Atlas / Biology / The Development Thread

Field · Emerged 1978 – 1988

Developmental Genetics

Which genes build an embryo, and how do they switch each other on in the right place?

5 chapters5 min read6 turning points 1 open problem

Branched from: Experimental Embryology + Genetics
Branched into: Evolutionary Developmental Biology
Figures: Edward Lewis, Sydney Brenner, John Sulston, Christiane Nüsslein-Volhard, Eric Wieschaus, William McGinnis, Walter Gehring, Matthew Scott, H. Robert Horvitz, Wolfgang Driever

In brief

Developmental genetics finds the genes that control development by breaking them. Researchers collect mutant animals whose embryos go wrong in a particular way, such as a missing segment or a leg where an antenna should be, and trace each defect to a gene. The fruit fly Drosophila and the roundworm C. elegans were the workhorses, chosen because they breed fast and can be screened by the thousand.

Between the late 1970s and the late 1980s the approach answered questions that surgery could not. The fly's body plan turned out to be laid down by a cascade of a few dozen genes, beginning with signals the mother places in the egg. Many of these genes make proteins that switch other genes on and off, and many share a short DNA sequence, the homeobox. The worm showed that cells can be programmed to die. Most of these genes turned out to have close relatives in humans.

Key ideas

Homeotic genesEnters 1978: Genes that give each body region its identity. Mutations in them turn one body part into another, such as a haltere into a second wing.
The segmentation cascadeEnters 1980: In the fly, maternal signals switch on gap genes in broad bands, which switch on pair-rule genes in seven stripes, which switch on segment-polarity genes in fourteen. Each tier refines the pattern of the one before.
The homeoboxEnters 1984: A DNA sequence of 180 letters, shared by many genes that control development. It encodes a protein region that binds DNA, so these genes work by switching other genes on and off.
MorphogenEnters 1988: A signal whose concentration varies across a tissue and tells cells what to become. Bicoid in the fly egg was the first shown to work this way.
Programmed cell deathEnters 1986: Cells can kill themselves in an orderly way, called apoptosis, under the control of specific genes. It sculpts organs and removes damaged cells.

Chapter I

From Embryos to Mutants

Thomas Hunt Morgan began as an embryologist. He studied regeneration and worked alongside Driesch at the Naples marine station before he turned to fruit flies in 1908 and founded genetics as a laboratory science. Genetics then drifted away from embryos for half a century. Geneticists studied how genes are passed on, embryologists studied how tissues interact, and neither could reach the other's questions.

A few kept the link alive. In 1915 Calvin Bridges found a fly whose tiny balancing organs, the halteres behind the wings, were partly turned into wings. Edward Lewis spent from the 1940s to the 1970s on the cluster of genes responsible, the bithorax complex. By combining mutations he made flies with a full second pair of wings. In 1978 he showed that the genes sit on the chromosome in the same order as the segments they control, front to back.

Chapter II

The Screen

In 1979 Christiane Nüsslein-Volhard and Eric Wieschaus set out to find every gene needed to lay out the body of a fly larva. They mutated flies, bred thousands of lines and examined the dead embryos of each under a two-headed microscope. The mutants fell into classes. Gap mutants lacked a broad block of segments. Pair-rule mutants lacked every other segment. Segment-polarity mutants had each segment's pattern half replaced by a mirror image of the other half. The classes turned out to be tiers of a cascade that divides the embryo more and more finely.

The cascade starts with the mother. Wolfgang Driever, Nüsslein-Volhard and colleagues showed in 1988 that the mother places the messenger RNA of bicoid at the front of the egg. Its protein spreads backwards and forms a gradient, and the genes below it read the concentration. Here was Wolpert's positional information, as a molecule.

Why did the genes work? In 1984 William McGinnis and Michael Levine in Walter Gehring's laboratory, and Matthew Scott and Amy Weiner in Indiana, found that homeotic genes share a stretch of DNA, the homeobox. It encodes part of a protein that binds DNA. These genes make switches that turn other genes on and off. Within months the homeobox turned up in vertebrates, and evolutionary developmental biology was born.

Chapter III

The Worm

Sydney Brenner chose a different animal. C. elegans is a transparent roundworm a millimetre long, with few enough cells to count. John Sulston watched its cells divide under the microscope, hour after hour, and by 1983 he and colleagues had traced the whole lineage from egg to adult. It is identical in every worm. Of 1,090 cells made, exactly 131 die, and the adult hermaphrodite has 959 body cells. The deaths are part of the plan. H. Robert Horvitz found the genes that carry them out, and their human versions control cell death in people, including its failure in cancer.

