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God’s Red Pencil? CRISPR and The Three Myths of Precise Genome Editing

April 25, 2016 Biotechnology, Commentaries, Science Media 10 Comments

by Jonathan Latham, PhD

For the benefit of those parts of the world where public acceptance of biotechnology is incomplete, a public relations blitz is at full tilt. It concerns an emerging set of methods for altering the DNA of living organisms. “Easy DNA Editing Will Remake the World. Buckle Up; “We Have the Technology to Destroy All Zika Mosquitoes“; and “CRISPR: gene editing is just the beginning”. (CRISPR is short for CRISPR/cas9, which is short for Clustered Regularly-Interspaced Short Palindromic Repeats/CRISPR associated protein 9; Jinek et al., 2012. It is a combination of a guide RNA and a protein that can cut DNA.)

The hubris is alarming; but the more subtle element of the propaganda campaign is the biggest and most dangerous improbability of them all: that CRISPR and related technologies are “genome editing” (Fichtner et al., 2014). That is, they are capable of creating precise, accurate and specific alterations to DNA.crispr-cas9

Even the “serious” media is in on it. Nature magazine in July 2015 published “Super-muscly pigs created by small genetic tweak“. Two value judgments in a seven word headline: “small” and “tweak”, neither supported by the content of the article. Still enthralled, if not wholly original, just last week the NY Times opinion section offered: “Tweaking genes to save species“.

How do I know this is a propaganda war? I heard it from the horse itself. In February I was at a UN meeting on biotechnology in Rome, Italy, where a senior representative of the Biotechnology Industry Organisation (BIO) explained to the assembled delegates the “exquisite specificity” and “precision” of genome editing.

Myth 1: Current genome editing technologies are not error prone

BIO’s exposition is belied by the evidence. If CRISPR were already precise, accurate and specific there would, for example, be no publications in prominent scientific journals titled “Improving CRISPR-Cas nuclease specificity using truncated guide RNAs“. And these would not begin by describing how ordinary CRISPR “can induce mutations at sites that differ by as many as five nucleotides from the intended target”, i.e. CRISPR may act at unknown sites in the genome where it is not wanted (Fu et al., 2014).

Thus CRISPR itself will need tweaking before it can be useful for safe commercial products, and that is the first error of the tweaking argument. So far, it is technically not possible to make a single (and only a single) genetic change to a genome using CRISPR and be sure one has done so (Fichtner et al., 2014). As Fichtner noted “in mammalian systems Cas9 causes a high degree of off-target effects”. And at least until modified versions come into use, this will limit the safety, and hopefully limit the application, of CRISPR and related biotechnologies. There is, furthermore, no guarantee that more precise versions of CRISPR are even biologically possible. Technically therefore, precision is a myth: no form of genome editing can do what is currently being claimed.

Myth 2: Precision equals control

The second key error of CRISPR boosters is to assume that, even if we had complete precision, this would allow control over the consequences for the resulting organism.

Suppose, as a non-Chinese speaker, I were to precisely remove from a Chinese text one character, one line, or one page. I would have one hundred percent precision, but zero control over the change in meaning. Precision, therefore, is only as useful as the understanding that underlies it, and surely no DNA biologist would propose we understand DNA–or else why are we studying it?

A classic example of how DNA can still reveal unexpected functions decades after discovery is the CaMV 35S promoter, a DNA sequence used in commercialised GMO plants for almost twenty years. The CaMV 35S DNA is described in every application for commercial use as a simple DNA “promoter” (an “on” switch for gene expression).

In 1999, however, the CaMV 35S “promoter” was found to encode a recombinational hotspot (Kohli et al., 1999). In 2011 it was found to produce massive quantities of small RNAs. These RNAs probably function as decoys to neutralise the plant immune system (Blevins et al., 2011). One year later still, regulators found it to contain an overlapping viral gene whose functions are still being elucidated (Podevin and du Jardin 2012).  Will we ever know enough about any DNA sequence to accurately describe changing it as “editing”?

Myth 3: DNA functions are modular and changes are predictable

The third error of CRISPR advocates is to imply that changes to gene functions can be presumed to be discrete and constrained.

The concept of the precise editing of a genome leading to a precise biological outcome depends heavily on the conception that genes give rise to simple outputs. This is the genetic paradigm taught in schools. It is also the paradigm presented to the public and that even plays a large role in the thinking of molecular genetic researchers.

