Professor of synthetic biology & chemical engineering. De Novo DNA founder. Engineering microbes with predictive models & algorithms.

UC Riverside, CA
Joined April 2009
Introducing the T7 Promoter Calculator, our newest model that predicts the T7 transcription rate for every start site across a genetic system's sequence, including both canonical & low-affinity sites; and redesigns T7 expression systems to remove production of long RNA byproducts
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Massively parallel assays using oligopools, barcoding, & deep sequencing follows the same story. Replaces 100s of microtiter plates (one assay per well) with 10000s of experiments run in one pooled assay. Work your 🧠, not just more 🤖.
Maybe controversial: the conversation about scientific bottlenecks is overfocused on automation. New measurement technologies deserve more attention. You could automate an assay that needs an entire facility – or you could REINVENT the assay so that it fits into just a few tubes.
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Maybe controversial: the conversation about scientific bottlenecks is overfocused on automation. New measurement technologies deserve more attention. You could automate an assay that needs an entire facility – or you could REINVENT the assay so that it fits into just a few tubes.
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Howard Salis retweeted
AI will not automate radiologists like you think We have been talking for years now about AI automating jobs. Radiology has been a prime target, with Geoff Hinton once claiming, “people should stop training radiologists now, it’s just completely obvious that within five years, deep learning is going to do better than radiologists”, which is funny since he said that in 2016. There is now more demand for radiologists than ever, so clearly things did not turn out the way many thought. Here I will make a prediction that while radiology will change in the coming decade, radiologists will not be automated away any time soon. I will use radiology as an example but I think these principles will broadly apply to any field where demand can be elastic and quality can scale with increased intelligence. First of all, we have seen in the short history of language models that there is a “jagged edge of intelligence”, where AI excels at verifiable tasks with a lot of data but is underwhelming on less common tasks. One thing most AI researchers underestimate about radiology is that it is actually extremely multi-task. There are at least a hundred conditions that can be diagnosed from x-rays alone, and thousands using CT and MRI. AI will first master common and easy-to-see conditions and it will not be as good as experts at less-common diseases just because there is less data for that. This jagged edge will certainly improve over time but this means that AI will certainly be used as a triage tool at first, rather than full automation in one go. I would guess that this process from solid triage tool to full automation would take 3-5 years in the best case scenario, because training AI to get all the edge cases right will be bottlenecked by data collection of rare diseases, and also because radiology isn’t currently a focus for frontier labs. Second, there will be elastic demand for radiology as it gets cheaper per unit. I think elastic demand (“Jevons paradox”) is the most underrated phenomenon when people think about AI automation. In software, it is obvious that I have way more demand than before because Claude Code makes it so easy. These days I ask Claude Code to build a custom three-thousand line html viewer to help me visualize every little RL run that I do. The same thing will happen in radiology. If there is essentially no cost or latency of interpreting an MRI, a physician can order many scans preemptively to better diagnose a case. So with AI tools, a radiologist might have to read only 20% of inbound scans, but there might be 5x more scans inbound. Many developing countries have fewer than one radiologist per million people and they will also want to send a lot of radiology to be interpreted. Longer term, cheap and fast radiology interpretation will also drive incentives to build cheaper radiology scanners. If an MRI had essentially no latency for interpretation, medical devices companies will want to build much cheaper MRI machines that can be used more frequently, perhaps even in the middle of a surgery. AI will accelerate the development of scanning technology, too. If a full body MRI was only $100 dollars I would totally want to get one every month instead of every two years. I can imagine a world where people get 10 or 100x the number of scans they do today, largely for preventative care, if radiology were 10-100x cheaper. Third, even if we did have a model that could outperform the world’s best radiologists today, that would not be the end of all work on radiology. Medicine is a field of change. We may develop new treatment protocols that require reading radiology images in a way that radiologists currently aren’t used to. New scanners may reveal diseases that we cannot currently diagnose today with radiology alone. Some radiologists will change their work from reading scans to doing frontier research to advance our understanding of radiology and translate new knowledge into updated models. Moreover, I am sure that we will ask for more out of our AI models than ever before. With a good flywheel, we may one day train AI models that can use radiology images to predict disease probabilities far into the future. With good prediction algorithms, cancer may be detected months earlier than we can detect it now. Society will invest a lot into this research and this will contribute even more to increased demand for radiology and the best AI around it. On top of all of this, the medical system is typically slower to adopt new technology and has more regulation compared to technology companies. There is legacy infrastructure and medical centers need to constantly support patients which makes it hard to integrate new technology. This is even more true in developing countries. Moreover data access tends to be limited due to HIPAA, deidentification, IRBs, etc. So I think radiologists will be in demand for a while. While some worry about radiology being totally automated, I think there is a more exciting future for radiology than ever before—one where there is more demand and we ask for more predictive power from our intelligence. This is similar to how many of us feel that programming will thrive more than ever before despite drastic change in the field. More generally, any domain where demand can be elastic and quality can scale with increased intelligence will, like radiology, similarly flourish with the development of AI. This is certainly a more exciting and nuanced future than what Hinton described in 2016! (Finally, to be fair to Hinton, he did acknowledge in a recent podcast that he was wrong and also agrees with the elastic demand argument.) Thanks @JayRothschild and @engyziedan for feedback on this post.
