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Big feat solving Little Feet's

In the Portuguese town of Póvoa do Varzim, Little Feet's disease (doença dos pezinhos), is an endemic problem affecting many families. The name may sound cute, but it's a neurodegenerative disorder that is deadly.

Structural representation of the transthyretin protein. FAP is triggered when this protein clusters in a person's peripheral nervous system. Image courtesy Carlos Simoes.

The term 'Little Feet' comes from the disease's first symptom: numbness and tickling of the feet. It's a rare genetic disease, belonging to a group called the Familial Amyloid Polyneuropathies (FAP), and is triggered when an aggregate of protein and fiber, called 'amyloid', cluster in a person's peripheral nervous system, killing and degrading neuron cells.

Symptoms of the disease start with loss of sensitivity to pain and temperature in the lower limbs. Then it expands to the rest of the body, and the only way to prevent a patient's death is a liver transplant.

Volunteer computing

The AMILOIDE project was set up to combat the disease. Its goal is to use people's computers globally, combined with a network called the volunteer desktop grid e-infrastructure, to search for small organic molecules capable of preventing neurodegenerative diseases.

AMILOIDE is the first Portuguese scientific application to be implemented with Ibercivis, a citizen-science distributed computing platform. Initiatives like this are essential in fighting well-known Alzheimer's and Parkinson's diseases and other lesser known conditions, such as Little Feet's.

There are no known cures for Little Feet's disease, although some compounds have shown promising results. But the task of finding the right drugs is a daunting one given the sheer number of possible compounds, which is in the order of hundreds of millions. The AMILOIDE project aims to find a shortcut and help in developing a cure.

Using the volunteers' desktop grid, the AMILOIDE team was able to screen 2.3 million chemical compounds against three 'transthyretin' structures, which is a cerebrospinal fluid that is known to deposit in the body as amyloid. This job would take a standard computer about 50 years to complete, but it was done in 15 months with the volunteer desktop gird.

Citizens from across the Spain and Portugal (blue dots) have volunteered with their computers to help the AMILOIDE project to find a cure for FAP. Yellow dots show the volunteers who did not state their location. Image courtesy Carlos Simoes.

Here is how it works: First, the volunteers install a small application called BOINC (Berkeley Open Infrastructure for Network Computing) in their computers to get connected to the volunteer desktop grid. The computer accesses a database of organic compounds and tries to fit each one into the structure of the transthyretin protein.

Testing organic compounds

This process, called 'docking', predicts the chemical similarity between the target protein and the tested compound. When the calculations are over, the results are reported back to the database, where they can be analyzed by a research team.

The biggest advantage of using the volunteer desktop grid to search for new drugs is "a drastic reduction in the cost of lab work, manpower and the actual time that is saved," said project leader Rui Brito, a structural biologist at the University of Coimbra, Portugal.

"It's important to keep in mind that the purpose of this exercise is to make predictions, not to find final answers," he added. "Any promising result highlighted by computerised analysis has to be validated experimentally in the lab."

So far, the results are very promising. The project has already identified a set of interesting compounds. The candidate-molecules are now being assessed 'in vitro' (non-living organisms) and the most successful will eventually proceed to be tested 'in vivo' (within living organisms), before being deployed in clinical trials.

Despite this initial suceess, the project still has to sieve through a library of about 1.2 million chemical compounds. "AMILOIDE will soon start searching for drugs to deploy against Alzheimer's and Parkinson's diseases," said Brito.

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