The End of Sex and the Future of Human Reproduction

By Henry T. Greely

“Will the future confront us with human GMOs? Greely provocatively declares yes, and, while clearly explaining the science, spells out the ethical, political, and practical ramifications.”—Paul Berg, Nobel Laureate and recipient of the National Medal of Science

Within twenty, maybe forty, years most people in developed countries will stop having sex for the purpose of reproduction. Instead, prospective parents will be told as much as they wish to know about the genetic makeup of dozens of embryos, and they will pick one or two for implantation, gestation, and birth. And it will be safe, lawful, and free. In this work of prophetic scholarship, Henry T. Greely explains the revolutionary biological technologies that make this future a seeming inevitability and sets out the deep ethical and legal challenges humanity faces as a result.

“Readers looking for a more in-depth analysis of human genome modifications and reproductive technologies and their legal and ethical implications should strongly consider picking up Greely’s The End of Sex and the Future of Human Reproduction… [It has] the potential to empower readers to make informed decisions about the implementation of advancements in genetics technologies.”
—Dov Greenbaum, Science

“[Greely] provides an extraordinarily sophisticated analysis of the practical, political, legal, and ethical implications of the new world of human reproduction. His book is a model of highly informed, rigorous, thought-provoking speculation about an immensely important topic.”
—Glenn C. Altschuler, Psychology Today

• Language: English
• Publisher: Harvard University Press
• Release date: May 30, 2016
• ISBN: 9780674545779

Book preview

THE END OF SEX AND THE FUTURE OF HUMAN REPRODUCTION

THE END OF SEX

and the Future of Human Reproduction

HENRY T. GREELY

Harvard University Press

Cambridge, Massachusetts, & London, England

2016

Copyright © 2016 by the President and Fellows of Harvard College

All rights reserved

Jacket design: Tim Jones

First printing

ISBN 978-0-674-54577-9 (EPUB)

The Library of Congress has catalogued the print edition of this book as follows:

Names: Greely, Henry T., author.

Title: The end of sex and the future of human reproduction / Henry T. Greely.

Description: Cambridge, Massachusetts: Harvard University Press, 2016. | Includes bibliographical references and index.

Identifiers: LCCN 2015043931| ISBN 9780674728967 (hc : alk. paper)

Subjects: LCSH: Preimplantation genetic diagnosis. | Preimplantation genetic diagnosis—Moral and ethical aspects. | Human reproduction.

Classification: LCC RG628.3.P74 G74 2016 | DDC 618.3/042—dc23

LC record available at http://lccn.loc.gov/2015043931

FOR LAURA.

Of course.

CONTENTS

Introduction: Changes

PART I—THE SCIENCE

1. Cells, Chromosomes, DNA, Genomes, and Genes

2. Reproduction: In General and in Humans

3. Infertility and Assisted Reproduction

4. Genetics

5. Genetic Testing

6. Stem Cells

First Interlude—Easy PGD: The Possibilities

PART II—THE PATHWAY

7. Genetic Analysis

8. Making Gametes

9. Research Investment, Industry, Medical Professionals, and Health Care Financing

10. Legal Factors

11. Politics

12. Some Other Possible Uses of New Technologies in Reproduction

Second Interlude—Easy PGD: The Future

PART III—THE IMPLICATIONS

13. Safety

14. Family Relationships

15. Fairness, Justice, and Equality

16. Coercion

17. Just Plain Wrong

18. Enforcement and Implementation

Conclusion: Choices

Notes

Glossary

Acknowledgments

Index

INTRODUCTION

CHANGES

This is a book about the future of our species, about the likely development of revolutionary biological technologies, and about the deep ethical and legal challenges our societies will face as a result. But the best way to sum it up, I think, is to say that it is about the coming obsolescence of sex.

It is not about the disappearance of all the things we mean by the word sex. Humans will still (usually) appear at birth having physical attributes of one sex or the other and will be loudly pronounced as either baby girls or baby boys, with the appropriately colored, and gendered, accessories. Our descendants will still (almost all the time) have genetic contributions from both an egg and a sperm, thereby achieving the mixing of parental genes that is also sex or, at least, sexual reproduction. And, I am confident, people will continue to practice sexual intercourse in myriad different ways and for almost all of the current varying, complicated (and uncomplicated) reasons. Except one.

