In 2003, when the Human Genome Project completed the first directory of all human genes, the stage seemed to be set for two great advances in medicine. First, we thought that scientists would be able to more quickly identify the genes that foster common, chronic diseases such as Alzheimer’s or high blood pressure. That, indeed, is happening.
Second, scientists stated that one day each person could have all of their genes read, early in life. Armed with that information, each person could adopt lifestyles — maybe even take medicines — tailored to his/her own needs. For example, someone who, according to his genes, is likely to get heart disease may be more aggressive about exercising, eating right, and watching his cholesterol level. Alas, “personalized genomics” is less easy to accomplish than it sounds. Using the best currently available technology, decoding one person’s entire genome would still be a very expensive endeavor. But the barriers are falling fast. Two brand-new techniques — a recently published database known as the HapMap, and an analytical technique called massively parallel DNA sequencing — could soon make the dream a reality.
Reading your own Genes to detect Disease
The human genome consists of three billion chemical bases, or letters, strung in a sequence over 23 pairs of chromosomes. Our individual genomes are largely identical, but there are 10 million points in the sequence where one individual codes can vary. These tiny discrepancies — known as SNPs, or single-nucleotide polymorphisms — can be important markers of disease risk. The first challenge, a daunting one, is to determine whether people who share a particular health problem have SNPs in common.
Imagine that someone gave you a picture of a very distinctive looking house, and then asked you to find it — knowing only that it is located in Europe. You could search every street on the continent, but chances are, you wouldn’t find it for a long time. The task would be much easier if you could first narrow your search to a particular region, country, city or, even better, a particular neighborhood.
That’s where the HapMap comes in. By analyzing DNA samples from people around the world, scientists recently identified a few hundred thousand SNPs. Each SNP is like a flag that identifies a specific “neighborhood” of the human genome. The HapMap, basically a directory of these neighborhoods, makes the search for disease links faster and cheaper, because only a few hundred thousand SNPs need to be examined instead of 10 million. If a group of people with a particular disease shares a particular SNP in common, it means that a disease-causing gene is found in the “neighborhood” identified by the SNP. For example, in a family in which an unusually large number of family members develop colon cancer, those who develop cancer may be found to share the same abnormality in one particular gene that is located in one particular SNP. Scientists can then figure out how that gene works, how it leads to colon cancer, and possibly develop treatments to fix the problem created by the defective gene.
Finding the likely neighborhood of a disease-related gene is just the first step. Finding the gene, and determining its role in the body, requires a meticulous search of the neighborhood. That means reading all the letters surrounding the SNP — tens of millions of them — to identify the specific gene. Reading all the letters in a neighborhood (called “sequencing”) is far easier than sequencing an entire genome, but it still takes a lot of time and money. Fortunately, sequencing is experiencing a revolution of its own.
In late 2005, researchers unveiled new technologies that could boost the speed of gene sequencing tenfold, while greatly reducing the cost. The new techniques involve shattering long strands of DNA into millions of pieces, and sequencing the letters simultaneously. Once this “massively parallel” sequencing is finished, computers knit the fragmented data into a single sequence. These new techniques still lack the accuracy of conventional sequencing, and they can’t yet handle extremely long DNA sequences. But they’re likely to become exponentially faster and cheaper as they evolve.
Together, the HapMap and the new sequencing technologies could transform science and medicine over the next 20 years. They make it much easier to identify genes that make us vulnerable to virtually all of the major diseases. And from that knowledge, greatly improved diagnostic tests and treatments, even cures, are likely to follow. Doctors will scan our genes to determine which treatments are most likely to cause side effects. Most important, many people born genetically vulnerable to serious disease will remain healthy — because they’ll know which bullets to dodge.
Silencing Wayward Genes
A six-year-old boy is suddenly engulfed by pain. It is his first attack, but he will suffer repeated agony, along with breathlessness and debilitating fatigue, for the rest of his short life.
Over the course of a few days, a 35-year-old lawyer loses his appetite and energy. Then the whites of his eyes turn yellow.
Trying to open a stuck window, a 55-year-old nurse feels a sudden sharp pain just above her wrist. The bone has broken, weakened by cancer cells that have silently spread from her breast.
In each case, wayward genes are the culprits. The boy inherited a defective gene that makes misshapen hemoglobin protein inside his red blood cells, causing sickle cell anemia. The lawyer has been infected by a hepatitis virus that has commandeered his liver cells, instructing them to make proteins from viral genes instead of from human genes. The nurse inherited a breast cancer gene from her parents, and the gene is ordering the cells to multiply.
Despite great progress in identifying which genes cause suffering, we still don’t know how to turn them off. Doctors have long dreamed of a magic bullet that could travel harmlessly through the body to the diseased cells — the boy’s red blood cells, the lawyer’s liver cells, the nurse’s cancer cells — and enter those cells, and turn off the wayward genes. Now, new research holds out hope for just such a treatment, through a technique called RNA interference.
Over the past 30 years, scientists have identified various proteins that activate or silence genes. However, those proteins are large and complex molecules that are hard for scientists to harness. A little over 10 years ago, scientists unexpectedly discovered that very small and simple molecules, called microRNAs, also can “interfere with” or “silence” the instructions of the gene.
Considered just a curiosity at first, RNA interference has since revolutionized biological research. As discussed above, science has recently identified every gene in humans that caused human disease. Now, scientists have a tool with which they can systematically silence one gene after another, and observe what happens to the cell or the experimental animal — a direct test of whether a specific gene influences a particular disease. If it does, that gene then becomes a target for developing a conventional or novel drug treatment. Indeed, the microRNAs themselves could become a new kind of treatment. The immune system does not recognize them as foreign. And in contrast to many conventional medicines, it will be easy and inexpensive to manufacture them.
The story of the discovery of RNA interference is just the latest example of how an investment in basic research can lead to completely unexpected, and enormously beneficial results. MicroRNAs were discovered when a team of plant scientists tried to make a purple petunia even more intensely purple by inserting into it a gene for purple pigment. Instead of turning a deeper purple, the flower’s color became paler. The scientists could have scratched their heads and moved on to something else, but their curiosity was piqued. They discovered that the inserted gene had stimulated the production of very small RNAs and that these microRNAs shut down the production of the purple pigment. Then other scientists later found microRNAs also in primitive animals and in man. Who could have imagined that trying to make a petunia more purple would reveal a potential new approach for shutting down the growth of cancer? No one. That is why it is wise for society to invest in curious people who try to understand how living things work.
None of these two landmark discoveries will revolutionize medicine this year or next. Much more needs to be done. But an enormous amount has already been learned in the past decade, and the pace of discovery is accelerating. And one thing is sure. We are at the threshold of an exciting and remarkable new frontier in medicine.