However, a defined, discrete or simple pathway from gene to trait probably never exists. Most gene function is mediated murkily through highly complex biochemical and other networks that depend on many conditional factors, such as the presence of other genes and their variants, on the environment, on the age of the organism, on chance, and so forth. Geneticists and molecular biologists, however, since the time of Gregor Mendel, have striven to find or create artificial experimental systems in which environmental or any other sources of variation are minimised so as not to distract from the more “important” business of genetic discovery.

But by discarding organisms or traits that do not follow their expectations, geneticists and molecular biologists have built themselves a circular argument in favour of a naive deterministic account of gene function. Their paradigm habitually downplays the enormous complexities by which information passes (in both directions) between organisms and their genomes. It has created an immense and mostly unexamined bias in the default public understanding of genes and DNA.

This is not my argument. It belongs to Richard Lewontin of Harvard University, probably the most famous geneticist of our time.

The benefits of naive genetic determinism to the architects of the genome-industrial complex are very great. Since it pretty much requires that organisms be seen as robots being operated by mini-dictators (rather than, for example, as systems with emergent properties) and those genes as having effects that are narrow and clearly defined rather than being diffuse and unpredictable, it simplifies their sales pitch and frames risk assessment as unnecessary.

The problem comes to a head, however, when this narrow conceptualisation of genetics is applied to the real world and situations that have not been, as it were, set up in advance. In the case of the “Super-muscly” pigs reported by Nature, strength is not their only feature. They must also have more skin to cover their bodies and stronger bones to carry themselves. They also, apparently, have difficulty giving birth; and if they were ever released into the wild, they would presumably have to eat more. Thus a supposedly simple genetic tweak can have wide effects on the organism throughout its lifecycle.

Nature also revealed that thirty of the thirty two experimentally-edited pigs died prematurely and only one animal was still considered healthy at the time the study authors were interviewed. So much for precision.

The neverending story

Why is this discussion of precision important? Because for the last seventy years all chemical and biological technologies, from genetic engineering to pesticides, have been built on a myth of precision and specificity. They have all been adopted under the pretense that they would function without side effects or unexpected complications. Yet the extraordinary disasters and repercussions of DDT, leaded paint, agent orange, atrazine, C8, asbestos, chlordane, PCBs, and so on, when all is said and done, have been stories of the steady unraveling of a founding myth of precision and specificity.

Nevertheless, with the help of industry propagandists, their friends in the media, even the United Nations, we are once again being preached the gospel of precision. But no matter how you look at it, precision is a fable and should be treated as such.

The issues of CRISPR and other related new “genome editing” biotechnologies are the subject of intense activity behind the scenes. The US Department of Agriculture has just explained that it will not be regulating organisms whose genomes have been edited since it doesn’t consider them to be GMOs at all. The EU was about to call them GMOs but the US has caused them to blink, meanwhile the US is in the process of revisiting its GMO regulatory environment entirely. Will future safety regulations of GMOs be based on a schoolboy version of genetics and an interpretation of genome editing crafted in a corporate public relations department? If history is any guide it will.

References

Blevins, Todd, Rajendran Rajeswaran, Michael Aregger, Basanta K. Borah, Mikhail Schepetilnikov, Loïc Baerlocher, Laurent Farinelli, Frederick Meins Jr, Thomas Hohn and Mikhail M. Pooggin (2011) Massive production of small RNAs from a non-coding region of Cauliflower mosaic virus in plant defense and viral counter-defense. Nucleic Acids Research 39: 5003-5014.
Franziska Fichtner, Reynel Urrea Castellanos, and Bekir Ülker  (2014) Precision genetic modifications: a new era in molecular biology and crop improvement. Planta 239: 921-939 (doi:10.1007/s00425-014-2029-y.
Fu Y, Foden JA, Khayter C, Maeder ML, Reyon D, Joung JK, Sander JD (2013) High-frequency off-target mutagenesis induced by CRISPR-Cas nucleases in human cells. Nat Biotechnol 31:822–826.
Fu Y, Jeffry D. Sander, Deepak Reyon, Vincent M. Cascio, and J. Keith Joung (2014) Improving CRISPR-Cas nuclease specificity using truncated guide RNAs. Nat Biotechnol. 32: 279–284.
Martin Jinek, Krzysztof Chylinski, Ines Fonfara, Michael Hauer, Jennifer A. Doudna, Emmanuelle Charpentier (2012) A Programmable Dual-RNA – Guided DNA Endonuclease in Adaptive Bacterial Immunity Science 337: 816-821.
Podevin N and  du Jardin P (2012) Possible consequences of the overlap between the CaMV 35S promoter regions in plant transformation vectors used and the viral gene VI in transgenic plants. GM Crops and Food 3: 1-5.