I expect that, sometime in the next twenty to forty years, among humans with good health coverage, sex, in one sense, will largely disappear, or at least decrease markedly. Most of those people will no longer use sexual intercourse to conceive their children. Instead of being conceived in a bed, in the backseat of a car, or under a Keep off the Grass sign, children will be conceived in clinics. Eggs and sperm will be united through in vitro fertilization (IVF). The DNA of the resulting embryos will then be sequenced and carefully analyzed before decisions are made (passive voice intentional) about which embryo or embryos to transfer to a womb for possible development into one or more living, breathing babies.

Prospective parents will be told as much as they want to know about the DNA of, say, 100 embryos and the implications of that DNA for the diseases, looks, behaviors, and other traits of the child each of those embryos might become. Then they will be asked to pick one or two to be transferred into a womb for possible gestation and birth. And it will all be safe, legal, and, to the prospective parents, free.

In short, we humans will begin, very broadly, to select consciously and knowingly the genetic variations and thus at least some of the traits and characteristics of our children. This idea is not new. It has been a subject of hundreds, probably thousands, of stories and novels—Brave New World by Aldous Huxley being, if not the first, certainly the first truly memorable example.¹ It has been the subject of other forms of fiction, notably the 1997 movie Gattaca.² And it has been the subject of tens of thousands of books, articles, sermons, and other nonfiction analyses—usually viewed with alarm, but occasionally with (prospective) pride.

This book is different. Not, at its heart, a discussion of the consequences of such a world (although Part III does try to analyze them to some extent), it is a description of precisely how and why that world is going to arrive. Two insights drive the book. The first is the way new techniques, drawn from several different areas of modern bioscience research, will combine to make this future not just possible but cheap and easy. The second is the way economic, social, legal, and political forces will combine to make this future not just achievable but, as I believe, inevitable, in the United States and in at least some other countries. Those insights turn these questions from interesting, goosebump-inducing speculation to real problems that will confront real people—ourselves, our children, and our grandchildren—in the next few decades.

The technical innovations will come from two worlds: genetics and stem cell research. We can already do preimplantation genetic diagnosis (PGD) on embryos. We can take away a few cells from an early test tube embryo, test them for a genetic trait or two, and use that information to decide whether to give the embryo a chance to become a baby. PGD sounds like science fiction to many people but it has been used for over a quarter century—the first child born after PGD is now over twenty-five years old. And every year now, around the world, thousands of new children are born after being subjected to PGD as embryos.

But today PGD is only weakly informative, as well as expensive, unpleasant, and even dangerous, thanks both to the limitations of genetic testing and to the necessity of using IVF as part of PGD. These constraints will change. Genetics will allow us to do cheap, accurate, and fast sequencing of the entire 6.4 billion base pair genome of an embryo and will give us an increasingly deep understanding of what that sequence means for disease risks, physical characteristics, behaviors, and other traits of the child that embryo would become. And stem cell research will allow couples to avoid the expensive and (for the women involved) unpleasant and physically risky process of maturing and retrieving human eggs by allowing us to make eggs (and sperm) from stem cells. The result will be a cheap, effective, and painless process I call Easy PGD.

Of course, just because technological innovations are possible does not mean they will be adopted. The supersonic commercial jetliner came and went; the flying car and the rocket backpack were never really launched, though both are technically feasible. But unlike those technologies, Easy PGD has a clear path to acceptance in the United States and likely paths to adoption in many other countries. It may not be approved everywhere, but in an increasingly global world, that could well be irrelevant.

The ideas in the last few paragraphs are the core of this book. I will also discuss some of the potential consequences that widespread adoption of DNA-based embryo selection using Easy PGD will have for individuals, for families, for societies, and for humanity. The fields of genetic selection have been frequently plowed before; I hope the specificity of Easy PGD as the method of choice for parents to select their children’s traits, as well as the near immediacy of the questions it raises, will add some value to my analysis over those that have come before.

Concretely, the book is divided into three parts. Part I provides background information on the science and technology involved in Easy PGD. It gives a nonscientist a guide to the varied ways living things reproduce; to the specifics of how humans reproduce, naturally and by IVF; to DNA, genes, chromosomes, and genetic testing; and to stem cell research. Much of it will be helpful in understanding what follows; I must confess that some of it is here in the hope that you will come to share the excitement and fascination of biology with me, a person whose last biology class was in tenth grade. Part II explains how and why Easy PGD will happen, looking first at the technical developments in genetics (or genomics) and in stem cell science and then at the medical, economic, legal, and political factors that will make it not just acceptable, but widely adopted. Part III examines the broader implications of Easy PGD. It looks at issues of safety, family, equality, coercion, and nature, along with some other more practical consequences of the technology.

