Genetically modified organisms

This is not an easy topic. Most of us misunderstand and very few of us know enough to grasp what genetic modification actually is. This includes the people who do it, who discover repeatedly that they were mistaken about some expected result. Genetics itself has changed enormously in the last couple of decades or so. What most people think of as genetic modification is simply not what it is. In addition, one of the first successful GMOs was designed to improve corporate profits, with improved crop yields as a side effect. This has raised suspicions about the motives the gene modifiers.

I’ll give my current understanding of GMOs, with two warnings: first, the following is inevitably incomplete and certainly wrong or misleading in several places. Second, the news about genetics is changing very rapidly.

Two very basic and fundamental points:
A, The genome (the collection of genes on all the chromosomes) is not like a blueprint. A much better metaphor is “recipe” or “program”. Like any program, different parts of the code are running at any given time. That’s why we have skin cells, and muscle cells, and liver cells, and brain cells, and so on, all of which contain the complete genome. That’s why a scratch or cut heals: the genes that promote skin cell growth and migration to heal the cut are normally inactive. That’s why we are awake or asleep: genes in neurons turn on and off, the neurons function differently, and we sleep or wake up. We say a gene is “expressed” when it’s doing its work.

B, Genetic modification happens all the time. New varieties and species all arise from genetic modification that’s passed on from one generation to the next. However, a large chunk of the genome does not change: natural selection preserves genes that necessary for life and reproduction. That’s why we share about 20% of our genome with snails. Natural selection ignores genes that have no net effect one way or the other; however, “genetic drift” may change the frequency of these genes. That’s a major reason that people from different parts of the world look different.

We humans have used selective breeding to concentrate genetic variations to suit ourselves.. This method gave us wheat, corn, potatoes, tomatoes, and so on. As well as a huge variety of dogs, cows that produce gallons of milk, woolly sheep, gentle buffaloes, and so on. Whenever you breed for some desirable trait, you also breed for other traits, some of which may be undesirable (think tough, bruise-resistant tomatoes with no taste, or roses lacking fragrance). Some selective breeding has resulted in infertile plants (bananas), or plants that need human help to breed (corn).

Selective breeding is possible because of the following mechanisms of genetic modification.

1) Recombination. The prime mode of modification from one generation to the next, and the reason none of us is a clone of our parents. Prime example: Apples. They don’t breed true. All of the delicious varieties we enjoy are the result of recombination. The only way to propagate these varieties is by cloning (grafting from one tree to another). If the chain of cloning breaks, that variety of apple disappears.

2) Hybridisation, also known as crossing. Easy with varieties of the same species, more difficult with related species. Easier with plants than with animals. It happens spontaneously, especially among microbes. Some hybrids between related species are fertile, which raises the question of whether they are new species, and whether the related species are really different species. "Species" is a fuzzy concept.

3) Mutation. Most mutations are repaired as they happen, others kill the cells in which they happen, the rest survive. If a surviving mutation is in an egg or a sperm, it may be passed on to the next generation, in which case it may spread through the species and modify it. Hairless cats are an example.

4) Gene exchange. This happens directly among bacteria, even across species, and is the reason that resistance to antibiotics has spread faster than originally estimated. It’s also the reason bacteria can be used to produce useful materials. It also happens with plants, and occasionally with vertebrates that breed externally, such as fish. Some plants even require “foreign” pollen to reproduce (currants, for example).

5) Polyploidy: more than two sets of chromosomes. Most common among plants (estimates range from 30 to 80% of all plant species). It’s possible to manipulate the process, and so produce new varieties of plants.

6) Methylation: during the organism’s life, methyl groups are attached to the genome, for many different reasons. This affects the gene expression. Methylation happens in all organs, including reproductive organs, which means it can affect gene expression for at least the next generation.

