Who’s lord of the cell?

For the latter half of the 20th century, the central dogma of biology was straight forward. DNA was the crown jewel of the cell and blue print for everything that was in the cell or so it was claimed.

Next, the sequence of bases in the DNA for selected protein encoding genes was transcribed (copied) into matching single-stranded molecules called messenger RNA (mRNA for short), which literally carried the “message” from the nucleus into the cytoplasm.

In the cytoplasm the message in the mRNA was then decoded in structures called ribosomes in a process aptly called translation, into a specific sequence of amino acids to form a specific protein. 

Finally, the sequence of amino acids dictated the form and hence the function of the protein. It all sounds very simple, and in outline, it is.

Unravelling that sequence took a lot of work and recently garnered two Nobel Prizes — one in 2018 shared by Frances Arnold, George Smith and Gregory Winter and the other in 2022 by Carolyn Bertozzi, Mortem Meldal and Barry Sharpless.

Toward the end of the 20th century, it almost seemed as if the central challenges of biology had been solved.

Indeed, once the human genome and those of many animals had been mapped, much fruitful work followed matching specific genes with specific functions in cells and correlating mutant single genes with a growing list of hereditary diseases caused by mutant versions of genes malfunctioning or failing to function at all. 

These findings lead to much optimism that many genetic diseases could be fixed by editing single pathological genes by knocking them out in part, or whole, or replacing them with normal versions of the mutant gene.

Here, the pioneering work of Jennifer Doudna and Emmanuelle Charpentier, provided a novel beguilingly simple technique for editing genes based on what bacteria had been doing for destroying invading viruses for billions of years. 

But there was a huge central question left unaddressed.

Beginning with the first cell following fertilization, how do successive generations of cells differentiate into thousands of cell types, yet all those differentiated cells contain the same genes?

They haven’t lost any genes or gained others. How then was differentiation possible?  

Differentiated cells look so different from one another and serve very different purposes.

There had to be some process in cells that, for example, in the case of columnar epithelial cells lining the intestine, select those genes, which made those epithelial cells possible, while silencing other genes required to make different cells — say liver, brain or heart cells. 

It’s not that the latter genes have been lost because, as Nobel Prize winners John Gurdon and Shinya Yamanaka clearly showed, cells continue to hold onto all the genes bequeathed to them from the original first cell, whatever their adult role might turn out to be. 

Proof of that latent potential was that certain transcription factors added to mature well differentiated cells were capable of restoring function to all those genes silenced during the differentiation process, and even in some instances, creating a whole animal from what were a few mature, well-differentiated cells, such as fibroblasts from the adult skin. 

In short, the process of differentiation can be reversed and even redirected under the right conditions to form specific tissues such as minibrains, skin, heart muscle and other tissues.

But how are genes silenced or activated?

In what is a now a growing field in biology, it’s become clear that genes can be silenced by tagging single genes or suites of related genes with methyl groups or transcription factors, some of which are proteins and others RNAs. 

On the other hand, other proteins RNAs as well as histone proteins can activate genes — again single ones or whole suites of related genes.

This puts DNA in a different light — DNA behaves like a blueprint of sorts, but is subject to selective activation or silencing by other molecules.

What seemed like a clear hierarchical system with DNA at the top looks more like a cooperative, where it’s hard to tell, at any one time, who’s in charge of what.

The whole process of differentiation and development is so exquisitely choreographed and timed that at least at this time in biology it’s obvious we’re a long way from solving how the whole process works from step to step. 

With some exceptions, progress in science is usually incremental and biology, especially biochemistry, is perhaps the most challenging of all the sciences, because there are so many moving parts and variables — certainly far more challenging than stars. 

The upcoming annual review of this year’s Nobel Prizes begins on Wednesday, Nov. 6 at 2 p.m. in the Niagara-on-the-Lake Public Library.

This will be the eighth year of this highly successful program. So, please register with Debbie Krause because space will be limited. 

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.