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Nothing Fishy Here: Researchers Explore Use of Human Biomarker to Study Head Injuries in Salmon

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Researchers at Pacific Northwest National Laboratory are fishing for an answer.

In what they say is the first study examining a human-based biomarker to assess risk management in non-humans, researchers at PNNL recently applied alpha 2-spectrin, a protein biomarker associated with traumatic brain injuries in humans, to juvenile salmon.

In an article published Feb. 13 in PLoS One, the researchers described how they used the biomarker to evaluate head injuries sustained by salmon as they navigate through man-made structures such as hydropower plants and dams on their way to the ocean.

Eventually, they hope to develop an assay based on the biomarker that hydropower operators can use to evaluate how their facilities may be affecting the survival of fish populations, especially those that may be endangered.

Research by others involving rats has shown that in cases of head injuries, alpha 2-spectrin levels increase, and Banyan Biomarker is investigating the use of the biomarker for humans as part of a clinical study funded by the US Department of Defense. The Florida firm is developing an assay to help doctors diagnose traumatic head injuries.

It was that work that got Ann Miracle, senior research scientist at PNNL and the corresponding author on the PLoS One study, curious about whether it had any relevance for salmon.

Along the Pacific Northwest's Columbia Basin, where PNNL is situated, 13 different salmon and steelhead populations are endangered, according to the laboratory, and debate is rampant about the role that hydropower plants may play in the fish's survival. Along the Columbia River and lower Snake River, there are about 15 hydropower dams, and some believe that they pose significant risk to the fish due to injuries resulting from impact with spillway structures and turbines and hydraulic forces associated with spill and sudden depth changes.

salmon2.jpgRecent studies have shown that salmon that have been exposed to high shear and turbulence not only suffer direct injury but also are more susceptible to predation than fish that have not had such exposure.

"There are a lot of interest groups that are concerned that the fish, as juveniles, as they migrate through the different dams … might be compromised in some way as they have to go through different structural passages that are constructed to help them pass safely through the dams," Miracle told ProteoMonitor recently.

Typically, evaluating salmon for possible head injuries involves looking for signs such as hemorrhaging around the eyes, scale loss, abrasions, and missing fins or eyes. The fish are kept for 48 hours "to see who dies," Miracle said.

However, such observation provides only limited information, and no information about long-term effects. "We don't know about delayed mortality, and we don't know how the fish [may be] compromised: Are they able to still avoid predators? Do they still have the correct swimming reflexes? Do they feed?" Miracle said.

"Now that we've used the biomarker to look at these, we actually see a high amount of expression in some fish [that] don't show any external injury at all," she added. "So these might be fish that would be compromised and might be a greater risk for predation somewhere downriver."

While veterinary and livestock medical procedures have often been taken from human health, the use of human-based biomarkers for animal-related studies is unusual. In their case, Miracle and her co-researchers were forced to use a cross-species approach because so little is known about the protein sequences of fish, although Miracle said there is a growing movement to sequence the genomes of fish other than zebrafish, whose genomic sequence is already known, "so that we can start using more sophisticated approaches in trying to come up with biomarkers."

Biomarker research in livestock health, in general, has been limited to analyzing the effects of chemical and biological exposures, she and her colleagues said in their study.

"No one's really used a clinical biomarker to say something about potential ecological risk assessment," Miracle said.

Prior work by others looking at rats has shown increased levels of certain alpha 2-spectrin breakdown products, or SBDPs, following traumatic brain injury. In the current study, authors found that salmon brains that had experienced spillway force-induced brain injury "robustly produces SBDPs parallel to those produced by their mammalian counterparts."

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The degree of physical injuries observed in the fish showed correlation with the presence of one breakdown product in particular, SBDP120: increasing expression of SBDP120 corresponded with increasing visible injury, Miracle and her colleagues wrote.

"Based on the known mammalian expression pattern, the increase in expression is hypothesized to be evidence of apoptotic breakdown of intact alpha 2-spectrin, a likely event that would occur following physical trauma to brain tissues," they said.

'Blunt Force Trauma'

To be sure, because the researchers are making conclusions about salmon based on what has been observed in mammals, any results are educated guesses. In their paper, they wrote, "Without a complete alpha 2-spectrin sequence in salmon, these [results] remain assumptions."

Miracle also acknowledged that "it's a hard correlation to draw between fish and humans in terms of overall levels of harm." The research, however, lays out a "framework for the biology — first of all, why we think this is similar to the human traumatic brain injury biomarker, and a similar approach to how it might be used in this case," she said.

Rather than trying to find a new biomarker, a course much proteomics work has taken, she said it made more sense here to work with an existing candidate biomarker and "just apply it in a completely different way. And it was something that was easily translatable … a blunt force trauma injury to the head is a blunt force trauma injury to the head."

She and her colleagues, however, were careful not to ascribe human traits onto the salmon or interpret results in ways that might not be true for the fish. In particular, Miracle said, she and her team stayed away from any prognostic interpretations.

In humans, studies suggest that the amount of alpha 2-spectrin expressed and the duration at which the fragments are present may be indicative of the severity of the trauma.

"I'm not making any assumptions with fish," she said. "We really don't understand how exactly the [fish] brain works necessarily, how resilient it might be." Indeed, in their research, she and her colleagues saw a "background level" of SBDPs even in control fish, a finding that puzzled them until they came across research that described a perpetual neurogenesis process that fish brains undergo throughout their lives.

"A lot of that process is apoptotic, which once we had looked at those studies we realized that was exactly what we were seeing in our fish," she said.

As they look to developing an assay, the researchers are trying to get at more salmon-specific antibodies. For their study, they used an antibody that was developed for use with rats and mice. While it reacts well with salmon, "it's just that we don't have exactly the same breakdown products," Miracle said.

"What we'd like to get down to are very specific antibodies that just detect specific breakdown products, something that's very clean so that we can go to something like an ELISA format and have something that's a quick screening tool … that would be more user friendly for the folks that are operating at the hydropower plants," she said.

They also are exploring the potential of other human-based biomarkers that might be translatable to fish for the evaluation of blunt force head injuries, though Miracle did not identify them. While alpha 2-spectrin undergoes clinical trials, she and her team will be looking for information from the trails they think may be of use for their purposes.

"The more corroborating evidence that we have, especially as we're trying to link this to risk of mortality, the more confident that we'll be able to be out in the field and use this in a way that will actually help protect the species," Miracle said.

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