Between 2000 and 2005, several ‘whole-genome’ papers were published on yeast and other model organisms, where the complete genome sequences were used to measure various cellular properties of the organisms. For example, a set of papers reported measuring gene expressions under different conditions. That was easy with the oligonucleotide microarray technology that leveraged on the genome sequences. Other papers reported measuring protein-protein interactions, transcription factor binding sites, cellular localization of proteins and so on, on a genome-wide scale.
Among them, one kind of experiment stood out, and it was Elizabeth Winzeler et al’s yeast gene deletion, extended later on by Amy Tong et al. I am not talking about experimental elegance here, but the conceptual difference between ‘gene deletion’ and all other types of experiments mentioned above.
What is the difference? If you think about it, gene expression or protein- protein interaction measured mechanistic properties inside the cells, whereas ‘gene deletion’ measured its death or a state change. Also, it was not just any state change, but the most important one. Answering ‘what is death’ is related to answering ‘what is life’ - the biggest unanswered question in biology. Use of the term ‘gene deletion’ obscured this point.
After recognizing the unusual nature of such experiments, we decided to extend the concept by measuring the gene expression of a cell during the dying process, where we could monitor the state change by observing the mechanistic properties over time. Our experiment involved another novelty. At that time (2005), we sensed (and reported) that the many genome had possible long non- coding RNAs, and therefore we
decided to take a look at the unknown non-coding RNAs in our experiment. Our data included all genes, but we only focused on non-coding RNAs to make matter even more interesting.
Unfortunately, the paper was not well received.
Me: We monitored gene expression of a dying cell, which we thought would be very interesting and can shed light on the state change.
Science editor: And what did you see?
Me: We discovered many putative long non-coding RNAs and some of them were hidden in the antisense regions of coding genes. We even determined the function of one such RNA.
Science editor: Noncoding RNA? You mean miRNA?
Me: No. These are RNAs nobody knows about yet.
Science editor: Hmmm…what organism?
Science editor: Bye for now.
This month I am reanalyzing data from that nine-year old experiment, and will report here, if I notice something interesting. Our earlier paper was published in PNAS in 2006, but I think we only scratched on the surface of what was there.