Genomic Messages: How the Evolving Science of Genetics Affects Our Health, Families, and Future - George Annas, Sherman Elias (2015)

Chapter 1. The Coming Flood of Genomic Messages

The replication of DNA is a copying of information.
The manufacture of proteins is a transfer of
information: the sending of a message.

—James Gleick, The Information (2011)

We are surrounded by genomic messages much the way fish are surrounded by water. Like fish, we pay little or no conscious attention to these messages. Our bodies, nonetheless, are constantly interpreting the messages, and the way our genes interact with each other and our environment determines the state of our health. These messages are contained in the most remarkable molecule in nature—deoxyribonucleic acid, or DNA. DNA contains the instructions for human development, survival, and physiologic functions, as well as ensuring that our biological information will be passed to our children and future generations.

Some genomic messages are visible on the surface of our bodies, including facial structure, skin color, and height. Other messages predispose us to illnesses that might be translated into diseases later in our lives. Genomic messages can also be read from DNA samples taken from fetuses and newborn babies. Whether translated, mistranslated, or ignored, our DNA and the messages we derive from it will affect (together with our environment) how we live and how we die, as well as the health and future of our siblings, children, and grandchildren. Some of us will live long, others of us will die young; some of us will develop colon or breast cancer, others will not; some of us will suffer from premature dementia, others will age with minds fully functional. Of course, the probability of death is still 100 percent for us humans. But we may be able to lengthen our lives and improve their quality, and those are worthy goals for medicine. The good news is that we may be able to prevent or treat some diseases by reading the genomic messages in our DNA. For the immediate future, however, we will only be able to probabilistically predict, but not prevent, most diseases.

This book will help you make your own decisions about whether and how to use the evolving genomics in your own life. To the extent that health insurance companies, the government, and even your employers think that genomics can save them money, they are likely to pressure you to use the new genomics. Also, to the extent that private corporations believe they can make money by getting you to use the new genomics, you will be subjected to commercials every bit as pervasive as current prescription drug advertising on TV. In this book we will tell you what we think and why, but we will strive to be as objective as we can to help you decide whether to embrace or reject invitations to genomic interventions. Our goal is to enable you to be a more informed and critical consumer of the evolving world of genomics that will invariably affect you, your family, and your ethnic community, perhaps profoundly.

Your ability to benefit from genomics will also depend, at least in part, on decisions made by physicians, the medical profession, hospitals, biotech and pharmaceutical companies, and public health officials—so we will suggest how they can act to most effectively and reasonably make the fruits of genomics available to the public, and how legislation and regulation could maximize the benefits of genomics and minimize its dangers. Every literate citizen in the United States will soon need to be familiar with genomic medicine, research, and privacy, and importantly, our rights and the limitations of government and corporate access to our DNA and that of our children.

Genomic Information

Most people use genetics and genomics interchangeably. This is consistent with both popular and scientific usage. Nonetheless, technically, genetics refers to the action of single genes, whereas genomics refers to the totality of our DNA and its interaction with the environment, and the broader term will ultimately replace the narrower one for most purposes. In most contexts, we will use genomics, but in some contexts, especially historical, genetics will be more accurate. Genomic messages are already beginning to change the practice of medicine and have the power to radically alter how your physician thinks about you and thus how your physician will talk to you and treat you and your family. Genomic messages will also likely transform what we now think about medical privacy, and could even affect the legal and ethical doctrine of informed consent.

How much of our medical future can our DNA tell us, and how much do we really want to know? How will our increasing knowledge of genetics and genomics change what medicine can do for us or how we think about our lives, our families, and ourselves? How can each of us take advantage of the coming flood of genomic information without getting drowned in information? Will, for example, genomic information simply overwhelm modern medicine by its sheer “big data” complexity? As medical historian Hallam Stevens put it, biology is “already obsessed with data. . . . [Our goal should] not be to be swept up in this data flood, but to understand how data mediate between the real and the virtual.” Stevens explains that digitalized genomic messages can change the way we think about life itself as “data bring the material [DNA] and the virtual [digital] into new relationships.” This is because, as he puts it, “data properly belong to computers—and within computers they obey different rules . . . and can enter into different kinds of relationships.” One way to think about the different kinds of relationships is to contrast the chemical language of DNA’s double helix with its digital representation in computer language. Exactly where digitalized and decoded DNA informatics takes us will depend to a large extent on our ability to interpret it and the ways we decide to use it. It is not inevitable that digitalized DNA will let us construct a “stairway to heaven,” or even a better life here on Earth.

