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Worm Spit May Lick Liver Cancer

Thai liver worn under microscope

ABOVE : A section of the Thai liver worm in the bile ducts within the liver, where it grows to adulthood and lives for decades.


By MICHAEL SMOUT

UPDATED:  

A liver worm is responsible for 26,000 cancer deaths every year, but a component in its spit could form the basis of a vaccine - and could even help to heal chronic wounds in diabetics.

A hidden killer resides in the rural regions of north-eastern Thailand - a parasitic worm infection spread by eating uncooked fish. This parasite is the Thai liver worm (Opistorchis viverrini), and it kills 26,000 people every year by inducing a deadly, mostly incurable liver cancer.

No cancer is ever good, but the variety of liver cancer the worm causes - cholangiocarcinoma - is especially aggressive and has a horrible life expectancy rating of 1. This means that a patient commonly won't survive more than 1 year after diagnosis.

Opisthorchiscauses cancer in one-sixth of infectcd patients. This is remarkable when compared with other high-impact cancer-causing pathogens such as the human papillomavirus, which causes cancer in less than 1% of infected individuals.

Opisthorchis predominantly infects the Isaan people of north.east Thailand, Laos and Cambodia, who share traditional meals of fermented (pla ra) or raw (koi pla) freshwater carp. (Don't worry, your sushi/sashimi is safe from this parasite as ocean fish don't get the infection.)

Although it will infect anyone who consumes the under-cooked fish, three decades of Thai education campaigns and treatment programs have begun to limit infections to more remote regions and older generations who are resistant to change. Although these programs have only begun to move across borders, neighboring countries with Isaan populations such as Laos, Cambodia and Vietnam still suffer from very high infection rates.

As a parasite, killing your human host is far from ideal - especially as the worm can live for decades. In fact, the cancerous transformations usually take more than five decades to develop, so this is only a minor issue for the parasite. A happy home for five decades is pretty good for any species.

Why Is It Causing Cancer?

We don't know why the parasite causes cancer, but we suspect it may be killing with kindness - trying to be a good house-guest by supercharging the healing of the wounds it causes each day by munching on your liver.

How might this happen? Well, imagine yourself as a car driven by a parasitic worm who is always running late (causing wounds) and always drives fast to compensate (worm-initiated supercharged healing). This is all fine when the car is new (the early decades of life), but eventually the constant high speeds (supercharged healing) can cause unnoticed minor damage (DNA mutations). Normally a mechanic (DNA repair) would fix the minor damage but the worm driver never stops for repairs (worm inhibition of DNA repair systems). Eventually there may be enough damage (mutations) to the car that a catastrophic failure occurs and the car crashes (cancer).

This crash may take decades to eventuate, if it occurs at all, but the chances of crashing are much greater when the worm drives fast. In other words, the worm creates an environment that promotes the likelihood of cancer by constantly wounding the host and supercharging repairs while overriding DNA repair systems. In the short term this healing reduces the worm-induced damage, which is good for the worm, but in the long term it may kill the host with an aggressive cancer.

Additionally, the type of car (a patient's genetics) matters, as a Ferrari can handle extreme driving conditions far better than a Datsun 120Y, so long-term damage (DNA mutations) and chances of crashing (cancer) will be less in the Ferrari.

Investigating the human side of the equation for infection-derived cancers is incredibly complex, but new genome - sequencing technologies are making it cheaper and more feasible every day - so it will be a while yet before we can tell if infected patients have "Ferrari" or "Datsun" genetics that predispose them to cancer.

Evading the Immune System

Thai fish worm cycle

TOP RIGHT : The lifecycle of cancer-causing liver worms.

BOTTOM RIGHT : The infective cyst stage (lifecycle stage 4) found in freshwater carp. When eaten, the encysted parasite (blue arrow) dissolves and the larval worm (red arrow) crawls up into our livers.

Developing new vaccines is really tough, especially when the target is a parasitic worm that can twist our immune system for its benefit and even remain effectively invisible to our systems.

For some invaders, like the flu, the challenge is fighting a constantly changing enemy that looks different every year - hence the need for a new flu shot each year. But the parasitic worms we study can live within your guts for decades without major changes and yet still evade our immune system.

Our understanding of how they can dodge the immune system is varied depending on where the parasite resides, but no matter what tricks the worm uses, a good vaccine can reveal the parasite invader and unleash the full power of our immune system to destroy it.

I think about worms as a Special Forces soldier hiding in the forest. They will wear green mottled clothcs with camouflage patterns, and to blend in further they will cover themselves in the local environment with items such as twigs and leaves. To the eyes of a sniper this soldier is effectively invisible, but the soldier is only hidden to visible light. By adding a thermal vision scope to the sniper's arsenal he can easily target the invading soldier.

In this example the worm (soldier) is hiding in the human host (forest) and wears an outer layer looking like the host's proteins (green mottled clothes) and will additionally cover itself in the host's proteins (twigs and leaves) to be effectively invisible to the immune system (sniper). But a vaccine (thermal scope) allows the immune system to target the worm and fight off the invader.

A Vaccine from Worm Spit

Thai fish bacteria

TOP RIGHT : The catch of the day may be infected with metacercaria.

MIDDLE RIGHT : Local warning signs inform the population not to eat raw fish!

BOTTOM RIGHT : The fish is mixed with chili and herbs to make delicious meals of koi pla (raw fish dish) or pra ra (fermented fish dish).


As parasitic worms are masters of evasion, diversion and camouflage, our immune systems often cannot effectively fight them.

However, we believe that components of the worm's spit (the various secretions of the worm) might be a chink in their immune-evading armour. The worm spit plays a variety of roles, including immune manipulation and digesting food, and is critical for the worm's survival.

One major effect of worm spit in the human host is that cells are driven to multiply quicker than they normally would, and this excessive constant cell growth can be a key stage in the initiation of many cancers.

My research has focused on cell growth induced by worm spit, and has identified the major growth component as a molecule very similar to human granulin - a growth factor molecule involved in early development, wound healing and many aggressive human cancers from a wide range of organs. We have produced worm granulin in the laboratory and found that, like worm spit, it induces excessive cell growth.

In addition, antibodies against worm granulin block the ability of worm spit to cause excessive cell growth. This demonstrates that the worm granulin is the major growth-inducing protein secreted by the worm.

Furthermore we have shown that preventing the worm from making granulin is very detrimental to the parasite's health.

The reason why the worm is causing cells to grow prolifically is unknown, but we suspect it may be farming the cells for nutrition or twisting the immune response in its favour.

Either way, our work suggests that this granulin molecule may be the "thermal scope" we need to reveal the invisible invader to our immune system.

But even if using granulin as a vaccine doesn't stop the parasite, we expect it to prevent the pathology of the infection: blocking the excess cell growth that the worm induces will drastically limit the initiation of cancer. Knowing this, we are investigating how to use the granulin molecule as a vaccine to hopefully help the nine million infected people in South-East Asia.

Healing Chronic Wounds

Our work may not just be beneficial for infected patients. Granulin has potent wound-healing properties, and we are exploring its application as a treatment of wounds that don't heal - an increasing problem for smokers, diabetics and an ageing population.

While it may not be added to band-aids any time soon, granulin has great potential to help chronic wound sufferers by overriding the roadblocks to wound healing experienced by sufferers of diabetic ulcers and other restricted wound-healing conditions.