Running with scissors – Part I

What is genome editing? (Part I)

[1]
slider-crisprNew methods in genome editing have been described as ushering in “a new era in molecular biology“. Even beyond the boundaries of genetics, genome modification has been called “transformative” [2] . It is likely to change social practices and alter the way society thinks. Given its paramount importance, it’s crucial to understand how genome modification works and what it can be used for. So at this early stage of this blog, this post describes what CRISPR and genome editing is in a layperson’s terms.

CRISPR/Cbreakthrough-prizeas9 is the spearhead of new developments in genome editing. It is a particular chemical substance tailor-made for use in the lab. The technological potential of its components was discovered in 2011, and by 2014, this potential had been further fleshed out through a “tsunami” of experiments and scientific papers. There has been talk of a Nobel prize for the original developers. Such hopes have remained unfulfilled – perhaps because of an ongoing patent dispute with billions of dollars involved. So for now, two particularly notable geneticists have to make do with the $3 million they each won with a “Breakthrough Prize“. CRISPR, meanwhile, has not been used on living humans, but steps have already been taken to change this. Other similar genome editing methods that have been used in humans, however, rely on chemical components called ZFNs and TALENs. The latter was used successfully to treat the cancer of two infants [3], but CRISPR is even simpler, cheaper, and more efficient.

Essentially, CRISPR and related technologies work like precision scissors that cut DNA at clearly defined positions. It had already been possible before to add a stretch of DNA to an existing one, but such insertions have become much more useful now with the possibility of making cuts reliably – and at sites that can be defined very precisely at that. These are technical considerations that require elaboration from the perspective of genetics. Such questions will be discussed in a later post, which will be part II of this “Running with scissors” post. At this point, in part I, I describe what gene editing can be used for.

A key reason why genome editing commands great attention is that scientists hope to combat diseases caused by genetic irregularities by “editing” the “malfunctioning” DNA. The World Health Organization estimates that worldwide, one percent of all live births are affected by a disease that has a clearly defined genetic cause, such as sickle cell anemia, haemophilia, or cystic fibrosis. Certain forms of cancer can also be tackled with gene editing [3], and the procedure is involved in attempts to develop a cure for HIV. Indeed, the attempts by a Chinese lab to confer immunity to HIV/AIDS to embryos – non-viable ones that were, however, not infected with HIV – that elicited much scepticism among scientists and observers.

imagesBeyond therapy, the technology also helps scientists understand the role of certain genes in an organism in the first place. With gene editing, genes can now be reliably “knocked out”, and the effects allow for a better analysis of that gene’s original function. Such studies typically involve mice. Researchers are primarily interested in the health of humans, however, and John Parrington points out that genome editing will make more common the use of animals that are more similar to humans, such as monkeys or even apes.

With gene editing, mice and other animals can also be more easily modified to imitate (“model”) human diseases, so researchers gain greater insight into therapeutic possibilities – perhaps even down to a level of specificity that corresponds to the particular genes of one individual person.

Update (Nov 2016): Last year, researchers at Emory modified macaques with CRISPR/Cas9 to model muscular dystrophy, while researchers in China did so with respect to a rare human disease named MECP2 duplication syndrome. A macaque is a monkey, a close relative of the baboon, part of a group that is distinct from the great apes. Difficulties with such approaches deal with developmental intervals, which are significantly longer in monkeys than in mice. So if a primate embryo is modified, it takes a lot more time until the animal has grown and the effects of a disease can be studied in a grown adult. In a fast-paced scientific field drawing on applications such as genome editing, the extra year that a study takes, or perhaps significantly more than that, can be a deal breaker. Studying the effects of modifications in the second generation of course takes even more time. There is work being done on “shortcuts”, but researchers also experiment on marmosets, a type of monkey that develops much faster. An overview of these procedures is given here.

But modifying animals may not only help understand organisms by inference from taking away functionality. With the help of genome editing, researchers and medical companies try to grow tissue and even human organs in other animals that would then be “harvested” for transplantation into humans (so-called “xenotransplantation” from a “chimera”). Due to ethical coheart_transplantncerns, the American regulatory body NIH withdrew public funding from such projects, and from a scientific perspective, much work is still required to make this feasible. In current studies, a baboon survived for a year with a heart grown in a pig. A few individual, large investments in projects within this niche of the biotechnology industry have more recently amounted to more than $60 million.