Further reading (added April 26): Are new biotechnologies GMOs?

Further excellent viewing: Its all about that base (Meghan Trainor Parody)

Currently there are "10 comments" on this Article:

  1. Bob says:

    Great article. Really sums up regulatory agency oversight that is consistent in this field. I also heard an additional hazard rests in the ease and cost of CRISPR technology itself — it is so affordable, many more are able to use the technology. Who knows if CRISPR continues to be unregulated as a GMO.

  2. Thank you for the article Jonathan. You have provided another informative view on more disturbing GMO developments. Before the onset of her illness, Dr. Mae-Wan Ho also wrote about CRISPR, and expressed concerns as well:

    “CRISPR Too Fast for Comfort,” by Dr. Mae-Wan Ho, Institute of Science in Society; January 12, 2016
    Excerpt:
    Finally, the ecological risks of gene drives are enormous, so warns conservation scientists from Australia’s Commonwealth Scientific and Industrial Research Organisation. They stated: “The question is no longer whether we can control invasive species using gene drive, but whether we should.” As the gene drive can in principle lead to the extinction of a species, this could involve the species in its native habitat as well as where it is considered invasive. As distinct from conventional biological control, which can be applied locally, there is no way to control gene flow. They point out that because the CRISPR/Cas gene drive remains fully functional in the mutated strain after it is created, the chance of off-target mutations also remain and the likelihood increases with every generation. “If there is any risk of gene flow between the target species and other species, then there is also a risk that the modified sequence could be transferred and the adverse trait manifested in non-target organisms.” (This commentary has not even begun to consider horizontal gene flow, which would multiply the risks many-fold.)
    There is also increasing awareness that many invasive species will have considerable niche overlap, such that removal of one species will enable another to rapidly take its place.
    They call for a thorough ecological risk assessment before any application of CRISPR/Cas gene drive is contemplated in the control of alien species, to prevent a ‘silver bullet’ becoming a ‘conservation threat’.
    **
    In July 2015, Greenpeace Research Laboratories also published an assessment:
    “Application of the EU and Cartagena definitions of a GMO to the classification of plants developed by cisgenesis and gene-editing techniques,” by Janet Cottera, Dirk Zimmermannb and Herman van Bekkemc, Greenpeace Research Laboratories; July, 2015 (18 pages)
    Excerpt:
    Like traditional genetic engineering techniques (including those used for cisgenesis/ intragenesis), unintended changes to plant chemistry arising from the use of gene-editing techniques may result from: unforeseen interactions between the new or altered gene(s) and the plant’s endogenous genes; genomic irregularities arising from the genetic engineering process itself and unintended alterations to plant biochemical pathways arising from the changed or new function(s) of the altered or novel gene(s).
    Unintended changes could impact food, feed and environmental safety but there would be no requirement for these to be detected and assessed under a product based approach, or if such plants are exempt from the GMO regulations. Exemption from the EU GMO regulations would also exempt products of NPBTs from GMO labelling requirements, which could restrict, or remove, consumer choice.
    **
    Here are more reports on the New Plant Breeding Techniques (NPBTs) to supplement the one by Jack Heinemann that is linked to (“Expert scientific opinion on the status of certain new techniques of genetic modification under Directive,” by Professor Jack A. Heinemann, PhD, Centre for Integrated Research in Biosafety; October 30, 2015 – 46 pages)
    :
    “Current status of emerging technologies for plant breeding: Biosafety and knowledge gaps of site directed nucleases and oligonucleotide-directed mutagenesis,” by Sarah Z. Agapito-Tenfen and Odd-Gunnar Wikmark, GenØk Biosafety report; February, 2015 (44 pages)

