The New Genetics
Chapter 4: Genes Are Us
For science, the sequencing of the human genome was a groundbreaking achievement, one that made a lot of news. But what does it actually mean? Will any of this information make a difference in your life?
A genome is all of the genetic material that an individual (or a species) has. The human genome differs from the gorilla genome, which differs from the rice genome, and so on. And while every person has a "human genome," it is not exactly the same in all people. Sequence variations within your genes makes your DNA different from that of your mother, your cousin or a complete stranger.
Think of the human genome as a long story that contains roughly 20,000 words (the genes). With few exceptions, each person has the same number of words, but certain words have slightly different spellings. In some cases, the spelling changes create words with new meanings— genes that code for different proteins. Other spelling changes appear to have no effect whatsoever, at least not ones that today's scientists know how to measure.
Researchers are beginning to use knowledge learned from genome sequencing research to figure out how being healthy and being sick are different at the level of molecules. And doctors are starting to use genetic information to make treatment choices.
For example, a diagnostic test can search for differences in the level of expression of a particular gene in breast cancer cells and predict whether a person will respond to a drug called Herceptin®.
The cancerous cells of some people who have breast cancer make an abundance of "HER2" proteins that are targeted by Herceptin. For those people, Herceptin is a miracle drug because it reduces the risk that their breast cancer will come back, and it also decreases their odds of dying from the disease.
For cancer patients whose tumor genes do not express HER2, Herceptin won't do a thing, though, so it shouldn't be prescribed. Research is proceeding quickly to develop other genetic tests that may help diagnose and treat a wide range of health problems beyond cancer.
Reading the Book of Human Genes
In April 2003, researchers across the world celebrated a milestone and an anniversary. Almost 50 years to the day after James Watson, Francis Crick and Maurice Wilkins unveiled their Nobel Prize-winning description of the DNA double helix, scientists completed the sequencing of the human genome, a momentous achievement in biology.
The day was long in coming. In the 1980s, geneticists realized that they had both the need and the ability to learn the complete layout of the human genome. They wanted to map the location of every gene within chromosomes and decipher the complete, letter-by-letter sequence of the genome's 3 billion nucleotides.
With that information in hand, scientists reasoned, it would eventually be possible to learn exactly what job each gene performs as well as how genes contribute to human health and disease.
Soon, thousands of scientists in labs all over the world got into the act. Critical to their success were new tools and technologies that made the work go faster and helped the researchers manage and analyze the flood of data.
Although the Human Genome Project is done, related genome sequencing efforts have continued. One involves sequencing the genomes of many other species (see Animals Helping People).
Another is roughly sequencing the genomes of 2,000 people to produce a detailed haplotype map showing both common and rare patterns of genetic variation. Researchers can link these variations to disease risk and health-related traits, such as individual reactions to medicines and environmental chemicals.
One way variations in our genes make a difference in our health is by affecting how our bodies react to medicines. The unsettling truth is that medicines work as expected in fewer than half of the people who take them.
While environmental and lifestyle factors can explain some of this, a good part of the individual variability in response to medicines can be attributed to variants in the genes that make cytochrome P450 proteins (see Genes Meet Environment). These proteins process many of the drugs we take.
Because each person's set of genes is a little different, the proteins that the genes encode are also slightly different. These changes can affect how the cytochrome P450 proteins (and many other types of proteins) work on drugs.
Doctors first realized this in the 1950s, when some patients had bad—sometimes fatal—reactions to an anesthetic medicine used in surgery. Experiments revealed that those who reacted poorly had a genetic variation in the enzyme that breaks down and disposes of the anesthetic after it's been in the body for a while.
People whose genes encode the variant enzyme had no trouble at all until they needed surgery that required general anesthesia. In the operating room, a normal human genetic variation suddenly led to a medical crisis!
Fortunately, this type of serious reaction to an anesthetic is very rare. But many reactions to medicines aren't so unusual. Researchers know that genetic variations can cause some common medicines to have dangerous side effects. For example, some people who take the colon cancer drug Camptosar® (also known as irinotecan) can develop diarrhea and a life-threatening infection if they have a variant form of the gene for the protein that metabolizes Camptosar.
Genetic variations can also cause drugs to have little effect at all. For example, in some people, pain medicines containing codeine, like Tylenol® with Codeine Elixir, offer no relief because their bodies break it down in an unusual way.
The use of genetic information to predict how people will respond to medicines is called pharmacogenetics. The ultimate goal of this field of study is to customize treatments based on an individual's genes.