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Howard Salis retweeted
Replying to @hhlee
Yes, it's a nuanced dialog because it really depends on the details, which can be wildly different across assays & measurements, even if they look superficially similar. imo, massively parallel assays (many experiments in one mixture) is a great route to increasing throughput
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Howard Salis retweeted
The main preprint from my postdoc is live! biorxiv.org/content/10.64898… The core idea is to try to make synthetic biology much more systematic and precise, akin to more mature fields of engineering. This was an ambitious project, it started all the way back in February of 2020 and is only just now wrapping up! Thankfully there were no events in that timeframe, either around the world or specifically here at Harvard, that made things any more difficult than they needed to be. The fundamental dilemma is that we are often forced to do one of two things when designing a synthetic circuits: either we can navigate a laborious design-build-test cycle where we iteratively optimize a circuit's performance tuning one parameter at a time, or we can screen a huge array of variants using techniques like directed evolution and pick the winners and have little insight into the molecular details of why one design worked better than the others. Our idea was to try to get the best of both worlds, to combine precise mechanistic insights with extremely high throughput in such a way that we could systematically study the whole design space of a given circuit architecture.
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Howard Salis retweeted
How grad school is just like kindergarten
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Howard Salis retweeted
This is a legitimately amazing paper. TL;DR: They made a microfluidic chip that can trap a million individual cells, hooked it up to a microscope, and used it to connect genetic circuits --> single-cell behaviors. Say you want to build a complicated gene circuit, like an oscillator with a period of six hours. Normally, you’d make a design, put it into cells, watch it fail, redesign it, and try again. With this system, you can instead make a million variants in a single tube, introduce them into cells, and trap those cells in the chip to see which designs work. You can then pull out a “winning” cell using optical tweezers, or identify which gene circuit it received via in situ sequencing. (Each circuit carries a short genetic barcode. You sequence the gene circuit variants beforehand to link each barcode to a design. Then, reading those barcodes inside the chip, using in situ sequencing, tells you which circuit each cell received.) This is a much more scalable way to test and optimize complex ideas in synthetic biology; not only gene circuits, but perhaps also metabolic pathways. I suspect it’ll be super useful for collecting data for predictive AI models, too. Congrats @NoahOlsman!
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Howard Salis retweeted
Replying to @parsecranberry
I never said no automation, not once. But many folks are saying that all labs must be automated. E.g. ~20% of biotech assays are high-volume, high-demand. Makes sense to automate. For the remaining 80%, nope. Assays are low-demand, not run in plates, use specialized equip, etc
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Howard Salis retweeted
Speaking as someone who spends most of their time building automation platforms and teaching people to do it (enough that I built a whole class around it)... but who also spent six years of my life splitting stem cells every 36 hours... I am split on this one. On one hand, @mkoeris is right that the primitives are learnable and that novel combinations are not some sacred skill. On the other, @hsalis is 💯 that the large majority of experiments are far from autonomous. Most methods that are truly automatable, I can still do way faster and probably better with a multichannel pipette, I just have better things to do with my time. Automating bespoke science is the hard part, but that is where the most exciting progress is to be made. I'd encourage all to challenge themselves to think beyond automating the mundane and ask what science simply could not be done in the absence of a robot: real time responsive feedback, or changing many parameters at once based on the data as it is generated. The kind of experiment where no amount of extra hands would ever get you there. We are only scratching the surface there. (Currently grading midterm proposals for my automation class at the moment. One aim has to justify a genuine *need* for automation, and any proposal that justifies it with throughput, combinations, scale, or time is a big yawn. Think bigger, people 🦾)
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This is fantastic, and I've carried out similar efforts & had similar ethical questions. e.g. increased ViennaRNA RNAfold speed by 2.5x. github.com/hsalis/ViennaRNA Renaming/republishing is 👎
Recently, I've been getting deep into [auto-optimization], which is basically a bubble-wrapped auto-research loop. Almost everything I point it at has led to massive speed/memory improvements. There is so much to improve about the genomics ecosystem.
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Jang et al. developed a clever DNA barcode system to measure pooled lipid nanoparticle (LNP) delivery in nonhuman primates by taking small samples of serum. This allows high-throughput NHP screening of LNP formulation efficacy without killing monkeys. nature.com/articles/s41587-0…
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Howard Salis retweeted
Replying to @hsalis @mkoeris
The most optimal scenario for the long-tail & $$ equipment: each is run by a small expert team with 100% utilization, and all such teams are connected via a programmable network enabling cross-lab autonomous science. /fin
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Here's some examples from my lab. We developed an algorithm that designed RNA hairpins with targeted folding kinetics & we needed to measure their folding rates in vitro. This is all published in JACS. URL: pubs.acs.org/jacsat/article-… /1
Replying to @hsalis
Let’s get into it. On the surface I agree, but the argument quickly breaks down. What’s the actual innovation: 1) equipment (rarely - who’s built new equipment rather than modding - happy to hear how wrong I am, bring it), 2) reagents (fair, needs generation or modification - shipment can help, still a LOT faster to FEDEX than to order), 3) combinations of existing things in novel ways - this one (a form of the tacit knowledge argument IMHO) already is not true anymore. There are a number of primitives we all learn, so it’s unreasonable to assume autonomous systems couldn’t learn and actually quality cross sync and learn ie Tesla) Let’s get into it. @jrkelly @andrewwhite01 @srikosuri @kevinweil for more fun
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Oligopools were available 10+ years ago, but few used them. Why? Existing practices had to be adapted/improved, e.g. library-based cloning, barcode design, NGS amplicon mapping. Most importantly: we asked bigger questions that motivated their usage. e.g. nature.com/articles/s41587-0…
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Last one: BTO has a RFI for protein purification. We submitted a new way to couple protein expression & purification w/o bulky equipment that directly introduces targeted proteins into the end device/material surface. Could it be automated? Likely! But invented by a LLM? Unlikely
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