Redesigning Life

John Parrington’s new book sets the stage for an informed debate on genetic modification

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This post originally appeared on Science Borealis

“Imagine if living things were as easy to modify as a computer Word file.” So begins John Parrington’s journey through the recent history and present-day pursuits of genetic modification in Redesigning Life. Beginning with its roots in conventional breeding and working right up to the cutting edge fields of optogenetics, gene editing, and synthetic biology, the book is accessible to those with some undergraduate-level genetics, or secondary school biology and a keen interest in the subject. This audience will be well served by a book whose stated goal is to educate the public so that a proper debate can take place over the acceptable uses of genome editing.

 

Parrington doesn’t shy away from the various ethical concerns inherent in this field. While he points out, for example, that many fears surrounding transgenic foods are the result of sensational media coverage, he also discusses the very real concerns relating to issues such as multinational companies asserting intellectual property rights over living organisms, and the potential problems of antibiotic resistance genes used in genetically modified organisms (GMOs). Conversely, he discusses the lives that have been improved with inventions such as vitamin A-enriched “golden rice”, which has saved many children from blindness and death due to vitamin deficiencies, and dairy cattle that have been engineered to lack horns, so they can be spared the excruciating process of having their horn buds burned off with a hot iron as calves. These are compelling examples of genetic modification doing good in the world.

 

This is Parrington’s approach throughout the book: both the positive and negative potential consequences of emerging technologies are discussed. Particular attention is paid to the pain and suffering of the many genetically modified animals used as test subjects and models for disease. This cost is weighed against the fact that life-saving research could not go ahead without these sacrifices. No conclusions are drawn, and Parrington’s sprawling final chapter, devoted solely to ethics, is meandering and unfocussed, perhaps reflecting the myriad quagmires to be negotiated.

 

Weaving in entertaining and surprising stories of the scientists involved, Parrington frequently brings the story back to a human level and avoids getting too bogged down in technical details. We learn that Gregor Mendel, of pea-breeding fame, originally worked with mice, until a bishop chastised him for not only encouraging rodent sex but watching it. Mendel later commented that it was lucky that the bishop “did not understand that plants also had sex!” We’re told that Antonie van Leeuwenhoek, known as the father of microscopy, was fond of using himself as a test subject. At one point, he tied a piece of stocking containing one male and two female lice to his leg and left it for 25 days to measure their reproductive capacity. Somewhat horrifyingly, he determined that two breeding females could produce 10,000 young in the space of eight weeks.

 

The applications of the fast moving, emerging technologies covered in Redesigning Life will astound even those with some familiarity with modern genetics. The new field of optogenetics, for example, uses light-sensitive proteins such as opsins to trigger changes in genetically modified neurons in the brain when light is shone upon them. In a useful, yet nevertheless disturbing proof-of-concept experiment, scientists created mind-controlled mice, which, at the flick of a switch, can be made to “run in circles, like a remote-controlled toy.” More recently, sound waves and magnetic fields have been used to trigger these reactions less invasively. This technique shows potential for the treatment of depression and epilepsy.

 

The book goes into some detail about CRISPR/CAS9 gene editing, a process that has the potential to transform genetic modification practices. This system is efficient, precise, broadly applicable to a range of cell types and organisms, and shortens the research timeline considerably compared to traditional methods of creating GMOs. It underpins most of the other technologies discussed in the book, and its applications seem to be expanding daily. In the words of one of its developers, Jennifer Doudna, “Most of the public does not appreciate what is coming.” These words could be applied to almost any technology discussed in this book. Already within reach are so-called “gene drive” technologies, which could render populations of malaria-bearing mosquitos – or any other troublesome species – sterile, potentially driving them to extinction, albeit with unknown ancillary consequences. Researchers have also developed a synthetic genetic code known as XNA, which sports two new nucleotides and can code for up to 172 amino acids, as opposed to the usual 20. Modifying organisms to contain XNA opens up the possibility of creating proteins with entirely novel functions, as well as the tantalizing prospect of plants and animals that are entirely immune to all current viruses, due to the viruses’ inability to hijack a foreign genetic code for their own uses.

 

While the book touches on agriculture, its main preoccupation is medical research. Despite many of the therapies covered being far from ready for use in humans, one can’t help but feel that a revolution in the treatment of diseases, both infectious and genetic, is at hand. Only a year ago, gene editing was used to cure a baby girl of leukemia by engineering her immune system to recognize and attack her own cancerous cells. In the lab, the health of mice with single gene disorders such as Huntington’s disease and Duchenne muscular dystrophy is being significantly improved. Writing in 1962 in his book The Genetic Code, Isaac Asimov speculated that someday “the precise points of deficiency in various inherited diseases and in the disorders of the cell’s chemical machinery may be spotted along the chromosome.” Some 54 years later, we have the technology not only to spot these points but to fix them as precisely as a typo in a manuscript.

Sex & the Reign of the Red Queen

Why sexual species beat clones every time.

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“Now, here, you see, it takes all the running you can do to keep in the same place.”

