A piece of cancer complexity puzzle

I’ve noted several times that there has been a lot of criticism lately of the genetics work of the past several years because it hasn’t fulfilled the expectations that were generated by the Human Genome Project. My response to that is that whole genome sequencing has raised as many biological questions as it has answered, a common part of the scientific process.

One of the questions raised is: how do really complex organisms like human beings get generated by a surprisingly few (~30,000) genes found in the genome? There are simple organisms with more genes than humans (e.g., rice with 50,000). On the other hand the fruit fly gets by on only 14,000 genes. This result is contrary to the initial assumption that each gene would correspond to one protein in the cell system. There is not a simple correspondence of genome size and complexity. Basically it means that other things are going on in the gene expression process that produce more alternative results.

Profs. Stefan Mass and Daniel Lopresti, computer scientists at Lehigh U, have been working on one important part of the process: RNA editing. For DNA to be turned into the protein building blocks of cells it must first be transcribed into RNA which is then translated into amino acid segments of proteins. But it turns out that for many genes the process can result in more than one protein because the RNA is “edited” by chemical modifications.

RNA editing, says Maas, includes a variety of mechanisms by which gene sequences are altered after DNA is transcribed into RNA and before RNA is translated to the proteins that determine an organism’s structural, enzymatic and regulatory functions. The most important of these mechanisms involves the modification of single nucleotides, the molecules that connect to form the structural units of RNA and DNA.

The human genome contains 3.4 billion nucleotides. Modifications in these molecules can cause changes to the amino acids in the proteins that are synthesized, which can lead in turn to an alteration of protein function. Thus, says Maas, who studies the genomes of humans, rats, mice and zebrafish, RNA editing yields a potentially “exponential” increase in the number of gene products that can be generated from a single gene—and a staggering volume of information to analyze.

That’s where the computer science comes in. The details of what is happening in the human genome as it is transformed into cell components become overwhelming. I mean, unraveling the 3.4 billion genes in our genome was an epic project itself; now they’ve found a kind of multiplier effect.

What the professors have done is create a computer model and software techniques to make educated queses about where along the RNA modifications can be made and what the impact might be on proteins. Diseases such as cancer and ALS result from abnormal processes involving the cell’s proteins, so the normal and abnormal steps need to be sussed out.

The space of chemical transitions at the heart of cellular processes is vast. How much needs to be understood to improve diagnosis, prevention, and treatment of cancer for instance? Nobody knows, but my personal hunch is that we’re not going to reach the goal of turning cancer into a non-problem until we’ve waded all the way through the swamp.


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