Tuesday, September 16, 2014

The precedent-setting effect of first-generation GMOs

Current debate between proponents and critics of "genetic engineering" is, by and large, engaged in a battle to determine whether or not GMO foodstuff can be proven safe for ingestion. Each side seems to rely on authority to build their argument, citing scientists that back their stance and ignoring studies that suggest otherwise. As a result, the broader ethical and philosophical questions about the consequences of genetic engineering, questions that have remained unresolved since they were first raised in the 1970s and 1980s, are being swept under the scientist's rug. This narrowing of the breadth of public debate should be a concern for those on both sides of the transgenic fence line.

It is simply a fact that most of the peer-reviewed studies available on commercialized GMOs currently attest to their safety, though there is reasonable concern about the independence of many of these studies, as well as the comprehensiveness of their scope and their methodology. Despite these concerns (and allied ones involving the control of seed supplies by corporations and patenting laws), I will assume for the sake of this article that currently approved GMOs for food consumption are 100% safe, as their advocates claim. After making this assumption, the next question is: Does this imply, as GMO advocates seem to declare, that we should no longer be concerned about further developments by the biotech industry? That 'labeling' or restricting the production of GMOs is unnecessary or misguided? Or that the debate as to whether GMOs are "good" or "bad" has been resoundingly solved?

I argue here that the safety of first-generation biotech crops (i.e Roundup Ready and Bt crops) not only fails to provide us of any evidence that future GMOs are safe, but for several reasons actually increases the likelihood of dangerous future crops. Their safety would set a precedent that would alter the risk assessment landscape of both researchers and the public in fundamental ways that would gradually erode our capacity to evaluate the progressive advancement of increasingly extreme employments of the technology. It is vital that society develops the means to ensure against such a "snowball effect."

Advocates of genetic engineering should understand that the level of testing and scrutiny that the first-generation of transgenic organisms have received is likely to be more rigorous than it will be for future organisms approved for commercial release. There are several reasons for this.

First, because Roundup Ready and Bt crops were the first crops approved for human consumption, they were perceived by scientists, governments, companies, and the public as having a greater potential risk. "Science" was introducing something new and controversial and therefore bore the burden of assuring the public of its safety for consumption and release into the environment. Scientists were more vigilant and they were forced to be even mores by an incensed consumer base. Regardless of whether or not you consider some biotech activists' positions on GMOs as 'extreme,' it is difficult to deny that the anti-GMO movement did influence policy, slow down the approval process, and ensure that more studies were undertaken than was perhaps anticipated. At the time, long-term studies on humans had never been conducted so no one really knew what would happen. Now, obviously, over the last decade or so, some sort of large human trial has gone on, and it has buttressed the confidence of industry and government in the safety of the products. If the public can be tranquilized, there is no reason to continue with the same level of scrutiny.

Second, at the time industry was also unsure about what sort of culpability they would have in the cases where their patented GMOs spread in the environment. At first, insurance companies refused to insure them and early lawsuits were yet to be resolved. Court cases since then have appeased these concerns by repeatedly letting industry off the hook, again facilitated a climate whereby we can expect less caution for the production and release of upcoming crops.

Third, while many geneticists remain quietly concerned about genetic engineering, some of the most vocal advocates against GMOs have been non-scientists who have made dubious claims confusing causation and correlation or who have a past that is easy to ridicule in ad hominem character assassinations. The result is that shareholders, governors and business leaders are not only unpersuaded by the anti-GMO crowd but actually galvanized in their belief that concern about GMOs is limited to those with fundamentalistic commitments to grand conspiracy theories instead of reason and commonsense. All said and done we can therefore expect to witness a new level of confidence emerging amongst corporations and lawmakers that first-generation biotech crops are safe.


As a result, it is unlikely that subsequent generations of GMO crops will be pushed through the same amount of testing as had occurred with first-generation crops. Industry itself has claimed that many of the studies that have been conducted by independent researchers to assess the safety or substantial equivalence of existing crops (such as proteomic studies) are unnecessary. We should expect that risk assessment procedures will get streamlined and optimized to save time and money based on the precedent-setting fact that existing GMOs have already allegedly been shown to be safe. As the depth and duration of testing is likely to taper, we will also expect to see the gradual increase in types of GMOs approved for commercialization. The types of approved GMO crops, animals, micro-organisms, both wild and domesticated, will increase as companies, now working in a climate that has attenuated the threat of non-GMO thinking, become more motivated to dedicated research and development funds into producing new biotechnologies. The number of companies will also predictably increase, as will the number of "garage biotech" tinkerers, who are increasingly able to purchase gene sequencers and genetic material online. A combinatorial explosion resulting from the interactions between these myriad novel crops introduced simultaneously would conveniently prevent the feasibility of any public health studies on them, effectively detonating the possibility of gathering conclusive data that would throw such releases into question.

More alarmingly, however, is that as this is occurring we should also expect to see a steady increase in the degree to which commercialized organisms have been genetically modified. Biotech proponents are fond of pointing out that commercialized GMOs only have 1-3 genes inserted into them, a trifling change in light of the vastness of their genomes. Even if we ignore the fact that these 1-3 genes can have nonlinear effects on other genes and regulatory molecules at different points in their expression, we can hardly take it for granted that there is some 'law' about genetic engineering limiting the number of transgenes to such a low number. We are already starting to see "stacking", where packets of genes coming from many different sources are inserted into host DNA with the goal of creating more significant alterations to the anatomy, physiology or behaviour of the transgenic organism. As the number of genes inserted moves steadily upward, we should also expect that genes themselves are going to be adjusted and edited in increasingly extreme ways with the computational assistance of computers. Researchers are even developing new chemical bases to add to the existing four-"letter" nucleic acid alphabet (Marris, 2005). Further, entire genetic regulatory networks are being created in labs as well as synthetic chromosomes, and even "gene drives" designed to intentionally spread genes through an entire population of a wild species through extremely small initial interventions.

The problem is that there is no dividing line between single-gene insertions and completely novel chimeras with genomes composed entirely of patched together, synthesized, or designed sequences. They are all considered to be GMOs. A very gradual slippery-slope exists between them. If we accept first-generation GMOs, we may find ourselves sliding into a world where the integrity of other organisms, the health of ecosystems, the deeply humble sense of awe and sustenance we derive from the natural world, and of course our health and vitality, are all increasingly compromised. The gravest possible consequences are not whether or not GMOs cause leaky gut syndrome or increased potential for allergenicity (as some charge Bt crops of doing), but in how their widespread acceptance will affect our very sense of what it means to be human in the biosphere and its prospects to continue functioning as the life-support system for all its varied creatures.

And we'll let it all unravel if only because we have already accepted the argument that GMOs are safe and that the governing bodies have the appropriate mechanisms to ensure our safety. Perhaps anti-GMO activists would have a more level-headed approach to genetic engineering if they could witness a more honest discussion of the medium and long-term risks of normalizing genetic engineering. Until we see a deeper level of engagement, a culturally democratic way of collectively thinking about our shared future, and a capacity of governments and industries to assess GMOs in less biased and more comprehensive ways, it remains entirely reasonable for biotech activists to continue their struggle. They are the only ones keeping this runaway train from flying off its tracks.

Thursday, August 28, 2014

Unpredictable genes

Genes are unpredictable.

A given gene may behave in many different ways, depending on the signals it is receiving from other parts of the genetic code, from other areas inside the cell, and from outside the cell. In this article, I want to outline the basic reasons it is wrong to say that a gene has a particular function, which is the basic assumption underlying much of commercial biotechnology (where the basis of their logic is something like this: if we take a gene "for X" and put it into organism "Y", then organism "Y" will now express the novel trait X indicated by that gene).

In a moment, I will explain some of the reasons why genes cannot by thought of in this way. I want to be clear that I am not proposing some radical and idiosyncratic version of the science of genetics. All of the points I raise can be found in basic undergrad textbooks (such as Gilbert, 2003). The problem we are facing is that the fact that genes are so complicated and adaptive is being ignored by companies seeking profits and by consumers who are being told a juvenile version of what genes are in an attempt to appease them. As long as geneticists remain coy and unwilling to express the overwhelmingly complex and interconnected nature of the genome in simple terms, influential people from Mark Lynas to Hilary Clinton are going to keep pushing a vision of the biosphere not based on reality. And with dire possible effects for those living within it.

But before I get into details, a very brief primer is needed for those of you who don't yet understand how genes do what they do...

