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Chapter 5: 21st-Century Genetics
PAUL KEIM (ANTHRAX), CDC/ WILLIAM A. CLARK (CHOLERA)
Medicine has evolved tremendously since the earliest human civilizations, when the diagnosis and treatment of disease were far from scientific.Medieval medicine, for example, relied heavily on supernatural beliefs. Limited scientific knowledge led to seemingly bizarre practices like opening the vein of a sick person and draining off quarts of precious blood!
Later, in the Renaissance period of the 15th and 16th centuries, scholars centered on anatomy. One of them, the Italian artist-inventor Leonardo da Vinci, created beautiful and accurate illustrations of the human body. His work and that of other scientists of his day focused on the practice of dissection, providing never-before-seen details of the body's architecture of limbs, joints, muscles, nerves, and vessels.
Modern medicine got its real start during the 19th century, after the microscope was invented.Medical school subjects like physiology, pathology, and microbiology were born. During this time, scientists discovered that bacteria—not evil spirits or other imaginary entities—caused human diseases like cholera, anthrax, and tuberculosis.
The birth of modern genetics, which occurred in the 20th century, accelerated the study of all these areas of science. Now, at the start of the 21st century, opportunities have never been greater for turning scientific knowledge into better health for all.
We often take for granted the amazing complexity of the human body.Without even thinking, we sweat to maintain body temperature, get hungry when we need energy, and feel tired when we need to sleep.
These seemingly simple actions require a sophisticated coordination of many different organs and the millions of molecules that work together inside them. Thousands of networks of interacting genes underlie these actions in our bodies.
One of today's challenges is to map the actions and interactions of all these molecules, a focus of the new field called systems biology. Genetic and genomic research is helping scientists tackle many questions in this area. By building models of cells, tissues, and organs in action, scientists hope to learn how these complex systems work.
Researchers need to know these basics in order to understand how the systems fail, when disease strikes. An essential tool in this research is the computer.
No Lab? No Problem!
Those who work at the intersection of computer science and biology often combine and analyze data from many different sources, looking for informative patterns.
ANDREY RZHETSKY AND KEVIN P. WHITE
Andrey Rzhetsky of Columbia University in New York City is one of these people. Through an approach known as knowledge engineering, Rzhetsky and his team write computer programs that scan the contents of thousands of published scientific papers. The "knowledge mining" tool they use, called GeneWays, focuses mainly on research literature about changes in genes and proteins.
The program first scans scientific papers using pre-set search terms, much like a Google™ search of the Web. Next, it evaluates the search results and makes sure they don't overlap. For example, if a molecule has 16 different names in different papers, the program simplifies it to just one.
Finally, after applying specific rules, sort of like "biological grammar," the computer program identifies associations, which are possible links between molecules. The information then goes to a database that Rzhetsky and other scientists use to build large networks of molecular interactions.
Rzhetsky and his team used GeneWays to identify risk genes for Alzheimer's disease, a complex condition thought to be caused by many factors. In analyzing the data, Rzhetsky found important "nodes," molecules that play key roles in the disease gene network that GeneWays modeled.
These predicted molecular interactions were later confirmed by other researchers working in a lab, underscoring the value of computer modeling as a way to learn more about the molecular basis of disease.
Green Fluorescent Protein
Here's an interesting news flash: "Glow-in- the-dark jellyfish revolutionizes genetic research!"
Although it may sound bizarre, the claim is true. A jellyfish protein is essential to modern cell biology experiments that track the movements, quantities, and interactions of the millions of proteins inside cells.
CATHERINE FERNANDEZ AND JERRY COYNE
Called green fluorescent protein, or GFP, this natural protein is found in specific parts of the jellyfish. Those parts glow because the protein absorbs energy from light in the environment and then produces a different color of light.
Scientists don't really know how and why jelly- fish use their glow. They do know that jellyfish don't flash at each other in the dark, nor do they glow continuously. And the glow is rarely seen in undisturbed animals.
MARTIN CHALFIE
Taken out of the jellyfish, GFP has played a major role in advancing the study of genes and the proteins they encode. The story of how GFP became a research tool began in 1992, when Martin Chalfie of Columbia University showed that the gene that makes GFP produced a fluorescent protein when it was removed from the jellyfish genome and transferred to the cells of other organisms (see Recombinant DNA and Cloning). Chalfie, a developmental biologist, first put the gene into bacteria and roundworms, creating glowing versions of these animals.
Since then, researchers have transferred the GFP gene into many other organisms, including fruit flies, mice, and rabbits—and even human cells growing in a lab dish. Recently, scientists used the GFP gene to create green-glowing zebrafish. Although the fish were created for the purpose of scientific research, they've also become an "exotic" species for home aquariums.
