Monday, April 05, 2021

Sharing our ignorance

One of the both wonderful and challenging things about working in a highly interdisciplinary area like synthetic biology is that all of us who work there are painfully ignorant. 

No matter how much of an expert one is in some areas, there is simply too much complexity and too many things to know to allow one to be an expert in all of the relevant aspects of the field. Even an apparently simple task like measuring fluorescence from simple genetic constructs often contains quite a number of rabbit holes of complexity that one can go down. 

Working in a field like this, it's easy to feel insecure about how much one doesn't know. But ignorance can be a gift as well, providing an outside perspective and shedding light on unexamined assumptions. Moreover, what is collaboration if not constructive use of complementary ignorance? Indeed, this is what Joy's law is all about: tackling complex challenges is effectively impossible for "lone geniuses" and always involves expertise dispersed among many different people.

This is a key part of what we are trying to address with the Synthetic Biology StackExchange proposal. Knowledge flows slowly and noisily through person-to-person networking, but much more quickly through well-curated community Q&A like StackExchange supports. Instead of one person getting their question answered through oral tradition, we all get an answer that's confirmed by many peer reviewers and made easy to find for the next several hundred people who need to know.

All we need now to make this happen is another few dozen people to support the proposal and then come ask three good questions on one of the existing sites like Biology.SE or Bioinformatics.SE (thus hitting the "people able to use StackExchange" criteria for launch).  I've really been enjoying this myself, asking questions about simple laboratory information that's outside of my experience, like how hard it is to pipette right and the shelf-life of frozen bacteria, and receiving interesting and informative answers.

Come join us today and make a gift of your ignorance!

Friday, March 12, 2021

One year of lockdown

One year ago today, I was in England, nervously finishing up a standards meeting and hoping that I could make safely home without either getting infected with Covid or getting stuck on the wrong side of the border. 

On March 13th, 2020, I flew home via Chicago, on the last day before the border closed. My wife and I embraced, and we put our household into lockdown. We waited nervously for a week of potential incubation time, but I had apparently escaped infection. Spring break began, and we wondered if there would still be school at the end of it.

We were fortunate. I had noticed the potential trouble building and we had at least a month's supplies laid in our basement for our household. My wife and I could both keep doing our jobs online, and despite some friction with the kids and cats, we settled into an enclosed routine. I miss being able to get together with friends in person, but between my work and family, my life is full and over-full with social interactions, and in the evenings I usually just want a quiet place of solace. 

Some things, I am surprised that I do not miss, like restaurants. We've gotten much better at cooking, and the food we eat is healthier. I've lost fifteen pounds or so, thanks to my healthier lifestyle. More time with the kids is a silver lining too. But what a world of change we've been through, all of us, and it's not over yet.

Tomorrow will be the anniversary, one full year since the last time our house was open to the world. One full year of living our pandemic lives. 

There's a light at the end of the tunnel now, I think, but we're a long way yet from done. Our indoor cats perch on the windowsill, looking at the world outside denied to them to roam, and I think I can identify.

Thursday, March 11, 2021

Building the SynBio StackExchange community

We're getting closer to launching the Synthetic Biology StackExchange Q&A site, but building a new community on StackExchange is hard, and we need more people to come help!

There are more than 150 different topic sites in the StackExchange network, and over the course of launching them, StackExchange has learned a lot about what causes a community to succeed or fail. Most important, it seems, is having critical mass at the start, and they've set the thresholds for site launch accordingly.

What this means for SynBio StackExchange is that we'll launch as soon as we have:

  • 250 people committing to use the site when it launches, and
  • at least 100 of those having 200+ reputation on some other StackExchange site.

I've believe that both of these are quite reasonable and achievable. The 250 people threshold is pretty straightforward, and we're on track to hit that around the end of March. The second criteria, however, is harder since most SynBio folks aren't yet contributing to StackExchange, and will be the one that determines when we can actually launch the site.

Getting 200 reputation is pretty easy: it only takes about 4 questions or 3 answers. It's a big deal, though, since it means you've put a little skin in the game and figured out how to contribute on StackExchange. And once you learn to play the game, it's often pretty fun: helping people feels good, getting your own problems solved is great, and StackExchange is set up to really reward people who put in just a few minutes on a regular basis.

