Jacob's Ladder: The History of the Human Genome [Hardcover]

Once human DNA had been completely charted, some used to think, we'd have answers to just how fertilized eggs turn into humans, and even what it is to be human. Sequencing the human genome would be the foundation that would explain everything that cells do to work together and produce a human. It hasn't come close to doing this, of course. There is too much going on within even that simplest first fertilized egg cell for us to understand. Certainly, there has been much learned, including some humbling lessons; our DNA shows we are still very close in many ways to the mice that share our mammalian evolutionary heritage, and we are even close to fish and other vertebrates. But scientists didn't start asking questions about the issues in genomics only when genes or DNA were discovered. In _Jacob's Ladder: The History of the Human Genome_ (Norton), Henry Gee has looked at the ways people tried to understand what genes do even before they knew there were any such things. His book is valuable in showing that many of the questions that are still being asked today were being asked by the first men to record their thoughts about how reproduction was accomplished.

Aristotle knew about eggs, bird eggs, and he knew about menstruation. He formed the idea that when menstruation stopped, the unshed blood stayed in the woman and when it met with semen from the male, it was sparked into life. This dogma was first challenged in 1651 by William Harvey, who is more famous for having charted the activity of the circulatory system. He had the insight that life came from an egg, even in mammals. Of course he had no understanding of cells, or eggs and sperm being cells. He thought the egg was formless matter that somehow gave forth form. When microscopists eventually saw sperm, they thought that they were mere parasites, like so many worms that writhe within tissue. Some suspected they also played a role in fertilization, but as late as 1835 they were classed as a distinct order of worms. The nature-philosophers, with Goethe the most prominent exponent, regarded the problem of generation as intractable. It wasn't just that the technology of the time could not make it plain; rather, there was a mystical natural force that impressed form on the formless egg. The force shaped the organic being and pushed for ever-greater perfection. Darwin, who was always frank about any weakness in his ideas of "descent with modification," knew that a blending of father's and mother's characteristics to produce children would eventually produce only blandness, and not the variability that his theory required. He had to guess that there was some sort of particulate inheritance, but he was guessing, and there was no evidence for him to base such a guess on. It was a flaw in evolutionary theory, a flaw eventually made good by genetics, but objections were less often made against this flaw than against the challenge evolution posed to social and religious ideas.

The nature-philosophers stressed unity and complexity, and while Gee cannot accept their mysticism, his explanation in the second part of the book of what genes actually do owes much to their basic ideas. Despite the push to find the gene for schizophrenia or the gene for obesity, genes almost never act on their own, but in networks. There are tangles of genes responding to gene products in many interlocking biochemical pathways. The study of such pathways is "systems biology," with a mutation in one gene affecting a great many pathways. Computer analysis of such systems shows that they are very stable, producing a viable output when the many input variables are widely changed. It is this flexibility that in itself produces the variety that is the powerhouse for evolutionary change, as well as allowing minor changes without letting them completely derail embryonic development. Gee is an editor for the weekly journal _Nature_, and as such has watched the dizzying increase in the speed of biological research in the past decade. It is probably the most important science of our times, with prospects for the conquest of disease as well as the scary possibilities of our someday directing our own development. Gee's account is a useful look at the history of an important part of biological research, as well as a primer on systems biology, which holds promise of much explicatory power in the future.

Since the announcement of the coarse mapping of the human genome, the media have deluged us with promises of great advances. Medicine, agriculture, psychology, even biotechnology, all seem to be potential beneficiaries of the the unravelling of "what makes us human". Henry Gee, in presenting a sweeping background to these attractive promises, sounds a cautionary note. How is it, he asks, that from the moment of conception a process is unleashed that produces a living child in a mere 200 days? From the merging of two single cells, each carrying their share of the information that built you and i, what led to each of us being distinct individuals, yet bearing an inheritance reaching billions of years back in time?

