A gracefully written and up-to-date account of the state of the field... well worth reading, not only for its fascinating tales of development, but also for its scrutiny of a vast, uncharted area of biology.

Times Literary Supplement

What produced the Hapsburg lip?

Many of us have followed the recent news about a two-headed Dominican infant who died during surgery to remove her extra head. According to Armand Marie Leroi, this case is not unique: "In 1982, a thirty-five year old Chinese man was reported with a parasitic head embedded in the right side of his own head. The extra head had a small brain, two weak eyes, two eyebrows, a nose, twelve teeth, a tongue and lots of hair. When the main head pursed its lips, stuck out its tongue or blinked its eyelids did the parasitic head; when the main head ate, the parasite drooled. Neurosurgeons removed it." Mutants is full of similar bizarre, disturbing, and often heartbreaking stories of physical abnormality. Yet it is no mere freak show; rather Leroi is concerned with how such mistakes occur. His premise is that errors of development, as seen in human mutants, give valuable insights into the normal mechanisms of development.

Leroi, a developmental biologist at Imperial College London, presents a gracefully written and up-to-date account of the state of the field. His approach is cunning: like a fairground barker, he first appeals to our voyeurism, but then adroitly bends our interests towards the science underlying the mutants. (Leroi includes as mutants not only hereditary disorders, such as albinos and dwarfs, but also those produced by non-genetic, environmental factors, such as conjoined twins and Thalidomide babies.)

Starting with Gregor Mendel's nineteenth-century crosses between wrinkled and discoloured peas, which first showed how genetics works, mutants have a long and distinguished record of service in biology. For example, fruit flies that have taught biologists much about the development of the insect body plan. These flies have a mutation in a gene that is critical for allowing body parts to form in their normal sequence from front to rear. Without the mutation, we wouldn't have found the gene. In fruit flies, scientists can actually induce such mutations with X-rays and DNA-altering chemicals. Ethical considerations, however, prohibit this option to human geneticists, who must study development by drawing on the panoply of naturally occurring mutations. It is here, in cataloguing and explaining these mutations that Leroi is at his best. In addition to touring the realms of medical genetics and molecular biology, Mutants roamsn engaging through great swathes of literature, mythology and history. In the process, we meet many unfortunates: Harry Eastlack, an American whose muscles turned into bone, encasing him in a double skeleton; the Ovitz family, a group of Transylvanian Jewish dwarfs studied and then tortured by Josef Mengele at Auschwitz; and the diminutive Henri Toulouse-Lautrec, whose mysterious bone disorder may have given him the low perspective that characterize his art.

While the parade of conjoined twins, piebald babies and individuals with "crab hands" sometimes threatens to over stimulate our appetite for the prurient, Leroi gently but persistently steers us towards what each of these sad tales tells us about development. Hypertrichosis, for instance, is a disfiguring but no life-threatening genetic disorder in which individuals are completely covered with long hair. We now know that "normal" levels of hairiness are regulated by the hairs themselves: their follicles secrete a chemical that represses adjacent skin cells from forming hairs. In hypertrichosis, a mutation has disabled this signalling system, allowing hairs to proliferate wildly.

Similarly, situs inversus, or "mirror image syndrome", is both rare and illuminating. Humans are not bilaterally symmetrical: out heart and spleen are on the left side, our liver on the right. But in one individual in 30,000, a genetic mutation reverses this asymmetry. These individuals are largely normal but suffer from "Kartagener syndrome", involving respiratory problems and, in men, infertility. These afflictions provide a clue to normal asymmetry. Our respiratory tract is lined with tiny hairs ("cilia") whose constant pulsing clears accumulated mucous, while sperm are propelled by beating tails. Cilia and sperm tails use the same molecular beating mechanism. The reverse asymmetry, it turns out, has a related cause: we are asymmetrical because a critical part of the early embryo, the "embryonic node" contains cilia that beat from right to left. This creates a directional fluid flow around the embryo that activates cells on only one side, producing asymmetry. The Kartagener's mutation stops this flow, leading half of the mutants to develop situs inversus.

Unfortunately, Leroi runs out of steam in the final chapters in which, with his supply of mutants exhausted, he wanders off into tangential issues like beauty and ageing, which shed little light on development. The weakness of this section reflects the limitations of a mutant-based approach. Firstly, Leroi's premise is sometimes wrong: the connection between deformities and normal development is not necessarily straightforward, and one cannot always understand normal processes by analysing their malfunctions. A mutation may, for example, create a new protein that simply acts as a poison, disrupting entire developmental systems and revealing nothing about the normal function of these systems. The sickle-cell anaemia mutation in haemoglobin molecules has diverse effects, including kidney failure and, in men, constant erections. But one cannot conclude that haemoglobin plays a vital role in the development of kidneys or sexual desire. Rather, these symptoms result from drastic perturbations of a complex system. Second, it is often difficult to understand complex developmental systems by relying on whatever mutants happen to appear.

The formation of a human kidney, for example, requires hundreds of genes. Some of these will not mutate; in others, mutations will be lethal in early development and not be detectable; while in others, mutations will have effects to small to be seen. Although the human genome harbours roughly 30,000 genes only about 1,000 are known to mutate in a way that causes detectable abnormalities. A mutant approach thus cannot reveal more than 3 per cent of functional genes.

The studies of the fruit flies with legs sprouting from their heads, though hugely successful, required exhaustive dissection of genetic and developmental pathways involving years of producing mutations and using them in complex genetic crosses ­ just the sort of experiment that cannot be done in humans. Identifying mutants is just the first step in understanding a developmental process. All too often, the enterprise stops here in humans: ethically there is nothing more to be said and done. The same problems prevent us from understanding the genetic differences between individuals, between members of different ethnic groups and between humans and our primate relatives. We may never know which genes produced the Hapsburg lip, the light skin of Scandinavians, or the large brains, hairlessness and erect skeletons that distinguish us from chimpanzees.

Amid his absorbing discussion of dwarfs, hermaphrodites and the hirsute, Leroi might have acknowledged these limitations. Nevertheless, Mutants is well worth reading, not only for its fascinating tales of development, but also for its scrutiny of a vast, uncharted area of biology. We have all heard loud hosannas from advocates of the Human Genome Project, proclaiming that our genetic code has at last told us "what it is to be human". In reality, we are very far from understanding how that code is translated into a human being.

Jerry Coyne
Times Literary Supplement (April 9 2004).