The Genetic Journey
Following DNA from cell to society
It is morning. You wake up, slurp some coffee and navigate your way to work. You say hello to people, and so begin your day. Unremarkable? Hardly.
Consider the complex biological symphony that makes it all possible. Let's start with the 100 trillion cells in your body. In nearly every one is coiled more than six feet of DNA containing the collective evolutionary history of humanity, as well as the special recipe of 3.2 billion chemical "letters" that make up the unique you. Along the DNA sequence are your 30,000 or so genes. They help create proteins, the body's busy bees that hustle among and within cells doing everything from escorting oxygen about the body to topping your head with hair.
Next, consider how all of your cells arrange themselves into essential organ systems (your stomach, your brain, etc.) and preserve that most desired of biological states—the even keel of homeostasis. Add to this the fact that parasites, viruses and other interlopers constantly come calling, many with insidious intent. Such biological pathogens and chemical toxins can gum up the genetic works and cause mistakes and mutations. And the subtlest change in a gene may lead to disease.
Given such dizzying intricacy and innumerable moving parts, veteran researcher Sharon Krag says, "You can sit back and say, 'My God, I'm here, and most days I'm normal.' That's a miracle in itself."
But how does this quotidian miracle happen? We're at least somewhat familiar with the players: deoxyribonucleic acid, genes, chromosomes, cells, proteins and so on. We bandy about the terms with casual insouciance (and, for most of us, superficial knowledge), but how do they actually figure into human health? And more importantly, exactly why do things go wrong? Can a better understanding of genes help us foil cancer, discover the source of bipolar disorder, eradicate dengue or yellow fever, prevent Alzheimer's or improve children's nutrition in the developing world?
To glimpse how scientists at the Bloomberg School are seeking answers to these and other questions, join us on an incredible journey as we follow DNA—the thread of life—from its minute chemical bonds to its dramatic effects on the health of human populations.
DNA's tiny chemical bonds make us individuals and influence the health of populations. Follow the thread of life as we trace its complexity and explain how Johns Hopkins Bloomberg School of Public Health researchers are uncovering new insights into disease and life.
SNPs: Cut to the Chase
Nearly 6 million American adults suffer from bipolar disorder, which can cause dramatic swings from manic to depressive episodes. Genetic epidemiologist Peter P. Zandi is part of a National Institute of Mental Health project that is hunting the genes that increase susceptibility to the disorder, which runs in families. Decades ago, scientists hoped they would find a single gene that was responsible and then come up with a drug treatment. Now they believe that multiple genes (perhaps more than a dozen) as well as other factors cause bipolar disorder. The NIMH project is enrolling 4,000 people with bipolar disorder and plans to examine 500,000 DNA markers called single nucleotide polymorphisms, or SNPs. "We use the SNPs as signposts to help locate genes that cause bipolar disorder," he says. "And by identifying the genes, we hope to develop more effective ways to prevent and treat the disorder."
And Now, the Epigenome
600 Icelanders may spark a revolution in the study of disease origins. It's long been known that chemical modifications to DNA (such as methylation) control gene expression. And, like genes themselves, these DNA modifications play a role in cancer and other diseases. What isn't known is how and why these modifications change over a lifetime. Do they act as slow-burn fuses that ignite genetic disorders later in life? "We think it may be one way to explain the age-dependent nature of some genetic problems," says genetic epidemiologist M. Daniele Fallin. She is studying the methylation changes in the DNA found in blood samples taken in the early 1990s compared to those taken recently from surviving participants of the Reykjavik Heart Study. In addition to shedding light on the best ways to measure methylation, the study may show that researching the epigenome is as important as studying the genome itself.