A gene is a segment of DNA that "expresses" a certain protein product. Because proteins are the building blocks of bodies, genes are continually orchestrating the building and rebuilding of the body, in all its forms and functions. However, on their own, genes are inert molecules capable of doing very little. Throw a bunch of DNA into water and it just sits there. What turns genes into a source of information are the cells that they are found in, which have the context to read meaning into the genes. Without going into details, what happens is this: the information contained in a gene is "transcribed" into RNA. It is then edited down so it only includes relevant information, and then it is sent to the ribosome. The ribosome then "translates" the information in the RNA by producing a specific protein based on the coding of the RNA (a visual overview of the process can be seen here).

What makes genetics so interesting and so beautiful is not the machine-like consistency by which this process occurs, but the fact that it is open. It is responsive and subtle, adapting and re-adapting with incredible versatility to what comes along as the cell (and the organism it is a part of) lives its life. A gene does not simply enable the production of a protein, like a fixed blueprint of operating instructions for a giant factory. Instead, the information in the gene is itself fluid and dexterous, changing depending on how it gets read and re-read by the cell. Depending on the evolving circumstances of the cell, a gene is capable of getting turned off, turned on, getting stimulated to work more rapidly or more slowly, capable of collaborating (or ceasing collaboration) with other genes, and even of producing new types of protein. There is therefore a wonderful circularity and mutual dependence between the form and function of the genes and that of the organism. Scientists are trying to model the infinitesimal interactions that occur every second within and between the various genes in a cell but even with extremely powerful computers, they are a very long way off from understanding the diverse behaviours of genes and how adaptive they are to the environments they occur in.

I will discuss two major ways by which the information within genes is adapted or modified by the cell: chromatin remodelling and alternative splicing. Both ways enable an indefinite variety of possibilities for new behavior and ongoing sensitive response and learning on behalf of the lifeform.

Chromatin remodelling

In multicellular organisms such plants and animals, DNA is not naked and floating around on its own. It is found in a giant string of molecules known as chromatin. Chromatin is made up of DNA coiled around proteins called histones. Depending on how tightly the histones are packed together, the genes in the DNA can behave in very different ways.

For example, if the histones are very tightly packed (forming solenoids), genes in the DNA will usually be pinched off and therefore not expressed. Conversely, if the chromatin is stretched out, the genes will usually be exposed, allowing RNA polymerase to come in and initiate transcription.

However, there are also an infinite number of middle states between a closed off segment of chromatin and one that is open. If the chromatin chain is bent or folded in different configurations, different active genes can be put closer or further away from one another. Depending on the architecture of chromatin, the interactional possibilities between the various genes and regulatory sequences in the DNA changes. Much of these structural changes in chromatin are a result of alterations in the shape of the histone proteins that the DNA is coiled around (Baker, 2011). Histones have chemically reactive ends and are known to form bonds with over a hundred different molecules (for example, histones can be methylated, acetylated, phosphoylated, etc.). Each molecule that a histone reacts with will create a slightly different shape of that region of the chromatin, and thereby nudge interactive possibilities between the genes one way or another.

In organisms, chromatin is being adjusted and readjusted all the time in continuous adaptation to ongoing circumstances. As this occurs, individual genes and clusters of genes become expressed, attenuated or silenced at different rates, altering the nature of the gene products.



Alternative splicing

Plants and animals' genes also undergo what is called "alternative splicing" (Sharp & Richards). After a gene is transcribed into RNA, it is then edited to produce "messenger RNA". A gene is typically a very long molecule of DNA, only some parts of which are used for expression. The parts that are not used are cut out before the RNA is delivered to the ribosome. Alternative splicing refers to the fact that the same gene can be edited in different ways, producing many different variations of messenger RNA, each which will be expressed slightly differently by the ribosome. It is estimated that half of human genes produce RNA that is alternatively spliced in certain circumstances (Wu, Yuan, & Havlioglu, 2007), and some genes (such as those active in the nervous system) are even capable of hundreds or thousands of different alternative splicings.

What is kept and what is edited out from the gene to create the messenger RNA again depends on signals received from other parts of the DNA, from within the cell, and from outside the cell. This is therefore another means by which genes are continually readjusting how they behave in ongoing adaptation to their environments.

I'll stop here, but readers should know that there are many other mechanisms making genes supple and flexible. For example, sometimes a gene is transcribed into RNA but the RNA does not reach the ribosome for translation because it gets censored along the way (Gagnon, 1992; Gilbert, 2003). The RNA is prevented from leaving the nucleus, implying that there is a "selection process" culling undesired RNA before it becomes expressed. There are also "post-translational modifications" that occur to regulate the shape of the proteins produced by the ribosome (Seo & Lee, 2004).

As long as activists can understand chromatin remodelling and alternative splicing and communicate these concepts in the comment sections of articles on GMOs, we will be able to lodge better arguments against those quartering us in as ignorant and irrational.

Take home message
Genes are complex, unpredictable, and still poorly understood.
Genes in multicellular organisms do not usually have specific and unalterable behaviours throughout the lifespan of the organism. To say that they do is obviously misleading. To create technologies that are based on this assumption is dangerous. The novel genes inserted into a genetically modified organism will interact in unpredictable ways, especially through the ways their expression changes through chromatin remodelling and through alternative splicing. We do not have the technical or financial capacity to test for all these changes, in part because we don't really yet know the extent of what we are looking for. Because the ways in which the new gene interacts within its new cellular environment can cause it to produce alternative chromatin structures and perhaps alternative splicings, the gene is unlikely to behave in the ways it did in its original cellular environment. OMIC studies, which catalogue snapshots of the expression products of genes at various stages of their transcription and translation are available but not required by regulatory bodies and therefore not conducted by biotech companies.

However, they are occasionally conducted by researchers and published in peer-reviewed journals. Tellingly, they reveal some of the true complexity of the genome. Let me quote from a proteomic study conducted on MON 810, one of the most commonly planted GMO maize varieties, produced by Monsanto: "Approximately 100 total proteins resulted differentially modulated in the expression level as a consequence of the environmental influence (WT06 vs WT05), whereas 43 proteins resulted up- or down-regulated in transgenic seeds with respect to their controls (T06 vs WT06), which could be specifically related to the insertion of a single gene into a maize genome by particle bombardment. Transgenic seeds responded differentially to the same environment as compared to their respective isogenic controls, as a result of the genome rearrangement derived from gene insertion" (Zolla et al, 2008). Approximately 100 unpredictable expression effects revealed from a proteomic study conducted at two different times! One might imagine what proteomic studies undertaken at other times but additionally reveal, and also what other differences would be exposed were transcriptomic or metabolic studies also conducted.

Establishing "substantial equivalence", which implies that the GMO should not bear any special scrutiny compared with its non-GMO counterparts, is a far off pipe-dream.

The attempt to convince policy makers and consumers that genes are not incredibly complex and contingent things is painfully immoral. The public has the right and the need to understand something about this complexity before they are fed arguments as to why genetic engineering is "safe" or why citizens concerned about it are "wrong".

And geneticists should become confident in expressing this wondrous complexity to the public. Indeed, they have a duty to do so.


References


Baker, Monya. 2011. Making sense of chromatin. Nature 8:717-722.

Gagnon, M.L, L.M. Angerer, and R.C. Angerer. 1992. Posttranscriptional regulation of ectoderm-specific gene expression in early sea urchin embryos. Development 114:457-467.

Gilbert, Scott F. 2003. Developmental biology. 7th ed. Sunderland, MA: Sinauer Associates, Inc.

Seo J1, Lee KJ. 2004. Post-translational modifications and their biological functions: proteomic analysis and systematic approaches. J Biochem Mol Biol. 2004 Jan 31;37(1):35-44.

Wu, Jane Y., Liya Yuan, and Necat Havlioglu. 2007. Alternatively spliced genes. In Genomics and genetics, edited by R. A. Meyers. Weinheim, Germany: Wiley-VCH.

Zolla, L., Rinalducci, S., Antonioli, P., & Righetti, G. (2008) Proteomics as a complementary tool for identifying unintended side effects occurring in transgenic maize seeds as a result of genetic modifications. Journal of Proteome Research, 7(5), p. 1850-1861

Thursday, February 6, 2014

De-extinction: Extreme GMOs in conversationist's clothing

De-extinction is the name given to several approaches that Biotech Boosters promise will eventually be able to bring back extinct species.

It is offered as a plausible solution for healing what Steward Brand calls "the huge hole" that humans have made in nature over the past 10,000 years.