And so it is with building this community. Come join us, and bring one friend. Ask another one tomorrow, and ask your friend to do the same. We're doing pre-launch Q&A using the Biology StackExchange synthetic biology tag, so come ask one question there. Then ask another one tomorrow. And if you want more, ask me for an invitation to the community-building Slack where we're sharing tips and helping each other.

One step at a time, we're working to build this community, and when it's big enough, we'll get to have a dedicated watering hole where everybody who needs help in synthetic biology knows that they can come and find it.

Thursday, February 25, 2021

Getting close to a SynBio StackExchange!

Synthetic Biology StackExchange is one step closer to launching! We've now passed the definition phase for the site, and as soon as we have a critical mass of people committing to participate in the beta, the site will be officially launched. 

I'm very excited about getting this site going, since I think it will be an extremely valuable resource for many thousands of folks working in the area. I know even as an expert, I'm quite naive about a lot of details in the laboratory and issues outside of my own areas of expertise, and really look forward to asking as well as answering questions.

If you're interested too, please go to the site and commit to the beta today!

Monday, February 08, 2021

Come help define a Synthetic Biology StackExchange!

In the actual practice of working in synthetic biology, there are so many pragmatic details that don't get captured well in scientific papers. Right now, they are basically passed around by word of mouth, through oral tradition amongst students in a lab or hallway conversations at conferences. But there is a better way.

Pretty much everybody who programs makes use of StackOverflow, which provides well-curated answers for programming questions. The greater network of StackExchange sites spun off of it provides a great one-stop-shop for lots of other communities as well, from math, physics, and chemistry to travel, cooking, and personal finance. The iGEM Engineering Committee, as part of its educational mission, is trying to do the same for synthetic biology

Synthetic biology field is rapidly growing, highly cross-disciplinary (which means none of us can be experts at everything), and we think it could use a good, universal database of questions and answers. It will be good for students learning the field, and also good for professionals who need to know things outside of their personal expertise.  

Right now, we're in the "definition" phase at StackExchange, and need about 100 more people to add example questions and vote for example questions they like. Just follow this link or click on the imagebelow, make an account, and you can start asking and voting too!

Sunday, January 24, 2021

From art to engineering in synthetic biology

 Two weeks ago, I gave a talk called "From art to engineering in synthetic biology" at the Build-a-Cell seminar series. This talk pulls together a lot of different threads of research that I've been working on, and there were some really enjoyable questions to answer afterwards, and Build-a-Cell has put the video recording of it up online, so if you're interested I hope you will enjoy and share!

Thursday, December 17, 2020

Autonomy in Synthetic Biology

A lot of work is going into laboratory automation and design tools, but how far is it actually getting and what are the real roadblocks? We examine these questions in a new article, "Levels of autonomy in synthetic biology," out today in Molecular Systems Biology.

I'm a big believer that a better toolkit is eventually going to radically transform the way that we engineer biological organisms. And I've certainly preached the gospel of data integration, design tools, reproducibility, etc. But somehow, two decades after the field began, we still find ourselves with lots of barriers to effective deployment of standards and automation to actually increase routine productivity. Way too much is still slow, manual, artisanal. So what's going wrong and what do we need to fix in order to get that transformation into a world of rapid, routine, and reliable engineering?

To understand this, we first developed a six-level framework for analyzing efficacy of automation, analogous to the one used for discussing autonomous vehicles. We don't necessarily need to go crazy-high in autonomy in order to get a lot of benefit. What I really want is at least some good Level 2 scientific "driver assistance" features to help me with the lab equivalents of lane-keeping, checking my blind spot, and parallel parking.

State of the art in autonomy for design-build-test-learn cycle, as shown in our article.

The problem is that right now, there's a bunch of good work being done on specific challenges in the prototypical "design", "build", "test", and "learn" stages of the engineering cycle, but not enough investment in the "glue" of standards that will allow things to connect together between stages or in curation tools that decrease the burden in setting up tools. We know from a number of demonstrations that we can do much better, but the marketplace is still too fragmented and just not enough work has been done on stringing these pieces together yet.