With this kind of approach, every patient won't be treated the same, because doctors will have the molecular tools to know ahead of time which drug, and how much of it, to prescribe—or whether to prescribe it at all.
The Healing Power of DNA
Pharmacogenetics is advancing quickly since scientists have a lot of new information from the Human Genome Project and new computer tools that help them analyze the information. One disease for which progress has been rapid is cancer.
Consider the fact that cancer is often treated with a chemotherapy "cocktail," a combination of several different medicines. Each of the drugs in the mixture interacts with different proteins that control how well that particular drug works and how quickly it is metabolized in the body. What's more, each drug may have its own set of unpleasant—even potentially life-threatening—side effects.
For these reasons, individually targeted, gene-based prescriptions for chemotherapy may offer a real benefit to people with cancer.
Currently, chemotherapy cures about 80 percent of the children who have been diagnosed with acute lymphoblastic leukemia, the most common childhood cancer. The remaining 20 percent are at risk of the cancer coming back.
Mary Relling, a research clinical pharmacist at St. Jude Children's Research Hospital in Memphis, Tennessee, discovered that variations in two genes can predict which patients with acute lymphoblastic leukemia are likely to be cured by chemotherapy. Her research team also identified more than 100 genes expressed only in cancer cells that can be used to predict resistance to chemotherapy drugs.
By taking patient and cancer cell genetic profiles into account, Relling says, researchers can develop more effective treatments for the disease.
Other pharmacogenetic scientists are studying the effects of gene variants on patients' responses to drugs used to treat AIDS, allergies, infections, asthma, heart disorders and many other conditions.
For example, researchers recently identified two different genetic variants that play a central role in determining the body's response to Coumadin® (also known as warfarin), a widely prescribed medicine given to people who are at risk for blood clots or heart attacks. Although 2 million Americans take this blood-thinning drug every day, it is very difficult to administer, since its effects vary widely in different people who are taking the same dose. Giving the right dose is essential, because too much Coumadin can cause excessive bleeding, while too little can allow blood clots to form.
Allan Rettie, a medicinal chemist at the University of Washington in Seattle, discovered that genetic variation among people influences the activity of a protein in the blood that is Coumadin's molecular target. He and other scientists are now trying to translate these findings into a genetic test that could help doctors predict what dose of Coumadin is appropriate based on each patient's DNA profile.
Genes Can Do That?
Did you know that, in addition to traits you can see like hair color and physique, genes also contribute to how we behave? It may come as a surprise that many researchers are answering basic questions about the genetics of behavior by studying insects.
For example, Gene Robinson, an entomologist at the University of Illinois at Urbana-Champaign, works with honeybees. Robinson says that if you look at honeybees in their natural hive environment, you'll quickly see that they are very outgoing. In fact, according to Robinson, honeybees can't survive without the social structure of their community within the hive.
This characteristic makes them a perfect species in which to study the genetics of behavior.
What's particularly interesting about bees is that rather than being stuck in a particular job, they change jobs according to the hive's needs. Robinson has identified certain genes whose activity changes during a job shift, suggesting that the insects' environment helps to shape their gene expression.
Researchers who are beginning to understand these connections are working in a brand-new field of investigation named by Robinson himself: sociogenomics.
What does all of this mean for humans, you wonder? It underscores the fact that, far from being set in stone, our genomes are influenced by both heredity and environment, fine-tuned and sculpted by our social life and the things we do every day.
Cause and Effect
What more do we need to know about how genes shape who we are and what we become?
"A lot," says Harvard's Richard Lewontin, who warned against oversimplifying the role of genes in health in his 2001 book, The Triple Helix. Lewontin's main point is that context plays an enormous role in determining how organisms grow and develop, and what diseases they get. A unique combination of genetic and environmental factors, which interact in a way that is very hard to predict, determines what each person is like.
Very few, if any, scientists would argue with this. Whether a gene is expressed, and even whether the mRNA transcript gets translated into a protein, depends on the environment. Few diseases—most of which are very rare—are caused completely by a mutated gene.
In most cases, getting or avoiding a disease depends not just on genes but on things within your control, such as diet, exercise and whether or not you smoke.
It will be many years before scientists clearly understand the detailed meaning of our DNA language and how it interacts with the environment in which we live. Still, it's a great idea to find out as much as you can about your family's health history. Did any of your relatives have diabetes? Do people in your family tree have cancer or heart disease?
Keep in mind that diseases such as these are relatively common, so it's pretty likely that at least one relative will have one of them. But if heart disease, diabetes or particular types of cancer "run in your family," especially if a lot of your relatives get the condition when they are fairly young, you may want to talk with your doctor about your own risk for developing the disease.