    “New Plant Breeding Techniques and Risks Associated with their Application,” by Michael Eckerstorfer, Marianne Miklau and Helmut Gaugitsch, Umweltbundesamt GmbH [Environment Agency Austria]; 2014 (94 pages)

    “New Plant Breeding Techniques Position paper,” by IFOAM EU; December 10, 2015 (6 pages)

    “Genetic Engineering in Plants and the ‘New Breeding Techniques (NBTs)’ Inherent risks and the need to regulate,” by Dr. Ricarda A. Steinbrecher, EcoNexus; December 2015 (10 pages)

    “Legal Questions Concerning New Methods for Changing the Genetic Conditions in Plants,” by Professor Dr. Ludwig Krämer, Testbiotech; September 2015 (23 pages)

    “Legal Analysis of the applicability of Directive 2001/18/EC on genome editing technologies,” by Dr. Tade Spranger, Commissioned by the German Federal Agency for Nature Conservation; October 2015 (51 pages)

  3. Bart Lambert says:

    Please note that making gene changes is not a new approach. Every cell that divides leads to gene changes. In plants, changes naturally happen all the time, even larger ones that can be created by Gene Editing. Crop plants have been improved for the benefit of mankind by mutagenesis since the early sixties. Seeds or cells have been treated with mutagenic chemicals or irradiated to created RANDOM changes in genomes and genes. Many fruits and vegetables and crops, INCLUDING ORGANIC, carry artificially induced mutations. These were transferred from the original mutated plants to commercial varieties by crossing. Since mutagenesis is a “cluster bomb technique”, many off-target changes happen next to the intended one(s). Not all of these can be eliminated during the transfer process, unless they have an obvious negative effect. The commercialization of new plant characteristics created by mutagenesis does not require any regulation, nowhere in the world. Time has proven that this poses no issue at all. CRISPR/cas9 technology is an elegant tool, a refinement of the natural process of changing genes, with a great potential for the benefit of mankind.

    • jrlatham says:

      Bart,
      New crop varieties do sometimes demonstrate health and safety problems, from lowered nutrient content to toxic effects (eg the Lenape potato). Biotechnology, in the form of CRISPR and GMOs is not however an alternative. It is additional. The modest safety issues associated with conventional plant breeding are therefore compounded by the effect of Genetic Engineering and CRISPR. And before you call it “elegant”, perhaps think whether those pigs would agree?

      • Bart Lambert says:

        Please note that muscly animals spontaneously arose in nature more than 2 ages ago. I refer to the Belgian Blue race of beef cattle which was reported for the first time in 1808 by the livestock observationist George Culley. The Belgian Blue has a natural mutation (deletion) in the myostatin gene. Myostatin is a protein that acts to inhibit muscle development. The mutated gene does not function in its normal capacity resulting in accelerated lean muscle growth. Healthy, lean meat without fat !!!!!!!!!!!!!!!! A similar mutation was recently introduced in pigs resulting in the same “phenotype”. Healthy, lean meat without fat. Just the same as nature did more than 200 years ago. For the benefit of many meat-loving humans that should avoid fats. WHAT IS THE PROBLEM ? Ideological fanaticism is the problem ….

        • jrlatham says:

          Bart,
          Thank you for including so many industry talking points common misconceptions in such short posts. These cattle arose without genome editing. They dont die before their time. Perhaps the production method had something to do with that? That is the question that Nature Magazine conveniently ignored.

    • joe says:

      Bart, “Ideological fanaticism” is more evident in your camp, who brush off serious concerns with this technique with industry PR hype like “CRISPR/cas9 technology is an elegant tool..”

      Frankly, that is a dishonest misrepresentation of the facts, as the article explains “CRISPR technology creates a high degree of off-target effects,” not to mention the FACT that gene expression is highly complex and very poorly understood.
      It is dishonest to imply that we have “precision technology” to alter a single gene at a time, (CRISPR is not that technology), not to mention the fact that we have not even begun to understand every effect changing any given gene would have on an organism.

      There is nothing elegant about muscle-bound franken-pigs with 94% premature mortality, and with 3% of the remaining 6% that survive being unhealthy.

  4. chris says:

    Thank You Dr. Latham for the extremely important insight into this ‘next generation technology’ of ‘improving nature’.