Having digitalized DNA, the goal now is to convert the resulting electronic information (data) into knowledge of biology, both population biology and individual biology. Most of us are much less interested in the risk an average American has of obesity than we are in our personal risk, and the risk faced by our children. But for the vast majority of diseases, population average risk is all we have to go on. Nonetheless, many of us will likely want to know whatever our genomes and the genomes of our children can tell us about our probabilistic medical future, at least if there is some action we can take to improve it. On the other hand, because genetic information can alter the way we think about ourselves and our future in both positive and negative ways, some of us will not want to participate in this new world of genomics, just as many of us choose not to participate in annual physical exams or various forms of cancer screenings. There is a risk that we could come to think of ourselves as sick—even though we are completely healthy—because we are at heightened genomic risk to get a disease in the future. Seeing ourselves and our children as born diseased and destined to suffer—rather than as born healthy and destined to live a healthy life, would, we think, be a major human tragedy. That is just one reason why as the quantity of genetic information grows, the right not to know will become as important as the right to know. The right not to hear the genetic messages that could be conveyed by our DNA is not a “right to be ignorant” but a right to live our lives as we see fit. It is a right that is fundamental to informed consent, and it applies to genomics just as it applies to all other areas of medical practice.

Genomics is technologically driven, and we will provide introductions to the major technologies that are driving genomics, including computer technology, IVF, noninvasive prenatal screening, cloning, and genome editing. All technologies change the way we think by changing what we can do. Genomic technologies are so powerful that they have changed the way we think about ourselves and our future even before they have substantially changed what we and our physicians can do. The world of medicine is just beginning to incorporate genomic information into medical practice, and the evolving use of genomic information will ultimately change the practice of medicine itself, at least once your whole genome sequence is made part of your electronic health record. Changes in medical practice will include the tests your physician will want to perform on you, the drugs that can be safely prescribed for you, and the actions, such as diet and exercise, that your physician may suggest you take to reduce your risk of specific diseases.

For now, one of the major challenges posed by genomic information is its sheer size, only hinted at by the phrase big data. Our DNA has been described as a master blueprint, a musical score, and even a data bank. But perhaps the most useful and widespread analogy is to think of your DNA as a recipe. The way your cake comes out depends not just on the recipe but on the ingredients—their quality, quantity, and how they are mixed and prepared. Nonetheless, the most common metaphor remains the book. You could think of DNA as the “book of life,” or even as your biography. A DNA data bank (a collection of genomes from hundreds or even millions of people, stored on one or more servers) can be thought of as a library, like the imaginary library of the Argentine fable writer Jorge Luis Borges. Borges describes an infinite library that contains not only every book ever written but every book that could possibly be written—in every combination of letters and words. The fictional library is both completely inclusive and completely incomprehensible.

Our genomes are currently much like the books in Borges’s library, each holding an incredible amount of complex information contained within 3 billion tiny bits of paired code, called DNA, orderly arranged within a tightly wound double-helix formation. Like the letters of a book, they contain seemingly infinite combinations composed of four chemical bases (which can be thought of as composing a four-letter alphabet): adenine, thymine, cytosine, and guanine (abbreviated A, T, C, and G, respectively). The sequences of these letters are responsible for the formation and development of almost all living organisms, as well as for preserving genetic information from generation to generation, and for cell function. Even this description is inadequate: the DNA molecule is not linear, but is bunched together in loops and folds. This means that a particular strand of DNA may be in physical contact with another strand that is millions of letters away, and this contact may affect its function. The U.S. Supreme Court’s definition of DNA is so scientifically accurate we have included it as Appendix A. Having adopted the language metaphor, as James Gleick has noted, it seemed natural for biologists to also adopt related concepts, including “alphabet, library, editing, proofreading, transcription, translation, nonsense, synonym, and redundancy.”

Unlike the books in the Borges library, which can never be given meaning, we are slowly learning how to read our DNA and translate or “decode” the genetic messages contained in the approximately 22,000 genes in our forty-six chromosomes. This is being accomplished primarily by collecting and comparing vast numbers of individual genomes. Interpreting what genetic messages mean for you is currently the most challenging aspect of genomics. This is because genes interact in ways we do not understand, and our internal and external environments directly affect how our genes express themselves. Gene expression, for example, can be controlled by “switches” in the non-coding regions of the genome which can turn genes on or off. Another major influence on our genes is our “microbiome.” We are home to 100 trillion microbes (bacteria, yeasts, parasites, and viruses), which affect whether and how our genes are expressed. Until recently it was also assumed that our DNA was stable and that its functioning could not be easily modified. We now know that environmental factors modify the functioning of genes, and this has enabled a new scientific area of research, epigenetics (“on top of” or “over” genetics).

