The Spurious Foundation of Genetic Engineering

[Guest guest]

Did anyone else read this? Well, my replies are much shorter.

 

EBbrewpunx wrote:

>

> 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. 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 tra!

 

In summary, Barry explains what the so-called " central dogma of

molecular biology " is, and then quotes several exceptions to it that he

claims demolish it. They don't. They're just exceptions. I never liked

the name " central dogma " anyway.

 

The Human Genome project was still a good idea, and the central dogma is

not demolished.

 

Despite this, much of the science in this missive is right. And most of

the " exceptions " Barry points out are also, like he says, ways in which

GMOs can go badly wrong.

 

> its 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 " 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.

>

 

Although some geneticists are extremely skeptical about the safety of GM

foods, the alleged skepticism about the central dogma (retroviruses

notwithstanding) is simply untrue.

 

> 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.

>

 

Not really true. There are other, less important, inheritable paths.

Although scientists can hyperbole like anyone else, when writing down in

a paper they do a better job of hedging their bets .

 

> 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. "

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 their 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. "

>

> 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.

 

Well, biochemistry is fuzzy, tangible thing, full of exceptions.

 

> 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. " 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 mustardlike 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.

 

This is all true. Someone appears to be operating from a prejudice that

just because we have a larger frontal lobe, we have to have more genes.

As women have been consoling men ever since sex began in 1967, it's not

how big your genome is, but what you do with it that matters.

 

> 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.

 

Okay, this is an exception.

 

> 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 hy!

> potheses.

 

No. It's an exception. An *exception*.

 

> 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 precede 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. 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 m!

> ixture of its four constituent nucleotides, will line them up with about one

in a hundred of them out its proper place. On the other hand, when the

appropriate protein enzymes are added to the test tube, 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.

 

Replication in vivo is still using the mechanism that Watson and Crick

suggested. It's just getting helped by molecules.

 

> 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 - 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 - unles!

> s they come in contract with a special type of " chaperone " protein that

properly folds them.

 

If anyone was interested enough to read this far, this is what I did my

PhD in.

 

> 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.

 

A point, but not a crushing one.

 

> 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). " 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 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.

 

I wouldn't call corporate takeovers predictable! But yes, this is

rethoric, and rhetoric that would make most scientists groan.

 

> 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 plants' protein-mediated systems.

Higher plants, such as corn, soybeans, and cotton, are known to possess proteins

that repair DNA miscoding; proteins that alternatively splice messenger RNA and

thereby produce a multiplicity of different proteins from a single gene; and

proteins that chaperone the proper folding of other, nascent proteins. 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 su!ccessfully transferred.

>

> 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. " 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.

>

> One way that such mystery DNA might

 

Barry then goes on to say that all these exceptions add up to more

things that can go wrong than are tested for. He's got a point there.

 

(He also says that the central dogma is rubbish because the first cells

must have had proteins without DNA. More likely, the first life forms

used related molecule ribonucleic acid to do the work that proteins do

today.)

 

> Barry Commoner is a senior scientist at the Center for Biology of Natural

Systems at Queen's

> College, City University of New York where he directs the Critical Genetics

Project.

 

Ian McDonald did a PhD in the biochemistry of protein stuctures.

 

--

Ian McDonald

 

http://www.mcdonald.me.uk/