Genomic Messages: How the Evolving Science of Genetics Affects Our Health, Families, and Future

Dedication

To our grandchildren

Contents

Dedication

Introduction

 1.  The Coming Flood of Genomic Messages

What is genomic information?

What is genomic privacy?

What is genomic medicine and why might it change how we think?

Can we strike a genetic balance in our health care?

 2.  Personalized (Genomic) Medicine

What is a genetic family history and why does it matter?

How can personalized medicine become impersonal medicine?

How did genetically isolated populations help DNA researchers?

Why will genomic medicine require electronic health records?

 3.  Nature, Nurture, and the Microbiome

How do twins help us understand that it’s nature and nurture?

How do genomics and the environment affect the fetus?

How do genomics and the environment work in diabetes?

How does your microbiome affect your health?

 4.  Pharmacogenomics

How have racism and stereotyping plagued genomics?

What does warfarin tell us about pharmacogenomics?

How do foods and genes interact?

Why is it unlikely that your physician will use your genome to prescribe drugs?

What will pharmacogenomics look like in the future?

 5.  Reprogenomics

Why is reprogenomics based on genetic relationships?

What are the social policy issues in reprogenomics?

What new issues do embryo and stem cell research create?

Is regulation of the fertility industry necessary?

 6.  Genomic Messages from Fetuses

How does prenatal diagnosis work?

What are karyotypes and microarrays?

Is whole-genome sequencing of fetuses in our future?

 7.  Genomic Messages from Newborns and Children

When is whole-genome sequencing of sick children indicated?

What is newborn screening and how does it work?

Why shouldn’t all newborns have their DNA sequenced?

 8.  Cancer Genomics

Is cancer a genetic disease?

How can the hallmarks of cancer suggest novel treatments?

Why does cancer sequencing hold promise for personalized medicine?

 9.  Genomic Privacy and DNA Data Banks

How do big data and big DNA banks affect our privacy?

How do criminal DNA data banks work?

How do commercial DNA data banks work?

How can we make informed consent to DNA data banking meaningful?

Can companies patent our DNA?

10. Genomics Future

How does genomics affect how we see death and our future?

What are species-endangering experiments?

What are posthumans and transhumans?

How can we tell the difference between genomics fact and fantasy?

How can individuals influence the genomics research agenda?

Acknowledgments

Appendix A: DNA and the Human Genome

Appendix B: Limitations of Screening Tests

Notes

Glossary

Index

Copyright

About the Publisher

Introduction

Genomics has captured the attention of presidents and physicians, of science enthusiasts and health-conscious Americans. Genomic Messages is about what your genome, as read and interpreted by a skilled geneticist, can tell you about your health and your family’s health, today and in the near future. Genomics will change how we think about ourselves and our fellow humans, and is powerful enough that it could transform American medicine in the coming decades. Because of its transformational potential, it is critical that the evolving science of genomics is introduced into medical care in a way that makes the health system better and more responsive to patients, improves communication and the physician-patient relationship, improves overall health, and contains cost, all the while avoiding the past pitfalls of the old genetics: eugenics, stigmatization, and discrimination. That’s a big order!

A genomics that improves our medical care and our lives is only possible if we as citizens, consumers, and patients all critically engage with the science of genomics. Critical engagement is possible because genomics can and should be made accessible to non-specialists and the lay public. It is also a good time for public engagement because genomics has so far been actively introduced into clinical medicine primarily in two areas: prenatal screening and cancer research. Cancer research is also at the core of the genomic medicine initiative which President Obama announced in his 2015 State of the Union address, relabeling personalized medicine, precision medicine. As the president later put it, jump-starting genomic research with new federal funding is one of his few budget proposals that has strong bipartisan support. A major component of the president’s new genomic initiative is the planned construction of a massive DNA data bank with a million Americans sharing their personal, medical, and genomic information. This data bank can only be built and used, the president underscored, if the privacy of the participants can be credibly protected. Four of the ten chapters of this book specifically address each of these areas: precision (genomic) medicine, prenatal screening, cancer treatment, and genomic privacy. The other six are interconnected: the nature of genomic information, nature and nurture, pharmacogenomics, reprogenomics, children, and genomics future. One of the themes of this book is that the coming flood of genomic information is likely to make at least some of your medical treatment more precise and personalized, but this flood of genomic information will also bring you and your physician new levels of uncertainty. The cliché is true: we do not know the future, and even with genomics we can no more predict our future health with certainty than we can predict the weather, or even the next terrorist attack.

We are a health lawyer-bioethicist (George) and an obstetrician-gynecologist-geneticist (Sherman) team who have worked together on the clinical aspects of genomics for more than three decades, during which we have published academic books and articles, participated in national and international clinical and legal programs, and worked together on ethics panels. Our working partnership is unusual. Physicians routinely see lawyers as predators, and themselves as their prey. On the contrary, our work together has reinforced our view that cooperation between medicine and law, and genomics and society, is an essential ingredient for progress. Only a genomic medicine that accounts for the values and concerns of the public and patients, is likely to produce useful, accessible, and affordable innovations that can improve your life and health. Genomic Messages contains many stories of real patients. These stories are from Sherman’s own patients (with identities masked), cases published in the medical literature, and celebrity patients who have made their own stories public.

When we began Genomic Messages, Sherman had no reason to even suspect that he might not live to see it published. But shortly after the manuscript was completed, Sherman died. His ideas, of course, live on in this book, and in the lives of his family, colleagues, and the patients he cared for. George dedicates Genomic Messages to Sherman; but Sherman and George had agreed to dedicate this book to the future: to our grandchildren.

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