It is hard to deny we have created a "hole" in nature. Ever since the dawn of agriculture, we certainly have been messing things up, and we sure aren't slowing down. We have now converted most of the world's arable land into farms and fields. We are pushing the rest of the biosphere into fragmented "nature reserves" while we line the Earth with rows and rows of the few dozen species of plants and animals that we've come to depend on. This massive conversion of the world's diversity into human foodstuff created a food surplus that spurred the rapid growth of the human population. Further, it provided the opportunity to specialize human labour: in the past, everyone had to subsist through finding their daily bread. Now, we have food production systems that allow us to become soldiers, scientists, politicians, miners and bankers. Many of these professions devastate the land, air, and sea through feverish cycle of extraction, production, consumption, and waste. And the "hole" gets bigger.

Thousands of species have been driven to extinction, and with accelerating industrialization, hundreds of thousands more are either endangered or vulnerable (Barnosky et al., 2011). Environmentalists have been sounding the alarm for decades but their appeals to change course are hushed by the clamour of progress. Industries are digging their claws ever further into ecosystems that have been until now "off limits" --the steepest mountains, the thickest jungles of the Amazon and Congo basins, the deep ocean waters, the once permanently frozen Arctic-- and an increasing population expects and demands the very lifestyle responsible for ripping the hole Brand claims we've made ever more wide.

In light of this harrowing situation, de-extinction is being tossed around in newspaper articles and magazines, from the New York Times to National Geographic, as a radical and powerful way of healing the wounds we've cut and are cutting still every day. Indeed, Brand himself has claimed that because we have the technology to bring back lost species we may have "the moral obligation, to repair some of the damage." With his wife, he's co-founded a nonprofit organization to get the idea up and running.

Not all are so enthusiastic, however. Perhaps the hesitant tone of many feature articles indicates just how well Jurassic Park's dystopic lesson was burnt into our memory cells with a dire warning as to what could happen if we don't keep our hubris in check.

Of course, few people are intent on bringing back velociraptors or tyrannosaurus (let alone another opportunistic sequel with Goldblum repeating (again!) the lines: life will find a way!). Instead, on the table are what appear to be relatively benign discussions about resurrecting those beings we've personally had a hand wiping off the face of the Earth: the passenger pigeon, the wooly mammoth, the thylacine, to name a few. (Needless to say, however, we shouldn't rule out what they may try to do: scientists are stretching their genome sequencers into the remote depths of the past as best they can and have recently decoded a 700,000 year old horse ancestor's genome (Shapiro & Hofreiter, 2014)). In any case, perhaps the more mouth-watering prospect amongst such conservation-minded technophiles is that of resuscitating species now poised at the edge of the abyss, such as the Javan rhino, with its 40-60 kettled souls, or the Siberian tiger, whose numbers have slunk below 400. Some of these critically endangered species do not breed in captivity and producing these species in labs could protect them from what is otherwise certain annihilation. The World Wildlife Federation has called the possibility "exciting."

But, like every fairy tale, we should know that "happily ever after" is really just a literary device employed to make us feel good, not something that is actually conceivable in a complex, messy and everchanging world. This article's intent is to inject an ounce of sobriety into the discussion. Of course, you may now be thinking that I am making the typical "safe is better than sorry" claim that holds back great ideas. Perhaps you want to quote Goethe at me, reminding me that boldness has genius and power and magic in it. Perhaps you would like to bring to my attention that Jurassic Park's "worst case scenario" is highly unlikely (do we really expect the removable ceiling panels to collapse, only to leave our feet dangling for the vicious fangs of the velociraptor poised below?). Indeed, what do we really have to worry about? That passenger pigeons are going to take over our cities? We already have those spikes on every possible roosting spot to prevent our urban pigeons... surely they will also prevent passenger pigeons from causing similar sorts of mischief?

1. De-extinction may well be just a promissory note for laissez-faire economics
One of the biggest problems with de-extinction is that it keeps us complacent towards the environmental crisis. It helps prop up the attitude that the march of science will essentially guarantee that all of our ills are solved. We will not need to change our lifestyles and can continue existing under the spell of consumerism and infotainment. It is not our responsibility to take personal initiative in helping address issues like "extinction" because we have technical experts working on it.

And yet, one might wonder what would happen if we continue to plunder and destroy while leaving extinction to the experts. The experts may well bring back the Eastern Elk (that disappeared in 1896) or the Newfoundland Wolf (the last one was shot in 1911), and dozens of other species to boot. But in what meaningful way can we be healing the "huge hole" in nature if the habitats that these creatures would live in no longer exist? What is the value of de-extinction if the resurrected species end up in zoos or in the über-affluent's bizarre collection of personal curios to show off with?

Nor should we underestimate the impact that de-extinction technologies could have on pushing ahead the business-as-usual agenda. In a recent interview, Stanford University's Hank Greely warns that in a world where resurrection is a technical possibility, rare species may cease to be a political inconvenience suppressing the free pace of economic development. As he notes: "suppose developers want to build on a last bit of land where an endangered bird lives. And suppose they say, ‘We will be happy to pay for freezing [the DNA or eggs]. Now let us build our golf course’” (link). Like the worthless "fish ladders" and "wilderness corridors" used to squelch out concern over hydro-dams and mining projects, de-extinction could easily become a part of the repertoire of options that corporations have to sway public sentiment. In the simplest terms, we may be trained not fear extinction anymore because the marvels of biotechnology have made extinction itself go extinct!

In a broader sense, de-extinction could thereby functions like advertising for the biotech industry. Like "golden rice" engineered to "cure" vitamin A deficiency in children, de-extinction would be an idea with considerable moral force, useful to compel people that the biotech industry is a beacon of good in the world. This is a particularly important message to promote, considering the scrutinizing public continues to paint the industry as secretly hiding its trident and diabolical horns (Geez, I mean Monsanto has been voted the world's most unethical company for how many years now?). De-extinction can boost the dividends of these companies immeasurably if it is part of an integrated strategy to sway the Average Josephine from reluctantly accepting unlabeled foods (as they do now) to praising the industry for its ethics and responsibility.

2. Hodge-podge biology
Beyond economics, the biology itself turns out to be less promising that it seems. The term "de-extinction" is itself a lie. Scientists are not actually capable of bringing back anything. This is not hyperbole. There are solid genetic, epigenetic, and environmental reasons why current plans to de-extinct a lost species amount to nothing more than risky, transgenic chimera-making; extreme GMOs masquarading as restored species.

First off, it is unlikely that scientists will have access to a full genome of an extinct species. Without this access, they will have to either take the missing genes from a related species or synthesize them in the lab. In both cases, this means that the genetic code is not the genetic code of the extinct species. It is a trans-species hybrid, a genetically modified organism, modified to an extent far surpassing anything that has ever appeared on earth before. If you don't know anything about the risks of GMOs, browse this blog site and familiarize yourself with the subject. I will not repeat the arguments here.

Still, we can ask the question: Is it possible to imagine a scenario where patching together DNA from an extinct species with its closest known relative avoids these risks? Consider humans, chimpanzees and bonobos. We are said to share 99% of our DNA with chimps, and 98.7% with bonobos. And yet, we are widely different from either of them. In turn, chimps and bonobos apparently share over 99% of their DNA with each other, but again, there are significant differences in the physiology, form, and behavior of both these species. The take home message is that small differences in DNA can have huge impacts (especially when multiplied by the effects of epigenetic and environmental factors, see below). If rock pigeons and passenger pigeons differ in 1% of their DNA and we are only missing fragments of the passenger pigeon genome, then the likelihood that the missing DNA is different from a rock pigeon is certainly less than 1%. But it is also certainly more than 0%, and the only way to ascertain with absolute confidence that the difference is 0% is if we had an intact passenger pigeon genome to compare it to. But if we did, then this would make the whole enterprise of substituting rock pigeon DNA for passenger pigeon DNA superfluous. So we are left gambling.

Even if scientists have the entire genome of an extinct organism, they are not out of hot water just yet. In fact, this is where the real problems come in. It is vastly unlikely that the scientists would have the full genome of a sufficiently different number of organisms needed to create a viable population. A minimum amount of genetic diversity is necessary in a population in order for the species to propagate sustainably without entering into an ever-weakening cul-de-sac through interbreeding. To create such a viable population, scientists would have to insert random differences into the genes of the different organisms of the species. This would be to mimic the normal genetic diversity that makes up a healthy wild population of any species. In practice, this implies undertaking hundreds of separate transgenic modifications on hundreds of genomes, or zapping the genomes with doses of radiation to induce mutagenesis, in either case multiplying exponentially the opportunities for something to go wrong by way of disrupting genetic networks, pleiotropic factors, etc. (see my Genetics 101 for details on this).
Beyond the gene, we have epigenetic factors. Epigenetic factors can be thought of as all of the cellular elements that contribute to how a gene is expressed. Now because passenger pigeons died a long time ago, we no longer have access to viable eggs. We have passenger pigeon genome but we do not have a passenger pigeon egg. What we do have are eggs from related species, such as rock pigeons and band-tailed pigeons. We would need to somehow put the passenger pigeon's genome into one of these other pigeon's eggs so to initiate embryological development. The main de-extinction technique to accomplish this would be to take one of the other pigeon species' cells and modify the DNA within to match the cells of the passenger pigeon genome. We would end up with a rock or band-tailed pigeon egg interpreting and expressing a passenger's pigeon's DNA.