Thanks to GFP and related technologies, scientists can now view living cells and their constantly moving contents. GFP is also used in diagnostic tests for drugs, foods, herbicides, and hazardous chemicals.
Hard Questions
While the task of sorting through large volumes of genomic data remains a central challenge in modern biology and medicine, one of the knottiest dilemmas to emerge from this research is a social and ethical one. That is, how should people make use of information about their own genes?
Because genetic information is both powerful and incredibly personal, there are deep societal concerns regarding its use. These concerns include the potential for discrimination from health insurance companies or employers who learn about a person's risk of disease, or susceptibility to toxicity from an environmental chemical.
Some laws are already in place to protect individuals from the misuse of their genetic information.When you visit a new doctor, nurse practitioner, or dentist, you'll be asked to read and sign a form that outlines your medical privacy rights under the Health Insurance Portability and Accountability Act, or HIPAA. This law protects your genetic and other personal health information from being used or shared without your knowledge.
It's important to realize that, in most cases, genetic information cannot offer definitive proof that a disease will occur. But if you have a very strong family history of breast cancer, for example, there may be a faulty gene in your family that increases your risk of getting the disease.
Doctors can now test for two known gene variants associated with inherited forms of breast cancer, BRCA1 and BRCA2. If you carry either of these gene variants, your lifetime risk of getting breast cancer is significantly higher than it would be for someone without either variant. But some people who have BRCA gene variants never get breast cancer.
Only about 5 percent of all breast cancer can be traced to a known, inherited gene variant. Since so many breast cancers are not linked to BRCA1 or BRCA2, genetic testing for these variants is irrelevant for the vast majority of people who do not have a family history of breast cancer.
But let's say you do have a relative who tested positive for BRCA1 or 2. Should you get tested, too?
A difficult question, for sure, but consider this: Knowing about this risk ahead of time might save your life. For example, you might want to begin getting mammograms or other screening tests at an early age. If cancer is found very early, it is usually more treatable, and the odds for a cure are much higher.
Currently, diagnostic laboratories across the United States offer genetic tests for more than 1,000 disorders. Some of these tests detect problems with entire chromosomes, not just individual genes. Perhaps the most well-known example of a chromosome problem is Down syndrome, in which cells have an extra copy of chromosome 21 (see Let's Call It Even).
Most genetic diseases aren't caused by a chromosome abnormality, or even by one gene variant. Cystic fibrosis, for example, is due to a faulty gene, but more than 30 different variants of this gene can cause the disease, and those are just the ones researchers know about!
How can there be 30 different variants of one gene? Remember that a gene is a long DNA sequence, consisting of hundreds of nucleotides. A change in one of those nucleotides produces one variant, a change in another produces another variant, and so on.
Because there are so many possibilities, it's hard to tell whether a person has a variant form of the cystic fibrosis gene. So the standard genetic screening test for this disease scans for all of the more than 30 variants known to cause cystic fibrosis.
Doctors usually order a genetic test only if a person has a strong family history of a disease. But even so, deciding to have such a test is not a simple choice. Think about what you would do with the information.
One thing you might consider is whether you could do something with what you learn from a genetic test.
You've already read about what you could do if you discovered that you were at high risk for developing breast cancer. But what about a condition that shows up in middle-aged or older people—or one for which there is currently no cure?
As a teen or young adult, would you want to know that you'd get a serious, perhaps incurable, disease later in life?
Patients and doctors face these tough issues every day. Even years from now, when researchers know more about the molecular roots of disease, genetic tests will rarely provide easy answers. In most cases, they won't even provide "yes" or "no" answers.
Rather, much like a cholesterol test, they will predict whether a person's risk of getting a disease is relatively high, low, or somewhere in between. This is because many factors besides genes, including lifestyle choices such as diet and exercise, also play a role in determining your health.
Good Advice
Since the story of genes and health is so complicated and is likely to stay that way for a while, it is very important to consider genetic information in context. Health care professionals known as genetic counselors can be a big help to people who are thinking about getting a genetic test.
As a profession, genetic counseling has been around since the mid-1900s. However, only a few specialty clinics offered counseling at that time. Now, genetic counseling is much more widely available.
Today's genetic counselors have gone through a rigorous training process in which they earn a master's degree and learn genetics, medicine, laboratory procedures, counseling, social work, and ethics. Genetic counselors do their work in many different settings, including hospitals, private clinics, government agencies, and university laboratories.
An interesting aspect of the job is that genetic counselors address the needs of entire families, rather than just individual patients. To evaluate genetic risk and its potential consequences, these professionals gather a family medical history covering generations.
