Presenting Millstone: Genome Engineering in the Cloud

Screen shot 2014-03-21 at 4.38.03 PM

Next Tuesday we are unveiling Millstone, a web platform for genome engineering and analysis at the SynBERC 2014 Spring symposium. The product of a team led by myself and Gleb Kuznetsov, Millstone is the culmination of bioinformatics tool development that came out of the reColi project and other genome engineering efforts in the lab.

Millstone is a distributed bioinformatics software platform designed to facilitate genome engineering for synthetic biology. It allows you to automate iterative design, analysis, and debugging for projects involving hundreds of bacterial genomes.

Using synthetic DNA to test genetic elements and improve gene expression


We’ve recently published two papers involving the use of synthetic DNA libraries from microarrays. The first paper, published in The Proceedings of the National Academy of Sciences, details our work to build and test large libraries of synthetic genetic elements in high throughput. We developed a method called Flow-Seq, which combines next-generation sequencing and FACS (fluorescence-activated cell sorting) to measure many thousands of combinations of genetic elements simultaneously.

Fig S1

In our second paper, published in Science, we generated a synthetic gene library that extensively varied codon usage for natural E. coli genes and showed that rare codon usage at the N-terminus tends to increase gene expression. This effect is due to not to the codons themselves, but rather their low GC content and consequent effect on RNA secondary structure. This finding gives scientists a new way to easily optimize heterologous gene expression in bacteria, sometimes by as much as 100-fold.

As DNA synthesis and sequencing becomes cheaper, faster, and more accurate, designing and building large synthetic libraries of genetic elements, genes, and even whole genomes will become widespread. The bottleneck is now shifting to better methods for designing and analyzing these megabase-scale libraries.

I spoke about some of this work recently at my Synthetic Biology 6.0 talk, and GetSynBio also wrote an article about our research and the implications for the future of design and testing in synthetic biology.

Causes and effects of N-Terminal codon bias in bacterial genes. Goodman et al. Science. 6157:475-479 2013

Composability of regulatory sequences controlling transcription and translation in Escherichia coli. Kosuri, Goodman et al. PNAS. Aug 7, 2013.

Removing a codon from E. coli

The CAGE method for genome modification.

A new paper from the Church lab appears in July 15th’s issue of Science Magazine. I worked on aspects of this project during my initial rotation in the lab. In particular, I used conjugative assembly to combine together subunits of the modified genome (the CAGE method). I also led the genome re-sequencing effort. We sequenced many of the intermediate recoded strains to confirm that our changes were made successfully, to characterize the mutation rate over the replacement and assembly process, and to ensure that we did not introduce large numbers of additional point mutations or structural changes to the genome.

In addition to the paper itself, you can read popular press coverage of the research from several places:

New York Times
MIT News
And more…

Joined the George Church Lab at Harvard Medical School

The Wyss Institute, Boston
The Wyss Institute, Boston

As of July of 2010, I have finished my laboratory rotations and joined George Church’s lab at the Harvard Medical School Department of Genetics. I’m working in Dr. Church’s lab space at the Wyss Institute of Biologically Inspired Engineering across the river in Boston.

My work in the Church lab will focus on manipulating bacterial and mammalian genomes and assaying the phenotypic effects of these changes using high-throughput methods. I plan to harness and improve a number of new technologies that the lab has been developing, including oligo chip-based gene synthesis and MAGE (multiplex automated genome engineering).

Classes and Rotations

Another update is in order, now that the semester is more than half-over. My HST courses are keeping me busy, and the fall weather here is turning colder by the day. The leaves are quite pretty though!

I’ve started a rotation in the Ron Weiss lab, who has recently moved to MIT from Princeton University. We share some interests in combining simulation and modeling with synthetic biology, an I’m taking the opportunity to branch out into the wet lab and get my hands dirty. My project as it currently stands involves replicating some of the experiments in the Voigt/Lim lab’s recent Nature paper; we are interested in using their light-activated construct to specify synaptic partners for neurons grown in-vitro. My iGEM experience has given me a bit of a head start, but now I’m learning the ‘art’ of mammalian cell culture, using lentiviral vectors, as well as some fancy microscopy techniques.

I’ve also uploaded PDFs of a poster and a presentation from my previous work at the Cancer Research Institute in Cambridge, UK. They’re on my poster/presentation page.

