Masterminds: Genius, DNA, and the Quest to Rewrite Life

Try saying deoxyribonucleic acid. It’s not too hard, even if it sounds sciency. Die-ox-ee-ribe-o-nuke-lay-eek acid. DNA is a three-dimensional information-storage molecule—a collection of atoms joined together by chemical bonds—drawn by chemists as a two-dimensional figure on a page that looks like this:

DNA is composed of three materials: first, a microscopic hunk of sugar called a deoxyribose that is joined to a second component, a phosphate, that links the deoxyribose sugars. This sugar-phosphate “ladder” is the superstructure of DNA, its outer backbone supporting the third ingredient, the nucleic acids, also known as bases. These bases are much like the zeros and ones in binary computer code, except that instead of two elements to the code, DNA contains four bases: adenine (A), cytosine (C), guanine (G), and thymine (T). And instead of encoding programs on a computer, the sequence of these bases provides instructions to create and maintain a living organism.

Are your eyes already glazing? Well, think of this as learning to drink wine, which most people don’t like at first but keep trying until it becomes quite a nice sensation. Scientific concepts will not be quite so sweet, or dry, for most nonscientists. Nor will they give you a pleasant buzz. But having at least a rudimentary knowledge of the language and concepts of modern biology could save your life, or your children’s. It could prevent you or others from becoming unduly frightened of new discoveries that are safe or it could make you knowledgeable enough to be frightened of science that is not. If you can use a recipe to bake mustard-lemon halibut, or comprehend the difference between a concerto and a symphony, you can get this stuff. Absorb these ideas as you might the basics of how to write a haiku poem or a rock lyric, or read box scores in the sports section.

You don’t need to know how to say the chemical name for DNA to read this book, but it’s a little like reading a Dickens novel without really learning the names of Oliver Twist, Nicholas Nickleby, and David Copperfield. Granted, mitochondria, enzyme, and polymorphism lack the ring of Twist and Copperfield. They seem to have been decided on by scientists whose imagination did not include concocting snappy names, a misfortune that has hardly helped the cause of enlivening the scientific debate. Scientists, along with lawyers and engineers, have created over the centuries a complicated language that makes it easy for members of their science-speak caste to talk to one another, but sounds like mumbo jumbo to everyone else.

The story begins with a cell—the basic unit of life, the universe where most of the action takes place in the science part of this story. Nearly all life-forms are comprised of cells, either just one or, in the case of humans, about 100 trillion. Many cells contain a central glob called a nucleus filled with chromosomes, twenty-three pairs in humans, and various numbers in other organisms. In most of the living creatures you see (such as ourselves, mice, goats, fish, plants, starfish), these chromosomes contain two complete sets of the genome, one each from the organism’s parents—except sperm and egg cells, which contain only one complete set, and red blood cells, which have no nucleus. (There a few exceptions to this, but they are not important to understanding the concept.) The chromosomes are made out of DNA, which in a human consists of around 3 billion base pairs from each parent, for a total of 6 billion. The DNA is arranged in pairs like the rungs on a ladder, the rungs twisted elegantly into the famous double helix, discovered by Watson and Crick in 1953. If each base pair were the size of a letter on the page of this book, the strand would run from my office in San Francisco to my hometown of Kansas City, Missouri. Writing it all down in a book would take 500,000 pages.

These pairs are arranged in linear sequences of up to several thousand bases called genes—some thirty thousand of them in a human, and a few hundred of them in the simplest single-celled bacterium. (The exact number of human genes is still debated; there also are millions of base pairs that apparently do nothing, so-called junk DNA, though recent findings suggest that more may be going on amid this “junk” than has been previously realized.) The arrangement of the base pairs into sequences of As, Ts, Cs, and Gs is the basic code of life. Remarkably, DNA figured out eons ago how to replicate itself and to be read by the cell to perform functions. (Little is known about how primordial DNA molecules on the ancient Earth figured out how to copy themselves; efforts to piece together a mechanistic picture of how this happened have been ongoing since the 1950s). This is because each nucleotide is designed by evolution to pair with another specific nucleotide. As like to pair with Ts, and Gs with Cs. When DNA replicates it splits in half, with the assistance of certain proteins, with each strand of the double-helix ladder separating like a zipper unzipping. The exposed bases then have the ability to pair with complementary nucleotides. Processes in the cell then help seek out loose nucleotides floating around and chemically incorporate them into the growing DNA chain—As pair with Ts, Gs with Cs, and so forth, voilà, a new set of complete chromosomes.

