Based in Adelaide, Australia, Empire Times is the student publication of Flinders University. It covers campus news and provides a platform for emerging student talent.

By Design

By Design

Medical researchers ask the big questions to try and save us from disease. As medical technology advances, we have more and more choice. Over the last decade, scientists unlocked the potential for humans to edit DNA, greatly increasing our control over our bodies (1). Using the CRISPR-Cas9 system, we could change the instructions given to our cells that determine if we get sick, how we process information and even what we look like (2).

As you can imagine, this control gives us an overwhelming amount of choices. Some of these have the potential to make a real difference – we could end genetic disease and make future children faster, stronger and smarter. But what are the long-term consequences, and is it ethical to edit children who can’t consent to their treatment? Have designer babies even been created successfully?

 

‘He’ did it
As it turns out, someone already tried it late last year. In a world-first, Dr He Jiankui used CRISPR gene editing to change the DNA of human embryos. He deleted the CCR5 gene from the DNA of twin babies when they were only starting to develop from a handful of cells. Because gene editing was done in this early embryo, the DNA changes now remain in every cell of the twins’ bodies forever. Jiankui said his experiments made positive changes, because HIV uses CCR5 receptors to attack our immune system – without the CCR5 gene, you can’t be infected with HIV (3).

Despite his seemingly good intentions, the scientific community was outraged. The Director for America’s National Institutes of Health, Dr Francis Collins, slammed Jiankui’s decision – labelling his actions and motivations as ‘utterly unconvincing’, ‘highly questionable’ and ‘[possibly] damaging’ (4). Jiankui also broke Chinese law by undertaking the experiment. ABC News reports that Jiankui,  dubbed ‘Frankenstein doctor,’ went into hiding after his announcement and the international backlash (5). He was fired early this year by his former university, the Southern University of Science and Technology. Authorities argue Jiankui knowingly broke ethics laws for ‘fame and fortune’. It’s not hard to see why – the now infamous scientist broadcasted his findings across YouTube (6).

Gene editing 101
But how does CRISPR work anyway? Our bodies are made of cells, which are controlled by the unique code stored in DNA (our genome). DNA is made of up thousands of genes – each gene has instructions to keep us running, including the process for making enzymes. Our cells use enzymes to get things done quickly. They perform chemical reactions inside our cells to give us energy, maintain our temperature, and dispose of waste… Just to name a few.

The CRISPR system involves an enzyme (Cas9), but this particular enzyme actually comes from bacteria, not human cells. CRISPR’s usual job is to cut up and destroy invading bits of virus DNA that try and infect bacteria. Bacteria use CRISPR as part of their own immune system so they don’t get taken over by viruses (7).

This ‘molecular scissors’ property of CRISPR translates directly to its use in humans. Scientists can inject CRISPR into our cells, along with the piece of DNA they wish to add to our cell’s existing DNA set. With just the CRISPR enzyme and the desired DNA sequence, though, nothing happens – CRISPR just chops up the piece of naked DNA! Scientists need to add a third part to the gene editing system – a piece of guide RNA (gRNA). This gRNA is made in the lab, and tells CRISPR two things: where to cut our genome, and where to put the desired DNA sequence (7). There are four main possible outcomes when we edit DNA: a gene doesn’t work, a gene is removed, a faulty gene is fixed or an entirely new gene is added (8). The CRISPR system now enables scientists – and even backyard enthusiasts, with the right tech – the ability to edit DNA with minimal resources.

 

Curing disease and creating ideals – the human master race?
That’s the science – so how can CRISPR help us? For one thing, CRISPR gene editing could cure genetic diseases. Cystic fibrosis (CF) is a cruel condition that is not only deadly, but costs more than $10,000 per patient, per year in drug treatments (9). CF sufferers have extra mucous in their lungs because their cell drainage controller, the CFTR ion channel, is broken. What causes the faulty drain? A faulty gene. The result? A salt-water imbalance leading to fluid build-up in patients’ lungs (10). If you’ve ever swallowed water “down the wrong way,” you can imagine why this is a real problem. Now imagine a chronic (long-lasting) condition that involves really thick fluids, as they slowly damage your airways.