    Bart, if “Every cell that divides leads to gene changes.”, why do we sequence human genome once, only, while having x^x^x divisions in our life??
    Also :” Crop plants have been improved for the benefit of mankind by mutagenesis since the early sixties.”, yes but not in the way PCR it allowed to since ~1973-75.. Chemicals and radiation can change or gene expression or knock out of a single nucleotide, which might be repaired or changed, BY the plant in its own body. The next generation might carry that new feature, but it was the plant and its progeny, which decided how to proceed, and not a biochemist! What do you think, whom shall we trust more, the original plants or the scientists?
    And Bart, “CRISPR/cas9 technology is an elegant tool, a refinement of the natural process of changing genes,”, has nothing to do with natural process. The synthetic enzymes, nucleotides, come from OUTSIDE, deliberately inserted into the cells by people who do not understand genetics and how it really works, otherwise there would be so many issues Dr. Latham is writing here about.
    Dr. Then from ‘Test Biotech Institute for Independent Impact Assesment in Biotechnology’ states: “CRISP-Cas can establish so-called gene drives, which allow rapid spread of the artificial DNA in the targeted populations.”, which sounds like the second generation of GMO bioweapons..

    And Bart, the last remark, regarding the “Ideological fanaticism is the problem”. Do you mean, the fanaticism of those who forcefully want to change the nature by playing Gods over the genes of all species, which they do not even fully grasp, since clearly, they are not the ones who were making the genes from their very begin…

    There seem to be a huge problem with a generation of scientists who devoted their lives in order to ‘improve’
    nature, that was already perfect from its begin.

  5. Thank you very much, Jonathan, for this very inforamtive and much needed article. The perspective that Bart Lambert defends is pervasive and required a radical critique (radical in the sense of going to its roots). Many scientists are aware that humanity faces a planetary crisis with climate change taking a lot of attention but being just one aspect of it. The plantery crisis is an existential threat to humanity and much of life on earth. However, relatively few scientists are aware that the planetary crisis is rooted in what is called the Anthropocene (New Man). Ecologist Eugene F. Stoermer and atmospheric chemist Paul Crutzen who coined the term and popularized it in the West have suggested that the Anthropocene could be have been started with the introduction of the steam engine in the English Industrial Revolution. What happened about 250 years ago was the combination of recently emerging capitalist mode of production and technologies that were termed as the Industrial Revolution. Capitalist industrialization has put science and technology at the service of commerical profit making. In capitalist ideology every extension of industrialization of life is seen as “progress in the interest of humanity.” However, nothing less than a desire to make a profit has driven the trend. You can see it in the behavior of corporations. For example, Exxon knew by the late 1970s if not by 1957 from the work of its scientists that fossil fuels can cause global warming but kept it a secret and the fossil fuel industry went on a disinformation campaign to deny what it knew to be true–climate change caused by greenhouses emissions. Wealth is produced from nature through human labor (itself part of nature). Thus, capitalist industrialization is nothing less than an all out effort to dominate and control nature. Gene editing is just one of the latest manifestation of this trend that is called the Anthropocene.

    If humanity is to survive the planetary crisis, we have no choice but to confront the age old desire to dominate and control, including through science and technology, nature and humanity which a part of it. It is not just gene editing but much more besides as understood by those who research the Anthropocene. But the desire to dominate and control nature dates back to the Agricultural Revolution about 10,000 years ago. It was then when some hunter-gatherer bands broke off from the ecocentric worldview shared by humanity–one that viewed and still views humanity as a small part of nature–to anthropocentrism, the human superiority worldview that now dominate the world. But the current anthropocentric capitalist culture is only 250 years old and anthopocentrism only 10,000 years old. For 190,000 years hunter-gathers survived and thrived on the basis of an ecocentric culture.

    We need not become hunter-gatherers to return to ecocentrism. But unless we relearn to value all life and Mother Nature as we value humanity and learn to live in harmony with it we are doomed to extinction. Gene editing is just one manifestation of the Anthropocene. To defend it and the commercial interests that promotes it is to be blind to the existential crisis humanity has created for ourselves.

  6. Alan says:

    It should be noted the Belgian Blue breed would struggle to survive without human intervention as a large proportion of calves need to be born via caesarian section. Such a mutation in a wild population would very quickly disappear. I strongly doubt whether grain fed Belgian Blue meat is any healthier than standard grass fed beef. If you want low-fat meat, eat venison!

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