Does this matter?
It turns out it does. The cytoplasm, mitochondria, biochemistry, size, temperature, and a host of other factors are all different in the two species. But these factors all influence how the passenger pigeon's DNA will be read. In other words, the context of the genome influences how it is expressed. Genes do not have functions independent of context, their context defines their function. A temperature difference, for example, can turn off certain genes and turn on others, and alter the way that groups of genes interact together. Genetics without epigenetics is just a bunch of inert strings of DNA floating around in a soup. Epigenetics is what activates the genes and plays a strong role in directing what exactly it is that they do. In other words, we may have created some sort of pigeon but it is not a member of either of those two species. We would have created an entirely new species and called it de-extinction just to make ourselves feel better and perhaps to excite the big conservation organizations.

The problems don't end here either. At some point, presumably, the new organism (with its bricolage of a patched-up genome and its cellular structure lifted from another species) is born. What does it do? How does it live? People like to think that animals are unlike people in that the young of our species require an upbringing and initiation into culture by their caregivers, whereas animals can essentially make it on their own. This is increasingly recognized as an anthropocentric illusion. Countless species, from parrots to pumas, depend on interaction with their caregivers and peers to develop in such a way that they can make it in the world. Interestingly, some of this behaviour appears to be handed down, tweaking and adjusting itself generation upon generation, showing evidence of "cultures" or "traditions" in the animal kingdom (Avital and Jablonka, 2000). A human denied contact with other people during its critical early years ends up missing something essential. Its "humanity" is compromised. To some extent, this is true for other species as well. The relationship between organisms and what they pass on through their networks of relations, are all a part of their species just as much as their genes or their epigenetics.

And then there's the ecosystems. Stewart Brand hopes that we may able to produce an organism that is "functionally identical" to how the original organism behaved in its ecosystem, but this is obviously untestable and unverifiable and therefore something that scientists would merely have to take on faith. Nevertheless, his hope is itself shortsighted for the simple reason that ecosystems do not remain static. They evolve so it makes as little sense to try and match an extinct species' DNA to an extinct ecosystem as it does to try and match an extinct species' DNA to a contemporary ecosystem. If, say, 500 years ago we compromised an ecosystem by destroying some species in it, the ecosystem has had 500 years to mend this hole through evolving new interconnections and relations. Because the ecosystem has evolved since that species went extinct, it may not be fair to either the introduced species or the persisting species to mess things up in the name of "healing the wounds."

Stewart Brand: Ecosystems are self-healing if we let them.

Or, dare I say... "life will find a way"?

3. Summary

De-extinction is trying to pull a fast one on us: it is an extreme form of genetic engineering being pushed on the public for what are likely largely economic reasons (I am obviously not denying that there are some scientists that are pursuing this purely because they are interested and think it is "cool" or "ethical"). This does not mean that ethical and sustainable de-extinction is not possible. I could imagine a situation where large quantities of still living populations' DNA (and epigenetic structures) are conserved as a last resort in case their populations started plummeting. Such a bio-bank would provide some insurance in the case of a major catastrophe (human induced, or perhaps from an asteroid, etc.). If done correctly, it would need no transgenic (GMO) technology, no epigenetic cross-species shortcuts (it would be cloning instead of genetic engineering), and could even be part of a program introducing the new organisms into actual biological relationships ecologically established members of its species.

However, I have very little faith that this is how de-extinction is likely to proceed, especially considering its main proponents are also those promoting synthetic biology, geo-engineering, and other extreme forms of human-induced changes to the biosphere (such as Church (2013) and Brand (2013)). It is therefore up to us to foster the dialogue we need to in order to ensure that de-extinction (if done at all) is done safely, humanely, and ethically. If we don't then overzealousness, economic interest, and hubris will continue to run their course and into the tragedy of our age another scene will be written.

References

Avital, E., & Jablonka, E. (2000). Animal traditions: Behavioural inheritance in evolution. Cambridge, UK: Cambridge University Press.

Barnosky, A. D., et al. 2011. Has the Earth's sixth mass extinction already arrived? Nature 471:51– 57.

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Tuesday, February 4, 2014

Genetics 101: Why you should be concerned about GMOs.

When genetic engineering hits the news, the headlines are so confusing and contradictory that it is hard for any of us to make sense of it. On the one hand, biotech proponents claim that genetic engineering is just a more precise way of breeding, one that holds great promise for ending malnutrition and alleviating ecological collapse. On the other hand, biotech activists claim that genetic engineering is unnatural, unethical and inherently dangerous. Is this a case of crazy, hypochondriac foodies picking fights they know nothing about with an established and highly regulated science? Or of biotech companies claiming science as their authority in order to force unwanted products on hapless consumers?

As is often the case with polarized issues, each side overstates their own case. The fact is that there are many novel risks associated with genetically modified organisms (“GMOs”), many of which are not adequately acknowledged. This does not mean that every GMO will be perilous to humanity or to life on this planet. Indeed, some of them may turn out to be safe (though still not necessarily desirable). What is not safe is that many governments, regulatory bodies, and citizens are persuaded that the biotech companies' version of the story is the accurate "scientific" version. As it turns out, genetics as a science can hardly condone the haphazard mixing and matching of genes undertaken in company labs. It is simply false for anyone to claim that people concerned about GMOs are anti-science (though many of them do make scientifically questionable claims). To understand why the science of genetics leads to skepticism about genetic engineering, we need to familiarize ourselves with some basics of how genes and genetic engineering work. Doing so will provide the clarity we need to understand the risks of GMOs and enable us to make better choices in maintaining a safe and sustainable food system.

1. How is "genetic engineering" different from "traditional breeding"?
Traditional breeding occurs by having two organisms of a single species mate (see footnote i. below). When they mate, their offspring will have a set of genes, some of which come from the male and others from the female. By controlling which organisms breed, breeders can gradually enable certain traits to get expressed more strongly. For instance, if I wanted to breed cats with longer ears, I would choose a male and female with long ears, create the conditions for them to mate, and wait for the results. Of their children, some in turn will have longer ears than others and I can choose to continue breeding them with other long- eared cats. Eventually, over many generations, the cats’ ears would get longer and longer, (provided, of course, that this trait was able to grow while maintaining the integrity of the rest of the organism's physiology). The point is that what can and cannot be bred is dictated strictly by what is possible for each species based on variations that are already occurring within it.

With genetic engineering, something quite different is going on. A scientist will isolate a specific gene or genes that seem to be responsible for a specific trait and will then insert it into another organism with the aim of getting that trait expressed in the new organism. So, for example, scientists have isolated the genes responsible for making petunia plants resistant to the herbicide known as glyphosate and have inserted the gene into a number of stable crops, such as soy and alfalfa for animal feed, to produce plants that can withstand applications of herbicides. Biotech companies are doing similar experiments on a variety of lifeforms, from bacteria, to trees, to animals. In one particularly shocking experiment, scientists identified the genes that make fireflies glow in the dark and have inserted those genes into the genetic code of cats. As a result, they have now produced cats that glow in the dark (pictures on Google).

While this may seem like a neat sci-fi tricks, and certainly appeals to the tech-geek in some of us, there are a number of well-documented ways in which these sorts of experiments can, and do go wrong. There are certainly ethical issues to be carefully considered when conducting these sorts of experiments too. These issues need to be steadfastly separated from the thrilling power and curiosity some scientists feel at being able to create a seemingly endless number of wild and wacky things simply by combining and recombining genes. Many bioethicists have opened discussions as to whether other species have a right not to be experimented on and modified in these ways (Vorstenbosch, 1993; Oritz, 2004). My purpose here is more modest. I seek simply to outline some of the established reasons why there are real risks associated with the production, release, and consumption of GMOs. Radical and exciting developments in our understanding of the genetic code have emerged in the last decade or so, casting serious doubt on the innocent-until-proven-guilty stance of proponents of GMO technology. At the very least, these developments indicate that a great deal more regulatory scrutiny is necessary than is currently required.