From a simple reproductive perspective, males are not a good investment. With apologies to my Y chromosome-bearing readers, let me explain. Consider for a moment a population of clones. Let’s go with lizards, since this actually occurs in lizards. So we have our population of lizard clones. They are all female, and are all able to reproduce, leading to twice the potential for creating more individuals as we see in a species that reproduces sexually, in which only 50% of the members can bear young. Males require all the same resources to survive to maturity, but cannot directly produce young. From this viewpoint alone, the population of clones should out-compete a bunch of sexually-reproducing lizards every time. Greater growth potential. What’s more, the clonal lizards can better exploit a well-adapted set of genes (a “genotype”); if one of them is well-suited to survive in its environment, they all are.

Now consider a parasite that preys upon our hypothetical lizards. The parasites themselves have different genotypes, and a given parasite genotype can attack certain host (i.e. lizard) genotypes, like keys that fit certain locks. Over time, they will evolve to be able to attack the most common host genotype, because that results in their best chance of survival. If there’s an abundance of host type A, but not much B or C, then more A-type parasites will succeed in reproducing, and over time, there will be more A-type parasites overall. This is called a selection pressure, in favour of A-type parasites. In a population of clones, however, there is only one genotype, and once the parasites have evolved to specialise in attacking it, the clones have met their match. They are all equally vulnerable.

The sexual species, however, presents a moving target. This is where males become absolutely worth the resources it takes to create and maintain their existence (See? No hard feelings). Each time a sexual species mates, its genes are shuffled and recombined in novel ways. There are both common and rare genotypes in a sexual population. The parasite population will evolve to be able to attack the most common genotype, as they do with the clones, but in this case, it will be a far smaller portion of the total host population. And as soon as that particular genotype starts to die off and become less common, a new genotype, once rare (and now highly successful due to its current resistance to parasites), will fill the vacuum and become the new ‘most common’ genotype. And so on, over generations and generations.

Both species, parasite and host, must constantly evolve simply to maintain the status quo. This is where the Red Queen hypothesis gets its name: in Wonderland, the Red Queen tells Alice, “here, you see, it takes all the running you can do to keep in the same place.” For many years, evolution was thought of as a journey with an endpoint: species would evolve until they were optimally adapted to their environment, and then stay that way until the environment changed in some fashion. If this was the case, however, we would expect that a given species would be less likely to go extinct the longer it had existed, because it would be better and better adapted over time. And yet, the evidence didn’t seem to bear this prediction out. The probability of extinction seemed to stay the same regardless of the species’ age. We now know that this is because the primary driver of evolution isn’t the environment, but competition between species. And that’s a game you can lose at any time.

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Passionflower. Photo by Yone Moreno on Wikimedia Commons.

Now the parasite attacking the lizards was just a (very plausible) hypothetical scenario, but there are many interesting cases of the Red Queen at work in nature. And it’s not all subtly shifting genotypes, either; sometimes it’s a full on arms race. Behold the passionflower. In the time of the dinosaurs, passionflowers developed a mutually beneficial pollinator relationship with longwing butterflies. The flowers got pollinated, the butterflies got nectar. But then, over time, the butterflies began to lay their eggs on the vines’ leaves. Once the eggs hatched, the young would devour the leaves, leaving the plant much the worse for wear. In response, the passionflowers evolved to produce cyanide in their leaves, poisoning the butterfly larvae. The butterflies then turned the situation to their advantage by evolving the ability to not only eat the poisonous leaves, but to sequester the cyanide in their bodies and use it to themselves become poisonous to their predators, such as birds. The plants’ next strategy was to mimic the butterflies’ eggs. Longwing butterflies will not lay their eggs on a leaf which is already holding eggs, so the passionflowers evolved nectar glands of the same size and shape as a butterfly egg. After aeons of this back and forth, the butterflies are currently laying their eggs on the tendrils of the passionflower vines rather than the leaves, and we might expect that passionflowers will next develop tendrils which appear to have butterfly eggs on them. These sorts of endless, millennia-spanning arms races are common in nature. Check out my article on cuckoos for a much more murderous example.

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Egg-like glands at the base of the passionflower leaf (the white dots on my index finger).

Had the passionflowers in this example been a clonal species, they wouldn’t likely have stood a chance. Innovations such as higher-than-average levels of cyanide or slightly more bulbous nectar glands upon which defences can be built come from uncommon genotypes. Uncommon genotypes produced by the shuffling of genes that occurs in every generation in sexual species.

And that, kids, is why sex is such as fantastic innovation. (Right?) Every time an illness goes through your workplace, and everybody seems to get it but you, you’ve probably got the Red Queen (and your uncommon genotype) to thank.

 

Sources

  • Brockhurst et al. (2014) Proc. R. Soc. B 281: 20141382.
  • Lively (2010) Journal of Heredity 101 (supple.): S13-S20 [See this paper for a very interesting full explanation of this links between the Red Queen hypothesis and the story by Lewis Carroll.]
  • Vanderplank, John. “Passion Flowers, 2nd Ed.” Cambridge: MIT Press, 1996.

*The illustration at the top of the page is by Sir John Tenniel for Lewis Carroll’s “Through the Looking Glass,” and is now in the public domain.