I’ve gotten lots of good advice in writing this book, but I haven’t taken all of it. Although IVF, the fountainhead of modern assisted reproductive technologies, is less than forty years old, it has already spawned a vast literature on a wide range of issues, including many fascinating and important matters for which Easy PGD would be relevant, such as surrogacy, parental status, gamete donor rights (and duties), and the positions and roles of religious beliefs, among others. This book could and perhaps should be longer; however, practical considerations mean that the likely interactions between Easy PGD and other issues I do not analyze must await future treatments.

More fundamentally, some people have told me to make an argument—to take a position and fight for it, guns blazing. But I’m a law professor, trained as a lawyer. Lawyers do many things. Sometimes they argue zealously in court for their clients’ positions, whether they believe them or not. But sometimes they lay out all the facts and implications, as they see them, to help clients make their own decisions. I have some views about ways we might want to regulate Easy PGD, but they are tentative, based on glimpses and guesses of the future and on my own preferences and principles. I will share them, but I do not insist on them. But I will ask you to develop opinions. Easy PGD will give prospective parents—including perhaps some who are reading these words—more choices but it will also set some hard questions for all of us. My goals are, first, to get you interested in those questions—as parents, as grandparents, as citizens, as humans—and second, to give you information to help you come to your own conclusions.

Aldous Huxley’s famous novel takes its title from one of Shakespeare’s last plays, The Tempest. Years before the play starts, plotters abandon Prospero, who is both the Duke of Milan and a magician, at sea with his infant daughter, Miranda. They survive on an island with only non-human company. The years go by—Miranda grows up, and fate, working through Shakespeare, delivers the plotters to the island and into Prospero’s hands. Miranda sees them, almost the very first humans she ever remembers seeing, and, not knowing that some of them had long ago plotted her death along with her father’s, she famously exclaims:

O, wonder!

How many goodly creatures are there here!

How beauteous mankind is! O brave new world,

That has such people in’t!³

That is often remembered. What few recall (though I am sure Huxley did) was Prospero’s immediate reply: ’Tis new to thee. My hope is that when Easy PGD opens the prospects of some kind of brave new world, you will be more knowledgeable, and more sophisticated, than Miranda. (And that things will work out as well for you as, happily, they do for her in the end.)

PART I

THE SCIENCE

This part of the book sets out, in six chapters, the scientific background that I think is useful for understanding Easy PGD and its implications. The chapters cover basic information about cells, DNA, and genes; normal reproduction among living things, including humans; assisted reproduction in humans, genetics, genetic testing, and stem cells. I have tried to write about them to make the information understandable to anyone interested, even those of you who, like me, last took a biology course at the age of fifteen.

Some of you will have educational and professional backgrounds that give you far more knowledge of the areas than I can convey, or know (although, given the increasing specialization of science and medicine, I suspect very few of you will be expert in all of these fields). I will not be offended if you skip some or all of these chapters. Others of you, without a background in these sciences, will be determined to stay that way and will not want to read these chapters. I hope you change your minds. I came to biology late in life, as an amateur, and I fell in love with it—with its breadth, its combination of deep unities and myriad complexities, its many rules—each with exceptions and every exception with provisos—and its infinite surprises. In many ways it reminds me of my professional field, the law. One of my goals for this book is to bring to some of you a love of biology. For that, I need you to read the next six chapters. And I think even those of you who plan to read the next six chapters may want to read the rest of this introduction—it should be useful to guide your deeper reading, though it does mean that some parts of the next chapters will be familiar.

Part I of the book is a fairly shallow look at the science; before my last edits it was twice as long and still shallow. But I know that for some of you even those shortened chapters will be far too long, so the rest of this introduction is for you: it is the relevant biology in a nutshell—and not a big one (pistachio, maybe?). Please remember that everything that follows is incomplete and much of it is, at least in some particular and unusual applications, wrong—or at least not quite right. (And if you want references, read the endnotes to the following chapters.)

Living organisms are made out of cells, sacks of materials held together like water balloons by membranes or walls. Most living things have only one cell; the vast majority of them are bacteria or archaebacteria, which have only very simple cells. Some one-celled organisms and all multicelled organisms, from plants to ants to us, have more complicated types of cells, which have distinct different organelles inside them. One of those little organs is the nucleus of the cell. The nucleus contains (almost) the cell’s entire DNA, a molecule known more fully as deoxyribonucleic acid. The DNA in the nucleus is organized into distinct bodies called chromosomes, which come (mainly) in pairs. Humans normally have 46 chromosomes, one pair each of chromosomes 1 through 22 (the autosomes) and two sex chromosomes, either two X chromosomes (in women) or an X and a Y chromosome (in men).