At the same time, I have a lot of hope.  The work we've been doing in partnership with lots of others on the DARPA SD2 program is producing a lot of interesting tools for lowering barriers to curation and making it easier to use automation. I'm also seeing a big push in iGEM, where we've been spreading the word on measurement and engineering methods. And a lot of folks I talk to in government, industry, and around the world all seem to be seeing similar needs and trends, so I hope we're building momentum toward a phase change, and I'm going to see if I can do my part to help.

Check out the full details of our discussion of autonomy in our open access article.

Thursday, September 17, 2020

Robust estimation of bacterial cell count from optical density

The iGEM 2018 interlab article is published today in Nature Communications Biology! This article, which I wrote about last October when we posted on bioRxiv, presents a cheap and easy protocol for estimating cell count and per-cell fluorescence on plate readers. This is so cheap (reagents <$1) and easy, as validated by hundreds of iGEM teams around the world, that I believe no paper should ever be accepted again if it has plate reader data in uncalibrated units, any more than we would accept a paper that measured length in cubits.

The core idea is pretty simple: basically, you calibrate against dilutions of silica microspheres with similar size and optical properties to cells. As long as your cells are in liquid culture that's not too opaque and the cells aren't doing anything really odd optically themselves, this should give a good relationship between optical density and cell count.

We validated this by combining our microsphere protocol and previously published fluorescence estimation protocol to get a close match between flow cytometer and plate reader estimates of per-cell fluorescence, which wouldn't work if either of the protocols was problematic.
Per-cell fluorescence from flow cytometer and plate reader (article Figure 5)

Ironically, the most challenging part of the whole publication was the author list. All the data was supplied by a lot of iGEMers: our consortium author list included approximately1400 people from about 250 teams all around the world.  I had to write scripts to manage the author list and to format and reformat it as we went back and forth with the journal to figure out how to match their formatting requirements. All said and done, however, I wouldn't have it any other way: I am proud to have been able to work with so many capable collaborators and with so many eager young contributors to synthetic biology.

Wednesday, July 22, 2020

Plate reader & flow cytometry tutorials

Over the last two weeks, I've given two measurement tutorials in the iGEM Summer Webinar Series, one focused on plate readers and the other focused on flow cytometry. Both are posted in a repository on GitHub, along with example data and code to help people get started with effective calibration and interpretation of these instruments.
  • The first tutorial, "Quantifying fluorescence and cell count with plate readers," starts with a general introduction to fluorescence and OD, including a comparison of plate readers and other types of instruments, factors affecting fluorescence, and how to pick colors based on excitation and emission spectra. The second block focuses on calibration of measurements for fluorescence and OD, and on debugging such measurements. Finally, the session ends with a discussion of how to interpret and debug calibrated plate reader data.
  • The second tutorial, "Quantifying fluorescence and cell phenotypes with flow cytometry," starts with an introduction to flow cytometry, including how these instruments operate and the types of data that they produce. The second block focuses on calibration of measurements for fluorescence and cell size, and on debugging such measurements. Finally, the session ends with a discussion of how to interpret and debug calibrated flow cytometry data.
Under the hood of a flow cytometer, showing its optical path.
I hope that you will find these useful and redistribute them to others who may find the same!

Friday, June 26, 2020

Closing in on fast, cheap, point-of-care testing for COVID-19

In mid-March, as the COVID-19 pandemic slammed down on America, it just so happened that our group at BBN had just finished sending DARPA a proposal for fast, cheap point-of-care testing for emerging diseases.  So rather than wait for a response on the proposal, we just organized things up ourselves and started working on testing.

The test plan has evolved a bit as we've worked through details, as more information about the virus has emerged and as we've made sure manufacturing will be able to roll these things out at scale. In the end, as has just been announced, it looks like we'll be able to just have people spit out a bit of saliva for the test (no more nasal swabs!) and give accurate answers in less than an hour.

My own role in the project has been on the bioinformatics: the FAST-NA software I've written about here a few times before has been critical for fast and effective design of our detection targets, both ensuring that we will be able to detect all known variants of the virus and that we won't get false positives from other organisms.  And I still love that FAST-NA's core is technology that has been repurposed from hunting for computer viruses to hunting for real ones.

It's not in the field yet, but we're on a good track, and I hope we'll be able to make a real contribution to helping manage the pandemic...