End of the Molecular Line
Look at your shoestrings. Each end has a tiny plastic cap, called an aglet, to keep them from fraying. Your chromosomes are similarly protected by a long repetition of DNA letters. As you age or are exposed to toxins, your chromosomal aglets (known as telomeres) are shortened. It's not a problem until the protective DNA letters are used up and vital DNA is damaged. When this happens, the cell usually knows not to replicate its DNA. If it does, genetic material may be damaged, which can sometimes lead to cancer. With Alan Meeker and Angelo De Marzo from Hopkins Medicine, cancer epidemiologist Elizabeth Platz focuses on telomeres and prostate cancer. They want to know if shorter telomeres can predict risk of prostate cancer, or its aggressiveness. They also are examining whether different telomere lengths explain why African Americans have a 60 percent higher risk of prostate cancer than whites.
Mosquitoes, Worms and You
Human health cannot advance if we only study humans. Consider the work of George Dimopoulos and Alan Scott. Dimopoulos, a molecular entomologist, is analyzing the sequence of the Aedes aegypti mosquito, which transmits dengue, yellow fever and other diseases. Depositing synthesized mosquito DNA onto a glass slide called a microarray, Dimopoulos sees which segments bind to the mosquito's RNA. When one does, it's a real gene. His team has confirmed 9,143 of the mosquito's 15,000+ genes—an essential step for finding Aedes' weak points. Similarly, molecular parasitologist Alan Scott uses sequencing and microarrays to characterize a filarial parasite's genome. (Filarial worms infect more than 120 million people and cause elephantiasis.) Besides developing a vaccine, Scott hopes to learn how the worms survive in the body's lymphatic system, home to our immune response cells. This insight could help prevent autoimmune diseases and reduce the body's rejection of transplanted organs, says Scott.
Taming Information Overload
A decade ago, researchers measured gene expression one gene at a time. Now they use microarrays to measure expression for tens of thousands of genes simultaneously. And the technology is also used to genotype up to a million SNPs at once, identify transcription binding sites, detect methylation and so on. Typical experiments result in hundreds of thousands of numbers per sample. But with the surge of data came more noise and less signal. That's why scientists turn to biostatisticians like Rafael Irizarry to help sift the mountains of digital data for accurate results. A bent glass slide, an errant thumbprint or other contamination can ruin an experiment. Irizarry uses "exploratory data analysis" to discover problems in the data and then applies different models to extract the most useful information. "It turns out you need to be imaginative and creative to do it right," says Irizarry.
A Powerful Pathway: Part One
What if you could make some genes better protect cells against environmental carcinogens and toxins? Toxicologists Thomas Kensler, John Groopman and colleagues began with this premise a quarter-century ago and soon concentrated on one cellular pathway, Keap1-Nrf2-ARE. The Keap1 protein is anchored onto the cell's cytoskeleton, where, like some mythic beast, it continually consumes another protein, Nrf2. But in certain circumstances, Keap1 releases Nrf2, which then heads straight to the cell's nucleus and to docking sites called AREs in the DNA sequences of different chromosomes. Nrf2's arrival causes genes containing ARE to produce carcinogen-fighting enzymes. Using this pathway, the team has sought to prevent liver cancer in parts of China where it is epidemic. They've found that new drugs and compounds in foods like broccoli prime this pathway. A clinical trial using tea made from broccoli sprouts has yielded encouraging results in protecting people against environmental carcinogens.
A Powerful Pathway: Part Two
In cell biology, a signaling cascade occurs when one protein activates another protein, which in turn triggers another, and so on to perform a task. Research works the same way. One scientist's discovery sparks another's mission. Thomas Kensler and colleagues have demonstrated Nrf2's promise in preventing liver cancer (previous story). Now pulmonary toxicologist Shyam Biswal has taken the Nrf2 ball and run with it. In 2001, Nrf2 was known to regulate the expression of less than a dozen genes. With new technology, Biswal discovered that Nrf2 regulates more than 500 genes—clearly demonstrating its broad detoxification powers. Biswal expects to show that Nrf2 plays a key role in defending the body against everything from infectious agents to allergic asthma, emphysema and Parkinson's disease. The discoveries have made the researchers optimistic: "We want to make humans as resistant as possible to challenges from environmental agents," says Kensler.