In 2005, the U.S. Surgeon General developed a Web-based tool for organizing family health information. Called "My Family Health Portrait" (see http://www.hhs.gov/familyhistory ), this tool arranges information into a printout that you can carry to the doctor's office. The information can help you and your doctor determine your risks for various conditions.
If you do discover that you are at higher-than usual risk for a disease like breast cancer or heart disease, you may be able to prevent the disease, or delay its onset, by altering your diet, exercising more or making other lifestyle changes. You may also be able to take advantage of screening tests like mammograms (breast X rays that detect signs of cancer) colonoscopies (imaging tests for colon cancer) or blood sugar tests for diabetes. Screening tests can catch diseases early, when treatment is most successful.
Us vs. Them
Many scientists focus on human genes, most of which have counterparts in the genomes of model organisms. However, in the case of infections caused by microorganisms, understanding how the genomes of bacteria, viruses and parasites differ from ours is a very important area of health research.
Most of the medicines we take to treat infections by bacteria and viruses have come from scientists' search for molecular weak points in these tiny organisms. As mentioned in Chapter 1, for example, some antibiotics kill bacteria by disarming their protein-making ribosomes.
So why don't they kill human cells, too? The answer is that human and bacterial ribosomes are different. Genome sequencing is a powerful tool for identifying differences that might be promising targets for new drugs.
Comparing genetic sequences in organisms that are resistant and non-resistant to drugs can reveal new approaches to fighting resistance. Drug resistance is a worldwide problem for a number of diseases, including malaria.
Although researchers have developed several different types of medicines to treat this disease— caused by parasites carried by mosquitoes, not by a bacterium or a virus—malaria is rampant, especially in the developing world.
This is partly because not all people have access to treatment, or to simple preventive measures like bed nets, which protect sleeping people from mosquito bites. But another problem is the malaria parasite itself, which has rapidly evolved ways to avoid the effects of antimalarial drugs.
Scientists are trying to counter this process by studying microbial genetic information. In the case of malaria, geneticists like Dyann Wirth of the Harvard School of Public Health compare the genomes of drug-resistant parasites and those that can still be killed by antimalarial medicines.
Wirth's research suggests that it should be possible to develop a simple, inexpensive genetic test that could be given to people with malaria, anywhere in the world. This test would identify drugs that are likely to be most effective and help decrease the rate at which parasites become resistant to the antimalarial medicines we already have.
Genetics and You: Eat Less, Live Longer?
Would you consume an extremely low-calorie diet if it meant you would live longer? The kind of diet we're talking about isn't just cutting back here and there. It involves severely reducing calorie intake to about 60 percent of what we normally eat, enough to make most people ravenously hungry.
A 19th-century French doctor, Maurice Gueniot, thought the tradeoff would be worth it. Throughout his adult life, he ate very little. He died at the ripe old age of 102!
Later, in the 1930s, researchers followed up on this observation by showing that rats on a diet containing 20 percent indigestible fiber—calories that can't be used—lived much longer than their normally fed peers.
Intrigued by the health connection, scientists are continuing to investigate potential links between diet and aging, and genetic studies are starting to turn up some clues.
For example, geneticist David Sinclair of Harvard Medical School has found that proteins known as sirtuins may be able to stall aging. As yeast cells age, they accumulate extra DNA, which eventually kills them. Sinclair discovered that sirtuins become more active in yeast cells that are on a low-nutrient "diet." He reasons that by restricting the formation of extra DNA, sirtuins keep the yeast young.
Not so fast, say other scientists like geneticist Stanley Fields of the University of Washington. His experiments have turned up other, unrelated genes linked to lifespan in yeast. He argues that while calorie restriction is the only intervention that has been shown to extend lifespan in a wide range of organisms, including mammals, the accumulation of extra DNA does not always appear to play a role in this process.
What's the final answer, you ask? It's probably a bit of both.
Molecules like sirtuins, which are involved in cellular metabolism, may protect cells against the harmful effects of stress, extending lifespan. Other molecules that affect different aspects of cell health may be just as important.
Lifespan in complex, multicellular organisms like people is affected by many different factors, most of which we know very little about. For sure, understanding more about these mystery molecules could have a considerable benefit—perhaps providing you a chance to add years to your life without starving!
Did you know that scientists are using genetics to break up gangs ... of microbes, that is? These gangs, known as biofilms, are layers of slime that develop naturally when bacteria congregate on surfaces like stone, metal and wood. Or on your teeth: yuck!