Genetics and You: Crime-Fighting DNA
Like your thumbprint, your genes are unique, unless you have an identical twin. As such, DNA "fingerprinting" has become a powerful crime-fighting tool. DNA forensics is a fast-growing specialty that has applications beyond putting criminals behind bars.
In addition to identifying suspects who leave traces at the scene of a crime (for example, strands of hair, drops of blood, or skin cells), DNA forensic technology can identify victims in a natural disaster, such as the December 2004 tsunami that ravaged Indonesia and other Asian countries. DNA fingerprinting can also match a transplant patient to an organ donor or establish paternity and other family relationships.
Genetic fingerprinting is not limited to people. It can find small but potentially deadly traces of disease-causing bacteria in food or water, determine whether an expensive horse was sired by a Kentucky Derby winner, or figure out whether a puppy's parents were first cousins.
DNA fingerprinting techniques work by looking for differences among gene sequences that are known to vary between people (or between individuals from any species). Scientists read the sequence in a dozen or so places to create a molecular profile. The chances of a molecular fingerprint being the same in two people or two organisms are vanishingly small.
Genetics, Business, and the Law
Can a scientist claim rights to a gene that he discovered in worms and that has a nearly identical counterpart in humans?
Is a person who gave a blood or tissue sample entitled to profits from a company that develops a drug based on genetic information in her sample, or to a lifetime supply of the drug?
Can a blood or tissue sample that was donated for one purpose be used for an entirely different study several years later, without asking the donor if that's OK?
These and other issues are hotly debated in ethics and legal circles. Many of the most controversial topics have to do with the idea of patenting life forms.
Traditionally, when an inventor comes up with a new idea and wants to sell it—whether it's a radio-controlled toy boat or a customized laboratory chemical—he or she submits an application to the U.S. Patent and Trademark Office.
By issuing patents, the Federal Government gives an inventor ownership of his or her creation. Patents give inventors time to optimize their products and control how their inventions are used, allowing them to make money from their creativity.
However, nobody invented a gene, a naturally occurring chemical, or a protein, so why should a person or a company be able to own it and control its destiny in the marketplace?
Patent laws in the United States and Europe prohibit anyone from patenting a gene as it exists in the human body. But for many years, scientists, universities, and companies have earned patents for methods of isolating genes or for specific medical uses of genetic information. The breast cancer gene test is one example.
Patents are great for business, but they have the potential to slow research because patent-holders control how information related to the patent is used. For example, researchers who wish to study patented genetic information may need to acquire a license first. This can be time-consuming and expensive.
Concerned about possible negative effects of patenting genes, the U.S. National Institutes of Health has worked with the U.S. Patent and Trademark Office to establish guidelines for what kind of genetic information can be patented. Since this area of medical research is an ever-moving target, government scientists and policymakers continue to clarify patent and licensing issues in the hope of keeping data that is valuable for research in the public domain.
Field Study
The word most often used to refer to applications of genetic research, especially those leading to products for human use, is biotechnology. It involves techniques that use living organisms—or substances derived from those organisms—for various practical purposes, such as making a biological product.
One major application of biotechnology is in agriculture. Actually, this is hardly new: Humanity has engaged in agricultural biotechnology for 10,000 years or more. Many traditional farming practices, from plant breeding to animal husbandry, are really forms of biotechnology.
But in today's agricultural industry, biotechnology generally means the use of molecular biology, recombinant DNA technology, cloning, and other recent scientific approaches to produce plants and animals with new traits.
This usually involves transferring genetic material from one kind of organism into another. Using the same techniques that were developed for putting genes into animals for research purposes, scientists can create crop plants with desirable traits, such as improved flavor or better resistance to insect pests. Transferring specific genes is faster and more efficient than traditional breeding approaches.
The United States is home to far more genetically modified crops than anywhere else in the world. In 2005, 52 percent of the country's corn, 79 percent of its cotton, and 87 percent of its soybeans were cultivated from seeds genetically modified to resist viruses and other plant pests.
Many believe that agricultural biotechnology is an important driver for improving world health. They say that genetic modifications may be the only hope for pest-ravaged crops, such as bananas, that are essential to the economies of poor countries. The creation of edible plants that contain medicine, serve as a form of vaccination, or deliver extra nutrients—such as the recently developed rice that makes vitamin A—could also contribute in major ways to global health.
But opposition from farmers and consumers within and outside the United States has clouded agricultural biotechnology's future. Some object to the development of plants that are naturally resistant to herbicides, partly out of concern that the trait might jump to weeds, making them impossible to destroy.