Medicine is still very early in the genomic quest for a longer life, as well as the quests to cure or prevent Alzheimer disease, Parkinson disease, diabetes, or cancer by attacking their genetic roots. The massive project to develop an Encyclopedia of DNA Elements, known by the acronym ENCODE, for example, in 2012 published its first results, which described functional elements (other than our 22,000 protein-coding genes) that make up the human genome. It appears there is very little “junk,” or nonfunctioning DNA. “The ENCODE consortium has assigned some sort of function to roughly 80% of the genome, including more than 70,000 promoter regions . . . and nearly 4,000,000 enhancer regions that regulate expression of distant genes.”

Genomics leader Eric Lander of MIT has described the current state of genomics using another metaphor, a map: “It’s Google Maps. . . . [T]he human genome project was like getting a picture of Earth from space. It doesn’t tell you where the roads are, it doesn’t tell you what traffic is like at what time of the day, it doesn’t tell you where the good restaurants are, or the hospitals or the cities or the rivers. . . . My head explodes at the amount of data.” We’re with Lander in marveling over the vastness of information that is being added to genetic messages, as well as the effort that will have to be devoted to deciphering and interpreting them.

In February 2015, after it was determined that gene “switching areas” in the genome could turn genes on and off, Lander commented that it was extremely complicated to figure out which switches went with which genes. Boston was still digging out from a series of major snow storms that crippled the city’s transportation system, and Lander used the Boston subway system as his new metaphor. He thought it would be possible to figure out which subways lines were disrupted by the storm by determining which employees were late for work. Similarly, when a genetic circuit is shut down, Lander thought it possible to determine which genes were affected, and thus which genes are likely to be associated with the circuit. The name of the new project is the Roadmap Epigenomics Project, which the researchers involved described as an effort to construct a “road map to the human epigenome (a collection of chemical modifications of DNA that alter the way genetic information is used in different cells). This is powerful new research, but as the editors of Nature put it in announcing some of the results, “despite the progress, each question that the genome helps answer throws up further questions. Much remains to be understood about how genetic information is interpreted by the individual cells in our body.” All of this confirms our initial intuition: scientists are early in the genomics research phase, and many if not most clinical applications remain in the distant future. For the immediate future, we are confronted with one of what former secretary of defense Donald Rumsfeld described as the “known unknowns,” things we know we don’t know.

Your genes are a vital part of you, but you are much more than just your genes, more than even your entire genome. This means we will never be able to understand human life or humanity no matter how much we understand about our genome; humans simply do not live their lives on the genetic or molecular level. Nonetheless, the more we discover about our genomes, the more difficult it becomes to resist thinking that the more we know about the tiny parts that make up our DNA, the more we will know about ourselves and our lives. This is evident whenever someone defines a person or a fetus based only on a specific genetic characteristic. We have already lowered the cost of whole-genome sequencing for research to $1,000, and this (or less) will likely be available in the clinic soon. The $1,000 genome has always seemed like a reasonable technological goal, and a necessary one to bring the genome into clinical medicine by pricing it on the level of an MRI.

At the clinical level, however, the decreasing price of a genomic sequence has so far primarily produced more complex translation questions. Our current situation is sometimes described by the only half-joking observation that we will soon have “the $1,000 genome with the $1,000,000 interpretation.” This is a purposeful exaggeration but it underlines two points. The first is that cost alone cannot determine use. The famous story of the $5 elephant makes the point: you would not buy an elephant, even for only $5, if you did not want an elephant. The elephant is much more trouble to most people than its price alone would suggest. The second point is that regardless of price, interpreting genetic information is much more difficult than collecting it. This is the primary reason why companies in the United States, China, and Europe are collecting genomes from tens of thousands of people: to do research on these collections to identify genetic sequences that matter to health. It is also why President Obama called for a new project to collect DNA and medical records from a million Americans in 2015. Collecting genomic data is, of course, a means to an end (better health), not a goal in itself. Stockpiles of genomic information alone will not help anyone and could hurt us all by enabling genetic discrimination. We will need to shift the focus of our research projects from simply collecting and sequencing DNA to figuring out how, like the “switching” research, genomic information can be used to help us.

