived from fetal and adult mammalian cells. Nature.
1997. 385(6619):810-3.
2: ANDi.
Chan AWS, Chong KY, Martinovich C, Simerly C, and Schatten G.
Transgenic Monkeys Produced by Retroviral Gene Transfer into Mature
Oocytes. Science. 2001. 291:309-312.
3: Pigs that carry a
gene for bovine growth hormone.
Pursel VG, Pinkert CA, Miller
KF, Bolt DJ, Campbell RG, Palmiter RD, Brinster RL, Hammer RE.
Genetic engineering of livestock. Science. 1989. 244(4910):1281-8.
4: Genetically
engineered corn and soybean plants.
Thayer AM. Agbiotech. Chem. Engin. News. Oct 2, 2000. page.....
5: Developmental
failure and malformations in clones.
Jaenisch R and Wilmut I.
Don't Clone Humans. Science. 2001. 291:2552
6: Altered host
genome in transgenic soybeans.
Windels P., Taverniers I.,
Depicker A., Van Bockstaele E., and De Loose M.. Characterisation of
the Roundup Ready soybean insert. Eur Food Res Technol. 2001.
213:107-112
7: The central dogma.
Crick F.H.C. On Protein Synthesis. In: Symposium of the society for
experimental biology XII, p153. New York: Academic Press, 1958. This
carefully reasoned account describes the molecular processes, as
then known, that enable the DNA gene to govern the synthesis of a
specific protein. Crick's basic hypotheses, the Sequence Hypothesis
and the Central Dogma, are summarized.
8: Watson
quotation.
Gorner P., and Kotulak R. Life by Design. Chicago Tribune. Apr 8,
1990.
9: Gilbert
quotation.
Gilbert W. A Vision of the
Grail. In: Daniel J Kevles and Leroy Hoof, eds. The Code of Codes:
Scientific and Social Issues in the Human Genome Project, p96,
Cambridge Harvard University Press. 1992.
10: Clinton quotation.
Press Conference, White
House, Office of Press Secretary, June 26, 2000.
11: Crick quotation.
Crick 1958 (above), page 152.
12: Crick
quotation.
Crick 1958 (above), page 153.
13: Crick
quotation.
Crick F.H.C. The Central
Dogma of Molecular Biology. 1970, Nature 227:561-563 (see page 563).
14: Nature article on
Human Genome Project (public funding).
International Human Genome
Sequencing Consortium. Initial sequencing and analysis of the human
genome. Nature. 2001. 409(6822): 860-921
15: Science article
on Human Genome Project (private funding).
Venter JC, Adams MD, Myers EW,
et al. The Sequence of the Human Genome. Science. 2001.
291:1304-1351.
16: Wade
quotation.
Wade N. Genetic Sequence of
Mouse is also Decoded. New York Times. Feb 13, 2001.
17: Lander quotation.
Dentzer S. "Sequencing Life", PBS Online News Hour. Feb 12
2001.
18: Alternative
splicing quotation.
Venter et al 2001 (above), page 1345.
19: The role of the
spliceosome in alternative splicing.
Collins CA, and Guthrie C.
Allele specific genetic interactions between Prp8 and RNA active
site residues suggest a function for Prp8 at the catalytic core of
the spliceosome. Genes Dev. 1999. 13(15):1970-82.
20: Alternative
splicing; 576 inner ear variant proteins.
Black DL. Splicing in the
inner ear: a familiar tune, but what are the instruments? Neuron.
1998. 20(2):165-8.
21: Alternative
splicing; 38,016 variant fruit fly proteins.
Schmucker D, Clemens JC, Shu H, Worby CA, Xiao J, Muda M, Dixon JE,
Zipursky SL. Drosophila Dscam is an axon guidance receptor
exhibiting extraordinary molecular diversity. Cell. 2000 Jun
9;101(6):671-84.
22: The role of
spliceosome proteins in the genetic information created by
alternative splicing.
See Collins et al 1999 (above).
23: Alternative
splicing in virus replication, 1078.
Nevins R, and Darnell JE Jr. Steps in the processing of Ad2 mRNA:
Poly(A)+ nuclear sequences are conserved and Poly(A) addition
precedes splicing. Cell. 1978. 15:14771493.
24: Alternative
splicing in human cells, 1981.