DNA’s second mission is to carry the code used to create proteins, which are encoded by genes. Proteins are sequences of amino acids; they look something like a linear pearl necklace bunched up into a ball, with each pearl being a different amino acid (there are twenty different types of amino acids generally used in proteins). Even though humans are thought to have only 30,000 genes, our cells make many times that number of different proteins. Proteins are the key structural components of life and also serve as the machines that accelerate chemical reactions (if a protein accelerates a chemical reaction, it is called an enzyme). Proteins turn genes on and off, proteins recognize and eliminate invading infectious organisms, proteins unzip and help copy DNA. In short, life as we know it is largely handled by these elegantly designed protein nano-machines designed over the millennia by evolution.

Proteins wad up into specific three-dimensional shapes that interact with other three-dimensional shapes, including other proteins, the blobs often attracted to each other by chemical and electrical bonds that cause reactions that regulate everything from memory storage in a brain cell to tears in our eyes when we are sad. Each amino acid is coded by a three-base sequence. For instance, the amino acid alanine—abbreviated A—is coded by GCG, and the amino acid histidine—an H—is coded by CAC. So let’s say the gene sequence of my crooked toe starts with GCG, which makes an A, and then CAC, which makes an H. Then repeat GCGCAC six times. The resulting protein would have an amino acid sequence like this: AHAHAHAHAHAH, and on and on, depending on the sequence of the DNA.

Proteins are not made directly from the master code recorded on your DNA. Rather, they are manufactured with the help of an intermediary molecule called RNA that carries nucleotide instructions to direct the assembly of each protein molecule (a single RNA molecule can be used to direct the synthesis of multiple copies of the same protein molecule). Like DNA, RNA is composed of a linear sequence of bases, As, Cs, and Gs, but it has a U for uracil instead of a T. In a process called transcription, special proteins called RNA polymerases sit on top of a region of DNA containing a gene. These RNA polymerases then synthesize an RNA molecule based on the linear sequence of the gene. This special RNA molecule is called messenger RNA, and its sole purpose is to direct the synthesis of proteins based on its sequence. Messenger RNAs are assisted by ribosomes, a tiny protein assembly factory in the cell that is partly made up of RNA and partly made of protein. Its job is to chemically build proteins using the assembly instructions contained on the messenger RNA. Each three-letter base code in the messenger RNA designates a specific amino acid. Loose amino acids in the cell are recruited to the ribosome and chemically linked together into a growing protein chain. (Amino acids come from food we eat.)

Sometimes when genes are replicated, mistakes are made—a letter (base) is missing, or the order of bases is scrambled or duplicated too many times. These errors are mutations, which happen frequently, it seems—though how often is open to debate as certain researchers say the rate of mutation is constant, while others say it goes up and down based on whether or not an organism needs to mutate or not. Most mutations have a neutral effect, though some simple mutations—swapping an A for a G, for example, in a particular gene—can be fatal or helpful, by offering some sort of evolutionary advantage. The idea of mutation is one of the key tenets of Charles Darwin’s theory of natural selection, though he knew nothing about DNA—that mutations and differences in hereditary material from one generation to another account for adaptations that favor some organisms over others. For instance, at some point early humanoids figured out that by standing upright on the savannas of Africa they could see quarry to hunt or a hungry saber-toothed tiger bearing down on them. Those humanoids had a tiny difference in their DNA that allowed them to stand more upright than other humanoids did not get eaten, and therefore survived—along with the genes for uprightness.

Not all genes are found in chromosomes. A few live inside little structures within cells called mitochondria, which billions of years ago were parasites that entered primitive cells and became a crucial part of the cell’s energy-processing machinery. With a circular band of genes separate from an organism’s chromosomes, mitochondria provide most of the power to cells, helping convert food into energy.

Most base pairs—over 99 percent of them—are identical in every human, with only about one in a thousand bases diverging to make us distinct. These differences in the human recipe account for variations in everything from eye color to disease. They account for the differences between James Watson and a supermodel, an Olympic pentathlete with no hair and a math whiz with dreadlocks.