In her futuristic MaddAddam trilogy, Canadian novelist Margaret Atwood imagines a different kind of flood of information, a “waterless flood,” in which a lethal pandemic of a bioengineered virus destroys most life on the planet. Atwood’s cautionary tale reminds us that genetic information has a dark side. We have properly begun to take steps to regulate plague-related research, such as research designed to make a virus more virulent or deadly, for our own protection and that of the planet. We will address the regulation of international research in chapter 10, but mostly this book is about helping you make your own decisions about using the evolving science of genomics in your own life.

To take full advantage of the evolving genomics, you will need to know more than just the scientific and medical aspects—you’ll also need to know the relevant legal and ethical aspects. Physicians and lawyers must work together in this realm. Although often seen as natural enemies, even as prey and predator, we believe that not having doctors and lawyers working together is counterproductive and shortsighted. Just as genetics cannot be isolated from medical practice, so too medical practice and genetics cannot be understood without an appreciation for the legal and ethical issues they raise. This is true not only in the courtroom and legislative hearing room but at the bedside as well. The intimate relationship of medicine and law in genomics is perhaps most apparent in the realm of what has come to be known as genomic privacy.

Genomic Privacy

Both physicians and lawyers have historically protected privacy. We believe that your genome, which George has called your “future diary,” should be considered as private as your diary. No one should be able to “open” it or “read” it without your authorization. To put it another way, your genome is so personal and important to how you view yourself, and potentially to how others view you, that you should always be considered the owner and person in charge of your genome and the information it contains.

The idea for the “future diary” metaphor came from the late New York Times commentator William Safire, who argued that diaries should remain private because they are uniquely our own. We keep a diary “to reveal our youthful selves to our aging selves.” We think Safire is correct and that his reasoning applies to our genomes as well: we open our genomes “to inform our younger selves about our aging selves,” and only we should be able to determine if our “future diary” will be opened and read. Genomes can also be used by individuals to help them identify risk factors—but this suggests a less benevolent metaphor: the DNA profile as a “personalized health threat matrix” that identifies the conditions most likely to kill or sicken us.

Neither of these metaphors means that we think your DNA alone is capable of telling a coherent story about your life, or even your health. We agree with linguist Ann Jurecic that “genome sequences aren’t like stories. . . . [T]here is a profound difference between genetic data and a story that seeks to define a life’s meaning.” She believes making sense of our interactions with genomic information “will require experimentation with new literary forms” that will enable us to tell stories about ourselves not focused on the molecular level but entangled with the whole “earth in which we live.” Another writer, Christine Kenneally, has eloquently argued that our DNA tells us more about our past than our future. You are a product of humanity’s history. “The millions of bits that initially made you—all the cultural bits and the genetic bits, each with its risk factors, predispositions, and probabilities—were shaped by the past.” She seems right about this, and the “past and future diary” may be a better metaphor for DNA privacy (figure 1.1).

Our DNA’s inability to define us, however, should not make it a public resource, any more than it makes our blood or organs public resources. Instead, society should take genomic privacy seriously enough to outlaw the collection of an individual’s DNA for testing without authorization. This should be done not only because knowledge of one’s genome can probabilistically predict at least some of our future health problems, but also because DNA information can be easily distorted and used against us. This potential for misuse and stigmatization is also why we remain surprised that no one has tried to use the DNA of a presidential candidate (taken from a drinking glass) against the candidate. An opponent could suggest, for example, that the candidate is genetically predisposed to a condition that could adversely affect his judgment, such as dementia. This tactic can be labeled “genetic McCarthyism.” This misguided use of genetics is in the same category as trying to identify a “mass-murderer gene.” For example, University of Connecticut researchers wanted to examine the DNA of Adam Lanza—the killer of twenty-eight people in Newtown, Connecticut—to see if they could identify a “mass-shooter gene.” We are easily seduced by genomics and need to keep our common sense fully engaged when genomic answers to complex human behavior questions are suggested. DNA-centric thinking is an example of what psychologist Daniel Kahneman termed “thinking fast,” when what is called for in genomics is “thinking slow.”

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1.1  Artist’s rendition of George’s DNA “Future Diary” in USA Today. Marcia Staimer, “Future diary,” in M. Snider, “Genetic Privacy Laws Sought,” USA Today, November 17, 1993, 9D.

