Dibs on a RNA Computer!

I’ve given DNA a lot of love over the years -- DNA as a storage medium, as a computing platform, as the basis for robots, as the tool for synthetic biology/biohacking, even used for the DNA-of-Things (DoT).   DNA is the basis for all life as we know it, in every category of life we’ve found anywhere on earth. That we are now using it to achieve technological goals seems like one of humankind’s greatest accomplishments.

But where’s the love for RNA, DNA’s putative ancestor and still-partner?  A few recent developments in RNA caught my eye that I wanted to give their due.

As you may remember from high school biology, RNA has a crucial role in how DNA transmits genetic information.  As one source explains it: “DNA holds information, but it generally does not actively apply that information. DNA does not make things.”  Instead, it transcribes the information onto RNA, which then actually makes things happen. 

Just last week researchers from Northwestern University were able to show RNA switching genes off and on, using a simulation model they “affectionately” call R2D2 (short for “reconstructing RNA dynamics from data”).  The researchers believe the “strand displacement” mechanism is what switches genes “on” or “off.” 

Professor Julius B. Lucks, who co-led the research, believes: “Many diseases are likely caused by something going awry at the RNA level.  The more we know about this, the better we can design RNA targeting drugs and RNA therapeutics.”  For example, genes could be “engineered to turn “on” in the presence of an environmental contaminant.” 

Amazing stuff.  But that’s not all. 

Researchers at the University of Tokyo have created an RNA molecule that can not just replicate but evolve.  There has long been a hypothesis, called “RNA World,” which speculates that RNA is the basis for the origin of life, with DNA coming along at some later point (DNA is believed not to be stable enough to survive, much less evolve, in the primordial environment).  The research makes that hypothesis even more plausible.

The team seeded an RNA molecule, which evolved into several lineages before stabilizing: “The final population, comprising five RNA lineages, forms a replicator network with diverse interactions, including cooperation to help the replication of all other members.” 

The results were somewhat surprising, even to the researchers.  “Honestly, we initially doubted that such diverse RNAs could evolve and coexist,” said Ryo Mizuuchi, corresponding author of the study.

We will probably never know how life on earth actually emerged, but the researchers claim:

Our results demonstrate an evolutionary transition scenario of molecular replicators from a single common ancestor to a multi-membered network…Thus, our simple experimental setup offers a unique approach to deeply look into evolutionary phenomena.

OK, that’s two long-time mysteries answered, or at least addressed, by RNA.  Here’s an even more fun one: RNA computers.

There has been discussion of DNA computers for many years.  However, as NIST (National Institute of Standards and Technology) says:

Tiny biological computers made of DNA could revolutionize the way we diagnose and treat a slew of diseases, once the technology is fully fleshed out. However, a major stumbling block for these DNA-based devices, which can operate in both cells and liquid solutions, has been how short-lived they are. Just one use and the computers are spent. 

Instead, in a new paper, NIST researchers used RNA to build computers.  Or, more precisely:

Here, we develop scalable cotranscriptionally encoded RNA strand displacement (ctRSD) circuits that are rationally programmed via base pairing interactions. ctRSD circuits address the limitations of DNA-based strand displacement circuits by isothermally producing circuit components via transcription.

Samuel Schaffter, the lead author and a NIST postdoc researcher, explained how DNA and RNA computing differs from typical computing: “The difference is, instead of coding with ones and zeroes, you write strings of A, T, C and G, which are the four chemical bases that make up DNA.”  The authors tested whether the RNA-based circuits could perform logical operations (I won’t even attempt to describe exactly how they did this).

Credit: Shaffter and Strychalski

Dr. Schaffter said: “For me, these needed to work in a test tube as predictively as DNA computing. The nice thing with DNA circuits is most of the time, you can just write out a sequence on a piece of paper, and it'll work the way you want. The key thing here is that we did find the RNA circuits were very predictable and programmable, much more so than I thought they would be, actually.”

The authors are quite excited about future applications.  E.g., “We envision ctRSD circuits enabling many new applications in nucleic acid computing and synthetic biology. For example, the inclusion of ribonucleases in ctRSD circuits would allow continuous circuit turnover. Circuits could then respond multiple times to changing input signals, overcoming a current challenge in DNA computing.” 

As for the next step, Dr. Schaffter sees: “We’re interested in putting these in bacteria next. We want to know: Can we package circuit designs into genetic material using our strategy? Can we get the same sort of performance and behavior when the circuits are inside cells? We have the potential to.”

I can’t wait for Raspberry Pi to come out with their RNA-based computer.  You watch.

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All this sounds very esoteric and perhaps not applicable to the immediate woes of our healthcare system, but I’m thinking about the rest of the 21^st century and beyond.  As I’ve said before, the 20^th century may have been the age of computers, but the 21^st century is going to be the age of biology.  

If we believe that the 20^th century ushered in “modern medicine,” with more rigorously trained professionals using more scientific tools (think antibiotics, imaging, laparoscopic surgeries, A.I., etc.), then 21^st century healthcare is going to be about synthetic biology.  Thinking about DNA and RNA isn’t going to just be something healthcare professionals do to satisfy their undergraduate requirements; it’s going to be integral to their toolset.

What’s going to be very interesting – and highly disruptive -- is not just how this change will impact our health and our healthcare, but also what happens to physicians, nurses, pharmacies in a world where biologists/biochemists/geneticists may play the more important role.