Laboratory for the Physics of Life Thomas Gregor, Professor of Physics, Princeton University

Gasper Tkačik, Julien O. Dubuis, Mariela D. Petkova, and Thomas Gregor. Genetics 199 (1): 39–59 (2015).  (more…)

Thomas Gregor, Hernan G. Garcia, Shawn C. Little. Trends in Genetics 30 (8): 364–375 (2014).
(more…)

Jacques P. Bothma, Hernan G. Garcia, Emilia Esposito, Gavin Schlissel, Thomas Gregor, Michael S. Levine. PNAS 111 (29): 10598–10603 (2014).
(more…)

Laurent Abouchar, Mariela D. Petkova, Cynthia R. Steinhardt, and Thomas Gregor.  J. Roy. Soc. Interface 11 (97): 20140443 (2014).
(more…)

“Seeing the Pattern”
Nature Reviews Genetics (PDF)

“Measuring Transcription to Follow Embryo Development”
BioTechniques News Highlight

“Scientist to watch: Thomas Gregor – Biological Quantifier”
The Scientist

“Development: Lights, Camera, Action — The Drosophila Embryo Goes Live!”
Current Biology Dispatch by Bothma and Levine (PDF)

“Nature – the IT wizard”
Nautilus Magazine

Mariela D. Petkova, Shawn C. Little, Feng Liu, and Thomas Gregor. Current Biology 24 (11): 1283–1288 (2014).
(more…)

Dmitry Krotov, Julien O. Dubuis, Thomas Gregor, and William Bialek. PNAS 111 (10): 3683–3688 (2014).
(more…)

Hernan G. Garcia, Mikhail Tikhonov, Albert Lin and Thomas Gregor. Current Biology 23, 2140–2145 (2013).
(more…)

Laurent Abouchar, Mariela D. Petkova, Cynthia R. Steinhardt, and Thomas Gregor (2013).  arXiv.org:1309.6273 [q-bio.TO].
(more…)

Julien O. Dubuis, Gasper Tkacik, Eric F. Wieschaus, Thomas Gregor and William Bialek, PNAS 110, 16301-16308 (2013).
(more…)

Shawn C. Little, Mikhail Tikhonov and Thomas Gregor, Cell 154, 789–800 (2013).
(more…)

Feng Liu, Alexander H. Morrison and Thomas Gregor, PNAS 110: 6724–6729 (2013).
(more…)

Julien O. Dubuis, Reba Samanta and Thomas Gregor, Molecular Systems Biology 9: 639 (2013).
(more…)

Alexander H. Morrison, Martin Scheeler Julien O. Dubuis and Thomas Gregor, Cold Spring Harb Protoc. 2012(4): 398-406 (2012).
(more…)

The advent of Drosophila melanogaster (fruit fly) as a model organism has transformed modern biology in the 20th century. A brief history of how Drosophila opened new ways of seeing genes and helped understand the construction and the functioning of organisms can be found in this short article by Alfonso Martinez Arias entitled “Drosophila melanogaster and the Development of Biology in the 20th Century“.

More to the point of our first paper, the experiments that earned Nüsslein-Volhard and Wieschaus their Nobel prize aimed to identify genes involved in the development of Drosophila melanogaster embryos. At this point (the late 1970s and early 1980s) little was known about the genetic and molecular mechanisms by which multicellular organisms develop from single cells to morphologically complex forms during embryogenesis.

