Proteomics: The Human Genome, Part 2

by Food and Drug Administration (FDA)

(Page 2 of 2)

Besides disease, proteomics holds the promise of identifying early markers in blood and other body fluids of drug-induced damage to the heart and other body organs. Proteomics also may be used to develop tools to evaluate the purity, potency, and consistency of drug and biological products such as cellular therapies.

For the last 25 years, the mainstay in proteomics research has been two-dimensional gel electrophoresis (2DE), a process that separates large mixtures of proteins by their size and by their electrical charge.

The advantage of 2DE is that many proteins — 3,000 to 10,000 — can be separated visually. A disadvantage to using 2DE is that very large or very small proteins, proteins present in minute amounts, or certain kinds of proteins such as membrane proteins, are difficult or impossible to visualize using 2DE.

Since the mid-1990s, mass spectrometry has been used more and more to analyze complex protein samples. The technique itself is complex and involves the measurement of two properties — the mass-to-charge ratio of a mixture of particles with an electric charge (ions) and the number of ions present at each mass-to-charge ratio in a protein sample.

Mass spectrometry has an advantage over other technologies. It has the ability to detect and rapidly measure thousands of elements in several drops of blood quickly and cheaply using powerful computers.

The end product, called a mass spectrum, is a chart with a series of peaks, which each represent the ion present in a sample. The height of the peak is related to the amount of the protein in the sample. The size of the peaks and the distance between them provide hints on which proteins are present.

"Proteomics has provided an opportunity to look at the characteristics of cells," says Puri. "We now have a global view. Using biomarkers, you can compare medicine A and medicine B and how they work in a person."

The FDA's Role

Regulating the proteomics revolution won't be easy. Competition is fierce. Hundreds of new companies staffed by thousands of researchers have sprung up in recent years, drawn by the potential of identifying biomarkers or by the potential of developing treatments for defective proteins.

"It's an evolving field," says Puri. "The FDA has a major role to play as a regulatory agency."

Part of the challenge for the agency, according to Puri, is the variety of proteomics technology platforms used by scientists and the lack of standards. "There are different systems, even homemade systems in some labs," he says. "The FDA needs to stay current in these technologies in order to evaluate the products and their safety. We are interested in working to establish the standards that will allow us to validate data across different platforms."

The FDA is collaborating with technical experts, companies, and academic representatives who will help develop future guidance documents for proteomics and related rapidly growing technologies.

"There are many ways to look at the proteome," says Puri. "We have to understand the different platforms and set a standard."

A Challenging Future

The Human Genome Project and technical advances in computers during the 1990s set the stage for the proteomics revolution and the accompanying race among drug developers to find protein drug "targets."

Some are focusing their efforts on how proteins relate, how they change, what they do, and which are present in healthy tissue and which are evident in disease.

"When you are looking at millions of proteins at a time, you need bioinformatics, the organization and use of computers to analyze data and databases, to analyze the results," says Puri. "Are they meaningful or not?"

Researchers are learning that analyzing patterns of proteins, rather than identifying every protein active in a disease, may be sufficient to diagnose diseases such as cancer.

For example, National Cancer Institute and FDA scientists collected blood samples from a group of patients with diagnosed ovarian cancer and used mass spectrometry to obtain the protein profiles in the serum samples. While there was some variation from patient to patient, clinicians were able to determine what subset of proteins consistently was a biomarker to cervical cancer by pooling samples of those with confirmed ovarian cancer.

"The typical way to diagnose cancer is by having a pathologist looking at a slide containing cells," says Edmondson. "However, looking isn't always enough. Many times, there is a disease within a disease."

New technologies such as laser capture microdissection (LCM) allow scientists to capture single cells out of a section of tissue and to collect all the proteins contained in the selected cells. The protein patterns, if any, are then stored in a computer database.

LCM allows researchers to collect sets of cells from normal, cancerous, and precancerous tissue from the same biopsy sample.

"This new technology will allow us to design better drugs to better treat cancer and other diseases," says Edmondson.

About the Author

www.fda.gov
FDA is A United States government body that oversees medical devices, including contact lenses, intraocular lenses, excimer lasers and eyedrops. In the US, these products must be approved by the FDA before they can be marketed.