Every human is unique in their biological makeup, and this presents a major challenge for scientists who study how the environment affects health and well-being. For example, one individual’s exposure to a toxin may increase their chance of experiencing an adverse health effect, and in another person, there may be little or no cause for concern. Research models sometimes fail to account for this population diversity, limiting understanding of complex gene-environment interactions as well as the ability to apply new findings in clinical settings.
Fernando Pardo Manuel de Villena, Ph.D.D., chair of the Department of Genetics at the University of North Carolina at Chapel Hill, recently spoke to me about his work to incorporate greater genetic variation into his study designs, thereby increasing their human significance. A recipient of an NIEHS scholarship, Pardo Manuel de Villena has been a world leader in related efforts for more than two decades. I spoke with him about his latest research, how environmental health scientists can better integrate ideas from genetics, and his early intellectual influences (see sidebar).
Focus on the importance of the human being
Rick and Wishek: Can you talk about the history behind efforts by you and other scientists from around the world to incorporate greater genetic diversity into toxicology research?
“Ultimately, our research is supported by tax money, and we have a huge responsibility to make sure that what we do ultimately benefits society and is relevant to human health,” said Pardo-Manuel de Villena. (Photo courtesy of Pardo Manuel de Villena)Fernando Pardo, Manuel de Villina: In 2001, we were in Edinburgh, Scotland, for the International Mammal Genome Society meeting, along with about 500 other researchers – a huge gathering. We decided we needed to move beyond the 20th century idea of genetics, where you look at one gene at a time and make generalizations, or else human geneticists will leave us in the dust. Remember, this was around the time of the first sequencing of the human genome, and we knew such an advance would be revolutionary.
Therefore, we thought about how to form mammalian populations that include enough genetic diversity to become relevant not for a single disease but for every biomedical trait. In other words, rather than choosing for a single effect or health condition, we decided to think broadly and develop an approach that would be useful for research involving toxicology, cancer, mental health, etc. These conversations initiated the important work of integrating biological data across a variety of diseases and time points and building the necessary research tools.
We understood that a single inbred mouse strain is not a model for human disease. It is impossible to make generalizations about everything you are studying, such as the effects of a drug or environmental exposure. You can have the data, but this data is not broadly applicable – you don’t know if it matters for the average population, or the extreme strains, and the inbred strains tend to be extreme in nature.
This thinking eventually led to the development of various intersecting and collaborative intersecting models. The first enables highly accurate genetic mapping, helping researchers to better understand complex genetic traits and how they relate to a phenotype, or an observable characteristic. The latter is based on 100 years of mouse genetics, creating a population-based model in which genomes are reproducible and nearly all genetic variations are captured, helping scientists identify specific genes associated with a particular health effect.
In my view, understanding individual susceptibility to disease requires scientists to integrate insights from genetics and environmental health sciences. (Photo courtesy of Sashkin / Shutterstock.com)Arsenic exposure, complex genetic interactions
RW: Yes, the single mouse strain is very artificial — it’s perfect for conducting experiments, but it’s not a really viable way to model a complex human disease, which is why it’s great that the methods I mentioned are now available to the scientific community. Can you talk a little bit about your current research?
FPMdV: surely. So, for now, we’re looking at the consequences of arsenic exposure – specifically, the interaction between genetic variation, arsenic exposure, nutrition, obesity, and type 2 diabetes. We want to expand upon what has been a somewhat limited way to study arsenic, which is a substance A very important toxicant, affecting hundreds of millions of people around the world.
There are fundamental physiological differences between mice and humans, and if we’re going to try to discover the complex interplay between environment and genetics, we need to make sure we’re doing it in a way that works for humans.
In the context of arsenic, the reason rats are not relevant to humans is that rats metabolize arsenic very well, which is not the case with humans. So, our collaborators developed a single mouse line in which they replaced the mouse gene of interest with the functionally equivalent human gene, and they did so in a very elegant way. Mice now metabolize arsenic in a similar way to humans, which is great because we combined this strain of rats into our co-operative criss-cross collection, and we’re starting to see very exciting things.
We have a fit model, and we have genetic diversity. We can now begin to dig deeper and discover the complex features involved in arsenic exposure. After exposure to the substance is ubiquitous in the organism, and we do not know if the rate of detoxification is different in the liver than in the bladder, kidneys, etc. With our current study design, we can address these questions, which is why this project is so exciting to me.
Education, the key to new partnerships
RW: Given the broad environmental health science community, what knowledge gaps or issues do you think need to be addressed so that researchers can begin to incorporate greater genetic diversity into their studies and increase the human relevance of their work?
FPMdV: One area that will be particularly important going forward is data science infrastructure. The information generated by the type of lookup you’re talking about isn’t something we can do in an Excel spreadsheet – it just won’t work. Developing and maintaining a robust infrastructure is absolutely essential.
Education is also important. Geneticists need education in toxicology and environmental health sciences, and toxicologists and environmental health scientists need education in complex genetics. It’s not about “who’s right” but about working together to solve complex problems.
Take the collaborative shared model as an example. It mainly depends on the integration, which in turn depends on the number of users, the number of phenotypes and doing strict science. If there was only a small community doing this kind of research, it wouldn’t be strong; What we need is for scientists from different disciplines to come together to identify the gaps and improve our models.
(Rick Woichick, Ph.D., directs the NIEHS and the National Toxicology Program.)
from San Jose News Bulletin https://sjnewsbulletin.com/environmental-factor-august-2021-genetics-key-to-making-research-more-relevant-to-humans/
No comments:
Post a Comment