7) Viral or bacterial infections which alter the genome. Prime example: tulips. Viral infection of the bulb affects the colour, shape, etc of the of bloom. It does not affect the seed, which means that the only way to propagate such varieties is by cloning them. Viral infections work by inserting genes into the host DNA, so that the infected cell then produces viruses.

8) Artificial gene modification. Humans have been doing this as long as they’ve been human, through selective breeding. Later, humans discovered cloning (grafting), which led to plants that cannot propagate on their own (seedless watermelons, bananas).
     What’s new is the ability to use some of the natural processes that change DNA. In particular, enzymes that bacteria and viruses use to replace bits of host DNA with the infector’s DNA can be used to insert or replace genes that are useful from our point of view. The most recent method of altering DNA is CRISPR, a method to edit DNA directly, in order add, delete, or replace a gene.

But it’s not easy. Any change to DNA may have unexpected effects. Manipulating the genomes of bacteria is easiest: they are naturally prolific adapters of foreign genes. It’s more difficult with plants, and most difficult with animals. In general, it’s easy to replace a gene, more difficult to insert one. Removing a gene is easy enough: it’s been done with selective breeding of lab mice.

Replacing genes is the basis of gene therapy, which has had some small success. Exchanging genes from the same species is a good way to produce new varieties. Selective breeding is the slow way; CRISPR is quicker.

Inserting genes is difficult because the gene may not even work, let alone work as desired. The success of doing this is highest with bacteria, which do it naturally, and with abandon. For example, there are some bacteria that can eat some plastics. Would be nice to grow a bacterium that needs some specialised environment in a vat, dump in the plastic, and drain off the waste.

Editing the genome, by replacing one version of a gene with another version, turns out to be relatively easy. It’s also hugely successful: after all, a different version of the same gene will usually be expressed just like the one you replaced. The genes for blue eyes and brown eyes are simply different versions of the same genes.

An important fact is that related species share most of their genes. How much do they share? That depends on how closely related they are. We are more closely related to horses than to snails, so we share more genes with horses than with snails. But we are more closely related to snails than to roses, so we share more genes with snails than with roses. Sharing genes with other organisms makes gene exchange possible.

But it’s not really that simple. Just because we share certain genes doesn’t mean that they work exactly the same way. The gene’s environment affects gene expression. Which genes, when, and to what effect, all depend on the gene’s environment. That environment operates over several systems: , first, the cell itself, ie, which other genes are working in that cell. Then the organism itself, ie, which organ the cell is part of. Then the physical environment of the organism, ie, temperature, food, and so on. Finally, other organisms, ie, mates, predators, food sources, and so on. Pretty complicated, really.

And that’s why genetic modification, by any method, is more art than science, and results in more failures than successes.

Nevertheless, we humans have been doing it as much as possible for a long time. The newest insights into how genes work and how to change the genome have merely made the process quicker, and a little more certain.

Revised 2019/03/21

Sam Berns, progeria patient (link)

Progeria is a genetic disorder that results in premature aging. I've seen a number of documentaries about it. Here's Sam Berns talking about his philosophy of life. He died on January 10th of this year, a little less than one month after giving this talk.

Matt Ridley. Nature Via Nurture (2003)

     Matt Ridley. Nature Via Nurture (2003) Ridley’s densely argued thesis that the genes cannot work without input from the environment is a pleasure to read. Much of his research is first-hand: he has read the papers he cites or alludes to, and/or has spoken with the people who wrote them (including his own wife.) Unfortunately most of his older research is third or fourth hand; his comments on Skinner show a thorough (and very common) misunderstanding of behaviourism. (1) But that’s a minor flaw in a well-done book, one that unlike many of its kind reflects current research.
     A book that anyone who wishes to understand where biology is going should read. Some of its inferences will no doubt soon prove wrong, but that’s because the field is expanding so quickly. Something like a coherent vision of how organisms become what they are is emerging. The central message: we, like all other organisms, are the product of an exquisite interplay between what we are born with and what our environment foists upon us. **** (2006)

 See also https://kirkwood40.blogspot.com/2013/05/matt-ridley-nature-via-nurture-2004.html for an extended review.