As important as genomic privacy is to political candidates, it is likely that you will find it much more important to yourself, your family, and your physician. Genomic privacy is really about control of your genomic information, including whether to seek it at all and with whom to share it. Sharing your DNA, even with your family, should, we will argue, be a personal choice. But we also think it should be an educated and well-considered choice. Current federal law prohibits discrimination on the basis of genetics in employment and health insurance but not in life, long-term care, or disability insurance. Of course, the importance of genomic privacy is based on medicine’s ability to extract and interpret messages contained in your genome, and that ability is improving daily.

Genomic Medicine

The ability to sequence an individual’s entire genome (whole-genome sequencing, or WGS) has also opened a door to a whole new field of medicine known as “personalized medicine,” “precision medicine,” or simply “genomic medicine.” By sequencing an individual’s genome, physicians will be able to obtain a genetic profile to guide them in diagnosis, treatment, and possibly even prevention of disease. Some genomic messages are already informing medical treatment, particularly in certain cancers. As an overview, we briefly discuss four examples, one involving a medical treatment based on a genetic finding, another involving a series of preventive measures taken based on a genetic finding, a third in which the primary result of a genetic finding was uncertainty, and a final example of noninformative genetics: Angelina Jolie Pitt; Sergey Brin; Donna, one of Sherman’s patients; and Robert Green, a colleague of George and Sherman.

Genetic screening for cancer-predisposing genes, coupled with fear of cancer, has led to interventions to remove the tissue most at risk for developing cancer. Angelina Jolie Pitt is the public face of a strategy to prevent BRCA1and/or BRCA2 mutation carriers from developing breast or ovarian cancer by removing the breasts and ovaries before there is any evidence of the disease. Jolie Pitt told her story to the world in an op-ed published in the New York Times in May 2013. The following week she was on the cover of both Time magazine (figure 1.2) and People magazine. Her mother had died of ovarian cancer at fifty-nine, and Angelina herself was found to have a mutation in the BRCA1 gene, which her physicians told her gave her a lifetime 87 percent risk of breast cancer and a 50 percent risk of ovarian cancer. As she put it, “Once I knew that this was my reality, I decided to be proactive and to minimize the risk as much as I could. I made a decision to have a preventive double mastectomy.”

Angelina Jolie said she wrote about her experience in the hope that other women could benefit from it: “Cancer is still a word that strikes fear into people’s hearts, producing a deep sense of powerlessness. But today it is possible to discover through a blood test whether you are highly susceptible to breast and ovarian cancer, and then take action.” She wrote that her decision was “not easy” but is one “I am very happy that I made.” She continued, “My chances of developing breast cancer have dropped from 87% to under 5%. I can tell my children that they don’t need to fear they will lose me to breast cancer.” She noted that 458,000 women worldwide die of breast cancer each year and that she wanted it to be a priority “that more women can access gene testing and lifesaving preventive treatment, whatever their means . . . and wherever they live.” She concluded, “There are many women who do not know that they might be living under the shadow of cancer. It is my hope that they, too, will be able to get gene testing, and that if they have a high risk they, too, will know that they have strong options.”

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1.2  Angelina Jolie on the cover of Time, May 27, 2013.

Americans often emulate celebrities, and Time magazine suggested that even women who have no medical indication for a double mastectomy might find a rationale in their genes to have this radical surgery. The chief medical officer for the American Cancer Society, Otis Brawley, for example, tells the story of a woman with no family history of breast cancer getting screened for BRCA1 and BRCA2 anyway. Her test revealed a mutation of “unknown significance.” She had a double mastectomy. The mutation of unknown significance was later determined not to be associated with an increased risk of breast cancer. Brawley uses this story to illustrate what he terms “the pinking of America” with its overreaction to breast cancer: “We have overemphasized and scared people too much.” That certainly seems to be true, and without in any way criticizing the decision Jolie Pitt made, it should be underlined that no one should make the same decision simply because she made it. Worried that others may follow her example with insufficient genetic information, the U.S. Food and Drug Administration (FDA), in late 2013, shut down the gene interpretation portion of the leading direct-to-consumer genetic testing company 23andMe. The company’s TV ad included the claim, “The more you know about your DNA the more you know about yourself.”