Fruit flies have long been an important model organism in genetics due to their small size and quick generation time, which makes even large numbers of them relatively easy to maintain and observe in the laboratory. Nüsslein-Volhard and Wieschaus identified genes involved in embryonic development by a series of genetic screens. They generated random mutations in fruit flies using a chemical. Some of these mutations affected genes involved in the development of the embryo. Nüsslein-Volhard and Weischaus took advantage of the segmentedform of Drosophila larvae to address the logic of the genes controlling development. In normal unmutated Drosophila, each segment produces bristles called denticles in a band arranged on the side of the segment closer to the head (the anterior). The researchers looked at the pattern of segments and denticles in each mutant under the microscope, and were therefore able to work out that particular genes were involved in different processes during development based on their differing mutant phenotypes (such as fewer segments, gaps in the normal segment pattern, and alterations in the patterns of denticles on the segments). Many of these genes were given descriptive names based on the appearance of the mutant larvae, such as hedgehog, gurken (German: “cucumbers”), and Krüppel ( “cripple”). Later, researchers identified exactly which gene had been affected by each mutation, thereby identifying a set of genes crucial for Drosophila embryogenesis. The subsequent study of these mutants and their interactions led to important new insights into early Drosophiladevelopment, especially the mechanisms that underlie the step-wise development of body segments.

These experiments are not only distinguished by their sheer scale (with the methods available at the time, they involved an enormous workload), but more importantly by their significance for organisms other than fruit flies. It was later found that many of the genes identified here had homologues in other species. In particular, the homeobox genes (coding for transcription factors critically involved in early body development) are found in all metazoans, and usually have similar roles in body segmentation.

These findings have also led to important realizations about evolution – for example, that protostomes and deuterostomes are likely to have had a relatively well-developed common ancestor with a much more complex body plan than had been conventionally thought. Additionally, they greatly increased our understanding of the regulation of transcription, as well as cell fate during development.

Here is a preparation of the cuticle from a Drosophila embryo, similar to those examined by Nüsslein-Volhard. Note the bands of denticles on the left hand side (towards the head) of each segment:

Source: Wikipedia

We will be discussing the following paper:

Nusslein-Volhard, C. and E. Wieschaus (1980). “Mutations affecting segment number and polarity in Drosophila.” Nature 287(5785): 795-801. (Nusslein-Volhard1980)

Some other papers that might be of interest are:

Nusslein-Volhard, C., E. Wieschaus, et al. (1984). “Mutations Affecting the Pattern of the Larval Cuticle in Drosophila-Melanogaster .1. Zygotic Loci on the 2nd Chromosome.” Wilhelm Rouxs Archives of Developmental Biology 193(5): 267-282. (Nusslein-Volhard1984-Part1, Nusslein-Volhard1984-Part2)

We’ll try to include talking points in this post before our meeting. It could be fun to have everybody participating in putting together those talking points.

Some interesting things to discuss:

• How do you screen for lethal mutants? What’s a good crossing scheme? Why are balancers key here?
• What’s the difference between an allele and a locus?
• Why do they talk about homeotic genes? What’s the difference between determining the existence and positioning of a segment and its identity?
• How can you tell which segment you lost if you can’t see it?
• When you do a screen how do you know when to give up, when you’ve seen most of the stuff there is to see? This is shown in fig. 5 of the 1984 paper.

Chromosomal mapping:

During our discussions the work by Sturtevant and Morgan came up. Here’s a link to the paper with an explanation of their reasoning and the genetic details. It’s fun to try to generate your own map from their data!

SturtevantMapPaper

PLoS Press Release for our first paper on mRNA quantification in whole embryos.

“How are biologic molecules arranged inside the embryo so that embryonic development occurs reliably every time? Princeton researchers, led by Thomas Gregor, an assistant professor of physics and the Lewis-Sigler Institute for Integrative Genomics, and Shawn Little, a postdoctoral fellow in the laboratory of Professor Eric Wieschaus in the Department of Molecular Biology, have developed a new method to better understand how an embryo’s basic molecular makeup helps ensure that the embryo’s development occurs reliably every time. The results of this research into the fruit fly Drosophila introduce a method for making precise measurements of biologic units (so-called mRNA molecules) that play a key role in development. The findings are published in the March 1st issue of  in the online, open access journal PLoS Biology.”

(more…)

Shawn Little, Gašper Tkačik, Thomas Kneeland, Eric Wieschaus and Thomas Gregor, PLoS Biology 9(3): e1000596 (2011).
(more…)