Cells normally reproduce by doubling their chromosomes and splitting in half, sending the right number of pairs of chromosomes to each daughter cell. Each of the two daughter cells is a clone of the parent cell—they are genetically identical. Most life on this planet reproduces by cloning, but most of the life visible to our naked eye does not. Instead, it reproduces sexually. Sexual reproduction around the biosphere is much more varied and complicated than it is in humans, but, at its core, it ensures that instead of being genetically identical copies, an organism’s offspring are a new combination of the chromosomes from two different gametes, sperm and eggs.

Human sexual reproduction is so complicated that it is amazing any of us gets born. But, basically, sperm from a man makes a long and arduous journey to meet with a woman’s ripe egg, which has made its own shorter but difficult trip. The sperm and the egg each carry 23 chromosomes from the man or woman, half the usual number. The sperm merges into the much larger egg (think of a small pea going into a basketball). After fertilization the egg is renamed a zygote and chromosomes from the egg and sperm eventually merge to form a new nucleus, which begins to divide. After four or five days of dividing, the resulting embryo is a hollow ball, about five one-thousandths of an inch wide, perhaps visible to someone with good eyes in good light. Shortly thereafter, it needs to be in the womb, attaching to its lining and becoming implanted, if it is to have any chance to be born.

Some couples cannot have babies the usual way. Sometimes the problem is with the woman’s eggs getting to or implanting in the womb, sometimes it is with the man’s sperm getting to and fertilizing the eggs, and sometimes the cause is unknown. In many cases assisted reproduction can help, often through IVF.

In IVF, the woman’s ovaries are artificially forced to ripen extra eggs, which are then surgically extracted. This process is expensive, unpleasant, and somewhat risky for the woman involved. The eggs are usually mixed with sperm and become fertilized, although often a procedure called intracytoplasmic sperm injection (ICSI) is used. (Of course, if one of the would-be parents has no eggs or sperm, IVF alone is insufficient and the couple will need donated eggs or sperm—often sold.) Either way, some of the eggs will be fertilized successfully, and the resulting zygotes will begin to divide in containers in the clinic. If the zygotes divide successfully for a long enough time, they will be transferred into a woman’s womb sometime between the third and sixth day after fertilization, in the hope that they will implant and eventually become babies.

Now we need to go back to the chromosomes and the DNA they contain. DNA is famously called the double helix. For those of you who, like me, don’t have a good mental image of a double helix, think of a very long ladder that has been twisted into a spiral. The sides of the DNA ladder are unimportant; the rungs are crucial. Each rung is made up of two out of four molecules: adenosine, cytosine, guanine, and thymine—widely known as A, C, G, and T. But A will only combine with T to make a rung and C will only combine with G. The rungs, therefore, are made up of base pairs consisting of either A-T, C-G, G-C, or T-A. By reading the bases attached to one side of the ladder, you get the DNA’s sequence—for example, AGCGAGTTTTCG. (The other sequence, attached to the other side of the ladder, must read TCGCTCAAAAGC.) But instead of just the twelve bases in that example, the sequence of a whole human chromosome is between 50 and 250 million bases long.

Humans normally have 46 chromosomes, one copy of chromosomes 1 to 22 plus a sex chromosome (either an X or a Y) from their fathers and another copy of those autosomes plus, necessarily, an X chromosome from their mothers (the mothers only have X chromosomes to give—if they had a Y chromosome, they would be male). The sequences of all chromosomes from one parent make up the human genome and are about 3.2 billion bases long. Each of us has two copies of the human genome, one from each parent. These copies are very similar to each other (except for men, whose Y chromosome is quite different—much smaller and less important—from the X chromosome), but they do differ in about one base, or letter, in one thousand. Your complete genome sequence then, is about 6.4 billion bases long. If you think of each base as a character in the English language—a letter, punctuation mark, or space—your genome is about as long as 700 copies of the King James Version of the Bible.

Most of the bases in the human genome have no known (and quite possibly no unknown) meaning, but about 1.5 percent of them spell out instructions (code) to the cell on how to make particular proteins, the molecules that make up most of the substance of our bodies. Another chunk of the DNA letters—whether it is 5 percent, 10 percent, or more is controversial—control when and how much those protein-coding regions will be turned on or off, up or down, as well as making other useful molecules of a type called RNA. The exact meaning of the term gene is surprisingly unclear, but the human genome contains about 23,000 protein-coding regions, which can make over 100,000 different human proteins. By reading the genetic code of the sequence, we can know what those proteins are made of and whether they are normal, dangerously abnormal, or abnormal in ways that might or might not be important.