DeNoto FM, Moore DD, and Goodman HM. Human growth hormone DNA
sequence and mRNA structure: possible alternative splicing. Nuc
Acids Res. 1981. 9:3719-30.
25: Papers on
alternative splicing in humans published by 1989.
Results of PubMed search for
articles containing "alternative splicing" AND
"human".
26: the $3 billion
project Venter et al 2001 (above).
page 1305
27: Watson and Crick
quotation.
Watson J.D. and Crick F.H.C. Molecular structure of nucleic acids: A
structure for deoxyribose nucleic acid. Nature. 1953. 171:737-738.
28: Processes that
improve fidelity of DNA replication.
Radman M., and Wagner R. The High Fidelity of DNA Replication.
Scientific American.1988. August:40-46
29: Enzymes that
synthesize DNA influence its nucleotide sequence.
Commoner B. The roles of deoxyribonucleic acid in inheritance.
Nature. 1964. 203:486-91 Commoner B. Failure of the WatsonCrick
theory as a chemical explanation of inheritance. Nature. 1968.
220:334-340.
30: Chaperones. Ellis
RJ. Proteins as molecular chaperones.
Nature. 1987. 328:378-379. Ellis RJ and Hemmingsen SM. Molecular
chaperones: proteins essential for the biogenesis of some
macromolecular structures. 1989. Trends Bioch Sci. 14(8):339-42
31: Prions.
S.B. Prusiner. The Prion Diseases One Protein, Two Shapes.
Scientific American. 1995. 272(1):48-57.
32: U.S. transgenic
crops.
Report released by the
National Agricultural Statistics Service, the Agricultural
Statistics Board, and the U.S. Department of Agriculture. Acreage.
June 29, 2001.
33: Hardy
quotation.
Hardy RWF. In Agricultural
Research and Development. Hearing, U.S Senate before Senate
Committee on Agriculture, Nutrition and Forestry. Oct 6, 1999.
34: DNA miscoding
repair in plants.
Tuteja N, Singh MB, Misra MK, Bhalla PL, Tuteja R. Molecular
mechanisms of damage and repair: progress in plants. Crit Rev
Biochem Mol Biol. 2001;36(4):337-97.
35: Alternatively
splicing in plants.
Comelli P, Konig J, Werr W. Alternative splicing of two leading
exons partitions promoter activity between the coding regions of the
maize homeobox gene Zmhox1a and Trap (transposon-associated
protein). Plant Mol Biol. 1999 Nov;41(5):615-25.
36: Chaperones in
plants.
Lund AA, Blum PH,
Bhattramakki D, Elthon TE. Heat-stress response of mitochondria.
Plant Physiol. 1998 Mar;116(3):1097-110.
37: Experimental
failures in transgenic organisms.
Pursel VG, Hammer RE, Bolt DJ, Palmiter RD, Brinster RL.
Integration, expression and germ-line transmission of growth-related
genes in pigs. Reprod Fertil Suppl . 1990;41:7787 Pursel VG, Rexroad
CE Jr, Bolt DJ, Miller KF, Wall RJ, Hammer RE, Pinkert CA, Palmiter
RD, Brinster RL. Progress on gene transfer in farm animals. Vet
Immunol Immunopathol 1987 Dec;17(1-4):303-12
38: Monsanto
quotation.
Monsanto Company Product
Safety Center. Confidential Report (MSL-16712). Updated Molecular
Characterization and Safety Assessment of Roundup Ready Soybean
Event 403-2. Monsanto Company. St Louis, MO.
39: Abnormal host DNA
in transgenic soybeans.
Windels et al 2001 (above).
40: Transgenic
plant's enzymes rearrange the alien gene's nucleotide
sequence.
Kohli A, Leech M, Vain P, Laurie DA, Christou P. Transgene
organization in rice engineered through direct DNA transfer supports
a two-phase integration mechanism mediated by the establishment of
integration hot spots. Proc Natl Acad Sci U S A. 1998 Jun
9;95(12):7203-8.
41: DNA did not
create life; life created DNA.
Commoner B. Relationship between biological information and the
origin of life. In: Matsuno K, Dose K, Harada K, Rohlfing DL, eds.
Molecular Evolution and Protobiology, p283, Plenum Press. New York.
1984.
Other material by
Barry Commoner.
Commoner B. Biochemical, biological and
atmospheric evolution. Proc Natl Acad Sci USA. 1965
Jun;53(6):1183-1194.
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