Biofilms grow in all sorts of conditions. For example, one biofilm known as "desert varnish" thrives on rocks, canyon walls or, sometimes, entire mountain ranges, leaving a reddish or other-colored stain. It is thought that petroglyphs left on boulders and cave walls by early desert dwellers were often formed by scraping through the coating of desert varnish formations with a hard object.
Sometimes, biofilms perform helpful functions. One of the best examples of the use of biofilms to solve an important problem is in the cleaning of wastewater.
But biofilms can be quite harmful, contributing to a wide range of serious health problems including cholera, tuberculosis, cystic fibrosis and food poisoning. They also underlie many conditions that are not life-threatening but are nonetheless troublesome, like tooth decay and ear infections.
Bacteria form biofilms as a survival measure. By living in big groups rather than in isolation, the organisms are able to share nutrients and conserve energy. How do they do it?
A biofilm is not just a loose clump of cells—it's a highly sophisticated structure. As in any community, the individuals in biofilms communicate with each other.
Beyond that, many aspects of biofilms are poorly understood. Bacterial geneticist Bonnie Bassler of Princeton University in New Jersey is working to understand biofilms better, with the goal of being able to use this knowledge to break up bacterial "gang meetings."
Bassler's research subjects have a definite visual appeal. They glow in the dark, but only when they are part of a group. The bioluminescence, as the glow is called, arises from chemical reactions taking place within the biofilm. It provides a way for the bacteria to talk to each other, estimate the population size of their community and distinguish themselves from other types of microorganisms.
Through her studies, Bassler has identified a set of molecules that biofilm-forming microorganisms use to pass messages to each other. By devising genetically based methods to cut off the chatter, Bassler reasons, she may be able to cause bacterial communities to fall apart. This approach would provide a whole new way to treat health problems linked to harmful biofilms.
The Tools of Genetics: Mathematics and Medicine
What if public health officials had a script for what to do in the face of an infectious disease outbreak that had never been seen before? One thing that would help them prepare for this sort of scenario is the ability to know, ahead of time, how an epidemic develops and spreads.
Toward this goal, some scientists are using mathematical tools to create simulations, or models, of infectious disease outbreaks. They can then use the models to test the effects of various intervention strategies. Part of the work involves plugging in genetic information about how infectious organisms evolve over time and how fast they change as they interact with human populations.
Since 2005, the Models of Infectious Disease Agent Study (MIDAS), a team of biologists, computer scientists, statisticians, mathematicians, social scientists and others, has been modeling a flu pandemic—a huge, global epidemic.
Initially, the models focused on avian influenza, a type of disease occurring naturally among wild birds. At the time, health experts worldwide worried that the virus' genetic material could mutate, making it much easier for the so-called "bird flu" to pass between humans.
To simulate the potential disease spread, the scientists wrote computer programs that incorporated information about the bird flu virus and actual communities. Including details about people—not just their ages and genders, but also where they live, work or go to school—let the researchers create a synthetic population that could mirror how a real one might get sick and spread disease.
The scientists ran the programs on large computers to see how the flu could spread with and without different interventions. The results indicated that to successfully contain an epidemic, health officials would need to find the first flu cases fast and implement a combination of public health measures very quickly.
This early work helped MIDAS scientists develop similar models of H1N1 or "swine flu," the first actual pandemic flu strain since 1968. Starting in April 2009, they gathered incoming public health data to simulate the potential spread of this global flu, identify the groups most likely to get sick and evaluate the usefulness of different public health measures, such as vaccination and quarantine. Their models suggested that vaccinating schoolchildren early in an outbreak could reduce overall disease spread and that people at risk of serious complications should be given antiviral medications to take at the first signs of illness.
During both the bird and swine flu modeling efforts, the MIDAS scientists worked closely with public health officials to address specific questions. The answers informed U.S. pandemic flu preparedness planning.
Influenza, however, is not the only infectious disease making people sick. MIDAS scientists are also modeling other major health threats, including cholera, dengue fever, malaria, tuberculosis and methicillin-resistant Staphylococcus aureus (MRSA).
Discuss how mathematics can help scientists ask questions about human health.
Would you contribute a sample of your DNA for genetic research on common diseases like heart disease, depression or cancer—even if you didn't have any of these health problems? Why or why not?
Drugs work like they're supposed to in only half the people who take them, so scientists are trying to make "personalized medicines" that work very well in an individual because they match his or her genetic make-up. Are there economic social or other issues that the development of such medicines might raise?