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Introducing the Unknome, Biology’s Black Box

Image credit: Zaeem Nawaz, via Unsplash.

“Ome” is not a mantra in science, but it is an increasingly common suffix in biochemistry, genetics, and molecular biology. We all know about the genome. Then there was the epigenome, followed by the proteome. Now there is the interactome, the metabolome, the transcriptome, and others. More “omes” seem to pop up in the literature from time to time. As in the genome representing the set of genes of an individual or species, the suffix -ome denotes a “body” or set of parts that can be described together: the proteome consists of all the proteins in a cell. The transcriptome is the set of DNA transcripts. The interactome is the set of all interacting parts in a process, and the metabolome is the full complement of metabolites in a cell, tissue, or organism at a particular state. A new one is the “unknome” — the set of all components we know nothing about. More on that later. The -ome suffix has also long been used on individual units like ribosome, cytochrome, cryptochrome, and chromosome. Poets should have an easy time writing verses about biochemistry.

The study of all omes can be called Omics, with family members like genomics, proteomics, and transcriptomics. Omics is not just a taxonomical exercise; it is an attempt to get a handle on the bewildering complexity facing cell biologists. And just when they think they’ve got all the members corralled in an ome, complications set in.

Your Genomes (Plural)

For example, the journal Science announced recently that “Your cells don’t have the genome you were born with.” Contrary to what most people were led to believe by 23andMe, none of us have “a” genome, except at conception. From then on, the genome changes cell by cell, tissue by tissue, throughout life. These can add up to tens of thousands of changes per somatic cell. Modifications to the genome by mutations or by developmental processes turn us into universes of genomes!

As a result, every person is actually a mosaic of genomes, varying across the body and often within the same organ or tissue. These DNA changes introduce a diversity to the body’s somatic, or nonreproductive, cells that may be as important to health as the more pervasive alterations inherited from parents. Now, the National Institutes of Health (NIH) has launched a 5-year, $140 million project to map this universe of genomic diversity — and probe why it matters. [Emphasis added.]

Dan Landau calls this “a huge revolution in human genetics.” He is eager to see the results. “We are just at the beginning of this incredible adventure.”

Omics in 3-D

Another review article in Science announces “The Dawn of Spatial Omics.” The editor’s review says,

All of biology happens in space. In living organisms, cells must interact and assemble in three-dimensional tissues. The position of each cell is just as important as its intrinsic nature in determining how a tissue functions or malfunctions in a disease. Recently, many technologies have been invented to profile cells without removing them from their natural context, measuring gene expression and the regulatory landscape of a cell’s genome alongside its spatial location within a tissue. In a review, Bressan et al. describe the features of these methods, collectively named spatial omics, and discuss what is missing for them to unlock their full potential.

The authors, Bressan, Battistoni, and Hannon, begin with a fanfare: “Just as single-cell sequencing has revolutionized many fields of biology, spatial ‘omics,’ in which molecular parameters are measured in situ on intact tissue samples, is set to empower a new generation of scientific discoveries.” 

Spatial molecular profiling at the tissue level (and sometimes at the cell level) with “multi-omic” technologies will allow researchers to study the genome, transcriptome, and proteome simultaneously in situ within an organ, tissue, or cell. This adds another layer of information that was hidden from earlier studies.

One of the first steps along this journey was the emergence of single-cell “omics” technologies that operate on disaggregated tissues. These methods enabled the discovery of new cell types, cast new light on organismal development, and launched the process of creating comprehensive catalogs of human and mouse tissues. However, biological processes happen in a spatial context, and the three-dimensional (3D) arrangement of cells in a tissue has a profound effect on their functions…. Regardless of their undisputed power, measurements made on disaggregated cells or nuclei lack this layer of information. The need for such knowledge has driven the development of “spatial omics”: methods capable of measuring the molecular characteristics of cells in their native 3D context.

The authors say that “we are at the very beginning of the spatial omics revolution” and that “progress is happening at breakneck speed” that will undoubtedly give scientists “a much deeper understanding of biology in context.”

As an example of the profound effect of spatial and environmental influences on an organism, researchers at Harvard found that specific neurons become active when a mouse makes an error navigating a virtual reality maze. 

The researchers found that when a mouse made and corrected a mistake while navigating, the subtype of neurons became active. This held true even when they guided the mouse to err, either by rotating the maze or changing the color cues. However, if the mouse didn’t make a mistake, or made a mistake but didn’t correct it, the neurons didn’t fire.

When the neurons became active, they did so in unison, prompting a follow-up experiment in which the researchers stimulated the cells with light. They found that the neurons are essentially hardwired to each other, meaning that the electrical current telling them to fire can flow directly from one cell to the next.

Studying these neurons in isolation would not have revealed this concerted, dynamic activity.

Interactome Sentries

Scientists at Leiden University in the Netherlands found that the “cytosolic interactome protects against protein unfolding” with a continuous process of “biological origami at the molecular level.” According to, the

Group leader, Alireza Mashaghi, said, “When a cell experiences stress, a protein can unfold to a completely unfolded chain. Once that has happened, it’s very hard to reverse. But we noticed the cytoplasm puts a break on this process, not allowing the unfolding to go all the way. This protects the proteins and ensures a proper functionality, and also makes it easier for proteins to refold once the stress in resolved.”

The research on this was published in Advanced Biology, “Cytosolic Interactome Protects Against Protein Unfolding in a Single Molecule Experiment.”

Unknome: The Final Frontier

From the Public Library of Science comes word of “The ‘unknome’: the set of gene transcripts we know almost nothing about.” This black box consists of “thousands of understudied proteins encoded by genes in the human genome, whose existence is known but whose functions are mostly not.”

The sequencing of the human genome has made it clear that it encodes thousands of likely protein sequences whose identities and functions are still unknown. There are multiple reasons for this, including the tendency to focus scarce research dollars on already-known targets, and the lack of tools, including antibodies, to interrogate cells about the function of these proteins. But the risks of ignoring these proteins are significant, the authors argue, since it is likely that some, perhaps many, play important roles in critical cell processes, and may both provide insight and targets for therapeutic intervention.

Echoed by, this news says that researchers in the UK are putting together a public database of these proteins that they trust will shrink over time. The Unknome [Unknown Genome] Project has started at The proteins are ranked by how little is known about them, stimulating researchers’ curiosity to find out what they do.

It’s clear that Omics is discovering additional layers of biological information in living systems. Antiquated 1960s-era concepts of genes and proteins, like the Central Dogma, are being overwhelmed by this new vista of multi-dimensional dynamic organization. If the earlier geneticists were looking at a 2-D flat map, the new generation is looking at a thriving city. Old dogmas about Darwinian evolution seem woefully inadequate to understand complexity at this level. Science in the 21st century will require a theoretical framework equipped to handle information flow in time and space. There is one. It’s known as intelligent design.