TREATMENTS FOR CANCER
Health at the cellular level
M illions of people die of cancer every year. What could lower future numbers? Early detection could make a big difference. Perhaps simple blood tests will someday accurately identify specific features in the blood – markers – that indicate cancerous changes before the disease silently reaches more advanced and more difficult-to-treat stages. The answers to this and many other questions about disease and potential treatment may lie in the relatively new field of study called proteomics.
BEYOND THE HUMAN GENOME
Scientists in 2001 unveiled the human genetic blueprint, the DNA sequence of roughly 34,000 genes. This study of human genomics – called the Human Genome Project – was complex enough. But the next level – of understanding the proteins encoded by these genes – is many times more complex. Proteomics has to do with these “geneencoded” proteins – not proteins as a nutritional element, but rather proteins as actors within the body’s moment-to-moment biological processes. The tissues in your body, such as muscle, brain, skin and your internal organs, are made up of thousands of proteins. All of these proteins are individual workhorses that collectively carry out the various functions of your tissues. Proteins are responsible for cell growth, cell division, energy use (metabolism) and cell death (apoptosis). In essence, proteins express (phenotype) the genetic information (genotype) in each cell of your body. Every protein in your body contains a specific sequence of amino acids linked together like a string of beads. These strings fold into unique shapes and configurations. Each shape created by these gene-directed proteins carries out a specific function in the cells and tissues. For instance, skin cells produce the protein keratin, the major component of skin cells that are sloughed off. At the same time, blood cells regularly produce hemoglobin, the major protein in red blood cells. Proteomics involves studying the variety of proteins produced by a particular cell or tissue.
ONE STEP CLOSER TO KNOWING
There are many more proteins in cells or tissues than there are genes. Different kinds of proteins in your body may number anywhere from several hundred thousand to more than a million – the figure has yet to be determined. These proteins fold and change shape and function over time. Among questions researchers hope to answer: How do proteins fold into unique shapes or conformations? How do proteins interact with other proteins and small molecules? How are proteins modified and with what type of modifications? When, where, why and how are proteins revealed (expressed) in the body? Answers to these questions may open the door to creating new approaches to both diagnosing and treating disease, as well as designing new drugs to treat disease. For example, if the characteristics and function of a key protein in a disease were known, it might be possible to design a drug molecule that could bind to that protein and disrupt its function in the cell. This could basically halt the progress of the disease. It would signal a domino effect that stops, starts or modifies a specific process.
Some especially promising areas of study in proteomics include methods of better detecting early ovarian cancer, prostate cancer, breast cancer, colon cancer, and certain types of malignant leukemias and lymphomas of the blood. For example researchers have found that comparing levels of certain protein biomarkers in the blood may prove significant to detecting ovarian cancer, in its earliest stages. One study, published in the Proceedings of the National Academy of Sciences of the United States of America, compared the levels of four proteins in healthy women, with levels in women diagnosed with ovarian cancer. Among the women who had ovarian cancer, there was significant elevation of two proteins and reduced levels of two others. The test correctly differentiated the women who had cancer from those who didn’t 95 per cent of the time. But until a more specific test is developed, researchers say it’s still too soon to leap from the success of these early results to screening women in the general population. It’s hoped that further proteomic discoveries can make it possible to accurately detect ovarian cancer at its earliest stages. As knowledge is gained about proteins and their role in determining health, researchers look forward to the day when there can be a more personalized approach to treating disease. Researchers say they hope to see personalized medicine in use within the next generation.
Proteomics is the study of proteins encoded by genes – not proteins as a nutritional element, but rather proteins as actors within the body’s momentto-moment biological processes.
PROTEOMICS GENOMICS VS.
Addressing the unique challenges each study poses The biggest conceptual challenge inherent in proteomics lies in the proteome’s increased degree of complexity compared to the genome. For example: ONE GENE CAN ENCODE MORE THAN ONE PROTEIN (even up to 1,000). The human genome contains about 21,000 protein-encoding genes, but the total number of proteins in human cells is estimated to be between 250,000 to one million. PROTEINS ARE DYNAMIC. Proteins are continually undergoing changes, e.g., binding to the cell membrane, partnering with other proteins to form complexes, or undergoing synthesis and degradation. The genome, on the other hand, is relatively static. PROTEINS ARE CO- AND POSTTRANSLATIONALLY MODIFIED. As a result, the types of proteins measured can vary considerably from one person to another under different environmental conditions, or even within the same person at different ages or states of health. Additionally, certain modifications can regulate the dynamics of proteins. PROTEINS EXIST IN A WIDE RANGE OF CONCENTRATIONS IN THE BODY. For example, the concentration of the protein albumin in blood is more than a billion times greater than that of interleukin-6, making it extremely difficult to detect the low abundance proteins in a complex biological matrix such as blood. Scientists believe that the most important proteins for cancer may be those found in the lowest concentrations.
APPLYING PROTEOMICS TO MEDICINE
Proteomic technologies will play an important role in drug discovery, diagnostics and molecular medicine because is the link between genes, proteins and disease. As researchers study defective proteins that cause particular diseases, their findings will help develop new drugs that either alter the shape of a defective protein or mimic a missing one. Already, many of the bestselling drugs today either act by targeting proteins or are proteins themselves. Advances in proteomics may help scientists eventually create medications that are “personalized” for different individuals to be more effective and have fewer side effects. Current research is looking at protein families linked to diseases including cancer, diabetes and heart disease. Identifying unique patterns of protein expression, or biomarkers, associated with specific diseases is one of the most promising areas of clinical proteomics. One of the first biomarkers used in disease diagnosis was prostate-specific antigen (PSA). Today, serum PSA levels are commonly used in diagnosing prostate cancer in men. Unfortunately, many single protein biomarkers have proven to be unreliable. Researchers are now developing diagnostic tests that simultaneously analyze the expression of multiple proteins in hopes of improving the specificity and sensitivity of these types of assays. Nanotechnology is the creation of manufacturing devices and components that range from 1 to 100 nanometers. A nanometer is one billionth of a meter, or 1/ the width of a 80,000 human hair. Nanotechnology devices have the potential to greatly expand the capabilities of proteomics, addressing current limitations in selectively reaching a target protein in vivo through physical and biological barriers, detecting low abundance targets, and providing a “toolbox” to translate the discovery of protein biomarkers to novel therapeutic and diagnostic tests. Typical nano-devices include nanoparticles used for the targeted delivery of anticancer drugs, energy-based therapeutics (including heat and radiation) and imaging contrast reagents. Nanowires and nanocantilever arrays can be used in biosensors that measure minute quantities of biomarkers in biological fluid.