Towards a CRISPR understanding of toxicology

 

Scientists create yellow, three-eyed, wingless mosquitoes by using gene editing tool

Plant geneticists develop a new application of CRISPR to break yield barriers in crops

Gene-Editing: New technique stops progression of muscular dystrophy in mice

 

You don’t have to search long to find eye-catching headlines about CRISPR/Cas9, a technique that allows scientists to more easily edit specific parts of the genome. It’s particularly exciting for the same reason that it’s particularly concerning: it opens up a whole new world of possibilities for gene manipulation in humans, animals, and plants. The technology offers hope for real scientific, societal and medical advances, from engineering oranges to be resistant to citrus greening and controlling mosquito populations by making them infertile to removing genetic mutations that cause disease in humans (as demonstrated on a mutation that causes heart muscle to thicken dangerously).

https://news.utexas.edu/2017/06/29/safer-gene-editing-therapy-using-crispr

However, since I’m a PhD student in Toxicology, I investigate the role of environmental exposures on human health. What happens in your body when you inhale polluted air or drink contaminated water, and how does this ultimately affect your risk for certain health effects?

So, while I had casually followed the news about CRISPR/Cas9 over the years, I had not seriously considered its application to my field until listening to the recent National Academies of Sciences workshop, The Promise of Genome Editing Tools of Advance Environmental Health Research. This workshop brought together experts from across the disciplines of environmental health to understand how these technologies can improve our understanding of the impacts of exposures.

It turns out, there’s a lot to be excited about. Here’s a snapshot of where they saw potential.

Identifying affected biological pathways

Much of the work of toxicologists is focused on understanding the specific biological mechanism, or “adverse outcome pathway,” that is affected by a pollutant when it enters the body. If the pollutant changes the normal signaling for a gene or protein, it could set off a domino effect of problems (like when bisphenol-A (BPA), an estrogen mimic, prompts inappropriate estrogen signaling in the body). CRISPR/Cas9 technology could allow researchers to alter different genes in different adverse outcome pathways of their model systems (either in vitro, cell-based, or in vivo, with whole animals) and then see how response to the exposure changes. If changing a specific gene leads to a change in biological response, it would provide insight to how the chemical exerts its effects.

https://www.epa.gov/sites/production/files/2016-10/aop1.png
https://www.epa.gov/sites/production/files/2016-10/aop1.png

For example, imagine that a pollutant activates a certain receptor by fitting into it perfectly, like a lock and key. Researchers could use CRISPR/Cas9 to alter the gene that determines the shape of the receptor so that the pollutant no longer fits – and thus could not activate the receptor and prompt associated changes in the cell. If, after this genetic modification, the pollutant does not trigger a response, we would know that it acts through the pathway that includes that specific receptor.

https://upload.wikimedia.org/wikipedia/commons/thumb/6/6b/Hormone_Receptor_Binding.png/440px-Hormone_Receptor_Binding.png

Incorporating and understanding human variability

Current toxicity testing approaches are usually based on genetically identical model systems, like mice, that do not represent the genetic diversity in humans. So, unsurprisingly, results from the lab do not reflect the full spectrum of effects that would be expected in the actual population. To remedy this issue, researchers could use CRISPR/Cas9 to introduce relevant human genetic variation into their models and then see how response to the exposure changes accordingly.

Information about which genetic variants are more vulnerable to specific exposures can be used to improve risk assessment. And, policy-makers could set regulations to protect even those individuals with highly sensitive genetic variants from harmful health effects. (This situation has come up with occupational beryllium exposure limits, since we know about a specific mutation that makes people much more likely to get chronic beryllium disease)

Elucidating effects of epigenetic changes

In recent years, toxicologists have become increasingly concerned about the potential for pollutants to make subtle changes in how genes are expressed without actually changing the genes themselves. This field of research is called “epigenetics” and is particularly relevant to the effects of early-life exposures. However, in many cases, we don’t fully understand the long-term implications of these changes. CRISPR/Cas9 could allow researchers to artificially induce epigenetic alterations of interest in the lab and then carefully track the consequences over time.

A slow start, but lots of potential

The applications described above, among others, clearly indicate that CRISPR/Cas9 gene editing technologies could hold great promise for advancing our understanding of the effects of environmental exposures across the population. While there are some studies that have already utilized this approach (for example, a 2016 study about the effects of the antimicrobial triclosan on human liver cells), its use across toxicology have been limited so far. Hopefully, the discussions and excitement following this workshop can prompt further widespread adoption.

Yet, tricky ethical questions also exist for CRISPR/Cas9’s potential environmental health applications. If we have the ability to eliminate a gene that makes someone susceptible to an environmental exposure, should we act to remove it from future generations? Once we start, where do we draw the line? Undoubtedly, these issues will be debated over the coming years. Nevertheless, when used for basic and translational toxicological research in the short term, CRISPR/Cas9 should be seen as an important tool to help us address the huge gaps in our understanding about the chemicals that we are exposed to on a daily basis.

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Rachel Shaffer

Rachel Shaffer

I graduated from Yale University with a BA in Environmental Studies/Environmental Health, and I'm currently pursuing a PhD in Environmental Toxicology at the University of Washington Seattle School of Public Health. Outside of school, I enjoy hiking and biking around in the beautiful Pacific Northwest!

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