Chapter IV

A Closer Look: Reading Position from a Gradient

Bicoid protein is made at the front of the egg and spreads backwards while being broken down. The result is close to an exponential gradient:

c(x) = c_0 \, e^{-x/\lambda} ,

where $x$ is the distance from the front, $c_0$ is the concentration there, and $\lambda$ , the length constant, is the distance over which it falls by a factor of $e \approx 2.72$ . Measurements give $\lambda$ close to a fifth of the egg's length. For an egg 500 micrometres long, take $\lambda = 100$ micrometres:

Position along egg	Distance from front	Bicoid, fraction of peak
0	0 µm	1.000
0.1	50 µm	0.607
0.2	100 µm	0.368
0.3	150 µm	0.223
0.4	200 µm	0.135
0.5	250 µm	0.082
0.6	300 µm	0.050

A gene such as hunchback switches on where Bicoid is above a threshold, and its boundary falls near the middle of the egg, where Bicoid is around a tenth of its peak. A nucleus reads its position by reading a concentration.

The model makes a sharp prediction. Double the amount of Bicoid, and every concentration is doubled, so the point where a given threshold is reached moves back by the distance over which the gradient halves:

\Delta x = \lambda \ln 2 \approx 100 \times 0.693 \approx 69 \ \mu\text{m} ,

about 14 per cent of the egg's length. Driever and Nüsslein-Volhard found that extra copies of bicoid do shift the pattern backwards, and fewer copies shift it forwards, as the model predicts.

How finely can position be read? Neighbouring nuclei at this stage are roughly 10 micrometres apart, and over 10 micrometres the gradient falls by $1 - e^{-0.1} \approx 9.5$ per cent. To tell one nucleus from its neighbour, the embryo must detect a concentration difference of about a tenth. Measurements in 2007 showed that the hunchback boundary is placed to about the width of one nucleus, so the embryo does roughly this well, close to the limit set by the random arrival of molecules.

Chapter V

Genes Everywhere

By 1990 the genes that build a fly and a worm were known in outline, and almost every one had a relative in vertebrates. The same few signalling pathways, named after fly mutants such as hedgehog, wingless and notch, were used again and again in every animal, in every organ. That discovery opened two new directions. One compared the genes across species to ask how bodies evolve, which became evo-devo. The other asked how cells hold onto the identity these genes give them, and whether it can be reversed, which fed stem cell biology.