Although the event is common, with 150 human births occuring every minute, Gee explains that understanding of the process was long in coming. From Aristotle, who thought babies came from menstrual blood to the Enlightenment, which accorded either eggs or sperm with possession of generations of nested individuals, there was a long, tortuous path to understanding conception. Behind that understanding lay much investigation, theorisation and speculation. Gee naturally positions Charles Darwin with a pivotal role in that understanding, but wants us to be aware of the host of other researchers and their contributions. A major hurdle was the distinction between "external" births such as chicken eggs and the delivery method of dogs, horses and humans.

Ironically, it was challenges to Darwin's great insight that led to major advances in genetics. William Bateson sharply criticised Darwin's notion of "gradualism" in forming new species. Bateson thought that gradual change should be visible in animal populations and went looking for them. At the same time, another Darwin critic, Thomas Hunt Morgan, was examining thousands of fruit flies to learn how to identify what Bateson was seeking. Morgan was probably the most reluctant Darwinian since Charles Lyell, but was finally won over by his labouring students who demonstrated how genes worked.

The buildup of the genome over the vast history of life on Earth becomes Gee's next topic. How did we get here and what's the present offer in the way of clues? He uses Graham Cairns Smith notion that the first step in creating a genome likely began in the dense environment of clay crystals. From this molecular origin, the author takes us to a menagerie of creatures, all of whom have something to contribute to the story. We are introduced to the mycoplasma - today's simplest creatures with less than 500 genes. Are they holdovers from an ancient form? We learn that parasites of bacteria have forced the trimming of genomes as a protective strategy. Why haven't we done the same, he asks, or are we in the process? The larger genome of humans, he reminds us, isn't sufficient to explain either our complexity or our uniqueness. Changes in our genome are traceable, with agriculture's introduction a major contributor.

When the history of the study of the genome, whether fruit fly, bacterium or human, has been delineated, Gee takes the investigation a step further. He notes the propensity of the media to tout "a gene for" any number of traits, physical or behavioural. We must use the Internet as a model, he urges. The networking of many computers serves as a template for the information management of the genome. Genes, selfish as they may be in trying to reproduce, must cooperate in complex organisms. Single steps to gain single goals is no longer feasible, if it ever was. The intricate network of genome activity demands further attention.

Like so many modern science writers, Gee chips away at Darwin iconology. He wants to demonstrate that all those "wrong" thinkers of the past made contributions. Unlike many iconoclasts, Gee keeps his critique muted, a welcome change. He also challenges us with questions about where the knowledge of the genome is leading. Knowledge of the human genome has the potential to elevate us from apes to angels. Are we prepared to face the issues that genome manipulation may generate? If you read this book, you will understand his concern. With the knowledge he provides, you will be more prepared. [stephen a. haines - Ottawa, Canada]

In _Jacob's Ladder_, science writer Henry Gee sets out to survey the thinking and research on evolution and genetics that led to the sequencing of the human genome and today's focus on genetics and genomics. He also tries to look into the future to make out the outlines of where our newfound genetic knowledge and power may lead.

If you're interested in a serious survey of the story of genetics starting in antiquity, before getting into the human genome and current research, this is the book for you. You'll learn a lot about embryology, about early theories of development and evolution, and about researchers and thinkers whose contributions to this field, broadly construed, you may not have known about, from Aristotle to Caspar Wolff.

I thought the book really got interesting when it began to deal with the question of the evolution of form. How all the intricate forms that define an organism come about, in terms of evolution, genetics and embryology, remains one of the great unanswered questions of biology. Much of _Jacob's Ladder_ is shaped by Gee's fascination with this issue. His answer, that the answer will be found through understanding and modeling the structure and dynamic functioning of genetic networks, makes excellent sense.

I also felt that Gee's speculations about what we as a species may do with our newfound ability to modify our own genes and genetic networks well thought out and provocative.

If you would like to understand the rich soil from which the next year's or the next decade's genetic discoveries and interventions will spring, this would be an excellent place to start.

Robert Adler, author of _Science Firsts: From the Creation of Science to the Science of Creation_ (Wiley, 2002), and _Medical Firsts: From Hippocrates to the Human Genome_ (Wiley, 2004).

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