Jennifer Ackerman
Author
"Understanding Heredity: Chance in the House of Fate"
September 9, 2001

Jennifer Ackerman: There are mysteries in all families. Those that arrest me, that set me back on my heels, are the mysteries of heredity. The past whispering in bones and blood, the dozens of ancestors rolled up in one skin to be read in curve and voice and eye. It seems astonishing that a sweep of eleven generations hardly modifies the night blindness of one family, or the trembling jaw of another. That fifty or a hundred years they fail to alter a familiar a pattern of the world eyebrow, the musical genius of the Bach family, or the dimpled chin of my husband's tribe.

In the last decade or so, a startling new message has come out about the long hold of heredity. Members of the human family carry traits that have held on down the line for not just generations, but ions--traits that mock all boundaries of time and kind. Scientists, probing the deep workings from yeast to humans, have turned up news that, despite our outward differences of life and limbs, we are run by similar genes and proteins and similar cell parts and mechanisms which have weathered evolution over the ages, passing nearly intact through hundreds of millions of years of rising and falling forms. These shared molecules and routines affect nearly all the turnings of life--from birth and growth , to perception and behavior.

This book is a pilgrimage to the heart of heredity. It is a telling of stories about life, lineage, chance and fate, about family, kin, and kind. It explores both the projecting traits of the human family--the one we are born into and the one we create--and also the bigger, deeper inheritance that ties us to the rest of life in profound, even shocking, ways. I like to hang around the doorway of biological surprise. For years I have collected news of curious findings--of young spiders that eat their mothers, of fish with fingers, caterpillars with lungs, genes with secrets. This is the news that sweeps me away--the gnomic workings of a living order; nature's inventive jack-in-the-box surprises that shift our view of life like the sudden twist of a kaleidoscope.

Here is an item from my files: When scientists deciphered the intimate details of mating in yeast, that lowly single-celled fungus that raises our bread and brews our beer, they got a shock. The molecule that draws two yeast cells into sex closely resembles our own brain cells to regulate reproduction. The likeness seemed a fluke at first, but then other examples popped out of the box--genes that shape the marvelous globe of the human eye are strangely similar to those that carve the compound eye of a fruit fly, the tiny genetic mechanisms that drive our biological rhythms match those in algae. So, too, it seems, do we share with other organisms the ancient genes that dictate cell death, the phenomenon that underlies metamorphosis--changing tadpoles into frogs, and caterpillars into butterflies, and also shapes our own bodies, whittling away the webbing between our fingers before birth. Disparate organisms, it seems, are more radically alike then we ever imagined. Our deepest selves, our very cells and molecules, are alive with reminders of old, enduring connections with other creatures--resemblances that run down to the very root of the tree of life.

The sixteenth century essayist, Michelle de Montagne, called heredity an incomprehensible wonder. Thomas Hardy called it "the family face," the eternal thing in man.

We have always been interested in where we came from--in the origins of our dimples, our red hair, our migraine headaches, our asthma, double-jointedness, our night-blindness. But the discoveries in genetics in the last century have made our understanding of heredity more urgent. Modern genetic engineering has given us the potential to read our own genes and to analyze them, to tease out the subtle differences and variations in genes from one person to the next (even to change our own genetic inheritance). It has given us the potential to correct genes that cause disease, to modify genes transmitted to future generations, so called "germ-line interventions," and even to design genomes for optimal health and longevity. Suddenly we are faced with choices we never even imagined before. To what end will we use the information that we have gained about our own genes and the genome of the species? To what extent will we categorize people based on the genes they possess, or try to shape and re-shape the genes that we pass on to our children? These are decisions that will, and should, be made not just by geneticists and bioethicists well grounded in the science of molecular biology, but by the whole society. We will all need to think for ourselves. What do we, the baker and the novelist, the plumber and the politician, need to know about heredity to confront choices and make good decisions (and how best to learn it)?

Chance in the House of Fate is an effort to explain the new understanding of heredity to the people not well versed in the language of science, mathematics, and technology. I am not a scientist, I write about biology and natural history, but my training is in humanities and my aim is to bridge the two worlds.

My interest in heredity is rooted in family history. My younger sister, Becky, was born microcephalic and profoundly retarded. Over the years, Becky has taught me a great deal about the curious dispensation of nature, about the value of difference and of life. Becky has my mother's slim build and dark hair, my father's brilliant blue eyes and ready laugh, and a brain so stunted that it will never allow her to progress beyond a developmental age of six months.

