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Beyond Genes: Biologists Seek Purpose in Unknown Substances, Processes

David Coppedge
Photo: Brassica rapa, by TeunSpaans, CC BY-SA 3.0 , via Wikimedia Commons.

The success of intelligent design predictions about codes and functions should inspire biologists to keep looking for purpose in unknown substances and processes in life. Rather than dismissing them outright, they might find good reasons for them. In some labs, that is happening.

Not All Functions Are in Proteins

The surprise of the non-coding RNAs is a good example. We all remember how non-coding regions seemed to confirm the “junk DNA” hypothesis in the first decade of the 21st century. But then, functions were found for some of them, and the tune began to change. In hindsight, why would molecular biologists assume that function must be restricted to a protein form? RNA molecules can fold and persist in cells. They can do more than simply carry DNA information to protein function.

Molecular biologists classified unknown RNA transcripts into long and short forms at first: the short noncoding RNAs (sncRNAs) and the long noncoding RNAs (lncRNAs), sometimes dubbed long intergenic noncoding RNAs (lincRNAs, pronounced the same). Kyle Palos from the Boyce Thompson Institute at Cornell, under the guidance of Assistant Professor Andrew Nelson, decided to look deeper into what some of them were doing in plant cells. A news item, “The Missing Links: Finding Function in lincRNAs,” tells how Palos and Nelson went on a hunt to find functions within these “enigmatic” and “cryptic” parts of the genome.

Surprisingly, “Up until now, there have been no systematic genome-wide studies that both confirmed DNA sequences that produce lincRNAs and proposed functions for those lincRNAs.” The data gap inspired his team “to take a comprehensive look at the identity, production and function of lincRNAs in four species in the mustard family, including the model organism Arabidopsis thaliana, and Brassica rapa, a species that produces bok choy, turnips and other food crops.” It was harder than expected because they faced a huge classification task first. But the suspicion that function was lurking in the data drove them on.

“This project started small and mushroomed after we realized we couldn’t begin to figure out lincRNA function without having thoroughly annotated genomes to know what lincRNAs were even present,” said Nelson, who is the corresponding author of the paper. “Kyle really led the charge on everything that went into this paper.”

The team hypothesized that lincRNA production and function are limited to certain cell types and environmental conditions. The more common data sets don’t cover that level of detail, “so it’s easy to miss a lot due to limited sampling,” Palos said. “Our comprehensive approach merges a high-throughput, top-level analysis that identifies lincRNAs with a deeper dive into their likely functions, to give the full picture.” [Emphasis added.]

Now That’s the Spirit

And so they looked for lincRNAs within 20,000 publicly available transcripts from the four mustard species and found thousands of them. Then they tried to figure out what they were doing. 

They assigned putative functions to the lincRNAs based on their similar expression patterns to protein-coding genes with known functions. Next, the team deleted a subset of lincRNAs that appeared to play roles in seed germination and development in Arabidopsis, which led to reductions in germination, thus validating their approach to determine lincRNA function.

The results so far have been published in The Plant Cell, but the work is only beginning. The BTI team plans to expand their searches into other crop species, like rice, maize, sorghum, millet, and more. Now, too, their “unified approach to gathering and annotating lincRNA data … could be easily adopted by other groups.” Is this hunt for function a mere academic exercise of interest only to lab geeks?

“Plant genome research often falls behind mammalian research, but with lincRNAs, we’re still very much in the dark across all species,” Nelson said. “Researching lincRNA in plants could have an impact on human health and crops alike, by helping us understand their fundamental properties, regardless of the species.”

Decision-Making Skills in Cells

Is it logical to attribute reasoning and decision making to cells? Well, ask if it is logical to attribute it to autonomous robots, like the rovers on Mars. Watching a rover in action might lead an observer to suspect that the whole is greater than the sum of its parts. Biochemists at the University of Zurich say, “Individual Cells Are Smarter than Thought.”

Humans make decisions based on various sensory information which is integrated into a holistic percept by the brain. But how do single cells make decisions? Much more autonomously than previously thought, as researchers from the University of Zurich have now shown. Cells base their decisions not only on outside signalslike growth factors, but also on information they receive from inside the cell.

When we humans integrate external cues coming in through our senses and from internal information, it’s called multisensory or multimodal perception. All that information is integrated into a holistic picture on which we base our decisions. The Swiss researchers say that’s what cells do. 

Single cells are no different than humans in this regard. They constantly make important decisions, such as whether to divide or not. Researchers at the University of Zurich (UZH) therefore extended the concept of contextual, multimodal perception found in humans to individual cells. And surprisingly, they found that single cells make decisions much more autonomously than previously thought.

More on this can be found in the paper by Kramer et al. in Science, “Multimodal perception links cellular state to decision-making in single cells.” They call it “cellular information processing” that can lead to “state-dependent decisions.” Bernhard Kramer comments,

“For any specific decision of a cell, all outside signals and internal cues have to be viewed in concert. Single cells are thus able to make adequate context-dependent decisions — and are therefore clearly smarter than previously thought,” says PhD candidate [Bernhard] Kramer.

This ability within a single cell exceeds the capabilities of the genome alone. A library does not make decisions. It only supplies information that the living being uses. The reductionism inherent in genome-centric thinking must give way to these more holistic concepts.

Not to Be Underestimated

Those were heady days in the age of genes from the 1950s to the Human Genome Project of the early 2000s. Biologists felt confident that they had revealed the secret of life. Now, we are peering beyond genes into integrated living systems. The wonder of a tiny cell being able to make autonomous decisions based on a holistic percept of its internal and external states rightly arouses our awe. Biologists will never again underestimate the living cell.