Most differences in humans involve just one set of base pairs called single-nucleotide polymorphisms—SNPs, pronounced “snips.” For instance, I might have a CG—an inherited mutation—that makes me susceptible to diabetes type II (non-in-sulin-dependent diabetes), and you might have a CC, which is more common and makes it far less likely that you will get this malady. But merely having the SNP for diabetes doesn’t condemn me to have diabetes. The relationship between having most disease SNPs and having a disorder is still not entirely understood, but it’s known that having a mutant SNP for most ills is only one factor in actually contracting the disease—there are other SNPs and genes that come into play that either increase one’s chances or decrease them. Environmental factors also play a role in triggering a rogue SNP. In this case, if I have the CG for diabetes I may need to lay off the Cheetoes and Snickers bars, since obesity is known to trigger the SNP for diabetes type II. Other SNPs—for hair color, height, and my crooked second toe on my left foot, which my father and my two boys both have—make people different from one another from the moment they form in the womb.

With the emphasis in the media on DNA, you may think that genes are everything in an organism. They are not. The double helix may be a beautiful symbol of dignity, fear, and hope, revolving as a giant mobile in the lobby of deCode in Iceland and as a model made by Watson and Crick that still sits in a glass case at Cambridge. But DNA itself is nothing more, or less, than a storage bank of information. On its own, it can do nothing. It’s an utterly passive strip of mathematics that can no more cause a reaction than a skeleton key can by itself open a lock on a door. Most of the business of biotech involves proteins—trying to understand them, their structures, how they work, how they can be turned on and off by drugs. When the environment triggers a genetic response, genes are activated or shut down as a result, but it is a protein or proteins encoded by a gene or genes that actually does the job in reaction to an outside stimulus.

The biotech and pharmaceutical industries are spending billions of dollars to design new drugs based on genomics, the use of genetics and genes to track the mechanics of which genes and SNPs cause disease. Some drug design is extremely crude. For instance, no one really knows why ramping up serotonin in Prozac makes people less depressed. Some medications are better understood—such as Lipitor, which reduces the amount of cholesterol in the blood by inhibiting the activity of an enzyme required for cholesterol synthesis. Many drugs also have side effects because the drug compounds interact with proteins other than the intended target or cause problems even when they adversely impact their intended target. A few people suffer from severe side effects or die, sometimes because their own genetics are different from the norm. Figuring out these differences in an individual’s genome is called personalized medicine. In the future, people will have their genetic profile tested so that drugs and other medical treatments, diet, and exercise can be custom designed for each person—called pharmacogenetics. At least this is the hope.

The same technology may also be used to enhance lifestyle—designer mood drugs, drugs to boost memory. It also may lead to genetic discrimination, a scenario described in the director and writer Andrew Niccol’s Gattaca as “genism.” In this 1997 film, the main character, played by Ethan Hawke, is a “natural”—naturally conceived—in a world where genetically superior individuals get the plum jobs and the perfect mates. We will talk more about this later.

Another potential method to treat inherited diseases would be to alter the genes themselves, the hereditary DNA in each person called the germ line. This would involve going into a fertilized human egg and replacing, say, the SNP for diabetes—the CG with a CC—by deleting the deleterious SNP and inserting a correction. Researchers routinely use germ-line modification to alter the genes of plants and animals. If you want to make a mouse fatter, you insert a gene that causes obesity. Or if you want to stop a cancerous tumor regulated by a certain gene, you can turn off the gene by removing it from the germ line. Human ethics and legitimate fears about what would happen if we permanently altered a person’s germ line, which could be passed on to offspring, have prevented this sort of tinkering from happening in humans, though some scientists believe that human germ-line modifications are inevitable.

This is the story so far. It’s the first chapter, or, more likely, the prologue, of a very long book.

1 PROMETHEUS Douglas Melton (#ulink_b0ae04c0-124b-5a86-8cba-8006eef5834d)

There’s a natural fear of the unknown. On the

other hand, I think it’s uninteresting to live in

a society where one is so afraid of the unknown

that you won’t try new things.

—Douglas Melton

Harvard embryologist

Why did Prometheus do it? Myths about this god who gave fire to mortals against the express wishes of Zeus never explain his motive. But I’m going to make a guess. He had mortal children who were cold and tired of eating berries and gnawing on raw meat. And father Prometheus, who sat around Olympus with other gods warming his hands with glowing embers on cold nights, felt guilty. And that’s how we got fire.