Again another use of gene editing lies in the modification not of the DNA bases themselves, but in changing the chemical components that an organism commonly adds onto DNA, thereby regulating the function of DNA. So while a stretch of DNA encodes a sequence of aminoacids, which then form the protein that makes up part of a body, an organism calibrates the level at which this protein is produced by means other than simple DNA expression. This takes place by grafting additional molecules onto the relevant stretch of DNA (“epigenetics”, “methylation”). So this concerns not the composition of DNA, but the use the organism makes of DNA. For example, studies suggest that persistent early childhood stress can modify the way the body draws on DNA to produce stress hormones, which can then lead to more sensitive stress reactions, even depression [4]. In describing the epigenetic influence that lifetime experiences can have on later generations, journalists have drawn on the Biblical notion of “the sins of the fathers” being visited upon theibart_simpsonr children. Indeed epigenetic changes can be inherited, which may explain characteristics of people whose parents, for example, endured extreme hardship such as Nazi concentration camps or the Dutch Famine 1944/45. Speaking of Biblical notions (“the sins of the fathers”): the Biblical book of Ezekiel announces that God would no longer act according to the principle of kin liability (rendering obsolete the saying, the parents have eaten sour grapes, and the children’s teeth are set on edge). With genome editing, that may become a reality on the biological level (although a theological disclaimer [5] needs to be made here).

Finally, CRISPR is often named in the “enhancement” discourse that centres around new bodily features that genome editing might bestow on an otherwise healthy person. Geneticist George Church names extra-strong bones, insensitivity to pain, logeorge_churchw odor production, and a lower disease risk as results of particular genetic modifications. A more powerful memory, a longer life span, enhanced colour vision, genetically reinforced monogamy, increased work discipline, and spontaneous tissue regeneration seem to have been achieved in rodents. How about owl-like night vision or photosynthesis for humans – or a resurrection of a genetic circuitry that, if restored to its erstwhile evolutionary function, would give the human body the capacity to synthesize its own vitamin C? In another example, the now-defunct drug Repoxygen altered the genome to increase production of the hormone Erythropoietin (EPO), which was intended as a treatment of anaemia, but would also give greater endurance to athletes (“gene doping”).

So is genetic modification with CRISPR a good or bad idea? This overview of the different functions of genome editing indicates already that the question can’t be that simple. There are lots of different ways to “run” with these new “scissors”. Moreover, the metaphor of running with scissors is what philosophers like to call a “thick concept” – i.e., to choose this metaphor for genome modification means already to evaluate it morally. The title of this post, however, should not be read as prejudging genome modification. So is genome modification indeed inadvisable? In what context, for which purpose? Why yes? Why no? What uses could be helpful, and how could lab practices be restricted if necessary?

Before this blog will look at these questions, the second part of this post will look in slightly greater detail at the technical side of genome modification. While this may sound complicated – probably more so than it actually is – these technical procedures certainly have strong implications for how we evaluate them from an ethical point of view. So we’ll take a look at them next time.

imagesIn the meantime, please let me know your questions and comments about genome editing and this post in the comments section below (please scroll down all the way). I’m looking forward to exploring this with you.

Notes

13. Oct.: This post was slightly edited to clarify the inheritance of epigenetic factors.

1

I stole the title “running with scissors” from John Harris’ review article in Nature 535 (21 July 2016).

2

Genome editing: An ethical review” by the Nuffield council on bioethics, p. 21

3

World first use of gene-edited immune cells to treat ‘incurable’ leukaemia“, “Cellectis hails success in ridding British infant of cancer

4

See the TV interview with Elisabeth Binder (German) and the studies “Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice“, “Youth offspring of mothers with posttraumatic stress disorder have altered stress reactivity in response to a laboratory stressor

5

From a theological perspective, the analogy between various unpleasant or harmful biological effects on the one hand and the theological notion of sin (as in, “epigenetics is about the biological sense in which the sins of the fathers are visited upon the children”) is less straightforward than it may seem. Theologically speaking, not everything undesirable is sinful (while a seemingly desirable behaviour may even be a candidate for sin). Further, the breaking of the link between sin and harmful consequences exceeds human capacities.

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