Environmental advocacy groups worry that genetically modified plants may impact the future biodiversity of our planet by harming beneficial insects and possibly other organisms. However, the U.S. Environmental Protection Agency has stated that there is no evidence to date that indicates that biotech crops have any adverse effects on non-targeted wildlife, plants, or beneficial insects.
Of course, careful field tests of newly created, genetically modified plants and animals are essential to be sure that they cause no harm to other organisms or to the environment.
Careers in Genetics
Opportunities to be part of genetic and genomic research have never been greater or more exciting. In addition to studying human genes, scientists are gathering information about the genes of many other living things, from microbes that cause disease to model organisms like mice and Drosophila, livestock, and crop plants.
Although computers do some of the work, this avalanche of information has to be analyzed by thousands and thousands of human brains. In addition to identifying genes, scientists must figure out what the genes do and—even more complicated—how they do it.
We need laboratory scientists, doctors to do clinical research and treat patients, genetic counselors to help people understand the information in their genes, and lawyers and ethical specialists who can address legal and policy concerns about the use of genetic information.
In especially high demand are people with expertise in mathematics, engineering, computer science, and physics. The field of bioinformatics, which develops hardware and software to store and analyze the huge amounts of data being generated by life scientists, is especially short of qualified workers. As a result, bioinformatics scientists are in high demand.
Many careers in genetics and genomics require advanced degrees such as a Ph.D. or M.D. But people with master's or bachelor's degrees are also needed to fill thousands of rewarding jobs as genetic counselors, research assistants, and lab technicians.
For more career information, see http://www.ornl.gov/sci/techresources/Human_genome/education/careers.shtml or http://science.education.nih.gov/LifeWorks.
The Tools of Genetics: Informatics and Databases
For most of its history, biology managed to amass its data mostly with the help of plain old arithmetic. Gregor Mendel did genetic analysis by simply counting the different kinds of offspring produced by his peas. By contrast, today's genetic research creates too much data for one person, or even a scientific team, to understand. New technologies are needed to manage this huge amount of data.
Consider this: Gene-sequencing machines can read hundreds of thousands of nucleotides a day. Gene chips are even faster. The information in GenBank®, a widely used database of DNA sequences, nearly doubles every year. It is said that a laboratory doing genetic research can generate hundreds of gigabytes of data a day, every day—more than 20,000 times the contents of the complete works of Shakespeare or J.S. Bach.
How can anyone make sense of all this information? The only way is to enlist the aid of computers and software that can store the data and make it possible for researchers to organize, search, and analyze it. In fact, many of today's challenges in biology, from gene analysis to drug discovery, are really challenges in information technology. This is not surprising when you remember that DNA is itself a form of information storage.
Where are genetic and genomic data stored? One of the first biological databases was created to store the huge volume of data from experiments with the fruit fly Drosophila melanogaster.
Called FlyBase, it has grown into a huge, comprehensive, international electronic repository for information on Drosophila genetics and molecular biology, run by scientists for scientists. The information includes nearly a century's worth of published scientific literature on fruit flies and data on the fruit fly's genome sequence as well as information about DNA sequences of some of Drosophila's fly relatives.
Databases like FlyBase are also useful to scientists working with other organisms, like mice or humans. A researcher who discovers a new mammalian gene may consult FlyBase to see if fruit flies have a similar gene and if the database contains hints about what the gene does. Since the functions of many genes are retained during evolution, knowing what a gene does in one organism often provides valuable clues about what it does in another organism, even if the two species are only distantly related.
Several other communities of researchers have created their own databases, including WormBase and DictyBase, dedicated to the investigation of the roundworm Caenorhabditis elegans and the soil-dwelling amoeba Dictyostelium discoideum.
A key goal is to make sure that all of these databases can "talk" to each other. That way, similar discoveries in different organisms—the important, common threads of all biology—can be identified quickly and analyzed further.
For this database communication to work, researchers in different fields must use the same terms to describe biological processes. The development and use of such a universal "ontology"—a common language—is helping scientists analyze the complex network of biology that underlies our health.
Got It?
Do you think modern research tools derived from genomics and bioinformatics will change the practice of medicine? How?
If a genetic test revealed that you had a 1 in 100 chance of developing a disease like type 2 diabetes, which can be prevented with lifestyle changes like eating a healthier diet and exercising more, would you change your behavior? What if the risk were 1 in 10?
How is genetic engineering similar to traditional farming? How is it different?
A biotechnology company uses genetic information from a patient volunteer and develops an effective, profitable medicine. Should the patient know that he or she was part of this process? Why or why not? What if the research did not lead to any medical advance?