When I was entering puberty, my mother took my sisters and me to genetic counseling to determine whether there might be a hereditary component to Becky's disorder. We searched the family tree, but found no pattern of mental retardation. The experts agree that Becky's microcephally was likely the result of a virus that my mother suffered in her first trimester. My chances of having a child with Becky's kind of disabilities were about the same as anyone else's. For me, this experience coupled with other confrontations of illness within my family--the Alzheimer's that struck my grandmother, the cancer that killed my mother at 51--have sparked a life-long interest in family patterns of inheritance. What endures and what changes within my own family, the human family, and by extension, the greater family of life.

I am fascinated by the idea that each of us is linked to a string of ancestors, very long indeed, and faithfully recalled, in stuttering voice, in our own genomes. This interest has grown with the discoveries in the last ten years of the striking biological similarities between humans and other organisms (on the level of genes and selves).

In Chance and the House of Fate, I wanted to explore heredity in its broadest terms. I also wanted to give myself and my readers tools for understanding the profusion of news about genetics, the rash of discoveries that we are experiencing, the sequencing of genomes from bacteria to humans, the findings of genes linked with traits--physical traits and even behavioral traits--and to explore how these new findings affect of understanding of family, heredity, and our place in the biological continuum.

What is a gene, anyway? Are there genes for a particular traits? Are the letters DNA and RNA an "open-sesame" to all the secrets of life?

Not long ago, while researching a story about genetically modified foods, I stumbled across the results of an opinion survey which suggested that some significant proportion of people in this country, even well-educated people, are under the impression that ordinary food does not contain DNA--that genetically modified food is unique and different and scary because it contains genes. If people don't understand that all living things are made of genes, then how can they decide for themselves about the potential benefits of embryonic stem cell research? How can they make informed decisions and reasoned choices about how or whether to proceed with cloning or with modifying genes that might be transmitted to future generations--to their children's children?

The physicist Mitch E. O'Cokoo (?), once wrote that understanding the weather required a leap into another dimension--up into the reaches of Earth's atmosphere. Understanding heredity requires just such a leap, but downward, into the dark, invisible world of genes and cells. Most of us find it a stretch to descend into this world. The human mind may have mastered the black hole and the quark, but most of us have difficulty grasping the very big and he very small. We tend to think easily only o f things at our own scale--midway between the atom and the sun. To make things worse, the language of this minute world veers into the cold domain of chemistry, where the common nouns are "nucleic acids" and "amino acids," the common verbs "regulate," "synthesize," and "catalyze." Those of us without backgrounds in biology have been trained to think that the science underlying genetics and heredity is over our heads. This perception has been reinforced by scientists, health care professionals and journalists who use jargon, abstractions and unnecessarily complex terminology in describing this world.

When I was 15 and a student in high school, my father gave me a slim little book that affected me deeply. It was Lives of the Cell by immunologist, Lewis Thomas. This was one of the firsts of a new breed of books, written by scientists for the general public, that sparked interest among those of us with no science background. What was so unique and refreshing about Thomas' book, was both his language and his outlook. He brought a poet's sensibility to hard science in essays about cancer, drug abuse, aging and disease. He blended philosophy and political commentary with complex science, and made us think through the difficult ethical and social questions raised by that science. He wrote in plain English with a moving and provocative personal voice.

In Chance in the House of Fate, I hope to do the same. I have used personal story and the language of nature writing to try to illuminate the difficult details of molecular biology, to relate the invisible, abstract world of genes and proteins to what we experience in our daily lives.

My hope is that people who would not ordinarily pick up a book on pure science, might try one that couches scientific material in stories and within the frame of personal and philosophical inquiry.

Here is a passage from the chapter introducing some of the genes that shape and pattern the body in its odyssey from fertilized egg to the fully formed being:

When I was pregnant with my first child, I was shocked by the idea that it required no thought at all for me to sculpt a whole other person. But, it was somehow built into my species, all species, to make copies of itself--not identical, of course, but remarkably alike in the spectrum of life. I imagine the baby's growth as a kind of slow motion silent explosion inside of me--neat and orderly like a chain reaction. I willed one perfect cell to form, and another. A million perfect cells, body shape uncurling, or building up, it would begin with bones, naked at first, then growing the thinnest silk of flesh. Cell after cell the bones would gain heft, the muscles thicken to bind the spaces of the network. But, at night, I worried about what I held--the genetic burst that delivers the potential knack for numbers or musical talent, the straight taste for chemistry, the hand for graphing, the bones to dance, can as easily blight limbs or punch a hole in the heart. That my sister Becky had been born microcephalic--head too small, body twisted, intelligence trapped in infancy--blunted the expectant buzz of maternity. Becky had slipped from dark into light, a primal piece of light--shaped and unshaped. Over the years I watched her helplessness drive my mother to resignation and at times to despair. My mother's grief belonged to the phylum of fatigue--the problem of how to get through the days, seasons, years, with a child that would never feed herself, never talk or walk without help, never know the childish pleasure of naming dinosaurs or birds. It was little comfort knowing that root of my sister's deformity lay not in ancestry, but in some other secret. Perhaps it was a first trimester virus, a wayward scrap of DNA that found its way into my mother's blood, and unhinged her baby's whole development. Though I knew that my chances of having a child like Becky were no greater than those of any other mother, I did not hold much stock in odds. My imagination played in a thousand dark ways--the baby would grow in the S-curve of a serpent, a sheathed continuity of form without limbs. Or, it would grow from one end only--lower limbs and torso withered--birdlike or less. I taunted myself with medieval ideas that pregnant women transmit marks of their fancies to the bodies of their children that they carry in their wombs. Old notions that my dark thoughts themselves might unfavorably alter the form of the fetus. As antidote, I thought of dancers and athletes, I summoned the nudes of Leonardo and Michelangelo--bodies of perfect proportion, form and grace. Still, it took a wing's stroke of will to loose the nightmares and find peaceful sleep. In the immense animal pressure of labor, my fears evaporated, and when my daughter arrived sweet and sound as a nut, I accepted her perfection as given.

The real genius of the embryo is an astonishing act of self-organization. In the 1980's, biologists zeroed in on some of the genes critical to this feat. One class, the hox genes (?) shaped the head-to-tail pattern of the body in the first few days of development, organizing it into front, middle and hind region, determining the location of head, chest and lower body, the general placement of limbs, digits and organs. As a growing embryo takes shape, each cell must know where to go and what to be, when to start making specific chemicals, and when to shut down the production. When hox genes switch on inside a developing cell, they help shape its identity. The protein they make screws itself in to a groove in the double helix, thereby switching on other genes that help form the cell-setting of a cascade of activity that ultimately shapes the emerging body plan. The secret of hox genes was revealed through a set of experiments with Newton's fruit flies. Since their discovery in 1984, more than a hundred such genes have surfaced in a wide variety of animals. Biologists fish for them, using the fruit fly genes as probes. To their astonishment, they have found hox genes in sea urchins, worms, mice, birds, cows, humans--suggesting that a hox gene, or a gene cluster--existed in primitive form in some ancient common ancestor of all animals alive today. The number of hox genes varies from creature to creature. Humans have 39 such genes, most of them grouped in four sets on four different chromosomes. Fruit flies possess just one cluster of eight. But, so close are these genes in form and function, that when scientists inserted a human hox gene into the embryo of a fruit fly, the human gene made a perfect little fly body.

I first learned of the hox genes when I was a few months pregnant with my second child. The idea that the molecular mechanisms shaping my baby's growth were the same as those fashioned in the fruit fly, I found oddly comforting. Think of all the bending and the breaking in the bows of life--that species as remotely related as humans and flies are shaped by the same genes, genes that have slipped in and out of the Cambrian, the Devonian, the Permian, the Flistisine, requiring little revision in all this time. This suggests that they must work beautifully and will not easily be wrenched by force.

Here was the first lesson that I learned in writing this book: That our genetic inheritance links us to virtually every part of the natural world--fish, fruit flies, wondrous babies. We may be a feast of distinct entities, but we share the genetic economies of nature in birth to death. In the discovery of our shared inheritance with other creatures lies a critical key to understanding to how the human body works in health and disease. When scientists find a gene or genetic mechanism in a worm or a fly that matches a human gene, they can study that gene and the way it works more easily in these simpler organisms. In this way, we have learned about normal vision, smell, aging, growth, and learning.

Last month, scientists studying again, announced that by comparing the DNA of siblings who were extremely long-lived, they had found a region on Chromosome 4 that holds a clue to human longevity. They were guided in their search by what they knew of the genetics of aging in lower organisms--fruit flies, yeast--whose life spans may be dramatically lengthened by altering only a few genes. Aging is an enormously complicated business, of course, but this is an intriguing window into its genetic components. We have also learned about disease by looking at those genes we share with other organisms. If the gene has been shared by a wide range of species, that is, it has been well conserved over evolutionary time, chances are good that it serves an important purpose. If something goes wrong with that gene, if it is disabled through mutation, the result may be disease. Right now we are aware of close to300 human genes linked with disease. Scientists have found that more than half of these disease genes have direct counterparts in the fruit fly. Human genes that in mutated form are linked with Alzheimer’s Disease, have counterpart genes in the roundworm. It is much easier to study these genes in a worm or a fruit fly and perhaps to devise treatments.