Human genetic testing has taken place for about fifty years, using many different methods. Today (and increasingly in the future) it involves looking at DNA sequences in regions of chromosomes that are known to be important and trying to figure out whether a person’s sequence is normal or dangerous. For example, the famous breast and ovarian cancer gene, BRCA1 (by convention, gene names should be italicized), is made up of about 80,000 bases near the end of the long arm of chromosome 17. It can be sequenced to see if a woman has a normal version (the vast majority of people), a version known to be dangerous (less than 1 percent of people), or a version that is not normal but may or may not be dangerous (another roughly 5 percent).

It has only been possible to sequence a person’s entire genome for less than fifteen years. The first whole genome sequence cost about $500 million and took years. Today you can get your genome sequenced in a few days for about $1,500. Observers expect this price to continue to fall, very soon to about $1,000 and eventually much further. Most people expect whole genome sequencing to be widely used for genetic tests in a few years as the price drops.

Genetic testing can be used in many different contexts. Adults or children can be tested to diagnose, or predict, diseases or traits. Fetuses can be tested before birth, through three different technologies, starting between the tenth and the eighteenth weeks of pregnancy. And embryos created through IVF can be tested before they are transferred for possible implantation and pregnancy, usually about five days after fertilization. The later process, PGD (short, recall, for preimplantation genetic diagnosis), involves taking a few cells from the embryo and then testing those cells. The results of those tests are then used to decide whether to transfer an embryo. In the past twenty-six plus years of PGD’s use, it could only be used to test any particular embryo for one or a handful of genes. PGD has been used to look for DNA associated with a genetic disease found in the family, for DNA that would allow an embryo to become a baby that could be a cord blood donor to a family member, or for the embryo’s future sex.

What all can genetic testing tell us? It depends. For some things, genetic tests reveal destiny. Anyone whose DNA has the version of the Huntingtin gene associated with Huntington disease can only avoid dying of that disease by dying first of something else. But a woman with a genetic variation of the BRCA1 gene has only about a 60 to 85 percent chance of being diagnosed with breast cancer during her lifetime and only about a 30 percent chance of an ovarian cancer diagnosis. A man with a dangerous variation in the BRCA2 gene has about 100 times the normal man’s risk of breast cancer, but his risk is still only a few percent. The percentage of people with a particular DNA variation who will get a disease or a trait associated with that variation is called the variation’s penetrance.

Today, genetic testing can give us strong information about a few thousand genetic diseases, almost all of them rare, as well as some nondisease traits, like ABO blood type. It can give us weaker information about other diseases or traits and very weak to no information about others. In the long run, though, DNA sequences should be able to reveal much, though not everything, about disease and trait risks that can be lumped into five categories: highly penetrant, serious, early-onset diseases; other diseases; cosmetic traits (hair color, eye color, and so on); behavioral traits (math ability, sports ability, personality type); and sex—boy or girl.

Whole genome sequencing has now been used experimentally on early embryos. Today it is too expensive and inaccurate to be widely used but that will change and when it does, PGD should become more popular because it will be able to make far more predictions about an embryo’s possible future. But there is still one more barrier—PGD requires IVF and IVF is difficult. The answer is our last area of science: stem cells.

Most human cells have limited lifespans. After a certain number of divisions, usually about forty to eighty depending on the cell type, they stop dividing and die. Stem cells don’t—they just keep dividing, perhaps indefinitely. Furthermore, some stem cells divide into different kinds of cells. So blood-forming stem cells can eventually make all the scores of different kinds of blood cells in our bodies.

Human embryonic stem cells (hESCs) are created by taking the cells inside the hollow ball that is a five-day-old embryo and growing them in a laboratory. They can become any cell type in the human body. We know that because those cells on the inside of the embryo go on to become every cell type in your body and mine. Extraction of hESCs has been extremely controversial because it requires the destruction of a human embryo. In 2007, Shinya Yamanaka in Japan produced the first human induced pluripotent stem cells (iPSCs). These are cells from normal body tissue (usually from the skin) that he treated in a way that made them act like hESCs. They, too, are expected to be able to become every human cell type, including eggs and sperm. And, in fact, baby mice have already been created from mouse eggs and mouse sperm derived from both mouse embryonic stem cells and mouse iPSCs.