Footnote (1): The common misconception of behaviourism is that conditioning can produce new behaviours. It can't. It can only re-direct and combine existing behaviours. Skinner called it "shaping". No amount of conditioning will make a pig fly, but conditioning could make a pig operate a car shaped like an airplane. Pigs poke at things with their snouts, and that behaviour could be redirected to push on various buttons and levers. Etc.

Matt Ridley. Nature via Nurture (2004)

 

    Matt Ridley. Nature via Nurture (2004) Argues and demonstrates that the dichotomy of Nature vs Nurture is not merely wrong, it’s profoundly misleading. The genes can operate only in response to nature (here broadly defined as the environment in general, including anything outside the cell itself, that is, including the rest of the body). And nurture can’t have its effects if there are no genes to respond to it. Much interesting bleeding-edge research supports this thesis, and there is perhaps more repetition of the thesis than strictly necessary. However, Ridley’s point is well-taken. On philosophic or logical grounds alone, the “nature versus nurture” argument is silly, since it’s obvious that any organism must be equipped to survive, which means that it must develop the requisite organs and behaviours. In other words, it must respond properly to it environment, hence nurture plays a role. But it can respond properly only if it has the proper genetic endowment, hence nature plays a role. The only puzzle is how nature and nurture interact to produce a viable organism.
     Ridley reviews what’s now known about this interaction, and in doing so suggests a fundamental shift in perspective. He stresses the role of genes in the development of an organism (and corrects the genome-as-blue-print metaphor as he does so). The most important single point I think is that the environment switches genes on and off in a fixed sequence during development, and that once a gene’s work is done, it usually cannot be reactivated. Moreover, it’s the timing of gene activity, i.e., how long it persists, what other genes are activated or not at the same time, etc, that determine the adult’s phenotype. These two factors, timing and sequencing, have lifelong effects, almost always irreversible. Yet each stage of development depends on environmental cues, both external to the organism, and internal (in the form of proteins etc produced by other genes’ actions).
     I think that it’s the rigidity of developmental response to the environment that encourages people to think that nature is all. For if nurture could have unlimited effects, it could change the organism at any time. This latter notion is said to be the dogma of radical behaviourism, and certainly Skinner was rash enough to make such claims in language that make them sound silly. No amount of Skinnerian conditioning can make a Newton; but given a Newton, an environment that suited him was essential to enable the kind of discoveries he made (including the ones histories of science ignore). In pushing his point of view, Skinner rarely made his underlying assumption explicit, that an organism’s behaviour can be shaped by the environment, but cannot be created by the environment. An organism must “emit” a behaviour, in the quaint jargon of the behaviourists; only then can behaviourist techniques shape it. Just where the emitted behaviour comes from is not a behaviourist concern, apart from denying that some non-material mind or soul causes it.
     Ironically, the neurologists’ methods and stance are thoroughly behaviourist. They investigate behaviour in terms of responses at the neural and even molecular level. Their results show that even at these levels, the environment shapes behaviour. The organism develops and exists as a pattern of interaction with its environment. Yeats said, Who can tell the dancer from the dance? Flip Wilson said, What you see is what you get. Marshall McLuhan says We construct the truth about the environment by building the environment with which we interact.  I say The self exists as the interface between inner and outer. These are I think different ways of saying that nature and nurture act together to make us what we are.
     Ridley makes other points along the way. One is that the one-gene-one-protein concept is thoroughly wrong. Proteins may be built (are usually built in fact) by several genes acting together. A single gene can be (usually is, in fact) implicated in the building of several different proteins. A gene may be (often is, in fact) partially activated, so the same gene can build different proteins at different times, even when acting alone. Moreover, a protein’s effects depend on the existence of other proteins, so that genes affect each other’s expression. Finally, since the expression of a gene is not a simple straight-line chain of cause and effect, but a complex web of interwoven strands and feedback loops, genes’ effects both cancel and complement each other, so that a single mutation rarely has a serious effect, or even a visible one. It’s no accident that so few diseases have been traced to the mutation of single genes.
     These facts explain why genetic engineering has been so unsuccessful thus far. One would think that, with hundreds of millions spent on R&D, by this time we would have hundreds of varieties of GE plants, but it seems that most of the time the efforts fail, a fact that is curiously not widely publicised. Or perhaps not so curiously: Neither the promoters nor the opponents of GE want the public to know the high failure rate, for opposite but thoroughly complementary reasons. Each side exaggerates the success of GE, one to generate enthusiasm, the other fear. However, those who advise caution have a good case: we don’t really know what the insertion of a foreign gene will do in an organism, since there are too many ways in which a gene’s expression will be controlled or affected by the other genes.
     Good book. **** (2004)

