An important industry
Fishing is Norway's second largest industry after oil and gas and plays a major role in Norwegian culture. Farmed fish, especially Atlantic salmon, are a growing part of this industry. But fish grown in farms are often plagued by health issues and too many of them are lost during smolting, the transition from fresh- to salt-water living. There is a lot of work left to do to make this industry sustainable and successful in the long term.
Professor Andreassen was part of the team that first studied the salmon genome. His recent work focuses on understanding not just the genetic instructions within cells, but how those instructions interact with each other to produce the right response to disease or the environment. He knows that one of the keys to improving aquaculture lies in the genes.
Instructions and counter-instructions
The nuclei of salmon cells — and those of most animal and plant cells — are filled with long strands of DNA that contain all the information needed to build healthy bodies as well as respond to threats like diseases.
In most cases, when a cell needs to make a protein, those instructions are copied from the DNA into "messenger-RNA" which the cellular machinery can understand and use. Scientists have studied this process to identify and treat many diseases. It even forms the basis for the Pfizer and Moderna Covid-19 vaccines.
But in the century since the discovery that these instructions are stored in DNA, researchers have struggled to understand how cells know which instructions to follow at any given time.
The answer lies in “non-coding” sequences, mRNAs that don’t make proteins. These sequences have confounded scientists for a long time: why would cells use energy to make mRNA that doesn’t produce proteins?
It turns out that while some of these non-coding mRNAs are in fact useless bits left over from viruses, others can play important regulatory roles in the cell. These are an essential part of making sure that cells produce proteins in the right amounts. For example, in humans a long non-coding RNA named Xist helps inactivate one of the two X chromosomes in genetic females.
It's the little ones
Until recently, scientists thought that only the longer mRNA strands were useful and assumed that the small ones were “junk RNA” that couldn’t do anything. Andreassen explains that "in the early days, we thought the small RNAs would interfere with our results, so we would just throw them away".
However, about 20 years ago, researchers discovered that some of these small non-coding RNAs — "micro-RNAs", or miRNAs — play an additional important role in regulating which mRNAs are activated.
There are two steps to regulating how much protein a cell makes: the first is whether DNA is transcribed to mRNA which determines which proteins are made. This step has been known for decades and studied in detail.
The second step is a new discovery.
"The miRNA are involved in regulating nearly all the different development processes in salmon, and also in fighting disease" says Andreassen. The tiny miRNAs select which mRNAs get to make proteins.
Even more exciting, these miRNA sequences are mostly the same across all vertebrate animals. A discovery in salmon, in other words, could also be relevant for other species, like humans.
Getting the data
Andreassen was one of the first researchers to start looking at miRNA in salmon back in 2013. His research team brings together researchers with expertise in biology, genomics, bioinformatics, and of course, fish diseases. Andreassen also partners with researchers at NOFIMA and the Veterinary Institute / Veterinary School as well as with international collaborators in Scotland and Canada.
The researchers set up what they call a "challenge experiment" to figure out which miRNA helps the salmon fight disease. In this experiment, they expose part of a group of healthy salmon to a virus or bacteria and measure how the miRNA changes. The different miRNA levels in the healthy and infected salmon indicate which miRNA are involved in the disease response.
Finding the targets
This is where the difficult part of Andreassen’s research really begins. There are hundreds of miRNAs in the cells, and as many as 20-40 of them will change levels in response to disease. Each of these could potentially affect up to a thousand mRNA targets.
To narrow down this huge set of possibilities, Andreassen uses computer models to identify likely targets and performs focused tests to confirm the computer results.
Over the next few years, he expects to identify the miRNAs in salmon that respond to infectious diseases and the genes they regulate. So far, he has found a small group of miRNAs that are important in several different viral and bacterial disease responses. This might mean that instead of the salmon producing tailor-made miRNA for each disease, it relies instead on a group of key miRNAs to regulate all of its immune system responses.
In a similar experiment, Andreassen and his team are identifying the miRNA that help salmon adapt to seawater. There are certain miRNAs that respond to this developmental transition; they change their expression when the fish migrate from freshwater to seawater. Understanding these miRNAs could lead to new techniques that improve overall salmon health and aquaculture yield.
A better dinner
Andreassen's findings will eventually change how farmers manage aquaculture. This could mean being able to select for fish with genetics that make them more resistant to infectious diseases or treatments to improve smolting survival. In the future, researchers could even use methods like CRISPR gene editing to directly modify the miRNAs for improved functions.
This ongoing research into how miRNAs regulate disease response and adaption to seawater will benefit all research related to salmon, whether wild or farmed. In the end, this will mean better, healthier, and more sustainable salmon for our dinner tables.
Andreassen’s research is funded by a grant from the Norwegian Research Council (NFR 280839).
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