If ripe human eggs could be derived from a person’s skin cells, it would avoid most of the cost, almost all of the discomfort, and all of the risk of IVF. It should also provide an unlimited supply of eggs, from women at any age. Along with accurate, inexpensive whole genome sequencing of early embryos, that should make PGD much easier and more attractive, leading to what this book calls Easy PGD.

For more information on any or all of the science discussed above, please read some or (better) all of the next six chapters. But if you have had enough, proceed to the First Interlude, between the end of Part I and the beginning of Part II, to pick up the story of The End of Sex.

1

CELLS, CHROMOSOMES, DNA, GENOMES, AND GENES

Nineteenth-century author Samuel Butler wrote, It has, I believe, been often remarked, that a hen is only an egg’s way of making another egg.¹ Butler could not have known it, but his statement could have been made more foundational by saying a hen is only chicken DNA’s way of making more chicken DNA. Richard Dawkins’s famous term selfish DNA encapsulates that idea.² Deoxyribonucleic acid—DNA—is the thread that connects generation with generation.

This book will have quite a lot to say about DNA, but some basic knowledge of cells, chromosomes, DNA, genomes, and genes is essential at the very beginning. This chapter provides that first, shallow background, starting with cells.³

Cells

Life as we know it is made up of cells that contain DNA. Cells make up tiny bacteria, enormous whales, and everything in between, including us. These cells are living containers of proteins, fats, sugars, and other molecules, held together within an external membrane. They are often busy things, taking in molecules, giving off molecules, expanding, contracting, moving, and otherwise interacting with their environments. And, from time to time, they split into two identical copies of themselves, using division to multiply.

Of course, in biology few if any bald statements are without exceptions. Viruses, which some consider living (though not me) are not made up of cells.⁴ Sometimes apparently multiple cells are actually contained within one vast membrane, along with multiple copies of DNA; examples include not only slime molds⁵ but also human skeletal muscles.⁶ Some unquestionable cells, like our red blood cells, contain no DNA. And some cells, like many neurons in our brains, after being created by cell division, will never divide again. Nonetheless, the DNA-containing cell is truly the building block of life.

Most biologists now divide the world of living things into three great branches, the domains of bacteria, archaea, and eukarya. Bacteria and archaea are single-celled organisms that are dramatically smaller that eukaryotic cells and lack much of the internal specialization found in those cells. In particular, they lack a cell nucleus. Bacteria and archaebacteria are collectively called prokaryotes, meaning, from Greek, pro (before) karyon (kernel or nut).

This chapter will focus on eukaryotes (good kernels), as all regularly multicellular organisms and, hence, (almost) all organisms visible to the naked eye are eukaryotes. Though remember that many eukaryotes are neither multicellular nor visible. Lots of single-celled microscopic beasties, from the malaria plasmodium to high school’s familiar paramecium, are eukaryotes.

Eukaryotes are organisms whose cells contain nuclei, an area inside the cell that is set off from the rest of the cell by its own nuclear membrane. All (well, almost all) eukaryotic cells have nuclei, along with various other specialized bodies known as organelles. Almost all the DNA in eukaryotic cells is normally contained in the nucleus, organized onto chromosomes.

Chromosomes

Chromosome just means colored body in Greek; the name comes from the fact that some dyes strongly stain these parts of the cell—they are not colorful without the dyes. Each chromosome is basically one very long molecule of DNA, wrapped around a backbone of protein. In eukaryotic cells chromosomes usually come in pairs. Thus, humans have 46 chromosomes. Forty-four of them are always paired and are named chromosomes 1 through 22. Geneticists refer to these chromosomes as the autosomes. Geneticists named the human autosomes in order from the largest, chromosome 1, which is made up of about 250 million base pairs of DNA, to the shortest, chromosome 22, with about 50 million base pairs. In two places, though, they goofed—chromosome 21 is actually shorter than chromosome 22 and chromosome 19 is shorter than chromosome 20.

In addition to these 22 pairs of autosomes, humans have two more chromosomes, the X and the Y chromosomes. These are called the sex chromosomes for the good reason that they (largely) determine a person’s sex. Someone whose cells have two copies of the X chromosome (and hence a grand total of 23 pairs of chromosomes) is (almost always) female; someone who has one X chromosome and one Y chromosome is (almost always) male. The X chromosome is moderately large, about as big as chromosome 7, and contains many genes. The Y chromosome is the third-smallest human chromosome and contains the fewest genes.

You may have seen pictures of a human cell’s chromosomes, neatly stained into a striped pattern and laid out in pairs, looking a bit like misshapen barber poles. These kinds of images of chromosomes are called karyotypes and have long been important in some forms of genetic testing. These pictures also nicely show the centromere, a special part of the chromosome that is usually near the middle and that separates each chromosome into two arms, a short one (called p for petit) and a long one (called q for the letter after p). Less clearly visible are the special structures at each end of the chromosomes, the telomeres, long stretches of repetitive and probably meaningless DNA.