See also https://kirkwood40.blogspot.com/2013/08/matt-ridley-nature-via-nurture-2003.html for a shorter review.

Michel Morange. The Misunderstood Gene (2001)

     Michel Morange. The Misunderstood Gene (2001) Mendel was lucky: in his experiments, he observed characters of peas governed by a single gene. He didn’t know this, of course, and neither do those who learned of genetics via his story, the standard story told in high school and college biology classes. The result is a profound misunderstanding of what genes do, and of what our manipulation can and cannot achieve. Morange tries to dispel these misunderstandings, and succeeds, but only with people willing to plow through his dense and in places highly technical text. His lycee-learned style is the main culprit, for despite his mastery of English idioms, he does not write with the clarity of an Ian Stewart, for example (who makes many of the same points in his Collapse of Chaos, written with Jack Cohen).
     Nevertheless, this book is worth the effort. I hope it is the first of many books and articles that will demystify the gene. His main point is that the "blue-print" and the "program" metaphors are so misleading as to be wrong. In particular, he makes great efforts to disabuse us of the notion that there is some kind of one-to-one mapping of genes and features, that there is a gene for blue eyes, for example, and a gene for brown eyes, and which eyes you get is decided by the genes you inherit from your parents. This one-to-one mapping of genes and features is extremely rare. Most traits are the result of several genes, whose precise interactions are not well understood. For most traits, the genes involved are not yet known. Hence genetic determinism is a mistaken concept. One consequence of this is that most “genetic engineering” is doomed to a priori failure. In developing this thesis. Morange makes several main points:
     1) Genes code for proteins, not for features or characteristics of organisms. It’s the interactions of proteins that determine how an organism develops and functions. But the same protein will have different functions at different times in the organism’s lifespan, and similar proteins will have different functions in different organisms. And some proteins are made only during a specific (and usually short) period in the organism’s development. For example, sexual maturation depends on various hormones whose production is modulated partly by a molecular clock, and partly by such things as the organism’s rate of metabolism, its food intake, its physical growth, and even external factors such as the time of year, and so on.
     2) Most features of organisms are determined by a suite of genes acting at different times during its development. For example, we normally have five fingers. But the embryo starts with a flipper-like appendage. To make fingers, certain cells must die: genes determine which cells will die, but there is no “gene for five fingers,” since the same genes, activated in different organs at different times in the embryo’s development, also control the growth of other organs and features of the human organism. How do the genes “know” when to activate the death process, and when not to? Well, that depends on signalling between and within cells, in other words, the cells’ environment, which is determined by still other genes that code for the proteins that make up, act as, or set up these signalling systems.
     3) The vast majority of features of an organism are the result of a complex interplay of proteins coded by many different genes at different times, as well as external factors such acidity, temperature, and so on. A mutation in any one of these genes can be and almost always is offset by the buffering action of the many other proteins involved. The system as whole tends towards a stable form regardless of the actual mutations in the genes. There are also repair mechanisms, which prevent mutations in the DNA of any one cell from destroying it, and also ensure that the daughter cells function properly.
     4) Although it’s possible (at least in principle) to trace backwards from effects to genetic causes, it’s not possible to predict what any given combination of genes will cause to happen. The reason is, again, the complexity of the protein interactions, and more importantly, the self-organising properties of biological systems.
