Of flies and fish

Kids: Don’t try this at home.

During her schooldays in 1950s Germany, Christiane Nüsslein-Volhard rarely did her homework. In 1995, she won the Nobel Prize for physiology and medicine.

Volhard is now director of the prestigious Max Planck Institute for Developmental Biology in Tübingen, where, decades before, she had been an undistinguished biochemistry undergraduate. She was at Harvard this week (March 4) to deliver a talk sponsored by the Radcliffe Institute for Advanced Study as part of its Dean’s Lecture Series.

About 250 listeners braved a rainy late afternoon, filling up Lecture Hall D at the Science Center to hear Volhard’s explication of the origin of vertebrates. They also got a layman’s overview of her continuing research into the genetics of embryonic development.

Volhard studies genes that are important in early animal development, some of which are the same even in widely disparate species. She has found early embryonic “patterning” genes in fruit flies that also function in humans. The goal is to use lower-order animals to identify genes implicated in human developmental defects.

Harvard developmental biologist Catherine Dulac, Higgins Professor of Molecular and Cellular Biology, introduced Volhard as “one of the world’s most influential scientists of modern biology.” She gave an overview of her guest’s research — and provided an explanation for the homework story: “She acquired very quickly,” Dulac said charitably, “a sense of what was worth her time.”

Volhard herself had told the homework story — and provided a description of her girlhood self as “lazy” — in an autobiographical essay required of all Nobel laureates.

She was born in wartime Germany, and spent her early years in a Frankfurt house with a yard that bordered a forest. Early on, Volhard was captivated by the world of plants and animals. Her love of the natural world was reinforced by vacations at the farm where her grandparents took refuge in the last year of the war. By age 12, she had decided to be a biologist.

The decision wasn’t enough for Volhard to get brilliant grades in high school, or even in her university studies. But from girlhood on she read widely and obsessively on her own, and astutely observed and studied nature.

It was as a graduate student in Tübingen that Volhard discovered the excitement and enchantment of the laboratory. By 1975, she began genetic experiments with Drosophila melanogaster. “I immediately loved,” she wrote in the Nobel sketch, “working with flies” — in this case, fruit flies. They have long been a favorite of gene researchers because their short lives, rapid propagation, and large numbers make it easy to study random mutations.

By the mid-1980s, Volhard had switched to zebrafish, a tropical relative of the minnow, and was screening the embryos for telltale mutations. A decade later she and her graduate students watched over thousands of fish tanks. Her work — and that of George Streisinger at the University of Oregon — popularized the zebrafish as a model vertebrate system for genetics research.

So it was flies and fish that dominated Volhard’s Radcliffe lecture — animals whose genetic cues to embryonic development may one day illuminate the genetic mutations responsible for human disease.

But how much can we upright vertebrates really learn from insects? After all, said Volhard, the last common ancestor shared by insects and animals with spines was bilateria, a classification of animals that goes back more than 600 million years.

Morphologically, vertebrates and insects seem like odd bedfellows. Vertebrates are highly complex, grow continuously, and have many cell types. They are soft-skinned and can grow to be very large. Insects have low complexity in cellular terms. They have rigid exoskeletons that limit growth to small steps between episodes of molting. They stay small.

But about 450 million years ago, the ancestors of both modern-day insects and vertebrates developed embryonic structures that allow genetic variations, giving rise to genetic specialization. In evolutionary terms, that was, said Volhard, life’s “biggest accomplishment.”

The neural crest, for instance, gives rise to the jaw, teeth, and skull. Epidermal placodes form the embryonic groundwork for the formation of the ears, nose, eye lens, and hair.

Embryos may also reveal ancient genetic secrets shared by animals that in adult form are unrelated. Why? Embryonic genetic material is “conserved” — kept the same. Adult genetic material, exposed to environmental stresses, undergoes the changes that drive evolution.

Zebrafish are a good way to study the genetics of embryonic development, said Volhard. They develop fast, their embryos are transparent, and researchers can track migrating cells with fluorescent dyes. Volhard’s presentation included time-lapse in vivo films of the rapid coordinated cell migration that carves out the circuitry of embryonic nerve cells.

Genetic mutations in these cellular building systems also illustrate the way embryonic development can go wrong. Sinuous chains of cells can migrate backwards, for instance, or stop before a nerve pathway is complete.

One challenge is, said Volhard, that embryonic structures are better known than the more complex adult cellular structures they give rise to. So her Tübingen lab is doing genetic screens of adult cells in zebrafish — from the skull, scales, fins, skin, stripes, and gonads.

A type of “naked” zebrafish — one that matures without scales — revealed a gene required for adult development but not for embryonic development. That and genes from a finless fish may be homologs — genetic ancestors — of human disease genes, said Volhard.

As a girl, Volhard discussed Johann Wolfgang von Goethe’s scientific papers with her father — and today is still fascinated by the German poet who thought of himself as a scientist. (His specialty was the morphology of animal skulls.)

She closed her lecture with an observation Goethe made in 1832, shortly before his death. It seems presciently relevant to genetic inquiry today: “What she hides,” Goethe wrote of nature, “she at least suggests.”