But chromosomes in cells almost never look like karyotypes. Not only are they largely invisible unless stained, but they are also rarely neat and compact. Most of the time, the DNA on a chromosome sprawls wildly through the nucleus, which will be like a sphere filled with 46 long strands of very, very thin pasta. Just how filled and just how thin is impressive. The chromosomes in any one human cell, if straightened out, would stretch for about 2 meters—roughly six and a half feet. But they all fit into a cell nucleus that is about six millionths of a meter in diameter. By comparison, that is as though a basketball held forty-six pieces of string, ranging from about 250 meters (810 feet) to 55 meters (180 feet) long. The string clearly would have to be very thin indeed and so are chromosomes.

The chromosomes cannot be condensed during most of the cell’s life because the cell cannot use the DNA in the chromosomes unless it is unwound. Only during the process of cell division do the chromosomes condense from this massive and tangled ball of angel hair pasta into the discrete, rodlike chromosomes we see in karyotypes.

Obviously, it is much easier to see, and to think about, the chromosomes in their condensed forms and so that is how they are imagined. Thanks to the bands made by the stains, and the more subtle subbands and sub-subbands within the bands, these condensed chromosomes can then be divided into particular parts and given addresses. For example, 5q32 means a location in the second subband on the third band of the long arm (q) of chromosome 5. 5q35.2 would be the second sub-subband on the fifth subband on the third band on the long arm of chromosome 5.

Deoxyribonucleic Acid—DNA

From chromosomes we now need to jump down to DNA before coming back to genes. And here we come to DNA’s famous double helix, the discovery of which made James Watson and Francis Crick immortal (and left Rosalind Franklin, whose work was essential to their discovery, largely out in the cold).⁷

When I first heard the term, double helix did not make sense to me, in large part because I did not have a good sense for what a helix was. It helped me to think of the double helix as a ladder twisted into spirals. Each side of the ladder is one helix, twisting around the other but connected to it by the rungs.

The sides of the ladder, which provide the structure of the DNA molecule, are made up of unvarying, and uninteresting, components. These backbones are made up of molecules of a particular kind of sugar (deoxyribose, which means a ribose sugar that is missing one oxygen molecule) connected to each other by phosphate molecules. It is just an unvarying sugar-phosphate-sugar-phosphate-sugar-phosphate combination, over and over for tens of millions of sugars and phosphates.

DNA’s power is in the twisted ladder’s rungs. The rungs of the ladder are made up of two other molecules, each attached to a deoxyribose sugar molecule on the side. These rungs are the famous base pairs, base because they are basic, not acidic, and pairs because, in DNA, they always come in pairs. Four kinds of bases make up the base pairs of DNA: adenine, cytosine, guanine, and thymine (A, C, G, and T). Collectively, along with another molecule, uracil, or U, which is not found in DNA but in its important cousin, RNA, they are called the nucleotides.

The deoxyribose sugars on the sides of the twisted ladder are happy to bond with any of the four DNA nucleotides and, in the DNA molecule, each of them will, in fact, be joined to an A, C, G, or T. But a nucleotide on one side of the ladder will connect in the middle with one and only one other kind of nucleotide. Adenine bonds only with thymine in DNA; cytosine bonds only with guanine: A with T, C with G. In normal DNA every rung is complete, so in every place where one side of the DNA molecule has an A, the other side must have a T, and so on. Every rung is either AT, CG, GC, or TA.

The sequence of the DNA is the order of these nucleotides, as attached to one side of the ladder. For example, ATTCGATAGACT would be the sequence for one stretch of a dozen nucleotides. Of course, that is the sequence on only one side of the DNA molecule. But once we know that sequence, we know that the sequence on the other side must be TAAGCTATCTGA, because A and T always bind to each other, as do C and G. (The two sides are identified as 5′—five prime—and 3′—three prime—and the sequence is, by convention, read from the 5′ side.)

This is the great secret of DNA because it provides a way for one cell to become two copies of itself. If the DNA is split down the middle—if the twisted ladder is, in what I hope will not be a confusing mixed metaphor, unzipped—each side of the ladder will be floating free with half rungs (unattached nucleotides) sticking out into the now-unconnected middle. Everywhere there is an A, a T will be attached; every unpaired G will match up with a C. One molecule of DNA, split down the middle, can become—in fact, normally does become—two molecules of DNA, identical to the first molecule. Here is the way to turn one twisted ladder into two twisted ladders, each identical to the other and to the ladder that split to produce them. And so, if the DNA contains the instructions for the cell, this is how it can become two identical copies of one set of instructions.

