CLINICAL MATTERS

As an infectious diseases doctor, my job is usually to kill worms and parasites. However, even I will admit that worms can be useful. This year’s Nobel Prize in Medicine/Physiology was awarded to a pair of American scientists for their work on a worm, the nematode (a type of roundworm) Caenorhabditis elegans. Victor Ambros and Gary Ruvkunwere awarded the prize for their discovery of a new type of RNA known as microRNA. RNA, or ribonucleic acid, is a biological molecule that is typically used by living things to produce proteins.MicroRNAis distinct from the known types of RNA - messenger RNA (mRNA), ribosomal RNA (rRNA), and transfer RNA (tRNA) - which are all crucial for assembling amino acids into proteins. Instead, microRNA is a key player in regulating the expression of genes in multi-celled organisms. The scientists discovered this form of RNA and its functions by studying C. elegans and its development from a single cell to an adult worm. 

C. elegans is a favorite model organism for studying biology. Aside from being easy to grow and propagate, it has relatively few cells. Its body is made up of exactly 959 cells for the usual hermaphrodite worm and exactly 1,033 cells for the rare male worm. This relatively small number of cells means that the origin and differentiation of each cell have been studied extensively, and the molecular biology of these processes can be described in great detail. By studying cellular mechanisms in such a simple and primitive animal, many insights have been gleaned into the development of much more complex organisms. 

Genes are segments of deoxyribonucleic acid or DNA that code for a specific protein. Genes that regulate critical functions in the cell such as energy production and cellular metabolism tend to be retained during evolution, i.e., they are conserved in more complex organisms. Studying these conserved genes which remain present in advanced lifeforms such as humansfacilitates ourunderstanding of how problems in these genes can affect our health and how to treat these defects.

One of the greatest mysteries in life is how a single cell can give rise to a complete organism. An adult human body is composed of anywhere between 28 to 36 trillion cells, each of which is differentiated for a specific purpose. Every single one of these cells at some point in its life contained the same genetic material which had the instructions for creating an entire organism. All humans start from a single-celled fertilized egg, the union of the sperm and the egg cell, which develops into an embryo and eventually into an adult human being.

While the composition and functions of different cell types is fairly straightforward, how these cells develop from a single initial cell is a much more challenging mystery. A solitary undifferentiated cell has very little material to work with and needs to produce all sorts of proteins to perform the bulk of cellular tasks. Proteins are made up of amino acids that are put together by reading instructions from the DNA of the cell. The DNA contained in the genes of a cell stays inside the central portion of the cell, or nucleus. DNA needs to be transcribed into messenger RNA to carry these instructions to the protein-making factories outside the nucleus, known as ribosomes. These ribosomes are where amino acids are assembled into proteins.

You can think of DNA that make up the genes as the permanent instruction book of the cell, like a cookbook, which carries all the “recipes” that the organism needs to function. Messenger RNA or mRNA transcripts are just copies of single recipes that can be sent outside the nucleus so as not to expose the DNA itself to any harm. Once the mRNA makes it outside the nucleus, it can be turned into proteins with the help of two other types of RNA: ribosomal RNA (rRNA), which helps “read” the mRNA instructions; and transfer RNA (tRNA) which brings individual amino acids to the ribosomes and puts them together into functional proteins. Proteins are the building blocks of the cell, making up essential structures and functioning as enzymes to drive different life processes. However, in the course of studying genes, it became apparent that there had to be other molecules that were controlling the type of cells that undifferentiated cells turn into. Something else other than protein was involved in determining gene expression, or which features actually showed up in a differentiated cell.

This is where Dr. Ambros and Dr. Ruvkun’s Nobel-prize-winning work came in. They were studying a gene called lin-4 which inhibited the protein expression of another gene called lin-14 in C. elegans. Proteins produced by lin-14 expression are essential in the normal larval development of the worm. They isolated the lin-4 gene, which was expected to also produce a protein that somehow inhibited lin-14. Instead, they were surprised that, rather than making an mRNA that was translated into a protein, lin-4 coded for short RNA segments that functioned on their own. These short RNA segments from lin-4 interfered with the mRNA produced by lin-14 and prevented production of the lin-14 protein. A gene coding for RNA that inhibited another gene was a novelty, and they initially thought it was just a peculiar trait found only in worms like C. elegans. 

As other scientists continued to study other worm genes, they found another microRNA. The genelet-7 represses the gene lin-41 which is involved in the maturation of the C. elegans worm by producing microRNA. The genelet-7, unlike lin-4, is also present in many other animals. This suggested that the function of microRNA was not just limited to worms but was quite common among multicellular organisms.

The more they looked, the more microRNAs they found. Interestingly, because microRNA blocks the expression of specific proteins in different cells, defects in its expression can lead to the development of some types of cancer. This gave scientists a way to better detect some kinds of cancer, prognosticate which cancers were more likely to respond to chemotherapy and provide a new target for treatment. Robust work on microRNA is ongoing and has transformed the field of molecular biology. These profound changes in our understanding of cellular processes have given better insight into the development of plants and animals, and are helping illuminate some longstanding mysteries of life. Not bad for a tiny worm.