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Cell Reports cover

The Ferrell lab is working to understand the design principles of biochemical switches, timers, and oscillators, especially those that control the cell cycle. We make use of quantitative experimental approaches, modeling, and theory.

* * * NEWS * * *

Oct 2017: The image above is the cover of the Oct 3 2017 issue of Cell Reports, which features an article from Graham Anderson and Lendert Gelens on the waves of cell division that pass through the Xenopus embryo during early development. The picuture shows a dividing embryo that was placed between two mirrors tilted at 45° angles to allow the embryo to be simultaneously filmed from the top and the side (two sides, actually). The work was a collaboration between the Ferrell lab and Julie Baker's lab in the Dept. of Genetics. Yay team!

Graham's and Lendert's work started with an old observation: when Xenopus embryos cleave, first in two, then in four, and so on, the cell divisions happen almost, but not quite, synchronously. If you look carefully you can see that there is actually a wave of cell division that sweeps from one side of the embryo to the other. Graham and Lendert set out to answer two questions: (1) how does the wave of cell divisions arise, and (2) is the near-synchrony of the embryonic divisions important for normal embryogenesis?

For question 1: They had two plausible working hypotheses. The first was that cell division happened in one cell first, and then spread (somehow) from cell to cell through the embryo. This is how a contraction wave spreads in the human heart. The second was that all of the cells in the embryo had their own independent cell cycle "clock", with some clocks pre-programmed to run faster and some to run slower. In this case the wave of cell divisions would be what is termed a kinematic wave, like the flashing lights on a movie marquee, with the apparent cell-to-cell spread being an illusion.

To distinguish between these possibilities, Graham and Lendert placed Xenopus embryos in a temperature gradient for an hour or so, yielding embryos where the cells on one side of the embryo were advanced in phase relative to the cells on the other side. The embryos were then restored to a constant temperature, and Graham and Lendert looked to see whether the desynchronized cells would come back into sync, as would be expected if cell cycles can spread from cell-to-cell. The resulty was that the cells never resynchronized. It seems that the cell division wave is a kinematic wave, an illusion due to differences in how fast the cell cycle clock runs in different parts of the embryo.

For question 2: One of the earliest differentiation events in embryogenesis is mesoderm induction. As early as the 32-64 cell stage, signals from the bottom (vegetal) half of the embryo cause cells just above the middle to turn into mesoderm, and then the mesoderm is patterned. It seemed plausible that if the cells doing the inducing/pattern and the cells receiving the inducing/patterning signals were out of sync with each other, mesoderm induction would be disrupted. And, indeed, Graham and Lendert found that it was. To our surprise, though, it turned out that this abnormal patterning was corrected later in embryogenesis, after the 4000-cell stage (the midblastula transition), so that the desynchronized embryos ultimately developed into normal tadpoles. This finding underscores the robustness of the overall program of embryogenesis.

Congratulations Graham and Lendert!

Sep 2017: It's time again for Stanford's own Loose Ends, with Jim on guitar, to make loud rock music while you all eat free burgers and drink free beer on the Clark Center's Nexus Cafe Patio. The happenings will be Friday Sep 29 from 4-6 PM—be there or be hungry, sober, and less deaf.

Andreas and the bongosSep 2017: And now we must bid a fond farewell to Andreas Meyerhans. During his time with us he learned some systems biology and taught us some immunology. He also came up with a great idea for a new trigger wave project that we plan to pursue collaboratively. And he got the chance to hit those bongos at the CSB Retreat this month, jamming with the Mighty Temblors. So long, Andreas!

Aug 2017: Upcoming talks—Jim will be speaking at the SystemsX Conference on Systems Biology in Zurich Sep 4; at the University of Amsterdam Sep 8; and at the Weizmann Institute in Rehovot Israel on Sep 11. If you are in the area, please stop by and say hello.

Jun 2017: Welcome Andreas Meyerhans! Andreas is spending the next four months with us as a sabbitical visitor. He hails from Barcelona, where he is an ICREA Research Professor at the University of Pompeu Fabra. His research focuses on the interactions between viruses and theire hosts in vivo, with a particular focus on what governs whether a viral infection will be acute but ultimately cleared, or chronic and persistent--questions that call out for some new insights from nonlinear dynamices. Welcome Andreas!