To introduce the reader to how geneticists are now thinking about the behaviour and properties of genes, I will outline the concept of "genetic networks" and "dynamic gene activity." Then, I will discuss the techniques that genetic engineers use in order to create GMOs, showing how these methods contrast with geneticists' emerging understanding of how genes work.

2. Our current understanding: Genetic networks
Biotech proponents usually tell a simplified and mechanical version of how genes work.The story, which some of you may remember from high school biology classes, goes something like this: DNA is a long string of molecules, most of which is random and meaningless. However, there are occasional segments of DNA which produce RNA which go on to produce specific proteins. These active segments of DNA are known as genes, and people generally abbreviate the process by saying that "genes code for proteins". These proteins are extremely varied and extremely important because they are the building blocks of the entire body. Not only do they build organs and tissues but they also metabolize many of the molecules that enable all the physiological processes that regulate the body. In other words, proteins are the stuff that make up both the form and the function of an organism. If the proteins change, the form and/or function of the organism changes as well.

As the story is told, each gene has a specific and discrete role, so a genetic engineer can simply "knock out" a gene that is doing something undesired or insert in another gene that produces a valued protein, and thereby enhance the organism's form or function. The novel gene can come from a number of sources, either from a different location in the organism's own code, from a closely related organism, from a completely different organism, or even from the lab after being manufactured synthetically (see footnote ii below).

The story is widespread in our textbooks, in the media, and on the internet. A part of the reason why it is difficult for people to see the dangers of genetic engineering is because when the process is framed in this way, it seems intuitive and logical. It appeals to our understanding of how machines work, for instance. We can (or should) be able to take out and replace or update parts of our car or computer. So why not bigger mechanical structures, like lifeforms? The problem is that the genome is not really built in the same way as a machine.

Genetic engineering is based on a misleading understanding of what the relationship between genes in the genetic code is like. In fact, "genes" as isolated entities may only very rarely exist. The logic that assumes otherwise long ago fell out of favor with scientists who now prefer to think about "genetic networks" (Dillon, 2003; for a debate on how such networks evolved, see Sansom, 2011). The basic idea of a genetic network is that the behavior of a gene depends on other genes, and that combinations of genes influence each other in complex ways that make it difficult to isolate what a gene "does" except in some rare cases. A gene often has strongest influence (and in turn is most strongly influenced by) the genes closest to it on the genetic code, but this is not always the case. Intricate chain reactions can occur between relatively faraway parts of the code, especially when the code is bent such that certain parts come into closer contact with one another (as occur through what are known as "histone modifications" (Fischle, Wang, & Allis, 2003)).

One way that genes can influence each other is through a process known as methylation. In methylation, a gene can be partially or completely silenced through having parts of its code bound to methyl molecules (Jaenisch & Bird, 2003). There are specific portions of the genetic code known as "regulatory DNA" that control the extent to which various genes are and are not methylated. Genes interact with each other directly but can also interact indirectly through influencing regulatory DNA, which in turn methylate or demethylate other genes. In addition to methylation and histone modifications, there are a number of other ways that genes influence one another, including acetylation, translocation, pleiotropy, and transvection. The field studying these processes is collectively known as "epigenetics" and it is a well-established field of research blossoming strong and fertile research programs (see Jablonka & Lamb, 1995; Francis, 2012, for accessible discussions; see footnote iii below). One of the most unexpected findings in epigenetic was the discovery that knocking out vital genes in animals often does not debilitate them because other genes will become activated to compensate for the loss (Suemori & Noguchi, 2000).

In 2000, entrepreneur Craig Venter's company Celera Genomics mapped the entire genetic code of a human. The news hit headlines worldwide but the excitement faded fast once people realized the limited relevance of what had actually been done. The active coding portions of the DNA (i.e. the genes) had been identified, and many had been assigned specific functions in terms of their role in producing the human organism. But without any mapping of the actual genetic networks, the project ended up being a lot of hot air. Without knowing the relationship between the genes, it was like the company had pulled a bunch of words out of a storybook, produced a crude list of definitions for each word, and were left with little understanding of the story itself. The important point here is that while individual genes may have specific functionality, it’s the interaction of these genes through their specific positions in the genome and their proximity to other genes that really dictates their true nature and consequently, that of the organism. If the genome is a machine, it is quite unlike anything humans have ever built before, its parts threaded together and interacting in complex ways, like how the precise meaning of words and sentences get defined by the paragraphs and stories in which they are found.


3. The dynamic genome: Context matters

But even the storybook metaphor is misleading because it relays the sense that the relationship between the genes are fixed, as are the words in a book. Not so with the genome. The story of the genetic code hasn't been written yet; or rather it gets written and rewritten constantly as an organism interacts in its changing environment. Not only are genes embedded in complex, interconnected networks but the networks themselves are themselves ever changing. For example, one gene will cause another to get expressed, which will down-regulate another, but only as long as a third is still coding for proteins. Whether or not a gene is expressed and what in fact its protein products go on to do are entirely contingent, depending on the state of the rest of the genetic code and of the organism in which the gene is found. In an organism's infancy, a gene may do something quite different than it does in an organism's adulthood, which in turn is different from what that gene might contribute to in periods of environment-induced stress. For example, a recent study found that 86% of a fruitflies' genes change significantly in expression throughout its lifespan (Arbeitman et al., 2002). On the other hand, parts of the DNA thought to be non-coding may activate in certain contexts (Makalowski 2003; Biémont & Vieira, 2006)). In fact, large sections of supposedly random and meaningless portions of the genetic code have turned out to have important roles in the changing behavior of the genome. Normally silent and lurking in the recesses of the genetic code, these genes and other DNA elements can be thought of as part of the built-in resiliency of the system, containing important back-up information and alternative routes and pathways that can kick in when critically needed (for example, Schlesinger, 1994).

The genome is therefore an incredibly complex and responsive system, adjusting itself to changes on multiple levels from changes within the cell, to changes between cells in the organism, to changes in the environment that the organism is continually adapting to. As a result, external changes can modify the way in which genes are or are not expressed. An intuitive way to think about it is to consider how a single fertilized egg cell eventually becomes a fetus and then a baby. That first cell, as we have all seen on TV, splits into two cells, and each of those cells split in turn, producing four cells. This splitting goes on and on until eventually a fetus emerges. But how did certain parts differentiate into separate body parts? The genes and the DNA in all of these cells are, after all, identical. How is it that some of the cells eventually become brain cells and others liver cells or blood cells? All of this happens precisely because of the genetic networks dynamically turning on and off certain genes at specific times, all based on the location of the cells relative to one another (Ridley, 1999). Context matters.

It isn't just the human fetus that bears this complexity. All multicellular organisms do. And because of this complexity, it cannot be stated with any certainty that the genes that a biotech company lodges into a genetic code are benign. It is difficult to know whether or not inserted genes will be interfering with a genetic network, disrupting, upregulating or downregulating other genes, or perhaps even splitting apart an important gene that goes unexpressed until an organism meets some specific stressful or demanding environmental situation. Even the most expensive and thorough current tests, which go far beyond any regulatory requirements for the industry, are not technologically capable of providing this information because we simply do not know the entire genetic networks (nor how they can and do change over time) of the species that we genetically engineer. For example, "OMIC tests", which are more specific forms of gene expression profiling, can catalogue gene products (such as transcripts, proteins, or metabolites) to give more detailed snapshots of some of the physiological changes that occur in the organism (Heinemann, Kurenbach, & Quisr, 2011), but these are themselves limited, difficult to interpret, and not required in any current safety evaluations of GMOs (Lay, & Liyanage, 2006). One of the biggest limitations of OMIC tests is that each test only gives results of changes at one point in time so many tests would need to be taken to understand how the dynamic genome changes during the organism's lifespan.

In the first two sections, I tried to show how the genome is connected in many still unknown ways such that the behavior of a gene depends on the behavior of other genes, its location relative to other genes, and that these connections themselves change over time as the organism adjusts to its internal and external environment. The "one gene, one protein/function" model is not reflective of the way scientist are now thinking about genetic networks and the interactions among them.

An important point here is that genetic networks are only jeopardized by genetic engineering and not by traditional plant or animal breeding. Traditional breeding, which mates organisms of a single species together, respects genetic networks because when the chromosomes of the male and female join, their genes (alleles) are nearly invariably located in corresponding locations and thereby match up. In other words, the gene(s) for eye colour, for example, are located in the same place of the same chromosome for almost all organisms of a given species, so when meiosis occurs in sexual reproduction, the genes are aligned and present no problem in the offspring when some genes come from the male and others from the female. By contrast, genetic engineering does not respect genetic networks but instead inserts genetic material into the genetic networks at random locations. Because context matters within the genetic network, the result of the insertion cannot be known, predicted, or controlled.