Watson and Crick acknowledge this in a famous understatement near the end of their very short first publication on the structure of DNA: It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.⁸ The need to copy, precisely, the genetic material that passes from one cell, and one organism, to another is crucial. The mechanisms by which DNA is copied turn out to be quite complex—Nobel prizes have been and continue to be won through clarifying them—but Watson and Crick saw the basic story—and transformed biology.

Looked at in gross, DNA is dull, a huge molecule made up of deoxyribose, phosphate, and, among its nucleotides, roughly 21 percent cytosine, 21 percent guanine, 29 percent adenine, and 29 percent thymine. It is at the level of detail, in the sequences of the millions of bases, that DNA becomes impressively complex. With four choices for every position and roughly 6.4 billion positions in a full human genome, the theoretical number of different genomes—of different sequences of the entire 6.4 billion base pairs of the genome—is four times four 6.4 billion times. It would take only about 130 base pairs to offer as many combinations as there are estimated elementary particles in the observable universe. The amount of information that a DNA sequence can carry is, quite literally, beyond astronomical.

Genomes

The sequence of the entire DNA in an organism’s chromosomes (and hence in its cells’ nuclei and thus its nuclear DNA) is called its genome. That is almost, but not quite, all the DNA in the cell. Some of the organelles, the little organs, inside eukaryotic cells have their own small bits of DNA, organized in circles. The mitochondria, the energy powerhouses of the cell, have their own genome; in humans it is made up of 16,569 base pairs, about one four-millionth the size of the human nuclear DNA. Green plants have, in addition to mitochondria, organelles called chloroplasts, necessary to photosynthesis, that have their own DNA. The human mitochondrial genome is important but we generally talk of it as separate from the human genome.

The human genome, then, is the sequence spelled out on the 46 chromosomes, the 22 pairs of autosomes and the individual’s two sex chromosomes. One member of each chromosome pair, as well as one of each of the sex chromosomes, came from each parent. In each pair of chromosomes, the paternal and maternal copies will be very similar. They normally will be the same length, have the same banding, and carry almost exactly the same sequence.

This leads to another tricky issue of vocabulary. Does a human genome have about 3.2 billion base pairs or about 6.4 billion? That depends on whether you are talking about the haploid genome, the genome on the chromosomes derived from just one parent, or the diploid genome, the (doubled) sequence that is the actual sequence of all the DNA in a person’s cell. Of course, if those two sequences, from the mother and the father, were absolutely identical, it would not matter. The diploid genome would be just the haploid genome printed twice. In fact, in each human, the two haploid genomes are almost identical—almost, but not quite.

On average, two diploid human genomes differ at about one base pair in a thousand. That may not sound like much, but, remember, each genome has over 3.2 billion base pairs. That means each of the two genomes inside any one person will differ about three million times; when two people compare their diploid genomes, they will vary about six million times.

These variations come in several different forms. Let’s pretend we are looking at one small length of DNA and that on the 5′ side of the maternal chromosome a nine-base stretch of DNA in that area reads CTTAGACTA while the corresponding stretch of the paternal chromosome reads CCTAGACTA. In this kind of change, the identity of just one of the bases in a stretch of DNA sequence is different. This is called a SNP (pronounced snip), a single nucleotide polymorphism, where polymorphism is just a fancy way of saying difference.

Now assume that, instead of a SNP, that maternal chromosome has three extra bases inserted—CAGATTAGACTA instead of CTTAGACTA—or is missing two of the bases, let’s say the first two Ts—CAGACTA instead of CTTAGACTA. When base pairs are added, it is called an insertion; when they are missing, it is a deletion. Insertions and deletions are collectively referred to as indels. SNPs and indels are among the most common variations found in human genomes.

Of course, in any particular pair of chromosomes, if one of them has two more base pairs in a particular location than the other one does, how do you know whether it is an insertion (two extra were added to the longer strand) or a deletion (two are missing from the shorter strand)? To do that you need to know something about the usual sequence in humans in that location. There is no one human genome sequence; there are currently over fourteen billion—two each for over seven billion people, minus a bit less than 1 percent for those of identical twins. But we could invent a so-called reference sequence by taking the most common sequence at each location. The current human reference sequence, compiled and maintained by the Genome Reference Consortium, is a more