Prometheus paid dearly. Zeus punished him for breaking a command to keep fire in Olympus by chaining him to a rocky crag, where his liver was eaten every morning by an eagle, only to grow back by the next morning, so the screeching bird could tear it out again.

The Harvard embryologist Doug Melton, fifty-one years old, makes no secret of his motive for pushing hard to develop a modern-day equivalent of fire—embryonic stem cells. These are special cells produced in the first days after an egg is fertilized that will develop into a heart, brain, skeleton, or any other part of the body of an organism. Melton wants to use stem cells to save his own children, fourteen-year-old Sam and eighteen-year-old Emma. They suffer from type I diabetes, which he hopes can be treated by understanding how stem cells grow into special cells called islets in the pancreas that normally produce insulin in a healthy person but shut down and stop functioning in a diabetic.

By extension, the cherub-faced Melton, with floppy, short, graying hair and round-rimmed glasses, hopes to save us all if he is successful in learning from stem cells how to cure his children, to spare them the organ failure, blindness, heart disease that eventually afflict many diabetics. If stem cells work as treatments, his work could be used to heal other illnesses, a list of maladies that afflict hundreds of millions of people around the world. That is, if Melton is allowed to continue his work by certain lawmakers in Washington, D.C., who today collectively play the role of Zeus.

1

Sitting in Melton’s office on a cool, bright spring day in Cambridge, I look at the faces of his children in photographs on his desk. Sam is lanky with short hair and a slightly awkward smile; Emma has long, dark hair and serious eyes. Now a college freshman, Emma once wrote in an essay that she wants to become an embryologist like her father. “I am also interested in becoming a member of Congress and petitioning for a cure that way,” she wrote. “I just hope she gets the chance,” says Melton. “In this, I am no different than any parent.”

Inside Sam and Emma and 1 million other in-sulin-dependent diabetics in the United States, the body’s immune system inexplicably attacks islet cells as it would a foreign invader such as a virus, an autoimmune response that destroys these cells’ ability to produce insulin. Insulin is an enzyme that helps transport sugars from the blood into cells for use as fuel. Without it, the sugars gum up in the blood vessels as sugar does in a gas tank, causing a patient with full-blown, in-sulin-dependent diabetes to go into shock and die. Most diabetics today are saved by frequent shots of synthetic insulin, though the balance between blood sugar and injected insulin is often a crude calculation. Almost all diabetics receive either too much or too little insulin at various times, a situation that can cause gradual damage to organs and muscles over the years. For Melton’s children, this imbalance may be an early death sentence, unless researchers can find a treatment or a cure for the islet dilemma. One of the most promising is for their father or another stem cell researcher to discover a stem-cell fix for pancreatic cells.

Melton’s resolve to give the embryological equivalent of fire to his children is evident from the floor plan of his office at Harvard. Unlike most senior science professors here and at other elite institutions, where offices of big shots often resemble the world headquarters of a company, or a nation, with staff, awards, and reprints of papers everywhere, Melton’s nondescript office is connected to a personal lab that is separate from his team’s main labs down the hall. His office has some of the expected awards and reprints, too, but as I sit with him at a small table near his desk, it’s clear where he would rather be. “I don’t want to waste any time,” he says, popping up to show me the small work station where he tries to tease out the mechanisms of how a stem cell makes the transformation into a pancreas.

Melton may be soft-spoken, but he has become a firebrand for his children, and for his science, openly defying the Olympians in Washington who oppose his research. Several times he has traveled to Washington to give testimony to Congress, especially after President Bush announced in August 2001 that federal funds for stem cell research would be restricted to sixty-four frozen embryonic stem cell lines already culled from existing embryos. These “lines” are special groupings of stem cells coaxed to replicate to produce more stem cells, and not to develop into other cells. These lines are critical for research, though acquiring them is controversial because the only source at the moment is to snatch them out of embryos grown in petri dishes, a process that causes the embryos to be destroyed. To some people, this is murder. To others, the embryos are simply a grouping of cells that are incapable of becoming human beings unless they are in a womb. As Melton and other scientists point out, thousands of embryos are discarded every year during in vitro fertilization procedures, though under the Bush rules, scientists using federal funds are banned from using them.