May 2017: And a fond farewell to Tek Hyung Lee, who is moving to a position at Lawrence Livermore National Laboratory. Tek Hyung will be working with Mimi Cho Yung, engineering bacteria for protein expression. All the best, Tek Hyung!

Apr 2017: And another bittersweet bye bye! We bid a fond farewell to Graham Anderson, who has joined Ferrell lab alum Zach Serber's company, Zymergen. Congratulations, Dr. Anderson--an era ends and another begins.

Feb 2017: Bye bye! We bid a fond farewell to Sang Hoon Ha, who is moving on to take a faculty position at Chonbuk National University in Korea. Congratulations on the new job, Sang Hoon, and all the best from all of us.

Feb 2017: Welcome Minjung Kang! Min was a Ph.D. student at Weill Cornell Medical School, working with Kat Hadjantonakis, and has now arrived in rainy California to do her postdoctoral work in the Ferrell lab. She is working on mitotic regulation in mammalian cells.

Feb 2017: Julia Kamenz and Jim have written a commentary on the temporal ordering of cell cycle phosphorylation, which was published Feb. 2 in Molecular Cell. Julia has also been selected to give a talk on her work on this topic at the Winter qBio Meeting in Kauai Feb 24-27.

Jan 2017: Jim gave a talk on Xianrui Cheng's work on apoptosis at the Gordon Research Conference on Stochastic Physics in Biology in Ventura CA, Jan 8-13. The high point of the conference was a talk by Dan Gillespie on the skeptical response his now-famous algorithm initially received from the chemical physics community, and on his new work extending the algorithm to systems where the reactants occupy non-negligible volumes (like living systems).

Dec 2016: Welcome, Connie Phong! Connie was a Ph.D. student in Mike Rust's lab at the University of Chicago, and has now joined us as a postdoctoral fellow. Connie will be working on temperature scaling in cell cycle regulation in collaboration with our old friend Lendert Gelens.

Oct 2016: Congratulations to Sarah Trosin, who successfully defended her Ph.D. thesis October 19. The title of her presentation was "Toward Understanding Cyclin Requirements for Mitotic Entry in the Mammalian Somatic Cell Cycle".

Oct 1 2016: Congratulations to our own Xianrui Cheng, who tied for the silver medal for best talk at the CSB Annual Retreat at Stanford Sierra Camp. And congratulations to the other medalists, Stephan Hamperl (form Karlene Cimprich's lab) and Opher Kornfeld (from Daria Mochly-Rosen's lab). And to everyone else too--the quality of the research and the talks was really extraordinary this year!

July 19 2016: Jim lectured at the 10th Annual q-Bio Summer School at Colorado State.

Loose EndsJuly 10 2016: The Loose Ends, a Stanford rock band with Jim on guitar, will be playing at the Clark Center this Friday, July 15, from 4:00-6:00 on the Nexus Cafe Patio. In addition to that loud rock music the kids all dig, there will be free food and beer.

July 4 2016: Cell Systems featured the Ha and Ferrell Science paper in the latest in their "Principles of Systems Biology" series (#6). A link to the feature can be found here. The paper was also recently recommended by the Faculty of 1000.

June 13 2016: Jim will be speaking this Thursday at the International Conference on Systems Biology of Human Disease (SBHD), at the Broad Institute in Cambridge.

June 6 2016: Congratulations to Julia Kamenz, who has been awarded a Deutsche Forschungsgemeinschaft (DFG) Postdoctoral Fellowship to support her work on the ordering of mitotic events!

May 25 2016: The latest issue of Science Signaling highlighted the recent Ha and Ferrell Science article as a "Paper of Note" (click here).

May 19 2016: Our own Julia Kamenz has been selected as a speaker for this year's Cold Spring Harbor Cell Cycle meeting. Julia will speak this Saturday (May 21) about her work on protein dephosphorylation during mitotic exit.

May 13 2016: We have a new paper out on thresholds and negative cooperativity. Here's a quick summary:

In the 1960's, Dan Koshland introduced the idea of "negative cooperativity" in the function of proteins with multiple subunits. In negative cooperativity, the binding of one ligand makes it harder for a second ligand to bind. The standard theory on negative cooperativity says that the higher the negative cooperativity, the more graded the receptor's response.

