A Few Links on microRNAs and Human Health
Another Nobel Prize win for model organisms genetics again shows the concrete influence of basic research on medicine
It’s that time of year again - Nobel week. This morning we learned that Victor Ambros and Gary Ruvkun won this year’s Nobel Prize in Physiology of Medicine for their discovery of microRNAs. If you want the capsule summary of their work, the Nobel site, as always, has an excellent write-up.
Ambros and Ruvkun were postdocs together. Building on their work in the Horvitz lab, the two, as independent PIs, discovered miRNAs in 1993, working in the model organism C. elegans. C. elegans was the perfect kind of model organism for this work: simple, genetically manipulable, and easy to assay. They published their work in back to back papers in Cell.
The original papers:
Wightman, Ha, Ruvkun, ‘Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans’.
Lee, Feinbaum, Ambros, ‘The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14’.
In 2000, Ruvkun et al later found the first miRNAs in mammals.
In 2004, Ambros wrote a history of the work leading up to the discovery of miRNAs.
miRNAs in Human Health and Disease Treatment
Over the past two decades, miRNAs have become a broad class of biomarkers and therapeutic targets. There is an enormous literature looking at miRNAs in cancer, heart disease, hepatitus C virus infection, diabetes, Alzheimer's… the list goes on an on.
In 2005, Robert Horvitz and Todd Golub showed that different human cancers can be classified by their miRNA profiles. miRNAs have since been shown to act as both tumor suppressors and oncogenes.
Early this year, a group of scientists out of University Hospital in Magdeburg in Germany presented some of the latest work in this area. They found a miRNA signature for pancreatic cancer, an aggressive form of cancer that is often detected late. miRNAs can be found circulating in the blood, and thus are an attractive biomarker for so-called liquid biopsies. The hope is that otherwise imperceptible cancers can be caught early by finding their miRNA signatures in routine blood samples.
On that larger topic, an informative review in Oncogene published earlier this year covers how new biosensors, combined with machine learning, might make this vision a reality.
miRNAs as Therapeutic Targets - Still Early Days
Because miRNAs are such powerful controllers of cellular pathways, they have been tested as both drug targets and therapeutics themselves, in the form of synthetic miRNAs.
None of this work has moved beyond phase I clinical trials, unfortunately. Because of their broad biological impact, miRNA therapies typically have severe side effects. A study of a synthetic mimic of miRNA-34a, aimed at inhibiting solid tumors, did show a positive anti-tumor effect, but four patients died due to a severe immune reaction.
Similarly, a trial of a miRNA therapeutic targeting the hepatitis C virus was able to reduce the virus in patients, but the side effects were severe.
There is still much interest in this area, and hope that the challenges of miRNA therparies can be overcome. A review published earlier this year on the “Trials and Tribulations of MicroRNA Therapeutics” dives deeply into biology and biotechnology of miRNA therapies. With the success of mRNA vaccines and renewed interest in RNA therapeutics, solutions to general problems of targeted RNA delivery and in vivo stability will likely benefit the miRNA therapeutic field as well.