4. How do they get the genes in anyway?

For a biotech company to produce a GMO they have to insert genes into an organism's genome and then get them expressed (i.e. coding for the desired protein). As it turns out, this is not an easy task and it is precisely here where many of the most concerning risks of genetic engineering are brought to the fore. In essence, the whole process involves shooting the desired gene randomly into the host organism's code with the hopes that it will get lodged in somewhere where it will not disrupt any genetic network too much. The gene, it should be pointed out, is not fired into the host code on its own. As it turns out, it is actually a part of a patched together assembly of genes from at least multiple different organisms (mostly viruses and bacteria) known as a "vector" or a "genetic cassette" (Ho, 1998). Among these genetic components there is an "origin of replication", which is used to replicate the desired genes in preparation to shoot them into the host code; a "multiple cloning site", which allows the scientists to insert the desired gene into the vector; a "genetic marker", which is used to establish whether or not the vector was successfully inserted into the host code; and a "promoter", which is used to ensure that once the vector is in the host code that the desired gene is being expressed.

The origin of replication, multiple cloning site, and promoters are of particular concern because they can make the desired gene, the vector, and the host organism's code more unstable. They are all acquired from different pathogenic organisms such as viruses, and may have been further altered in the lab through synthetic DNA modification. Viruses replicate by parasitizing host genetic codes to create further copies of the virus. Genetic engineers have isolated various parts of viral DNA in order to make use of these hijacking techniques by taking parts of the viral machinery of different organisms and parceling them together into a vector. So, for example, a viral promoter is a gene that viruses use to ensure that once they got into a host code, the viral genes would be recognized and expressed. This is necessary for genetic engineering because cells usually have mechanisms to ensure that foreign DNA is not continuously planting itself into the cell's genome.

It should be apparent here that genetic engineering is far from being simply a "more precise" way to breed for desired traits. By contrast, it is a technique to insert DNA into another organism through bypassing its own defense system by using DNA from viruses and other pathogens. It should also be noted that viruses insert their DNA into sex cells only very rarely. Why is this important? If a virus inserts itself into any other cell of my body and uses the cell to spread, its genes are not being passed down to my descendants. For example, the rhinovirus, responsible for the common cold, only inserts itself into certain respiratory epithelial cells. Its genes do not travel to my sex cells and therefore have no impact on my future offspring. This minimizes ecological and evolutionary impact. Sex cells are generally well-protected in the body to avoid the risky disruptions that occur through viral infection. When genetic engineers say that GMOs are natural because they are employing a form of gene transfer that viruses and bacteria have been using for eons, we should view their claims in a critical light. In fact, in multicellular organisms such as plants and animals, the body has mechanisms precisely to prevent viral transfer of genetic material into its sex cells. This should warn us of the risks of doing so.

Using promoters to express the desired gene in the host code is especially risky because promoters often overpromote. They upregulate the gene (just like the regulatory DNA discussed earlier) such that it produces far more of its protein products than would be normal in its original context. Further, its capacity to overpromote changes the ways in which the host genes surrounding the vector end up getting expressed. It thereby often ends up promoting unintended genes in the organism (Ho, Ryan, & Cummins, 1999). The concern here is that promoters have a strong capacity to modify the genetic networks of the host organism in unpredictable ways. When these are combined with other elements, such as the "origin of replication" genes, we sometimes find that the desired gene actually gets replicated and reinserted in different places across the genome, functioning like "jumping genes" (or, as they are technically known, transposons (Keller, 1983), see footnote 4, below). This further exacerbates the functional integrity of the genetic networks. Promoters and origin of replication genetic segments may also make the vector (or parts of it) unstable and more likely to jump out of the host's genome and into the environment. This now appears to be an uncommon process (de Vries & Wackernagel, 2004), though researchers point out that the colonization of the soil by bacteria that have incorporated such transgenic material should take much more time than has been assumed by many of these studies (Nielsen & Townsend, 2004). Further research is clearly necessary: if these genetic elements can be taken up by soil and gut bacteria, remaining in these micro-ecosystems indefinitely, they carry the risk that they will in turn incorporate themselves into other organisms at some point in the future (with obvious possible unpredictable results on those organismss genetic function).

5. Summary
The risks of genetic engineering emerge on various fronts. First, the "single gene, single function" model is not appropriate. Indeed it is destructive because it trains us to think of life as a machine made out of isolatable, detachable and replaceable parts. The organism is better thought of as an evolving and interconnected system, where its parts are always defined contextually and contingently. When viewed from the perspective of fluid and dynamic genetic networks, the effects of inserting a gene into a genome are not predictable or easily measurable. This is one clear reason why public concern about GMOs needs to be taken seriously by regulatory agencies. Second, the techniques of genetic engineering are problematic and may exacerbate the problems associated with inserting foreign DNA into organisms. Current biotech techniques, which use DNA material from pathogenic organisms, can make the desired gene, the vector, and the host organism's code unstable, and can cause the promotion of proteins and unintended genes, disrupting genetic networks and sometimes possibly jumping into the environment to get taken up by other organisms.

Although genetic engineering technologies are advancing rapidly, our understanding of the genome is undergoing a significant shift that puts into question many of the premises upon which GMOs are based. We can expect that genetic engineers will attempt to accommodate better the fact the genetic networks and epigenetic dynamics exist and cease to employ some of the riskier techniques described in this article. In any case, we must keep vigilant and continue to update ourselves on these evolving approaches so that we can publicly discuss and critically evaluate the technologies for their potential impacts on our health and on the environment. Above all, we must raise our concerns in a clear and articulate manner to our government officials, who themselves may well need some educating on the science of the genome in the 21st Century.

Footnotes

i. A third approach to breeding is called "mutagenesis" and it involves subjecting cells to high levels of radiation to induce mutations and selecting from the mutated cells those that have desirable traits. Mutagenesis has been around for about 100 years, but should not be considered a form of "traditional plant breeding". In any case, it will not be discussed in this article.

ii. Although these procedures have different technical names (known as cisgenic, linegenic, transgenic, and xenogenic engineering respectively), they are all forms of genetic engineering that rely on essentially the same technologies and bear many of the same risks. The common scientific name for them is usually simply "transgenic" engineering.

iii. Of course, as the science of epigenesis evolves so will the desire to apply the knowledge. Epigenetic engineering seeks to modify the behavior of genes through altering the way in which the genes are read and/or expressed in cells. Epigenetic engineering is not necessarily a benign alternative to genetic engineering because it can instigate many of the same interactional effects as genetic engineering. Consumers should be on the lookout for developments in this new field (will they be called EGMOs, as in "epigenetically modified organisms"?).

iv. Botanist Barbara McClintock discovered the presence of transposons, mobile genetic elements that are a part of an organism's genome and which jump around and can replicate inside that genome. Their evolutionary and immunological functions are a subject of great interest. In some ways, transposons may appear to be similar to the overactive promoters introduced by genetic engineers. Closer inspection reveals that the genome has actually evolved to let certain types of genes jump around while restricting this capacity in others. When genetic engineers add promoters to genes and insert them into the genome, the location of the promoter can create new types of transposons that do not have a history of interaction within the organism's genetic networks.


References

Arbeitman, M. N., Furlong, E. E. M., Farhad, Johnson, E., Null, B. H., Baker, B. S., Krasnow, M. A., et al. (2002). Gene expression during the life cycle of Drosophila melanogaster. Science, 297(5590), 2270-2275.

Biémont, C., & Vieira, C. (2006). Genetics: Junk DNA as an evolutionary force. Nature, 443, 521-524.

de Vries, J., & Wackernagel, W. (2004). Microbial horizontal gene transfer and the DNA release from transgenic crop plants. Plant and Soil, 266, 91-104.

Dillon, N. (2003). Gene autonomy: Positions, please... Nature, 425, 457.

Fischle, W., Wang, Y., & Allis, C. D. (2003). Histone and chromatin cross-talk. Current Opinion in Cell Biology, 15(2), 172-183.

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Thursday, May 30, 2013

Kickstarter's Ill-Conceived Support for Extreme Biotechnology

In late April, a Kickstarter campaign was launched to raise money to produce glowing plants. The venture was plugged as environmental: if trees could glow in the dark, we could save energy and resources because we wouldn't have to line our streets with streetlights.