The president banned the development of further lines with federal funds, although the restriction does not affect private or statesponsored funding. Bush’s position sounded like a compromise, but it quickly became evident that the sixty-four lines did not really exist. The actual number of cell lines widely available to researchers has turned out to be far fewer, a stem gap that is hampering research paid for with U.S. money—the lion’s share of all funding for scientific research. Some of the approved lines are either in the hands of private entities, or have been tainted by mouse cells that make them unusable for human research. “There was this idea now that there are these sixty or seventy cell lines which the administration claims exist,” says Melton. “I think the number is closer to five to ten.”

Soon after President Bush announced his policy, Melton and others launched various crusades to get around the restrictions. At Harvard, Melton worked to assemble funding from the privately endowed Howard Hughes Medical Institutes, where he is a chief investigator, the Juvenile Diabetes Research Foundation, and other nonfederal sources. In March 2004 Melton announced that he had developed seventeen new embryonic stem cell lines, available to any researcher who has access to nonfederal funds. He also is director of Harvard’s new stem cell institute, which has raised $100 million for stem cell research from private donors. In California, scientists, universities, and their political supporters sidestepped the Bush rules in November 2004 when voters passed a state referendum approving $3 billion in bonds to fund stem cell research at the state level—including research using embryonic stem cells. This referendum will fund stem cell research in California at $300 million a year for ten years.

Across the sea, the British Parliament has passed regulations allowing government-funded embryonic stem-cell research, with safeguards, which went into effect in 2003. Singapore, China, South Korea, and other nations are also vigorously moving ahead with stem cell research.

Researchers are a long way from using stem cells to cure Sam and Emma, or anyone else. Stem cells may never work as treatments for many diseases, though at the very least, says Melton, they will help scientists understand the basics of how organisms develop and why mistakes occur that cause people to suffer. Yet researchers hope that someday these microscopic blobs might be tweaked to grow into healthy aortas to replace cells damaged by heart disease, or into a pristine spinal cord for someone like the late actor Christopher Reeves, who was paralyzed when his backbone was shattered in a horseback-riding accident. Nancy Reagan has also talked about her hope that stem cells can regenerate cells in the brain damaged by Alzheimer’s disease, which killed her husband, the former president Ronald Reagan.

Researchers also experiment with adult stem cells, created in each of us throughout life by specific organs such as the skin, which uses these stem cells when they grow into specialized replacement cells. However, not all organs and bodily systems have adult stem cells, and even when they do, these cells are not always as useful in repairing and regenerating as embryonic stem cells that have the potential to differentiate into anything. In the summer of 2004, Melton announced the results of an experiment that indicates there are no adult stem cells to regrow islets in those who suffer from type I diabetes.

Before his children grew ill, Doug Melton was an ambitious young researcher conducting leading-edge research in developmental biology using frogs, though he was perfectly content with a high-profile position in academia, writing exceptional scientific papers and getting kudos from his peers. His forays into politics and the media began only after he discovered Sam and Emma had diabetes, when Melton made the switch into pancreatic stem cell research. “I’m an activist now, I guess,” he says, smiling shyly. Most of his testimony and appearances are on behalf of the Juvenile Diabetes Research Foundation, which also has helped to fund his new stem cell lines.

Melton has a calm, private energy compared to other more fiery egos who appear on these pages. He has an earnestness about his work, a sense of humility that is not feigned, and less of a restlessness and a need to accomplish fantastic feats for all to see. He is not trying to rankle people with grandstanding ideas or using science as a vehicle to fame and glory. With undergraduate degrees in both philosophy and biology, and a Ph.D. in molecular biology, Melton loves nothing more than a vigorous intellectual argument. This is how he likes to present his ideas, with a passionate, long-winded, fascinating discourse.

Later, Melton will surprise me by presenting in the form of intellectual “puzzles” ideas that most of us would consider out there, such as, What might happen if scientists inject human stem cells into a monkey embryo? What would grow? A human heart, brain, or toe? “Now, this won’t happen in the next few years,” he says, “or even in the next few decades. But that, to me, is a kind of new biology that I find a million times more interesting than these specious arguments over whether life begins at fertilization.”