The FDA ordered the company to cease marketing its product because 23andMe could not demonstrate that its results were reliable. The company had been offering to provide genetic profiling information for $99 and give their customers, as their advertising puts it, “health reports on 254 diseases and conditions,” such as heart disease, diabetes, and breast cancer. Its nationally run TV commercial, which began running in the summer of 2013 with the aim of getting one million people to purchase their product (about 500,000 had signed up when the FDA stepped in), used the following language, spoken by extremely attractive and physically fit young people: “My DNA . . . is me . . . it’s like a self-portrait . . . learn hundreds of things about your health . . . change what you can, manage what you can’t.” Regarding breast cancer, the FDA was concerned that a false-positive result (finding the presence of the BRCA1 or BRCA2 gene when it is not actually there) “could lead a patient to undergo prophylactic surgery, chemoprevention, intensive screening, or other morbidity-inducing actions, while a false negative could result in failure to recognize an actual risk.” This concern, however, seems far-fetched; no surgeon should operate for a genetic condition without independently confirming it.

The FDA was also worried, somewhat more plausibly, that patients who had genetic mutations that could affect the way some drugs are metabolized might change their dosage without consulting their physicians. Regarding the anticoagulant warfarin, for example, the FDA was concerned that patients taking warfarin to prevent blood clots might change the amount of the drug they were taking without consulting their physicians based on a false genotype result, and that this could lead to death or serious illness.

It also seems reasonable to conclude that the FDA acted because the agency thought it was time to regulate the entire consumer genomics industry. If so, the FDA is correct that more than just accuracy is at stake in the 23andMe debate. Other questions include whether you should have to go through your physician to obtain a genetic profile (we don’t think so), who “owns” your DNA (you do) and whether you have a “right” to the information it contains (you should have), and what the role of the federal government should be in regulating DNA-information products and practices. We think regulation should be at the federal level, and that the FDA is the right agency to do it. Other commentators disagree. Eric Topol, author of The Patient Will See You Now, sees Angelina Jolie Pitt’s public announcement as transforming her role from leading actress in action films to “playing a leading role for self-knowledge, freedom of information, and medical information ecology.” In this context Topol calls the FDA’s action against 23andMe unjustified paternalism.

The FDA is in talks with 23andMe, and in early 2015 the agency indicated that it was prepared to exempt genetic tests for autosomal recessive diseases that could be used by couples to determine whether or not they both carried such a gene, which would give them a one in four chance of having an affected child. The company issued a notice to their customers indicating that the FDA’s approval for Bloom syndrome carrier status was the first time the FDA had authorized a direct-to-consumer genetic test.

Two years after her double mastectomy, Angelina Jolie Pitt wrote another op-ed for the New York Times, this time about her decision to go further and have her ovaries and fallopian tubes removed. There are no good screening tests to detect early ovarian cancer, but because of her family history, various biologic markers were being tested annually. Nothing alarming or abnormal was detected. Nonetheless, Jolie Pitt opted to have her ovaries and fallopian tubes removed—not because she had the BRCA1 mutation, but because of family history. Three women in her family had died of cancer. Her doctors told her that preventive surgery was best done about a decade before the earliest cancer onset in her female relatives. In her words, “My mother’s ovarian cancer was diagnosed when she was 49. I’m 39.” With the full understanding that “it is not possible to remove all risk [of cancer]” Jolie Pitt repeated what she had said about breast cancer two years previously but this time in reference to ovarian cancer: “I know my children will never have to say, ‘Mom died of ovarian cancer.’”

Two points can be underlined. First, her decision was perhaps as fully informed as is possible. For example, she understood that no guarantees came with the surgery and that there are side effects (menopause, hormone replacement therapy, physical changes, and inability to have genetic children). Second, the decision is a personal one, a part of personalized medicine. In her words, “There is more than one way to deal with any health issue. The most important thing is to learn about the options and choose what is right for you personally.”

Sergey Brin’s well-known story is worth recounting in this context. Sergey was born in 1973 in Moscow and came to the United States with his parents when he was six. Sergey’s mother started to develop neurological problems when he was a teenager; she first experienced numbness in her hands, and later her left leg began to drag. She was evaluated at Johns Hopkins University, where she was diagnosed with Parkinson disease. During orientation for new PhD students at Stanford, Sergey met Larry Page. Working out of a garage, Sergey and Larry started Google. The owner of the garage had a sister, Anne Wojcicki, who later became Sergey’s wife (they are now separated). In 2006, Anne cofounded 23andMe, through which Sergey learned that he carried a specific mutation in a gene called LRRK2. This mutation was reported to give him between a 30 and 75 percent lifetime risk of developing Parkinson disease. Sergey’s mother was also tested by 23andMe, and she carried the same mutation. Today, 23andMe has the largest collection in the world of DNA from people with Parkinson disease.