     5) The value of a gene is determined by the environment in which the organism finds itself. What’s good in one time and place may be bad in another. This explains why sickle-cell anaemia, for example, persists in the human gene pool: it confers some resistance to malaria, and that resistance outweighs it deleterious effects where malaria is endemic. Malaria will kill many victims before they reproduce; while sickle cell anaemia usually doesn’t kill until later in life, after reproduction. The same mathematics accounts for Huntington’s and other late-onset diseases (including the diseases of old age): these strike a decade or more after the prime reproductive years.
     What I take from Morange’s book is that genetic engineering is to a large extent a fantasy. It will have at best very limited success. For one thing, so few features are controlled by a single gene that it’s just a matter of luck that features such as resistance to Roundup can be engineered at all. There was no a priori reason to suppose that such resistance would be governed by a single gene. On the other hand, the fact that Huntington’s is caused by a single mutation on a single gene means we can eliminate it.
     Secondly, the effect of a protein depends on its environment. A protein will not necessarily have the same effect in the host organism as it had in the donor. Again, it’s pure dumb luck that the protein for Roundup resistance has the same effect in the host plant as in the original donor plants. Also, the gene may be recessive, or the mutation we are interested in may act differently when paired with the unmutated allele.
     Thirdly, the odds are enormous that any given gene transferred to another organism will have unpredictable effects in addition to or in place of the effect(s) it had in the donor. Proteins initiate or intervene with many biochemical pathways. There is no guarantee that a given protein will act the same in the host as it did in the donor. Some of the end results may not show up in the host organism, but in the ones that eat it.
     Morange also points out that a clone made with current techniques is in fact less like the donor than identical twins are to each other. The current techniques involve harvesting a cell from the early embryo (of few dozen cells in size), removing the nucleus, and inserting the nucleus taken from the donor cell. The clone shares the nuclear DNA with the donor, but has the mitochondrial DNA of the host oocyte, which was determined by the maternal genes. Identical twins share both nuclear and mitochondrial DNA. Only if we can develop techniques that in effect convert a donated cell into a zygote will the clone be an identical copy of the donor. Of course, even then, the clone will be an independent individual subject to all the vagaries of an unpredictable environment, and so when fully developed will not be identical copy of the donor, any more than twins are identical copies of each other.
     Morange does see good things coming out of our increasing understanding of the effects of genes. How a gene affects its carrier depends hugely on the environment, and humans are able to control that, so they are also able to influence the effects of their own genetic heritage.
     Morange thinks that knowing one’s genetic heritage and its biological meaning will enable us to counteract otherwise damaging effects, and he thinks this a far easier mode of “genetic engineering” than attempts to change the genome itself. Changing the genome of the cells in some organs does hold great promise for individuals, but will not be passed on to their offspring. Changing the germ line itself is far more problematic. Apart from a few diseases like Huntington’s, most diseases and disabilities result from such a complex interplay of so many genes that changing one or even a few of them will not have any observable effect for several generations, if then. Lifestyle changes for the individual have a much greater payoff.
     Morange’s book, or rather its message, is important and deserves a wide audience. It also deserves interpretation to the general public, which still thinks of the genome as some sort of master plan that we are fated to follow. The truth is both more complex and more liberating. *** (2003)

Cohen and Stewart. The Collapse of Chaos. (1994)

