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Sunday, February 5, 2023
Dr. Brown: Caution and oversight needed when messing with Mother Nature
Dr. Brown’s love of chemistry might just be from his father. File Photo

You may have heard of gene editing and CRISPR. But what about minibrains, embryos without fathers, mothers and placentas, and brain implants?

The pace in biological research has been astounding in the last few decades, never more so than with the introduction by Emmanuel Charpentier and Jennifer Doudna of a reliable, relatively cheap, and precise method for editing the genome called CRISPR.

For their pioneering studies they shared a Nobel Prize in 2020.

Their method and modifications to the original method introduced by others have been widely adopted around the world and for good reason. They work and possess huge, as yet barely tapped, potential to treat hereditary diseases and some forms of cancer.

Not so well-known are studies in 1962 by John Gurdon and later by Shinya Yamanaka which revealed it was possible to nudge well-differentiated adult cells into what are called induced pluripotent stem cells (iPSCs). For their efforts the two shared the 2012 Nobel in medicine or physiology.

It wasn’t long before scientists employed iPSCs derived from human fibroblasts to create bits of human neocortex, several millimetres in size and grown in dishes.

This wonky idea turned out to be useful because it made it possible to track the genetically orchestrated development of the early neocortex into its several layers of specialized cells as well as the connections between those cells in the cortex.

By knocking out specific genes one at a time, scientists were able to figure out what those genes contribute to normal development of the neocortex. And by introducing mutant versions of those genes found in genetically transmitted diseases, known to affect the human brain, it was possible to learn how those mutant genes produced diseases linked to each mutant protein.

Interesting to me, were studies in which Neanderthal versions of human brain-related genes were introduced into minibrains to learn how Neanderthal brains might differ from those of modern humans, with the ultimate goal of answering questions such as: did they think differently than humans, and if so, in which ways?

As useful as they are, minibrains don’t last long, partly because they lack a blood supply. To extend the lifespan of minibrains, scientists recently implanted human minibrains into the brains of young rats whose immune system was suppressed.

The result was that the minibrains became vascularized from the host’s brain and some nerve cells in the implants developed functioning connections with the host’s brain.

Then this year, two teams, one at the University of Cambridge in the U.K. and the other at the California Institute for Technology, working independently of one another, managed to create synthetic mouse embryos grown without the aid of eggs or sperm.

Stem cells were used to create the embryos, which lasted longer if placental stem cells were added to the mix. The longest recorded survival for these budding embryos was 8.5 days – long enough for development of the brain to begin and the heart to beat but not much further. You might well ask, as I did: Why?

Because, like the mini-brain studies, these studies offer the opportunity to study in great detail the genetically choreographed development of the brain.

Or, in this case, other organs, in fine detail, far beyond what could be learned from embryos attached to their placentas – with the goal of better understanding the how and why of birth defects and perhaps how mutant genes sidetrack the development of the brain and other tissues.

Those are worthy goals and at this stage hold great promise and little risk. But messing with Mother Nature, especially at the genetic level is risky.

Genes often serve multiple functions, only one of which may be understood. In the case of gene editing, there’s the added worry the RNA template designed to target one specific gene might latch onto to other regions in the genome with similar base sequences – with unknown and undesirable consequences.

Most neuropsychiatric diseases lack specific pathologies. That was, until now. Recent post-mortem studies of brain biopsies from patients with autism spectrum disorders (ASD) revealed dysfunctional changes in regulatory genes and other gene expression pathologies.

This and recent evidence that cognitive and behavioural differences between Neanderthals and modern humans might be attributed to differences in a few genes, suggest we are on the threshold of understanding how the modern human brain came to be and how dysfunctional changes at the molecular level may explain some neuropsychiatric diseases and behaviours.

Manipulating Mother Nature at the genetic and developmental levels offers great hope for better understanding interspecies differences in brain function and the management of neuropsychiatric disorders.

Some of the recent methods used to get there may look a little bizarre and may be associated with some risks, especially when it comes to altering the genomes of humans and other species.

What’s needed therefore is caution and oversight, without unnecessarily stifling breakthrough methods, studies and research.

Dr. William Brown is a professor of neurology at McMaster University and co-founder of the InfoHealth series at the Niagara-on-the-Lake Public Library.  

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