Reaching the smallest unit of life

What does it mean to be alive? That is a question familiar to first year biology students who learn a series of definitions that usually have something to do with being able to reproduce, pass along genetic material, and use energy to do things. Subsequent classes will of course contradict the simple definitions with mention of viruses and other oddities like horizontal gene transfer. A new study out in bioRxiv last week details the discovery of a completely novel form of life that consists of just a single RNA molecule that is only ~1kb long. How is that even enough to be considered “alive”s this just some artifact produced in the microbial communities where it was discovered? How does it even work if it doesn’t make its own polymerase or anything that even resembles a cell?

Predicted rod-like structure of the Obelisk genome. Base pairing and circular structure (below) combine to create this linear superstructure.

Model of circular obelisk genome showing two oblin genes and base pairing (chords).

The new discovery, termed “Obelisks” for their rod like folded RNA structure, was found in deep sequencing produced for human gut microbiome studies. These phylogenetically distinct minimalist genomes contain just two genes that code for never before seen proteins that share no sequence homology with other known DNA, RNA, or protein (in the NCBI nt, nr, CDD, Pfam).

Despite this there appears to be a variety of obelisk genomes floating around the global microbiome. Researchers surveyed more than 5 million microbiome samples and found 29,959 obelisk genomes that all share ~90% sequence identity suggesting that these are capable of undergoing evolutionary processes to maintain a diverse but unified population. Further, researchers describe a global phylogeny of related Obelisk types with some genome modifications and adaptations to a variety of microbiome communities (below).

So how do these things get along if they don’t appear to have any cellular machinery of their own? There seems at least one known bacterial host observed from laboratory cultures, Streptococcus sanguinis, but likely other bacterial species as well. Much like viruses these Obelisk RNAs must be able to co-opt the polymerases of a host to replicate.

Obelisks may not check all of the boxes of being alive, but they represent a truly unique branch of life and may illuminate the origin of more complex life by illustrating how a simple organic molecule can exist in a stable form and propagate genetic material in the simplest form.

Citation:

Zheludev, I., R. Edgar, M. Lopez-Galiano, M. de la Peña, A. Babaian, A. Bhat, and A. Fire. 2024. Viroid-like colonists of human microbiomes. bioRxiv https://doi.org/10.1101/2024.01.20.576352.

Statistics: A Dying Art

AI is making traditional statistics irrelevant.

This is a statement I have been hearing and reading about. The premise is that AI models perform so well at predictive analytics that the traditional statistical models are only still used because it is what people know and that statistics has no real value in the modern world of AI driven analytics.

I disagree...

Fundamental statistical theory is and will continue to be a useful tool for data work. The basic models and all of their assumptions and shortcomings will continue to help people learn about and understand the data they work with. This is because these models are relatively simple mathematical abstractions of real probabilities. When our mathematical assumptions differ from reality this can be observed and understood through the models we apply. With the tools of statistics we can test hypotheses and build predictive models that reinforce how we look at and interpret the data. Are we always right? Of course not! (Lies, damn lies, and statistics! If only Mark Twain new about the coming of AI)

The analogy that I like to draw here is to compare a CNC machine to a modest chisel. The CNC (computer numerical control) machine is sort of the opposite of a 3D printer, it cuts material down very precisely following digital instructions. In theory it can make just about any 3D object and is popular for manufacturing wood products (there are also metal machining versions that operate with the same principles). The chisel on the other hand is about the simplest of tools; it's made of steel and one end is sharp. A skilled craftsman can use a chisel to make just about anything with a combination of precision, the proper application of force, and patience. Guess which tool is in more workshops around the world?

The CNC machines do not make chisels obsolete. I'm not even sure how much they compete with one another in the end. People reach for the tool that suits their needs and skills. AI and statistics, I think, share the same fate. Both will continue to be valuable in data analytics. Both will drive exploration and insights. The careful application of the modest tools of statistics will always have their place in my shop.