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PRYING INTO PROTEINS <br> SCIENTISTS HERE UNRAVELING MYSTERIES OF HUMAN BODY

Using crystals, just like the grains of sugar on a cookie, Herbert Hauptman and his team of scientists in Buffalo have been quietly solving some of the most profound mysteries about what makes the body tick.

The work at the Hauptman-Woodward Medical Research Institute goes largely unnoticed by the public, much like its vanilla-plain downtown headquarters on High Street.

Yet in scientific circles, it's known around the world.

Recent discoveries at the institute led to an improved insulin, and its research experiments have flown on a series of NASA space shuttle flights.

Other work is under way to pinpoint the chemical interactions that cause breast cancer and polycystic kidney disease, findings that could result in new treatments or cures.

Most drugs owe their existence to happy accidents or arduous trial and error. But if you know the shape and properties of the body's chemical building blocks, you can produce medications that truly act like magic bullets.

And, this is what the institute is exceptionally good at -- figuring out what the smallest units of life look like, protein molecules too tiny to be seen with a microscope. And Hauptman, a Nobel Prize winner, revolutionized the field.

"Solving the structures that control our bodies gives us a deeper understanding of how things work, how things go wrong and how we can design drugs that destroy diseases while causing minimal collateral damage," said Hauptman.

Hauptman says the institute, which has suffered from a lack of a large endowment to fund research, is starting to get more attention at a time when structural biology is to science what Ricky Martin is to music -- red hot.

Last year, the organization announced it had raised $3.5 million locally, most of it a $1.5 million matching grant from the John R. Oishei Foundation. The money was used to hire additional scientists at the institute, which supports itself through federal and private research grants.

Hauptman, the institute's president, and others said more private money may become available if the research facility becomes a part of the University at Buffalo, a plan that is close to coming to pass.

The object of all the research attention is a chemical essential to the structure and function of living things -- proteins.

Molecules of the material range from the long fibers that make up connective tissue -- it forms the structure of meat -- to compact globules that can pass through cell membranes.

Humans have tens of thousands of different proteins, of which only a small percentage have been described. There's hemoglobin, for instance, the molecule that carries oxygen throughout the body, and antibodies that react to invading organisms.

Diseases, from the common cold to cancer, arise from the interactions of proteins that join together, much like a key fits into a lock.

Map out every crack and crevice on a protein, and it's possible to design drugs to open those locks. Others may work by jamming them, preventing such invading organisms such as viruses from infecting a cell.

You might also improve an old treatment, as Hauptman-Woodward helped to do with insulin.

Diabetics take insulin to make up for deficient pancreas glands that produce too little of the essential hormone that controls blood sugar levels.

But insulin takes 30 to 45 minutes to start working. Diabetics must carefully time injections around mealtimes, when blood sugar levels quickly rise, to avoid complications.

In the 1990s, Eli Lilly Co. chemically altered insulin to create a faster-acting drug called Humalog, the first new therapy for diabetics in more than 75 years.

Trouble is the company didn't know exactly what it had done or why it worked.

"Insulin has been studied for decades, but we are still learning about it and being surprised," said David Smith, the Hauptman-Woodward scientist the pharmaceutical company turned to for answers before it started selling the new medication in 1998.

Smith, considered one of the world's two leading experts on the structure of insulin, has been concentrating on gaining greater insight into the hormone's molecular shape, down to the electrical charge around individual atoms.

He likens the task to a hiker peering across a valley to a distant forest. Over the years, he has slowly moved closer to seeing the individual trees, and then their leaves. Now, to find answers, he needs to sharpen his techniques to see the bugs on each leaf.

As it turned out, regular and fast-acting insulin look exactly alike, except for one subtle difference -- the space between a couple of atoms had changed by a few millionths of an inch.

Even with that new information, insulin remains a bit of a mystery.

Smith said scientists now know that insulin changes shape when it binds to the cells in our body, a brief chemical interaction that happens in the twinkling of an eye. No one knows precisely what happens or why, information that could lead to still better versions of drugs for diabetics.

"What insulin does is not happenstance. Nature has a plan for everything," he said.

Scientists at Hauptman-Woodward probe the inner workings of proteins with a technique called X-ray crystallography.

Anyone who has gone to the doctor for an X-ray has seen how the beams cause bones to cast a shadow on photographic film.

Likewise, bombard a crystal with X-rays, and the beams will produce a pattern on film that appears as a cluster of dots of varying intensity. The pattern can be interpreted to determine the three-dimensional shape of the molecules in the crystal, as well as the locations of the atoms that make up the molecules.

Scientists use crystals because the atoms are fixed in place, making them possible to study.

It's a tedious process.

Imagine yourself on a sandy shoreline as waves move past wooden posts in the water. Depending on the position of the posts, some waves will break on the beach stronger than others. Now, work backwards, and based on the intensity of the waves hitting the shore, figure out the location of the posts in the water.

X-rays are invisible but, like water, flow in waves, and crystallographers work backwards from the pattern on film to deduce the three-dimensional position of atoms in a crystallized material.

For years, it was a painstaking effort limited to the most simple crystals, such as salt. Crystallographers had to guess at the positions of atoms in a molecule, and the image they obtained was often blurry.

Hauptman and a colleague, Jerome Karle, both of them then working at the Naval Research Laboratory in Washington, D.C., took out the guesswork in the 1950s by devising a mathematical formula that allowed chemists to determine molecular structures routinely and quickly.

The two men had cracked one of the premier problems in science. But at the time, no one saw the formula's biomedical significance. Crystallography was devoted mainly to looking at minerals.

As scientists learned to turn proteins into crystals, the breakthrough allowed X-ray crystallographers to begin identifying the molecules of life. It became increasingly clear that with this information, researchers could finally learn directly what caused diseases and how to cure them.

Hauptman and Karle shared the Nobel Prize in Chemistry in 1985 for their work.

In recent years, Hauptman improved the formula -- by the way, you need a supercomputer for this -- that allows crystallographers to view many of the larger molecules important to human life.

"People began to see the biomedical applications," said Abraham Clearfield, a Texas A&M University chemistry professor and past president of the American Crystallographic Association. "Here was a method that could be used to understand the living processes."

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