I think it was the biologist David Baltimore who said that "we are not going to learn what makes us human by staring at the human genome." Making sense of the mass of information within our genes will come, in part, from comparing our genes to the genes of other species. This is true, too, of our making sense of our place in the greater natural world. We have, for so long, picked ourselves out from the horde of other creatures, reckoned ourselves separate and apart from the rest of nature. The discovery of our deep-down similarities with other organisms considerably shrinks the distance. We can no longer feel as separate as we did a decade ago. And now, more than ever, we see that we should be worrying that other species on this planet are going extinct, and that our children and their children may suffer deeply for the loss of these relatives.

The second lesson for me, in writing this book, was an understanding of the complex behavior of genes. Genes don’t behave as we once thought they did—as neat, indivisible units, each a set of tidy instructions for a single protein, with a fixed job and a fixed location on a chromosome. Genes have turned out to be decidedly unruly, to be split, spliced in different ways to make more than one kind of protein, to be nested, overlapping, redundant, even jumpy and apt to move around (occasionally between species). And, above all, genes are subject to the subtle play of their surroundings within the genome itself and within the cell, the organism, and its environment.

Here’s a passage from the book about this:

Next to my file of biological surprises is one labeled, "genes 4." Among the items is a report of two independent studies fingering a single gene, 4, for the love of novelty. The report claims that people who are intensely curious--adventurous, excitable, impulsive, novelty seekers, tend to have a longer version of this gene than those of us more stayed. This gene coats for a receptor that allows the brain to respond to dopamine, a chemical signal strongly linked to pleasure-seeking behavior. The findings have since been disputed by scientists who found no signs of the link in a study of Finish men. But, following on the heels of this find was the discovery of a gene linked with anxiety or worry—a shortened version of a gene on chromosome 17. Such announcements about a single gene linked with a particular behavioral trait are sprouting like spring leaves on a tree. The biologist Ruth Hubbard told me, "it is easy in all the excitement to confuse the genetic tendency toward a trait with the trait itself—to suppose that a single gene that contributes to intelligence, say, or sexual preference, actually specifies that trait." "It doesn’t," she said. Attributing biological process or behavioral traits to individual genes is about as meaningful as saying, "blood will tell." The way in which genes may or may not contribute to personality traits and behavior is multifarious and complex. Linear, reductive, simplistic attributions just will not do. "It is reasonable to think of genes as recipes," Hubbard said, "For a custard, say. I have an enormous respect for custard, almost as much as for personality, but they key is what happens from recipe to dish."

It is not enough to know the ingredients. A single gene almost never acts alone, but interacts with other genes in surprising ways. While one gene is firing off a signal for me to dive from the edge of that quarry cliff into the deep, blue waterhole--a molecular version of Edgar Allen Poe’s "Imp of the Perverse"—a dozen other genes may be pumping out the neurochemical equivalent of my overprotective grandmother. All genes are embedded in the layered environment of cell, organism, outside world. The response of genes to their surrounding s is nearly as complex as weather and just as complex to predict. "The only way to grasp a gene’s meaning," said Hubbard, "is to observe its activity throughout life in its full chemical and physical context."

What does all this mean? It means that we can’t always predict the action of a single gene within a genome, and that includes single genes linked with predisposition to disease. It means, too, that identical genes do not make identical people. This is, by no means, to argue that cloning a human would be okay. Just a reminder that our genetic identities unfold in different ways in response to the environment of the cell and the organism and all the other slap-dashery of life—sights and smells, diseases, variations in earth, water, air, exposures to parents, family, friends, to peace or to war.

The subtle nature of genes and their nature to genomes was further illuminated by a recent discovery from the human genome project—that we are made of surprisingly few genes. We used to think that the number of genes in a creature’s genome was a measure of biological complexity, that we humans, with our sophisticated immune systems and nimble thinking, possessed a large number of genes—something like one hundred thousand. The human genome project revealed, however, that we are made of a relatively modest compliment of genes—about thirty-five thousand (that is roughly twice the number in a fruit fly’s genome). And those genes we possess, as we have seen, are not so different from the genes of other creatures.

The real distinctions between one organism and another—the differences between humans and chimps (or fruit flies, for that matter)—arise not so much from the different numbers of genes, or from radical differences in the genes themselves, but from the way those genes are regulated, that is when and where they are turned on and off by a bevy of other players—other genes and proteins and enzymes and RNA models. We are what we are because of these interactions of our genes with the chemical players around them. Our sophistication, our amazing capacity for learning, thought, creative discovery, powerful immune response and precise finger movement, arise not so much from the super-abundance of genes, but from the abundance of interactions among them.