Sergey knew that there was accumulating evidence that lifestyle modifications might lower his risk of Parkinson disease. These include increasing exercise and coffee consumption. Sergey decided to begin exercising regularly. He goes to a pool near Google headquarters several times a week to swim. He drinks green tea on the assumption that it is caffeine intake, not coffee itself, that matters. Based on these changes, Sergey estimated that he could reduce his risk of Parkinson to 25 percent. When he includes the probable advances from Parkinson disease research in the future, including research he himself is funding, he calculated that his overall risk is only 13 percent.

It is difficult to overstate the potential of genomics to change the way we think about and treat our own medical conditions. Both health and health care will take on new genetic and genomic-driven meanings. Nevertheless, as we have emphasized, genetic information cannot explain everything in medicine, let alone in life. It is dangerous, if tempting, to take the significance of DNA information to an extreme that suggests we can both discover our human essence and precisely predict our health future by deciphering the entirety of the information encoded in the As, Ts, Gs, and Cs that make up our genomes. We are a product of our environment as well as our genomes. Sergey Brin understands this and knows that his genes do not alone determine his fate. Understanding that environment often plays an equal or greater role in our health future than do our genomes, he decided to reduce his risk of disease by modifying his environment through exercise and diet.

Even with significant advances in genetic testing, the information we gather can be misleading or impossible to interpret. Currently, the fastest-growing use of genomic testing is in prenatal care. Sometimes, even with access to important genomic messages, the messages are simply too complex to understand and apply to personalized medicine. For example, Sherman had a thirty-six-year-old patient, whom we’ll call Donna (not her real name), who was concerned about having a child with a chromosomal disorder. Sherman did a first-trimester chorionic villus sampling (CVS), in which placental tissue is removed and tested for chromosomal abnormalities. In addition to using the traditional method of chromosome analysis, Donna volunteered to participate in a National Institutes of Health research project to have the placental sample tested using a newly developed DNA-based test called microarray analysis. Though the results showed that the fetus was not affected with any known chromosomal abnormality, the laboratory reported a DNA “variant of uncertain significance.” Neither of the parents carried this variant. Although it was believed to be unlikely that the “variant” would cause significant problems in the child, Sherman could give Donna and her husband no guarantees. Instead of an answer, genetics provided a message of uncertainty, another thing to worry about. In addition to the risk of genomic tests failing to provide “actionable” information, there is also the risk that the plethora of genetic tests will simply confuse patients and their physicians and lead to anxiety and more testing.

Some physicians go overboard and provide an exhaustive list of all possible problems a variant could cause just in case lightning strikes. Their reasoning is that it’s better to give too much information than too little, just in case something unanticipated goes wrong, so the physician cannot be blamed (or sued) for failing to mention the possibility. Simply increasing the amount of information conveyed, however, risks confusing the patient, losing perspective of the most important and common issues that should be considered, and engendering needless worry. It is what we have already referred to as a “personalized health threat matrix.” It also illustrates an inherent paradox in modern obstetrics: in trying to make pregnancy and childbirth safer for women and increase the probability of having a healthy baby, it has been seen as necessary to perform an extensive number of tests and convey large amounts of technical, often confusing, information that predictably increase the anxiety of prospective patients.

Our final introductory example involves medical geneticist Robert C. Green of Harvard Medical School, who during the early days of direct-to-consumer genetics sent his DNA to be analyzed by all three of the new commercial companies, including 23andMe. His results indicated that he was at a lower risk of heart disease than the average person. Shortly after he got his results, he was diagnosed with serious heart disease that necessitated coronary bypass surgery. This does not, of course, mean that the results were either inaccurate or wrongly interpreted—many people with a “low” risk of heart disease in fact develop heart disease. All we have now are some population averages; we are unable to specify the risk for any given individual. The results of the famous Framingham heart study are similar. The Framingham data showed that men with a very high cholesterol level were at a much higher risk of heart attack than men with a low cholesterol level. What they could not tell, however (and we still can’t), is the risk of a heart attack for a particular individual.