I mention to him that these experiments might seem bizarre to many people, and he agrees, though he argues that they will become normal one day. “There was a time when surgery was abnormal,” he says, when it was considered a violation of the body as the sacred vessel of the soul. “I’m intrigued by this issue of what is normal and abnormal,” he tells me, indicating that his ideas of normal may be different from most people’s—and that, as many scientists do, he gets juiced up by imagining scenarios just beyond what is now possible. This is a crucial characteristic of scientists, that they need to live in a space at the leading edge of what is possible, operating within the outer boundaries of acceptable ethical norms, but also pushing these norms into potentially new territory. This is what Melton is talking about with his puzzles.

Hopefully, Melton’s work and ideas will not result in his being chained to a mountain with a daily assault on a vital organ by a giant predator bird. Indeed, his comments about human brains in monkeys were posed as Socratic suppositions about what is normal, and what is not. Yet I also think that given the chance, and if ethically it was allowed, he’d perform the experiment—out of curiosity, to save his kids, and perhaps, to usher us into a new age of fire.

2

A researcher in obstetrics and gynecology at the National University of Singapore, Ariff Bongso, first grew human stem cells in 1994. In 1998, the University of Wisconsin’s James Thompson isolated human stem cells for the first time. Yet scientists have known about stem cells in mice since the seventies. The original discovery in mice occurred when researchers were studying certain cancer cells, which they now know have many of the properties of a mouse’s embryonic stem cell that can grow into different types of cells. Melton says this promising line of research stopped, however, in the early eighties before a connection was made between what was going on in mice and humans.

“The field didn’t move forward at the time because of an historical accident,” he says, which was the discovery of recombinant DNA technology. This became all the rage and sidelined other research as scientists sought to learn about cell differentiation not through working with stem cells, but by recombining genes from different species, and also by removing, or “knocking out” genes in mice to see what impact all of this would have on a cell or organism. “It’s only now that people are going back to mouse [embryonic stem] ES cells, let alone human ES cells. And while they’re extremely useful for studying gene function in an animal, they also have their own inherent interest. Could you make body parts, tissues, ex vivo? That’s the field I’m very excited about, but we’re way behind.”

Since Bongso’s discovery in 1994, stem cells have ignited two firestorms. One is a creative fire, a breathtaking moment for Melton and other scientists, for whom a new world has been opened up for exploration that they believe will save countless Sams and Emmas. The other is political and ethical, the scorching debate that pits scientific optimists against skeptics who believe that this fledgling science may open up a Pandora’s box that could have unforeseen and catastrophic consequences.

For those who believe that life begins at conception, an experiment using embryonic stem cells is indeed a homicide. “We should not intentionally create life in order to destroy it, even for good purposes of scientific research,” says William Hurlbut, a Stanford physician and conservative bioethicist who was appointed by George W. Bush to sit on the President’s Bioethics Commission. He is not opposed to doing stem cell research, he says, just to acquiring the stem cells by destroying an embryo. “If we say that a human life in process should have a certain inviolable moral status,” he says, “then we protect ourselves against the dangers of both crossing a fundamental moral boundary and what other people call the slippery slope.” Hurlbut is closely connected to Catholic leaders and opposes abortion but says his convictions about the status of an embryo are based less on his religious convictions than on a fundamental belief that a line needs to be drawn to protect what it means to be a human.

Opposition does not arise from just the right-to-life camp. There are liberal secularists, too, who bring up Brave New World scenarios of baby farms where clones of you or me would be grown exclusively to provide spare parts—and farmed like a turnip or a chicken is now. Another fear is that stem cells will lead to designer babies engineered by using stem cells not merely to replace damaged cells in Melton’s children, but to add new cells designed to be supermemory cells, or super-muscle cells. The technoskeptic Bill McKibben frets that biotech companies and commercial interests are poised to patent stem cell discoveries, which may lead to biotech barons’ pushing stem cells and other bioenhancements on the public out of greed. “And they’ll be hard to police,” writes McKibben in his 2003 book Enough, “not only because they’ll contribute to political campaigns, but also because their work, day in and day out, won’t be dramatic enough to attract notice.” Many others who are not religious zealots or anticorporate warriors feel uneasy about the notion of creating a human embryo solely with the intention of harvesting its cells to benefit a full-grown human, though this unease may dissipate if cures are discovered.