The Move to Boston

View of my commute: Back Bay to MIT over the Harvard Bridge
View of my commute: Back Bay to MIT over the Harvard Bridge

After nine months, a brief update is in order. My year-long Whitaker Fellowship at the University of Cambridge has now come to a close. It was a tremendous experience, and I’m grateful to have had the opportunity to pursue a variety of both computational and experimental research at Simon Tavaré’s lab at the Cambridge Research Institute and through iGEM 2008. In May my group published a paper on our Bead Emulsion DNA Amplification technology in Analytical Chemistry, and with any luck, another one should be coming out later in the year.

So, now after a year in Cambridge, I’m moving to Cambridge! UK to MA, to be precise. Now that my Whitaker Fellowship at the University of Cambridge has come to a close, I’ve come back stateside to begin graduate school.

More precisely, I’ve just started a PhD at the Massachusetts Institute of Technology. I’m in a joint Harvard/MIT program called Health Sciences and Technology (HST). Within HST, I’m a Medical Physics and Medical Engineering student (MEMP), and I’m in a subprogram of MEMP called Bioinformatics and Integrative Genomics (BIG). A lot of acronyms.

I’m still getting settled here in Boston; I’m in temporary accomodation in the lovely Back Bay area, but looking for a more permanant (and closer) place across the river in Cambridge. That said, I do enjoy my beautiful commute across the Harvard Bridge every morning.

New Year Updates

Overhead Photo of iGEM 2008 Participants at MIT
Overhead Photo of iGEM 2008 Participants at MIT

The new year has rolled in, and a lot has happened. The 2008 iGEM summer project has come to a close. This November our Cambridge University team presented our Synthetic Biology project at the 2008 iGEM Jamboree at the Massachusetts Institute of Technology. We were working on several related projects involving bacterial self-organization. You can browse our iGEM project wiki, watch our Jamboree presentation, and view the presentation slides. I was also interviewed about the iGEM project by the BBC program The Leading Edge. There is a recording of the program available; the iGEM bit starts 21 minutes in. My experience with iGEM was pretty excruciating at times but I never imagined that I could learn so much in one summer.

I’ve moved full time to the Cambridge Research Institute at the University’s Addenbrookes Hospital. I’ve been working mostly with image processing and parallel computing in MATLAB, which, while not without problems, has been remarkably easy to use. We’re thinking about incorporating some of the modules from CellProfiler, a biological image recognition software package written for MATLAB by Anne Carpenter’s group at MIT. While it’s made for recognizing cells and nuclei, we’re hoping that it can be adapted for our emPCR bead images.

I’ve been on a semi-vacation back in sunny California for the holidays, mostly working on graduate school applications and visiting friends and family. I will return to the UK on January 10th. Being home is great, but I’m ready to get back to work Cambridge, especially now that I’ve had a chance to purchase some warmer clothes to take back with me!

iGEM Presentation, Cancer Research.

As my iGEM summer comes to a close, the team and I are finishing up work on our project and preparing to give a presentation at the 2008 iGEM Jamboree at MIT on November 8th, 2008. I am looking forward to giving my talk at MIT in a few weeks, meeting fellow iGEMers from across the planet, and showing off all our hard work! As soon as the talk is available online, I’ll link to it from my website here.

I’ve never seen Boston before, so I also plan to take the opportunity to visit Systems Biology labs in the Boston/Cambridge area and visit some old friends.

Since the start of October I’ve also been diving into my Whitaker Fellowship project at the Cambridge Research Institute on the Addenbrookes Hospital campus. My first task thus far is writing image analysis code to process the fluorescent em-PCR beads that hold our methylation data. Dry work at a comfy desk is a welcome and relaxing change from the hectic pace of lab work. But while MATLAB and R are much easier to debug than PCR primers and plasmid ligations, I’m sure I’ll miss the hands-on work soon enough.

Last but not least, I’ve finally gotten around to updating my curriculum vitae to include the Genome Research Paper that was recently published, as well as my work with iGEM and my current Whitaker Fellowship. It’s also linked on the menu bar.

Hopefully I’ll soon get a chance to add some summaries of my past research projects to this website, along with pictures and code. Look back soon for a completed Projects page.

Getting settled in Cambridge

After finishing my undergraduate studies this Spring, I spent two months travelling through Europe, mostly living in Barcelona. In July I relocated to Cambridge, UK. This summer I will be working with the 2008 Cambridge iGEM team. You can find more information about iGEM here, and visit out team wiki here. Starting in the Fall, I will begin work on my Whitaker-funded project, which focuses on the stochastic modeling of stem cell diffentiation using DNA methylation patterns.

iGEM has kept me busy so far this summer, but I hope to update my CV and detail some of my previous and current research projects. For now, you can check out my Flickr page for photos of me, my travels, Cambridge, and of my colleagues on the iGEM team.