In 2013 Green became one of the first few hundred healthy individuals to have his entire genome sequenced. In a 2014 interview in the Boston Globe, Green noted that in this sequencing he carried a rare genetic mutation in the TCOF1 gene that causes Treacher Collins syndrome. Treacher Collins affects bone development in the face and is disfiguring. Green had the mutation but insisted that he did not have the disease. This is because although the initial report described the mutation as pathogenic, he and the lab that issued the report later evaluated it as a variant of unknown significance. As reporter Carolyn Johnson put it, “Green only has to look in the mirror to know that he does not have the disorder.” This is, of course, true. It is also a good example of a major point in this opening chapter: genes are not destiny, and even dominant genes for serious conditions may not express themselves. On the other hand, when we identify such a gene in an adult, we have insufficient information to counsel the person. Perhaps the best we can do for now is to say, as Green says about himself, “Most likely this is not a meaningful mutation.” Finally, and most importantly, his case illustrates why it is premature to use whole-genome screening on fetuses. In Green’s words, “I know this is [likely not a meaningful mutation] but imagine if you’re a pregnant woman and someone reported that mutation out to you about your baby. Can you imagine?” Yes we can.

Striking a Genetic Balance

How can we maximize the good that modern medicine can do while minimizing the potential harm? This question recurs almost every time a new test, including a genomic test, is added to our medical arsenal. Couples in the near future will be faced with much more genomic information about their fetuses. Sharing these future genetic messages with a couple is imperative, but this could cause information overload and more uncertainty—and could even lead to the abortion of wanted, healthy fetuses. New methods will have to be developed to help physicians convey genomic messages to pregnant patients in a helpful and meaningful way.

Genomics will encourage some existing trends in American medicine and discourage others. American medicine, for example, mirrors four major characteristics of American society. It is wasteful, technologically-driven, individualistic, and death-denying. Restricting the use of drugs to people with genomic profiles that permit the drug to be safe and effective could actually cut down on waste. But genomics will likely reinforce the other three characteristics. The role physicians, patients and the public will play in the introduction of genomics into clinical care is uncertain. Is it reasonable to expect that our physicians will understand how to access, evaluate, and explain to us the medical implications of our genomes? How will the information coded in our genomes be read and interpreted, and by whom? Who will pay and who will want to know the content of the messages contained in our DNA? All of us have a stake in understanding genomics on at least four levels: the first is our own life and health; the second is in the lives and health of our family members; the third is in the health of our communities (including the rules under which genetic messages will be read and shared with others); and the fourth is as a member of the human species (and how we might try to modify or improve humanity).

Most centrally, we will keep asking how we can all use newly discovered and (re)interpreted genomic information in our own lives, and how we can be better prepared to deal with genomic information that could do us more harm than good. We will explore the impact of genomic messages on our potential children and our actual children. In addition to the prenatal diagnostics already in use, the future is likely to include the option of complete genome screening of newborns. How the resulting genomic messages are interpreted, and who has access to them are major public health policy questions. Should the entire genome of all newborns be sequenced and stored, or should we only screen newborns for specific genes linked to serious diseases? Should parents be able to have their children tested for genes correlated with traits such as athletic ability, perfect pitch, or eye-hand coordination as an aid to deciding what school, activity, or profession the child should be encouraged to pursue?

Some of the other topics we address in this book include the importance of genomics to fertility treatment, and the wide-ranging field of research genomics. We will examine genomic privacy in more detail and ask whether it should remain a central value, as well as whether and under what circumstances you should donate your DNA or your medical records to a research “biobank.” We will consider the impact of two U.S. Supreme Court decisions on DNA. The first permits the police to take your DNA for storage if you are arrested, and the second prohibits the patenting of DNA as it occurs naturally in your body. We will also highlight proposals, which may seem like science fiction, that well-respected figures in human genomics and synthetic biology are planning to implement in the hope that they will make our lives, or the lives of our children, better, or at least longer. We begin our exploration of how genomics will affect us and our health care system by examining the meaning of personalized (genomic) medicine in the context of the American health care system.

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WHEN THINKING GENOMICS,
CONSIDER THESE THOUGHTS

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Genomics can tell you some things about your
probable medical future, but it is not destiny.

DNA is like a recipe, but you can also think of it as
a book whose language is still being translated.

Genomics has already changed the way
we think about ourselves and how we
transmit conditions to our children.

Messages from DNA are personal and
private, as private as our diaries.

There will be times you won’t want (or
need) to know your possible medical future;
that choice should always be yours.

Genomics is evolving, and as it does, it will affect
you and the way physicians interact with you
in both predictable and unpredictable ways.