CRISPR could put an end to all of this. Experts suggest we could use the CRISPR enzyme system to cut and fix the mutated CFTR gene. We may not even need to introduce the correct sequence – we might even be able to simply fix the existing scrambled DNA code. This would reduce the risk of causing harmful off-target effects (more on that later) (11).

Here’s why this is huge: 1 in 25 people carry the faulty CFTR gene. Although you need two copies of the mutated CFTR gene to get CF, the “carriers” (people with only one copy) are still circulating the bad gene without knowing it (9). In theory, we could edit embryos using CRISPR so 0 in 25 people carry the faulty gene. In October last year, scientists from Utah State University made “designer sheep” that had a scrambled CFTR gene from birth (12). Using these findings, we could use CRISPR to reverse engineer the process in humans. This would eliminate the faulty CFTR mutation from existence. We could be a master race unaffected by genetic disease.

Speaking of which, have you ever wanted to be taller? Run faster? Learn more efficiently? CRISPR might be the answer. Researchers argue that editing the embryo, or the “germline” cells, enables us to permanently improve that child’s phenotype – in other words, their characteristics. Since these positive changes are made to that child’s core DNA instructions, every cell in their body contains the changes. So, any offspring these children have can also inherit “designer” genes. Such reproductive options could give almost endless choice to parents and make a society of better humans, almost like the next generation of cars or iPhones (13).

CRISPR Consequences and Consent
This same “SIMS style” build-your-own-baby approach could, however, also have permanent consequences for humanity. Many scientists have raised concerns over CRISPR’s impact on the gene pool. The “gene pool” describes all the DNA of every human who reproduces. It includes all of our genes, collectively. When you were conceived, your genes were a combination of your mother’s and your father’s genes – you pulled certain cards from the gene pool deck. This combination of genes became your own DNA sequence, or your own deck of cards. Now suppose that we change those genes you picked from your mum and dad. It would be like using a sharpie and changing the ‘6’ card in your hand to a ‘9’. This might be a good change, but it is a permanent change made to the human species as you continue to reproduce (14). Your altered card goes back in the deck, ready to be used in future generations.

That’s the thing, though – we don’t know if making artificial changes to the gene pool over time would be good or bad. We don’t know because we haven’t tried it. There is reason to believe, however, that not every CRISPR gene edit is good. Researchers have found the Cas9 enzyme can cut at the wrong place in a DNA sequence, or insert a gene in the wrong spot. Animal studies have demonstrated harmful CRISPR mistakes range from termination of pregnancy, increased cancer risk and creating new diseases (15). These unintended consequences are called “off-target effects,” because they were off-target from the original goal of gene editing. Off-target effects can also be invisible before anyone realises there’s a problem. CRISPR has the potential to not only introduce these permanent damages to DNA, but to make them part of people who don’t know better.

Which brings us to the issue of informed consent. When you go to the doctor or have surgery, you are told about what’s involved, what the risks are, and the outcomes. You then decide whether to continue with medical treatment. That’s informed consent – you were told about the medical intervention and made an informed decision based on the facts. You have a right to decide what happens to your body (16).

It’s impossible to obtain informed consent from a human embryo – it does not have a fully functioning brain or even ears yet. How can it be informed about anything, let alone gene editing? Since CRISPR changes the gene pool, we are also modifying unborn future generations without their consent. This cost would be more acceptable if we could guarantee that gene editing would only be beneficial. As discussed, though, CRISPR can produce horrific, unintentional outcomes. These consequences might affect the first child, or remain hidden and only appear several generations later (17).

Others argue that CRISPR is not the only technology that has changed our genome ‘without our consent’. Advances in agriculture, education and industrial machines have all changed the way we live our lives. These points of progress have indirectly altered our environment without us actively agreeing to the changes – they just happened. We, and by extension our DNA, have changed over generations to adapt to these advances in technology (13). Despite our “lack of consent,” however, we have still been aware of these changes around us. A human embryo is a collection of cells, and is therefore not aware of changes as they happen.

