ISMB 2001: Why protein folding is cool

by Lorrie LeJeune

Developing Bioinformatics Computer Skills

Developing Bioinformatics Computer Skills

By Cynthia Gibas & Per Jambeck

April 2001

1-56592-664-1, Order Number: 6641

446 pages, $34.95

ISMB 2001 -- the Ninth International Conference on Intelligent Systems for Molecular Biology -- is in full swing this week at Tivoli Gardens in Copenhagen, Denmark.
For those of you who've never been to Copenhagen, Tivoli is a combination of amusement park, public gardens, and food hall. The park was constructed in the mid-nineteenth century, so it has a kind of other-world, other-time feel to it. At quiet moments during the talks you can hear kids screaming as the roller coaster rumbles by. If you step outside the conference hall you see young couples, and mothers pushing baby prams (the old-fashioned kind with four big wheels and a spring suspension), and families, complete with kids and grandparents. All of Copenhagen is here enjoying a summer's day, unaware of the 1,300 slightly geeky biologists talking about proteomics and gene sequence analysis not 20 yards away.

The first keynote was given on Sunday by Christopher Dobson, a decidely un-geeky researcher from Oxford University in the U.K. Chris's eloquent and thoughtful presentation on protein folding and its potential impact on the disease process was, in my opinion, the epitome of a keynote. Hours later I'm still thinking about what he said, what it means, and why biology is such a fascinating science. At a meeting like ISMB it's easy to get caught up in the scientific detailia and lose sight of the big picture. Why does bioinformatics exist? Not for its own sake, but to help answer such questions as, why do proteins fold and what happens when they don't?

Here's an example. After a protein molecule is synthesized by the cell's ribosomal machinery, it folds up into a very complex configuration. The chemistry of the molecule affects how it folds, but exactly why it folds is one of the big, open questions in science. So what happens when genetic coding for a protein goes a little wrong? Let's say a genetic disorder affects how your body codes for and synthesizes a protein called alpha-1 antitrypsin. The protein is miscoded, it folds incorrectly, and eventually, you wind up with liver disease. But how does it happen?

As a result of research in his lab, Christopher has found that the folding patterns of certain proteins that are left to age in high concentrations are somehow changed. They begin to aggregate and form a new kind of molecular structure. As it turns out, this new structure is toxic, and often causes the cell to die. The implication is that as a protein ages, it begins to break down. It's an interesting parallel to the fact that as our bodies age, our biological systems begin to break down.

So why might some proteins cause disease by aggregation? It's likely the biology of the system that's to blame, not the gene sequence. As the body produces proteins in higher and higher concentrations due to genetic misfire, the proteins themselves trigger failure of the biological control mechanisms that prevent aggregation in the first place. The cytotoxic (cell death) effect of aggregated proteins could be a bodily defense mechanism (the errant cell dies before it can reproduce), but if enough cells die, you have another problem. I've simplified the science (and I hope I've simplified it correctly), but the end result is a fascinating glimpse into how a biological system works, and how it breaks down.

Christopher Dobson's resarch may give us some new insights into how genetics, protein chemistry, and aging are related, but much more examination is needed to prove his hypotheses. And if they are proven, yet more effort will go into looking for a solution to the problems they uncover. The tools and techniques of bioinformatics may help us handle all the data, and perhaps offer some insights into possible solutions, but not before basic biological research shows us how systems such as protein folding work.

The point of this long story is is that bioinformatics and biological research exist together. They're two sides of the same coin, and one is of no use without the other.