It turns out there is a little algebraic shortcut built into the standard theory--effectively it is an assumption that the binding of ligand molecules to receptors has no significant impact on the concentration of free ligand. In many situations, especially intracellular signaling, this assumption does not hold.

If one re-derives the theory without this little shortcut, the results are different, and kind of remarkable. Negative cooperativity can endow a receptor's response with a marked threshold, making it so there will be no response until the ligand concentration is higher than the receptor concentration. Sang Hoon Ha tested the new theory with a series of synthetic biology experiments, using DNA oligonucleotides to represent the receptor and ligand species and manipulating the cooperativity of their binding. The results are in beautiful agreement with the new theory.

The paper has just been published in Science (click here). Congratulations Sang Hoon!

Apr 29 2016: Jim is just back from the University of Texas Southwestern, where he presented the 16th annual Rupert E. Billingham Lecture in Cell Biology. Jim talked about trigger waves in intracellular communication.

Mar 2016: Bye bye! As of April 1, our own Lendert Gelens leaves Stanford Chemical and Systems Biology and begins as an Asst. Professor at the University of Leuven in Belgium. He will head the Dynamics in Biological Systems (DiBS) lab. We are all looking forward to watching this exceptionally able young scientist become one of the leading lights in quantitative biology. Good luck, Lendert!

Feb 2016: Jim speaks at the Biophysical Society's 60th Annual Meeting in the Synthetic Biology Symposium, which is Sun Feb 28 from 8:15-10:15 AM. So does Stanford Chemical and Systems Biology's own Mary Teruel. More info? Click here.

Feb 2016: Jim's review on perfect adaptation was just published in Cell Systems. The article disusses the Holy Trinity of adaptation mechanisms—negative feedback, incoherent feedforward regulation, and state-dependent inactivation—as well as a new twist on negative feedback recently proposed by Mustafa Khammash and his colleagues (click here). As important as at is to understand how signaling systems are turned on, it is nice to be getting a comprehensive picture of what nature does to ensure that they get turned back off.

Feb 2016: We are just back from the Winter q-Bio meeting in Honolulu. Lendert Gelens gave a talk about his and Graham Anderson's unpublished work on waves of mitosis in embryos. Jim presented Xianrui Cheng's unpublished work on apoptotic trigger waves (Hawaii is a good place for waves!) and Sanghoon Ha's unpublished work on negative cooperativity. Ferrell lab alumna Silvia Santos also spoke, presenting new stuff on the temporal modularity of mitosis in mammalian cells. A splendid time was had by all!

Feb 2016: Please check out the latest paper from Sanghoon Ha and Sun Young Kim, just published in Cell Reports. The paper takes on the question of why it is that the Suc1/Cks proteins, components of the cyclin B-Cdk1 complex, seem to both promote and inhibit cell cycle progression. The answer lies in the prozone effect, where adaptors like Cks proteins can promote complex formation at substoichiometric concentrations, but then inhibit complex formation at suprastoichiometric concentrations. The paper is a nice combination of theory, proof-of-principle experiments, and in vitro studies of cyclin B1-Cdk1-Cks2 biochemistry.

Nov 2015: The EMBL Symposium on "Biological Oscillators: Design, Mechanism, and Function" took place Nov 12-14 at EMBL in Heidelberg. Jim spoke about how the reactions underpinning a biological oscillator can determine the spatial organization of the oscillations.

Oct 2015: Congratulations to Graham Anderson, who successfully defended his Ph.D. thesis, in fine style, on Oct 30. The title of his presentation was "Embryonic Division Waves Develop Autonomously and Precede Proper Mesoderm Induction".

Oct 2015: Congratulations to Dr. Lendert Gelens, whose talk at the "Physics of Living Matter" symposium in Cambridge UK was awarded the "Best Young Researcher Prize". Dr. Gelens spoke on the spatial coordination of development in Xenopus embryos subject to temperature perturbations. The work was done in collaboration with Graham Anderson from the Ferrell lab and K. C. Huang from the Dept. of Bioengineering.