Turning points6

1978DISCOVERY
Lewis and the bithorax complex
Edward Lewis spends three decades studying a cluster of fly genes whose mutations transform body segments, and in 1978 publishes a model of how they work. Combining mutations, he had bred flies with four wings instead of two. The genes lie on the chromosome in the same order as the body segments they control, a correspondence later called colinearity.
Edward Lewis
› Sources (1)
- Lewis, E. B. (1978). A gene complex controlling segmentation in Drosophila. Nature 276(5688): 565–570.
1974 – 1983DISCOVERY
Every cell of a worm traced
Sydney Brenner adopts the millimetre-long roundworm C. elegans as a model for genetics and development. Watching living, transparent worms under the microscope for hours at a time, John Sulston and colleagues trace every cell division from the egg to the adult. The lineage is the same in every worm: 1,090 cells are made, 131 die, and the adult hermaphrodite has 959 body cells.
Sydney Brenner, John Sulston
› Sources (2)
- Brenner, S. (1974). The genetics of Caenorhabditis elegans. Genetics 77(1): 71–94.
- Sulston, J. E., Schierenberg, E., White, J. G. & Thomson, J. N. (1983). The embryonic cell lineage of the nematode Caenorhabditis elegans. Developmental Biology 100(1): 64–119.
1980TECHNIQUE-INVENTED
The Heidelberg screen
Christiane Nüsslein-Volhard and Eric Wieschaus, sharing a laboratory in Heidelberg, mutate flies and systematically search for every gene needed to pattern the larva. Sitting at a double microscope, they examine the embryos of thousands of lines. They find about fifteen genes that divide the embryo into segments, sorted into three classes by the defects they cause. With Lewis they shared the 1995 Nobel prize.
Christiane Nüsslein-Volhard, Eric Wieschaus
› Sources (1)
- Nüsslein-Volhard, C. & Wieschaus, E. (1980). Mutations affecting segment number and polarity in Drosophila. Nature 287(5785): 795–801.
1984DISCOVERY
The homeobox
Two groups, William McGinnis, Michael Levine and colleagues in Walter Gehring's laboratory in Basel, and Matthew Scott and Amy Weiner in Indiana, independently find that the fly's homeotic genes share a short stretch of nearly identical DNA. The protein region it encodes binds DNA. Within months the same sequence was found in frogs, mice and humans.
William McGinnis, Walter Gehring, Matthew Scott
› Sources (2)
- McGinnis, W., Levine, M. S., Hafen, E., Kuroiwa, A. & Gehring, W. J. (1984). A conserved DNA sequence in homoeotic genes of the Drosophila Antennapedia and bithorax complexes. Nature 308(5958): 428–433.
- Scott, M. P. & Weiner, A. J. (1984). Structural relationships among genes that control development: sequence homology between the Antennapedia, Ultrabithorax, and fushi tarazu loci of Drosophila. Proceedings of the National Academy of Sciences 81(13): 4115–4119.
1986DISCOVERY
Genes for cell death
H. Robert Horvitz and Hilary Ellis find mutant worms in which the 131 cells that normally die survive. Two genes, ced-3 and ced-4, are needed for the cells to kill themselves. Their human equivalents, and the protective gene BCL-2, turned out to control apoptosis in people. Brenner, Sulston and Horvitz shared the 2002 Nobel prize.
H. Robert Horvitz
› Sources (1)
- Ellis, H. M. & Horvitz, H. R. (1986). Genetic control of programmed cell death in the nematode C. elegans. Cell 44(6): 817–829.
1988DISCOVERY
The Bicoid gradient
Wolfgang Driever, Christiane Nüsslein-Volhard and colleagues show that the mother deposits the messenger RNA of the gene bicoid at the front end of the egg. Its protein spreads back to form a gradient, highest at the head. Adding extra copies of the gene shifts the pattern of the embryo towards the rear. It was the first molecule shown to act as a morphogen, as Wolpert had predicted.
Christiane Nüsslein-Volhard, Wolfgang Driever
› Sources (3)

Applications

Where it is used

Physics↗ Physics · Kinetic Theory of Gases
How precisely can a cell read a signal?
A nucleus in a fly embryo reads its position from Bicoid molecules that arrive by random diffusion, so the count it senses is noisy. Physicists showed that the embryo's precision is close to the limit set by the random motion of molecules, the same statistics that underlie the kinetic theory of gases. The fly embryo has become a test case for the physics of biological information.
› Sources (1)
- Gregor, T., Tank, D. W., Wieschaus, E. F. & Bialek, W. (2007). Probing the limits to positional information. Cell 130(1): 153–164.
Cancer medicine
Drugs from the fly's patterning genes
The Heidelberg screen found hedgehog, one of a handful of signalling pathways reused throughout development. When the pathway is stuck on in adult skin, it causes the commonest human cancer, basal-cell carcinoma, and a drug that blocks it, vismodegib, was approved in 2012.
› Sources (1)
- Von Hoff, D. D. et al. (2009). Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. New England Journal of Medicine 361(12): 1164–1172.
Cancer medicine
Switching cell death back on
Many cancer cells survive by making too much BCL-2, the human version of a worm gene that blocks cell death. Venetoclax, which blocks BCL-2, lets them die, and is used to treat chronic lymphocytic leukaemia.
› Sources (1)
- Roberts, A. W. et al. (2016). Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. New England Journal of Medicine 374(4): 311–322.

Open problems

Where the map runs out

Open

How do organs know when to stop growing?

Open as of 2026; several signalling pathways are known to be involved, but not how size itself is measured.

A mouse liver, a fly wing and a human hand each grow to a consistent size and stop. A fly wing made of fewer, larger cells still reaches the normal size, and a partly removed liver regrows to its original mass. Something measures the organ as a whole. What is it?

Why it is hard: Growth is controlled by many pathways at once, including hormones, the Hippo pathway that restrains cell division, and mechanical stretching of tissue. Each affects size when disturbed, but none has been shown to measure it. The signal may be a property of the whole tissue, not of any one molecule.
What resolving it unlocks: Better understanding of cancer, which is growth that fails to stop, and of how to grow tissues to the right size for repair.

› Sources (1)

Pan, D. (2010). The Hippo signaling pathway in development and cancer. Developmental Cell 19(4): 491–505.