      Jack Cohen and Ian Stewart. The Collapse of Chaos (1994) Cohen and Stewart attempt a meta-story here: that of how the chaotic, messy events on one level of reality (or perhaps merely analysis) produce regular and orderly features at a higher. An excellent book, often heavy going for anyone without at least a smattering of a variety of disciplines, but also often offering high spirits and sly irony.
I read it when it first appeared, but had forgotten almost all of it. Only a few marginal notes (typo-corrections, mostly) testify to my former reading.
     But I realise that many of its ideas have become commonplace for me. Chief of these are four. The first is that theories or models may or may not represent reality as it is. They are certainly work-alikes. That is, their observable external relations are the same as what they model, but there is no guarantee that their internal workings are the same. Nor is it ever possible to discover whether models are more than work-alikes, since attempts to get inside the black boxes merely produce more models with the same ontological deficiency.
     The second idea is that of emergent features: that it is impossible to predict, and often impossible in practice to explain, how the behaviour of one set of entities gives rise to features observable at a larger scale (or “higher level.”) Related to this is the idea that to explain how something happens is not the same as predicting what will happen. Science’s attempt to combine explicability and predictability, indeed most people’s belief that they are the same, has kept us from noting and investigating many things, or has misdirected our investigations. Ironically, it was just such a misdirected investigation (that of trying to derive a model of the weather from statistical data) that led to the discovery of chaotic systems, and prompted the development of chaos theory. Mandelbrot, also, testifies to this irony: according to Stewart, he said he had studied fractals a long time before he realised that he was looking at a new class of mathematical objects.
     The third idea is that the genome does not describe the organism, but merely the production the proteins that interact with each other and the environment to produce the organism. Understanding this puts a huge question mark over all genetic engineering. We simply cannot predict all the effects of transferring a gene from one organism to another. The fact that at present a very small minority of such transfers actually work to produce any result, let alone the desired one, shows that genetic engineering is still the crudest form of trial and error. But the genome-as-blueprint metaphor has great power, probably because of its simplicity, and because people do not understand blueprints, but think they do. Everyone has seen blueprints, for example in the weekly home-plans feature carried by many newspapers. The fact that such plans are really directions to the builder, and do not contain enough information to describe the final building, is lost on most people. That is why the metaphor misleads. People do not consider the blueprint as a recipe, which is really what it is. It might be better to make the metaphor explicit, and think of the genome as a program or recipe. A recipe for a cheese omelette does not describe the omelette, it describes how to make one. It takes ingredients and a cook and a stove to make an omelette. Just so, a genome does not describe an organism, it describes how to make one. It takes a zygote and a womb and an organism to make one.
     The description of the process of development is indirect, too, and consists mostly of instructions to make or stop making proteins. The proteins themselves react with each other and other chemicals, under the influence of temperature, pH, etc, and the result is a developing organism. What’s more, the proteins affect the genome’s functions: the products made under process A trigger instruction X, which stops process A and starts process B. B triggers instruction Y, which starts process C, which triggers instruction Z, which stops process B; and so, in all sorts of interlaced and intertwining instructions and processes.
     Finally, Stewart and Cohen have a healthy respect for the limits of scientific explanation. More than most popular science writers, they emphasise the fuzziness and tentativeness of science. This is a good thing, if only to remind us all that knowledge, even the most strongly supported, is never certain. If only religious folk understood this and accepted it, they might have more faith. **** (2002)
     Update 2013: It now appears that genetics is even more complicated than Cohen and Stewart knew. The environment (i.e, other cells, the chemical bath surrounding the cell, the organ of which it a part, the organism embedded the external environment, ...) turns genes on and off, which in turn affect the cells interaction with neighbouring cells, the chemical bath that surrounds it, and so on a wonderfully recursive dance. And just within the last year or so it's been discovered that genes can be transferred "horizontally" between species,probably via the microorganisms that inhabit it). See this National geographic article. The problem is that we don't have a language to describe the dynamic web of reactions that constitute an organism. In ordinary language, an organism is at best a gearbox. In fact it's something much more difficult to describe. we are thrown on the mercy of our metaphors. Her's one: an organism is shape created by its substrate, in the same that a fountain is a shape created by its substrate: water for the decorative fountain in your garden; plasma on the surface of the Sun.