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  • Writer's pictureDale DeBakcsy

Making the Gradient: Christiane Nüsslein-Volhard and the Mysteries of Embryo Development

How is it that, starting from a single fertilized egg, employing only mechanical processes, you can form a kangaroo, a housefly, or a human? It is one of the most complicated, perplexing questions life can ask of itself - how do a series of apparently identical dividing cells, carrying identical genetic codes, somehow "know" to change themselves into specialized cells that form tissues and organs that (almost) always end up in precisely the right place to do precisely the thing they were meant to do?

Until forty years ago, we did not have anything like a decent response to that question. Thanks to Franklin, Chargaff, Lindsey, Watson, and Crick, we knew the structure of DNA, because of Rita Levi-Montalcini we knew that particular chemicals could induce the growth of particular tissues, and after countless hours of watching the embryos of frogs in their transparent eggs we knew the standard set of divisions a living being undergoes on its journey from a single cell to a fully differentiated tadpole, but as to how those cells organized and differentiated themselves, we had some good guesses but no solid experiments that demonstrated how chemistry interacts with genetics to make stomachs and eyes and spleens and all the other little bits that make existence possible.

Then, in the late 1970s and early 1980s, a small lab in Germany run by Christiane Nüsslein-Volhard (b. 1942) and Erich Wieschaus, after years of labor-intensive work screening through mutated strains of Drosophila flies, hit upon a series of answers so breath-taking in their elegance and powerful in their deceptive simplicity that what was a question seemingly beyond the scope of human reckoning was, within a decade, the stuff of high school textbooks, and we as living organism became that much less a mystery to ourselves.

Nüsslein-Volhard grew up during the hard, lean years of the German post-war era, a time of ruin, exhaustion, demoralization, and self-criticism that only the most optimistic could see ending with the "miraculous" economic revitalization of the 1950s. Her parents were interested and engaged with her intellectual development without being smothering or dictatorial. In the hard years immediately following the war, when goods were scarce, they made toys and books for their daughter, and taught her the value in creating objects rather than buying them, allowing her an active hand in constructing the world about her. That habit of physical self-determination crossed over into the intellectual sphere, where she educated herself intensely in areas that interested her.

Unfortunately, as is often the case with children possessed of intense and deep interests, concurrent with the ability to shine in what interested in her was a tendency to neglect what didn't, or to be lax in turning in assignments, resulting in waves of alternating high performance and panic that her early teachers noted with concern. Graduating high school in 1962, it took some time to find her destiny academically. Attending Frankfurt University, she began in biology, found the material uninteresting, switched to physics for a while, and then transferred to Tübingen to study biochemistry. There, she had access to lectures from scientists working at the edge of genetic research, and after she earned her diploma in 1969 she did her thesis in DNA promoter sites (regions that allow for the transcription of DNA), but found after completing her thesis in 1973 that continuing the study of promoter regions wasn't what she wanted to do with her career.

So, it was back to the hunt for a research area that could be made into a lifelong study. And it was not long before Christiane Nüsslein-Volhard, biochemist, met Drosophila melanogaster, the common fruit fly.

Drosophila had been working minor miracles in the fields of heredity, mutation, and genetics for over half a century when Nüsslein-Volhard began to study their developmental mechanisms. They have a short life cycle, produce multiple offspring, are teeny and cheap, and boast a relatively small number of chromosomes (4 as compared to our 23), all meaning that genetic variations could be charted through generations without consuming vast gobs of time, space, and money. Beginning in 1975, she embarked on a program of research that began with developing new methods that simplified the categorization of developing fly embryos, and ended with answers to the profoundly simple and devilishly complicated question of How Flies Get That Way.

Working with Eric Wieschaus and the other researchers that soon populated their joint lab, they exhaustively categorized mutations that Drosophila is prone to, seeking out mutations that radically altered the development and subsequent bodily structure of fly embryos. They found evidence that mRNA (genetic material copied from DNA that is necessary for protein creation) derived from the mother's genome seemed to play a critical role in setting up axes of development for the embryo. Piece by piece, mutant by mutant, and gene by gene they built up the picture that now informs how we think of embryonic development. There are multiple mechanisms occurring simultaneously, but let's look at just one, the bicoid mechanism.

Imagine the egg as an oval, and on one side of it maternal signals have allowed bicoid mRNA to build up. This mRNA then starts making copies of bicoid protein, but that protein has a short life, meaning that there is a lot of it on the side of the egg near the mRNA, and decreasing amounts of it as you head towards the end where no bicoid mRNA was stored. This sets up a gradient, whereby you find different amounts of the protein at different locations along the length of the egg. The bicoid protein is a transcription factor, which is a chemical responsible for turning genes on or off. Where it is absent, certain genes crucial to the formation of the head are not activated and so those structures are not formed. Where it is medium-abundant, genes that strongly bind to bicoid are activated, but genes that weakly bind to it are not, and where it is super abundant, as at the end where the original mRNA dwelt, both strong and weakly binding DNA segments will be activated, resulting in a robust development of anterior structures.

Every cell has the same DNA, but for the protein that a gene codes for to be made, the gene must be made active by a transcription factor or collection of such factors. By setting up a myriad of gradients of different types of factors, an embryo can, through purely mechanical means, drive different cells into different developmental destinies. For their work in the genetics of embryonic development, Nüsslein-Volhard and Wieschaus shared a Nobel Prize in 1995, but Nüsslein-Volhard's work was not done. Having contributed so profoundly to our understanding of invertebrate development, she decided to determine what mechanisms might be present in vertebrates as well, and the year of her Nobel Prize was also the year that her zebrafish research group published the results of their study of 1200 mutants raised and screened in their seven thousand aquarium laboratory.

One of the truly landmark figures in late twentieth century developmental genetics, Nüsslein-Volhard is also active in the support of women scientists. Her Christiane-Nüsslein-Volhard-Stiftung, which commenced in 2004, awards financial support to women scientists with children so that they can afford child care, thereby addressing one of the great and recurring gender gaps in modern academia.

Holder of more honorary doctorates and national awards than any person could reasonably be expected to read through, Nüsslein-Volhard is many things to many people. To the young, she is an example that you don't need to know right away what you want to do with your life in order to make an outstanding career. To women, she is a figure of experience shining a light on systemic financial inequities in the academic system. And to the curious, and who among us can fail to be curious about how we came to be, she is the person who pulled the veil back on the elegantly choreographed dance of nucleic acids and transcription factors that pulls form from potential, and life from chemistry.


In 2006, Nüsslein-Volhard published Coming to Life: How Genes Drive Development, the best parts of which are of course those dealing with her descriptions of how different types of gradients drive the formation of different types of biological structures, but which also includes sections on basic genetic concepts to get a mid-level lay science enthusiast up to speed enough to understand those sections.


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