We could use trees instead.

The project falls under the radar of the typical biotech activist. It is not a food, so the growing number of health-conscious consumers may not care. It is also not being produced by a biotech giant, but rather by a handful of young businessmen/scientists. This might neutralize the concern of those fighting Monsanto because they hate monopolies and big business. Environmentalists may actually find themselves enamoured with the whole idea of "glowing plants": it is purportedly "sustainable", after all, allowing us to reduce our energy usage. Right?

Does this mean we shouldn't be concerned?

No. From what I understand, this initiative is potentially one of the most dangerous yet -not just because of very real ecological risks but also because of the precedence it could set. Even though the trees are not produced by Monsanto or Dupont, nor are they generating their own pesticides (such as some GMO foods), the potential risks are enormous. Let me outline them them briefly:

1) Like all engineered organisms, the glowing plants will have unintended side effects. The inserted firefly genes may well be benign in fireflies, but that does not provide any evidence that they will be harmless in plants. The interactions between the firefly genes and the plant's own genes will cause each to behave in potentially unpredictably ways. This is known as "pleiotropy" and I have written about it before. Even if their are no pleiotropic effects (and this would require extensive study) their may be direct ecological effects. For example, how might glowing trees affect the behavior of moths? Of bats? Of birds and squirrels that build nests in them? Or even of ants? Migrating birds already die in colossal numbers because they get confused at night from the lights in big buildings and fly right into the glass. Note that this was not anticipated (and probably not likely anticipatable!) when we began constructing tall glass buildings. We cannot assume that there will be not behavioral changes and it is easy to imagine some frightening scenarios that might occur.

2) The founder of the glowing plants campaign, Antony Evans (pictured on the left... by the way, don't send them hate mail - it is better to educate him), has a reckless marketing gimmick: they will send 100 free "glowing plant" seeds to anyone who contributes over $40 to their project. To date, over six thousand people have signed on, and so hundreds of thousands of these genetically engineered seeds are set to be distributed across North America to all these funders. The problem is that no government agency is testing, regulating, or overseeing these transactions. Kickstarter is allowing fundraising for a type of technology that no government even knows how to regulate.

3) The project is being fundraised through a crowdsourcing platform. If successful, then others, also intent on creating any number of chimeras and monsters, will be able to raise money as well. We may well see dozens or hundreds of independent biohackers raising money online to reprogram organisms. As Huffington Post writer Jim Thomas points out, in the near future, people may soon be able purchase organisms with designed characteristics off the internet as nonchalantly as we now purchase apps from iTunes. If these are not regulated, hundreds or thousands of novel organisms could flood our ecosystems. Keep in mind that the introduction of novel species into ecosystems is already the second biggest cause of species extinction (behind habitat destruction). If this project sets a precedent and hundreds like it are allowed to emerge, biodiversity and the ecosystems that life produces, are in grave danger. This is not an apocalyptic environmentalist fear-mongering. We have ample evidence that new species make other species go extinct and can destabilize the resilience and functionality of ecosystems.

4) Green-tech solutions often eclipse our vision of what really needs to be done. We spend millions of dollars tinkering in labs when we should be spending that money protecting ecosystems. The cheapest and most effective way of attending to the ecological crisis is by conserving ecosystems, which provide trillions of dollars in services for free every year. Green-tech solutions are often hopelessly misguided anyway. How green are glowing plants really expected to be? Are streetlights really what are draining our energy resources? Seems like the smallest fraction of the problem to me, and new LED streetlights are providing impressive advances in efficiency. Green-tech solutions feed the inner tech-geek in us, but they scarcely provide meaningful solutions to the real problems we face.

5) My fifth point is unabashedly sentimental. I admit, it might be "cool" to see a glowing tree. But I certainly don't want to live in a world where the trees lining the streets are glowing at night. Where the new "normal" is to not have the spontaneous beauty and elegance of a growing tree eclipsed by some nerdy tinkerer's get-famous-quick scheme. There is already far too little 'nature' allowed into our cities and the little that is here provides me with immeasurable peace and solace. Imagine how devastating it would be if, everywhere you turned, you saw just another human creation. In those glowing trees, you might hear chirping birds. Some of the birds were genetically altered to eat some insect pest more efficiently (and the insects themselves are pests because they, too, were an earlier green-tech GMO project gone awry (think: killerbees and superweeds)). Other birds were genetically engineered to produce 'cooler' songs or to have brighter colours (because Kickstarter would be especially appreciative of projects with a 'cool' factor). Everywhere you look, you are reminded of human imperfection, egoism, and greed. Richard Louv has documented the importance of nature for the health, sociality, and intelligence of children. We all need nature. We need life's wild and complex freedom around us. Evolution created us as it created the rest of the biological world, and we must maintain environments where we can witness and appreciate the complex birthing process of the Earth. What little we have left, we need to keep.

In a recent interview, Evans, the project founder, stated that Glowing Plants was "a demonstration project to inspire people to get involved with the amateur DIY Bio movement." This might be the 15 most frightening words I've heard in a long time. Listen up! Ecosystems aren't made of Lego blocks that can be built and rebuilt at will. I suggest that any biotech tinkerer who does not understand the concepts of ecological stability, resiliency, redundancy, or have a basic understanding of how the rate of evolutionary change optimally balances novelty and development, should spend more time learning about the world around them. Leave the childish games inside the game room if you must play them at all.

What you can do.

Kickstarter cannot continue to facilitate the widespread contamination of ecosystems by biohackers. Kickstarter has helped scores of fledging artists and entrepreneurs get off the ground. For this they should be commended. But their support for this project is ill-conceived. Please sign the Avaaz petition immediately to demand that they reconsider providing a platform for projects seeking to engineer and distribute unregulated modified organisms. A project called "Kickstopper" is raising money to stop the release of these untested seeds - well worth it to throw a few bucks at them!! Send a personal email to Kickstarter too. Share the news with your friends.

And, of course, there is always Kickstarter's Facebook page...

It is also worth emailing the USDA's agency that deals with the release of transgenic organisms into the environment. Send a brief, informed and polite email to BiotechQuery@aphis.usda.gov to ensure the most effective response.

We haven't got much time. Kickstarter will release the funds on June 7th unless we let them know loud and clear that this is an unacceptable risk!

JUNE 5th: BREAKING NEWS: Prestigious scientific journal, Nature, comes out with the following warning: "A controversial new project is seeking public donations to develop a glow-in-the-dark version of the thale cress (Arabidopsis thaliana) using genes from fireflies. If the effort succeeds, thousands of supporters will receive seeds to plant the hardy weed wherever they wish." (see full article). This has instigated some serious rhetorical back-peddling from the project founders.

Sunday, December 9, 2012

"Substantial equivalence" - A tricky, misleading term!

The biotech industry argues that genetically engineered organisms do not require labeling, should not be subjected to rigorous testing, and do not warrant careful public scrutiny.

This is because, the industry proclaims, genetically engineered organisms are "substantially equivalent" to their non-engineered counterparts.

Substantially equivalent? Say what??

The concept of "substantial equivalence" like so many words in the biotech industry's vocabulary, reeks of Orwellian Doublespeak. It is their attempt to have their cake and eat it too.

In other words, there is a deceptive ambivalence to "substantial equivalence".

Let's unpack the term.

Of course, the industry could not say that the GMO was "completely equivalent" because then they would have no basis for claiming a patent on the organism.

And they could not claim that it was "substantially different" either, because that would trigger concern that they'd rather not face.

The secret was to find a combination of words that make the invention seem just different enough to merit a patent but not different enough for people to be concerned about. With "substantial equivalence", they landed in a pot of gold.

Of course, the concept is absolutely misleading. But that was why it was valuable. It functions like a slippery snake, evading any attempt to pin down its meaning. When those concerned about GMOs speak out, it slithers over towards "equivalence". When the patent offices inquire, it nests in the serpentine ambiguity of the word "substantial".

(I apologize to the snakes out there for using this metaphor.)

"Substantial equivalence" shares that oxymoronic sneakiness that makes so many other industry concepts so enervating. Think of "sustainable development" or "clean coal" or "ethical oil".

The term "substantial equivalence" originally met with resistance from the Food and Drug Administration (FDA), who had internal documents describing the possible toxins, allergens, and new diseases that might arise from GMOs (Freese and Schubert, 2004).

However, for whatever reason, the documents were ignored and the FDA decided to go along with the term.

So did the FAO.

The FDA also decided that it would be sufficient if the biotech companies conducted the studies by themselves to establish whether or not their GMOs were "substantially equivalent". This would not be considered a conflict of interest.

