Photo: Department of Laboratory Medicine

Slimy, disgusting and useful

Medical researchersconduct cancer research on a primitive fish, and make astonishing finds.

The hagfish dwells in the cold depths and pitch black darkness at the bottom of the sea. It burrows in the mud and waits, nearly invisible, for the dying and dead fish that are its food. Fishing nets with their imprisoned fish provide a particularly appetizing feast for this mud dweller. And if you disturb it, it sends out a great cloud of sticky slime.

This jawless slimy creature may be revolting, but don’t be too disgusted: hagfish are our distant relatives.

Mysterious reproduction 
“The hagfish belongs to the roundmouth family, and lies on the same evolutionary line as humans”, says Professor Emeritus Sture Falkmer at the Department of Laboratory Medicine, Children’s and Women’s Health at NTNU. “The species has been around for 500 million years, and was among the first that developed something that was the beginning of a vertebral column. Its other anatomical structures are also quite ‘primitive’, but are also found among the higher vertebrates”.
Falkmer says the hagfish’s unusual features have interested scientists since the 18th century. Early research pioneers were all Scandinavian; among the most famous was Fridtjof Nansen. Yet much about the hagfish remains to be discovered, he said. For example, it’s still a mystery how the hagfish reproduces.

“One hundred and fifty years ago, the Royal Danish Academy of Sciences and Lettersannounced an award to anyone who could uncover the secret”, Falkmer said. “The award has not yet been claimed”.

“A pea-sized lump” 
Falkmer has studied this strange creature since the 1960s, when he was fresh out of medical school. His first encounters were as a result of diabetes research at the University of Uppsala. The project involved studying the production of insulin, which takes place in a group of pancreatic cells known as the islets of Langerhans. Falkmer and his colleagues studied these cells, first in vertebrate fish and later in hagfish, and compared their findings with the condition in humans. Along the way they made surprising and remarkable findings.

Hagfish produce insulin in a tiny organ called the islet organ, which lies on the wall of the bile duct where it opens into the bowels. This insulin is the most primitive of all known. Researchers eager to conduct biochemical analyses on this kind of insulin had to collect samples from tens of thousands of hagfish to come up with just one gram of insulin.

“As we were doing this, we noticed that some of the hagfish had strange knots in their livers. Some were the size of a pinhead, others the size of a pea. Closer examination revealed them to be tumours, mostly liver cancer”, Falkmer said. “For the first time ever it was scientifically established that even primitive species can develop cancer”.

Poisoned food 
The finding led to a systematic investigation. Researchers subsequently detected cancer of the liver or the insulin-producing organ in between one and eight out of every hundred hagfish, a cancer rate far higher than had ever been measured before in animals or humans. The hagfish were caught near the mouth of the Gullmar fjord in Sweden, and out in open sea. Every single hagfish that had cancer had been caught in the Gullmar fjord. As the investigation continued into the early 1970s, researchers found yet another surprise: the number of tumours had dropped dramatically. Eventually the tumours disappeared.

But why? Falkmer thinks he knows the reason. During the course of the investigation, sewage treatment plants were built in the Gullmar fjord, and Sweden banned the use of chlorinated pesticides and chemicals such as DDT and PCBs.

“The hagfish is a bottom dwelling scavenger”, Falkmer said. “It is easy to conclude that they developed cancer from eating fish that had died as a result of pollution”.

Modern-day canary 
The link between liver cancer and pollution is one that is highly debated. Hagfish, like humans, feed at the top of the food chain. Falkmer thinks that makes hagfish a good indicator of pollution levels in the sea. He sees the hagfish as a kind of modern-day canary in a coal mine. Just as canaries were used by miners to detect toxic gases in mine shafts, hagfish could be used to detect carcinogenic substances in the environment, Falkmer says.

Primary liver cancer in humans is uncommon in Western Europe, but is relatively common in Africa and China. Falkmer said his work with hagfish makes him think that polluted food may be part of the problem.

“This relationship has been explained by geographical differences in nutrition and infection rates”, he said. “That liver cancer is common in animals eating polluted food strengthens the hypothesis that bad food could be one of several reasons for this disease”.

Eating your research subjects 
Falkmer and his research colleague Kåre Emil Tvedt at NTNU have studied digestion and hydrochloric acid production in hagfish. Kidney researchers have looked to unlock the secrets of human kidney development by studying its primitive relative in the hagfish. Neuroanatomists have studied its brain.

“Organ development in earlier stages of evolution can tell us something about our situation today”, Falkmer says. “We need to see how anatomical structures and physiological functions work, even in their most primitive forms. The demands on an organism to survive makes for constant development and change”, Falkmer says.

Even after 50 years of research, Falkmer is still fascinated by the hagfish. He’s even eaten his research subjects, once as a casserole, with a garnish of hagfish eggs. “Not particularly tasty”, he admits.
Hagfish may taste bad, but their skin is durable and strong. Falkmer even has a wallet made from the stuff.

Gooey, but predator-free

The hagfish’s Latin name, Myxine glutinosa, comes from the Greek myxa, meaning mucus, and the Latin gluten, meaning glue. The name underlines the hagfish’s unique ability to respond to stress by quickly extruding a thick, protective layer of slime around its body. It can tie itself in knots and squirm free of this gooey cloud to avoid suffocating in its own slime. Researchers think this characteristic means that the hagfish probably has very few enemies. If a predatory fish decides to try to eat a hagfish, it will find itself with a mouth full of -slime.

Chewing the slime causes it to expand, eventually asphyxiating the fish. The slime is actually ‘armed’ with fibres half a meter long. Each fibre is just a thousandth of a millimetre thick, but very strong. Researchers have been trying for years to unlock the secrets of exactly how the slime fibres are put together. The answer could lead to new synthetic materials with great strength.

The hagfish dwells in most Norwegian fjords and can grow to be 40 centimetres long and as thick as a thumb. Related species can be found in all the world’s oceans where the water is at least 20 meters deep and the bottom is muddy.

The hagfish was first described by the Swede Per Kalm in “En resa till Norra America” (A Journey to Northern America) in 1753. Kalm began the journey from Uppsala in 1747, travelling at the request of Carl von Linné. Boat repairs delayed the party in Grimstad at the very beginning of the trip. Kalm discovered the hagfish during the delay, but thought it was a blind lamprey. He wrote down his observations, and shared them with Linné. Linné corresponded with the Norwegian Bishop and naturalist Johan Ernst Gunnerus about this strange creature. Gunnerus first wrote about the hagfish in 1763, calling it a Sleep-Marken. Both Gunnerus and Linné classified the hagfish as a worm. But in 1790-1792, however, it was found to be its own species in the roundmouth family under the name Myxine glutinosa.

Photo: Rudolf Svensen