CRISPR has made possible unprecedented leaps in genetics. There is now great potential to end suffering at the hands of genetic disease. With some more research, we could even upgrade our children to be better versions of ourselves. At present, though, we just don’t have enough evidence to say whether every genetic change would be a good change. CRISPR hasn’t been around long enough to know whether we can learn to control it safely.

One thing is for sure – if we start designing our children, there’s no going back. The changes are permanent and will leave their mark on our species. Are we ready to ask the big questions and embrace our new genetic options? Or should we take a step back and consider the long-term outcomes? Either way, CRISPR is waiting.

words by
ASH GOODMAN

References

1.         Adli M. The CRISPR tool kit for genome editing and beyond. Nature communications. 2018;9(1):1911.

2.         Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F. Genome engineering using the CRISPR-Cas9 system. Nature protocols. 2013;8(11):2281-308.

3.         Cyranoski D. Baby gene edits could affect a range of traits: Nature News; 2018 [Available from: https://www.nature.com/articles/d41586-018-07713-2.

4.         Collins FS. Statement on Claim of First Gene-Edited Babies by Chinese Researcher 2018 [Available from: https://www.nih.gov/about-nih/who-we-are/nih-director/statements/statement-claim-first-gene-edited-babies-chinese-researcher.

5.         Kilbride J, Xiao B. Chinese scientist who edited twin girls' genes He Jiankui missing for over a week 2018 [Available from: https://www.abc.net.au/news/2018-12-07/chinese-scientist-who-edited-twins-genes-he-jiankui-missing/10588528.

6.         Cyranoski D. CRISPR-baby scientist fired by university 2019 [Available from: https://www.nature.com/articles/d41586-019-00246-2.

7.         Kick L, Kirchner M, Schneider S. CRISPR-Cas9: From a bacterial immune system to genome-edited human cells in clinical trials. Bioengineered. 2017;8(3):280-6.

8.         Lino CA, Harper JC, Carney JP, Timlin JA. Delivering CRISPR: a review of the challenges and approaches. Drug delivery. 2018;25(1):1234-57.

9.         van Gool K, Norman R, Delatycki MB, Hall J, Massie J. Understanding the costs of care for cystic fibrosis: an analysis by age and health state. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research. 2013;16(2):345-55.

10.       Cutting GR. Cystic fibrosis genetics: from molecular understanding to clinical application. Nature reviews Genetics. 2015;16(1):45-56.

11.       Marangi M, Pistritto G. Innovative Therapeutic Strategies for Cystic Fibrosis: Moving Forward to CRISPR Technique. Frontiers in pharmacology. 2018;9:396.

12.       Fan Z, Perisse IV, Cotton CU, Regouski M, Meng Q, Domb C, et al. A sheep model of cystic fibrosis generated by CRISPR/Cas9 disruption of the CFTR gene. JCI insight. 2018;3(19).

13.       Cavaliere G. Genome editing and assisted reproduction: curing embryos, society or prospective parents? Medicine, health care, and philosophy. 2018;21(2):215-25.

14.       Vassena R, Heindryckx B, Peco R, Raya A, Veiga A, Pennings G, et al. Genome engineering through CRISPR/Cas9 technology in the human germline and pluripotent stem cells. Human Reproduction Update. 2016;22(4):411-9.

15.       Kohn DB, Porteus MH, Scharenberg AM. Ethical and regulatory aspects of genome editing. Blood. 2016;127(21):2553-60.

16.       Hall DE, Prochazka AV, Fink AS. Informed consent for clinical treatment. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 2012;184(5):533-40.

17.       Cribbs AP, Perera SMW. Science and Bioethics of CRISPR-Cas9 Gene Editing: An Analysis Towards Separating Facts and Fiction. The Yale journal of biology and medicine. 2017;90(4):625-34. 

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