And the FDA decided that the FDA itself would not need to conduct any testing of these novel organisms. It would just believe the biotech companies' reports.

The FDA's regulation gets even more stringent at this point. Listen up.

The actual experimental write-ups by the companies are classified so no independent scientists can access them. The FDA has no problem with this.

And, as icing for this overly saccharine transgenic cupcake... the biotech companies do not allow external scientists to conduct health or environment tests using their seeds. In fact, when you purchase the seeds, you have to sign a legal document assuring that you will not test them in any way.

They are not merely seeking a monopoly on our food source. They are also seeking a monopoly on the knowledge we can gain about their products.

Let's leave all of this (ahem....) impressively rigorous regulation for a moment, and ask ourselves: what is it exactly that the biotech companies claim to analyze in order to deem their products "substantially equivalent"?

A 2003 review in Trends in Biotechnology identified 7 main research foci. Now, we cannot actually see the studies that Monsanto or Dupont or Dow or Astra Zeneca conduct in these 7 areas because, as I said, they are company secrets. But even if we take their word for it and in good will assume that the reports they issue publicly are not biased, the seven areas themselves are not at all convincing.

In fact, with a little understanding of genetics and ecology, they all seem quite weak.

Allow me to indulge a little bit in each of them. Here is what biotech companies claim to do, and here are my answers:

1. Study the introduced DNA and the new proteins or metabolites that it produces.

Genes make mRNA which produce proteins. Understanding what new proteins are produced is crucial for understanding how the gene is altering the behaviour, physiology and biochemistry of the organism. This is because proteins are the building blocks of processes and products in the body. Of course regulators should be studying the proteins that the introduced DNA produces!

Unfortunately, studying the proteins that the introduced DNA produces is not enough.

Why?

Because the introduced DNA interacts with other genes, switching them on or off, upregulating or downregulating them. For example, in yeast, over 95% of the genes interact with their neighbours (Featherstone and Broadie, 2002). Genes do not behave in isolation, they operate in networks. When we introduce new DNA into an organism, an undefined number of other genes end up producing proteins in unexpected ways too. The same goes for metabolites, which are synthesized in complex networks of co-interacting chemicals.

2. Analyze the chemical composition of the relevant plant parts, measuring nutrients, anti nutrients as well as any natural toxins or known allergens.

The key word in this is "relevant". I assume that for GMOs intended for consumptions, the "relevant plant parts" are those parts which people eat. But the novel genes are not just in those relevant plant parts. They are in every single cell of the organism's body! And even if humans are not eating those other plant parts, SOMETHING is. And it is important to know how that something will react because it is part of a larger ecology and so changes to it could have ecological effects.

Second, it is easy to test for "known" allergens and anti-nutrients. But what about unknown ones? The concern is that novel proteins or novel combinations of proteins or metabolites might trigger some health problem. Given that it is impossible to test for an unknown allergen does not mean that the burden of proof should be placed on those concerned. Yes, it is a scientific problem to figure out how to conduct such tests. But that is the problem of those who produce the technology.

It is not acceptable for them to say (as they sometimes do): It is too complicated! How can you expect us to study each and every one of those unlikely scenarios? Doing so would throw a wrench into the cogs of progress!!

3. Assess the risk of gene transfer from the food to microorganisms in the human gut.

Unsurprisingly, there are problems with this one too. And again, they stem from a refusal of the biotech industry to respect living beings as complex interactive networks.

The quantity and variety of gut micro-organisms is continually shifting across time, is dependent on cultural, environmental and climatic factors, and numbers from 300 to 1000 bacteria species, and fungi and protozoa too. Can we possibly imagine that biotech companies test for all of these possible combinations? It is a permutational nightmare and would be exorbitantly costly. But it gets worse: the gut itself is an environment for the gut organisms, and as the gut changes (from sickness, from exposure to chemicals, etc.) they way the gut microorganism behave changes too. Some genes may switch on, others may downregulate, as the organisms co-evolve with their mini-ecosystem. What about all those factors? Further: considering the biotech companies do not actually conduct tests on humans (PRIOR to release, of course... we all know that they are conducting highly unscientific experiment on millions of us AFTER release!) we cannot assume that the environment within which these microorganisms are being tested for gene transfer is equivalent to the environment in the human gut. Finally, the context of the GMO is not stable. Environmental stressors can switch on certain genes or inhibit others, altering the way that the transgene behaves and potentially making it unstable. Alternatively, changes in the human could modify the degree to which the gene may jump.

Proponents of genetic engineering might say: Lighten up! It's just a gene! Why would it be more likely to jump out of the food and cause a nuisance than any of the other genes? Shut up and eat it, it is the most tested food to ever find itself onto your dinner plate!

Well, the answer, again, is clear: the gene didn't just arrive by some happy coincidence into the host code. It was forced in using viral vectors despite the defence mechanisms within the cell to prevent the invasion of foreign DNA. After in, it was shaken into activity using a viral promotor. These viral genes are aggressive and unpredictable. After all, it is through these genes that viruses can hijack other organisms' genetic codes. Viral genes increase the instability of the other transgenic genes. The same stuff that made it get in can also make it jump out.

4. Study the possibility that any new components in the food might be allergens.

It is interesting to ponder how this could be done without human studies. Anyway, I've addressed the concerns with this point in #2 and #3 above.

5. Estimate how much of a normal diet the food will make up.

How much of it we eat is simply not relevant to answering the question of how similar the novel organism is to its natural counterparts. There isn't much else to say about this one.

6. Estimate any toxicological or nutritional problems revealed by this data in light of data on equivalent foods.

This is potentially useful. The idea is this: suppose the novel proteins are present in some other food. The scientists study that food for toxicity so that they have likely scenarios with respect to their GMO. By all means this sort of analysis should be conducted! But it would be erroneous to assume that a given protein in one context has the same effects as that same protein in another. The other nutritive factors and metabolites in that food work synergistically or antagonistically in complex ways that render the protein's effect "context dependent".

7. Additional animal toxicity tests if there is the possibility that the food might pose a risk."

These are typically 90 day studies and are inadequate to assess health across the lifespan or multi-generationally.

So, what would better "substantial equivalence" look like?

It is possible that a gene might be inserted somewhere such that it did not do anything harmful to the organism, to the one consuming it, or to the surrounding ecology. Of course it is theoretically possible that some GMO is "safe" in these senses. But the point is that no study is anywhere near establishing this and there are sound genetic and ecological reasons to believe that this would be a rare phenomena.

Nevertheless, there are some technologies emerging that can show in much greater detail whether or not a GMO is "substantially equivalent". There are problems with these tests, but it is good for food activists to become familiar with them.

Proteomics, metabolomics, and transcriptomics (often known collectively simply as OMIC studies) provide much greater insight into the effects of transgenic alterations than any of the simplistic and limited biochemical tests conducted. For example, a proteomic study would show how the protein products in the new organism differ statistically from a natural organism of the same species. This would help identify pleiotropic effects. If an inserted gene altered the behaviour of some gene nearby it, this altered behaviour would (theoretically) show up as some change in the protein distribution relative to a non-engineered organism.

These studies are still insufficient due to statistical inadequacies, but also because they only provide snapshots into the behaviour of the GMO. The GMO might be tested in laboratory conditions, where the inserted gene behaves in one way with its neighbours. But in complex field conditions, the gene often behaves differently and its behaviour changes over its lifespan. It would be unrealistic to think that the biotech companies could comprehensively test for protein changes across every likely field condition because there is an enormous variety, dependent on humidity, temperature, interacting organisms, predators, nutrient availability, etc.

Needless to say, most biotech companies and their cheerleaders are arguing that ANY OMIC study is unnecessary and that current substantial equivalence protocols are more than sufficient.

I apologize that this article got pretty technical, but I really think we need to know this stuff. Anyway, my conclusion is simple:

"Substantial equivalence" is a misleading term. Current regulations provide many holes for potentially serious health and environmental effects to slip through. Newer OMIC studies exists, which would provide a finer grained filter to skim out potential problems, but these studies are certainly not foolproof. Activists should understand that this neologism is used for political gain and as a tool for ensuring compliance. It is not a scientific term and it is not likely to be in the near future, given our analytical limitations in understanding the genome.

It is important that we expose the regulation for what it is. The biotech industry constantly accuses those concerned with genetic engineering of ignorant fear-mongering. The techniques that these companies utilize and enthrone with the Godly title, "Science", are neither noble nor ingenious. Behind their cunning words lie a dearth of precision and a surplus of greed.