A Protein Early Warning System
Each year, millions of children die or suffer ill health and impaired development because their diets lack essential micronutrients like vitamin A, zinc, iron or iodine. But health workers do not have a practical way to identify such deficiencies. If a field-based test existed, they could quickly discover a community's nutritional needs and provide the required supplements. Enter a Bloomberg School team that includes nutritionist Keith West, toxicologist Jim Yager, biostatistician Ingo Ruczinski and molecular biologists Bob Cole (of Hopkins Medicine) and Peter Scholl. They think one solution may be to assess proteins in the bloodstream involved in the body's use of micronutrients. The team is using serum samples from pregnant women in Nepal to identify proteins that might signal several micronutrient deficiencies at the same time. The ultimate goal: Developing a method that can detect micronutrient deficiencies so they can be prevented before they lead to major public health problems.
And the Walls Come Tumbling Down
People with immune systems compromised by HIV, cancer therapy or an organ transplant have two potentially lethal enemies: 1) opportunistic fungal infections; and 2) the drugs used against them. One such drug, Amphotericin, is known as "Amphoterrible" because the dose needed to kill the fungal infection is just short of lethal for the patient. Molecular geneticist David Levin has uncovered a weakness in yeast that may result in new, less-terrible drugs. Like its pathogenic cousins Candida, Aspergillus and Cryptococcus, yeast must carefully maintain cell wall integrity as it grows. Levin has found proteins needed to build strong walls. Disrupt a few proteins, and the cellular walls will come tumbling down. A pharmaceutical company has licensed one of his discoveries and is evaluating drug compounds that could help save the thousands of people who die every year from fungal infections.
Trained to Explain
Genetic tests have awesome predictive power. They may reveal a predisposition to breast cancer or a lethal genetic abnormality in an unborn child. Between the science and the patient stand genetic counselors, trained to help people comprehend how a quirk of their DNA might increase their disease risk. They not only explain test results, but help patients beforehand. (Does a 20-something want to know that Huntington's disease will likely kill them in a few decades? Have parents considered what they will do if they learn their child is to be born with Down syndrome?) Genetic counselor Lori Erby and health communications expert Debra Roter are studying 177 genetic counselors to find their most effective techniques. (Is it better to lecture or to be interactive? What's the optimal use of body language or speed of speech?) They will feed those insights back into training programs at the Bloomberg School and elsewhere.
Ethics in a Brave New World
The privacy of health information is often regarded as a fundamental right, but what about your genetic information? "Genetic information is necessarily shared information. If you know something about me, odds are you know something about my kids and probably my parents," says bioethicist Ruth Faden. "If I have an identical twin, your information would be as definite about her as it is about me." These facts have obvious ramifications for people in terms of health insurance, employment and other areas. They also affect science itself. Consider how researchers should handle potentially negative results that impact not only a research subject, but also their first-degree relatives. "That ups the ante," says Faden, who directs the Berman Institute of Bioethics at Johns Hopkins. The Institute's Genetics and Public Policy Center educates policy leaders, decision makers and the public about ethical dimensions of emerging genetic science.
Now Comes the Hard Part
In recent decades, scientists plucked genomics's low-hanging fruit by identifying single genes that lead to specific diseases. The gene that causes cystic fibrosis was discovered in 1989. The gene for Huntington's disease, 1993... Now comes the hard part: Sorting through multiple genes and environmental interactions that control complex diseases. Like traditional epidemiologists, pioneering genetic epidemiologist Terri H. Beaty and colleagues Yin Yao and Wen Hong Linda Kao trace risk factors for disease in populations, but they specifically look at genetic variants. Their research seeks genetic links to birth defects, type 2 diabetes, chronic kidney disease, cancer, pulmonary disease and other common diseases and disorders. "We are at the point where we can look at root causes, these genetic variations at the nucleotide level," says Kao. "Through large population-based or family-based studies, we try to understand how genetic variations interact with behavioral and environmental risk factors leading to disease."