Hey! It was a big week in the world of biotechnology. A Bayesian optimization + robotics platform designed and validated enzymes that were more thermostable than their wild counterparts. And experiments at Tune Therapeutics showed that CRISPR epigenome editing — which doesn’t cut DNA at all, but merely silences genes by adding chemical groups to them — can curb “bad cholesterol” by more than 50% in monkeys.
Let’s dive in.
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🔥 Amazing Things
Biotech highlights in 5 minutes or less.
1/ AI Agents Design Proteins
An automated platform, called Self-driving Autonomous Machines for Protein Landscape Exploration (SAMPLE), can design and build proteins using intelligent agents and robotics. In an initial proof-of-concept, it was used to make glycoside hydrolase (sugar-cutting) enzymes that can withstand higher-than-normal temperatures.
How? The SAMPLE system used four different autonomous agents, each of which designed slightly different proteins. These agents search the fitness landscape for a protein and then proceed to test and refine it over 20 cycles. The entire process took just under six months. It took one hour to assemble genes for each protein, one hour to run PCR, three hours to express the proteins in a cell-free system, and three hours to measure each protein’s heat tolerance. That’s nine hours per data point! The agents had access to a microplate reader and Tecan automation system, and some work was also done at the Strateos Cloud Lab.
So what? Agents are taking off fast in biology. These ones use Bayesian Optimization to design and make sugar-cutting enzymes that could tolerate temperatures 10°C higher than even the best natural sequence, called Bgl3. The agents weren’t “told” to enhance catalytic efficiency, but their designs also had catalytic efficiencies that matched or exceeded Bgl3.
Just a few weeks ago, another group merged GPT4 with a pipetting robot and used it to synthesize different molecules. At the time, I wrote: “This looks like an early step toward a much different future for biology: One in which natural language is used to design experiments, program robots, and automate experiments in high-throughput. What appears simple now will be much more complex in one years’ time.”
Obviously, I was wrong. I should have said months.
Read more in bioRxiv.
Correction: An earlier version of this text said “AI agents,” which is only sorta true. They’re Bayesian Optimizers — often used in applied machine learning — with access to robots. Just a semantic clarification.
2/ Epigenome Editing Cuts Cholesterol
A variant of CRISPR technology that does not cut DNA, but rather silences genes by adding methyl groups to them, significantly reduced "bad" cholesterol in monkeys by more than 50%. Tune Therapeutics reported the results last Friday at the ASGCT conference in Los Angeles. This is the first case of CRISPR epigenome editing in a non-human primate. It’s a big deal.
How? Epigenome editors can add methyl groups to DNA, which silences their expression in living cells. I’m not 100% sure how Tune Therapeutics does this, but co-founder Charles Gersbach and others have shown that a ‘dead’ Cas9 enzyme, fused to a DNA methyltransferase, can add methyl groups to DNA in mice. These tools do not cut or nick DNA, and so they may be safer than other options.
For the Tune data, an epigenome editor was used to alter a cholesterol-associated gene, called PCSK9, in five cynomolgus monkeys. This gene is shared by monkeys and humans and, when it’s mutated in juuuust the right way, can lower LDL and reduce heart disease risk.
So what? Again, this is a big deal. Verve Therapeutics is using base editing to go after the same gene and, back in 2021, reported “that one-time editing of the PCSK9 gene in the liver of monkeys lowered blood levels of the resulting PCSK9 protein by 89% and dropped LDL cholesterol levels by 59%, reductions that endured as far out as six months,” according to an article in STAT. Verve already started a Phase 1b trial in New Zealand last July. Tune’s epigenome tool seems to work just as well, but it may be safer (the F.D.A. halted a Verve trial in the U.S. in December, but did not explain why.)
Read more in STAT.
Keep up with the biological revolution.
3/ Important Work on Non-Model Microbes
A new toolkit can help identify functional origins of replication, or ORIs, in non-model bacteria. ORIs are where DNA replication begins. Plasmids that don’t contain the correct ORI won’t get copied, so it’s really important to figure out this sequence for every organism that you want to engineer! The toolkit, called Possum, worked in 7 out of 12 species, including extremophiles.
How? The team made a large library of plasmids (192 in total) that contain 22 different ORIs and 20 antibiotic resistance markers. These plasmids were inserted into each microbe via conjugation. Each microbe was then killed and its DNA sequenced. If a microbe had “significantly higher” levels of DNA — a sign that the plasmids were being copied — compared to a negative control, then it suggests that the conjugated plasmid had the correct ORI for that organism. This technique was used to quickly test 374 different microbe-plasmid combinations.
So what? This toolkit is a simple way to figure out ORIs for organisms that don’t have a known replication sequence. It’s also an important first step toward engineering more non-model microbes, which often have super-unique metabolisms. Some “electroactive” bacteria can even make or consume electricity. It’d be cool to genetically engineer them!
Read more in bioRxiv.
🧪 From the Lab
Other wet-lab papers worth checking out. (* = Recommended)
*A temperature-sensitive genome-editing tool — which uses Cas9 — enhances adoptive T-cell therapy upon mild heating. Nature Nanotechnology. Read
*A feedback system controls the relative populations of microbes in a community. bioRxiv. Read
*Engineered bacteria make proteins that carry nitro (-NO2) chemical groups. This is very difficult to do. Nature Chemical Biology. Read
Microscopes reveal that a transcription factor, bound to DNA, can activate the gene within a few seconds. bioRxiv. Read
By putting human liver cells into a mouse, scientists figured out how this organ influences the body’s circadian rhythm. Science Advances. Read
Lipid nanoparticles coated in sugar boost CRISPR-based liver editing from 5% to 61%. Nature Communications. Read
A new toolkit edits the genomes of five different rhizobacteria that help plants grow. bioRxiv. Read
Honeybees with engineered microbiomes fight off parasites that contribute to hive collapse. Nature Communications. Read
Engineered P. taiwanensis make aromatic chemicals with yields of 32.4% from glycerol. Metabolic Engineering. Read
People that live to 100 have highly diverse viruses in their guts. Nature Microbiology. Read
CRISPR helps identify essential genes in two different bacteriophages. bioRxiv. Read
Multiple plants were engineered to make provitamin A carotenoids by endowing them with a metabolic pathway from fungi. Molecular Plant. Read
Attaching a chemical — called 5-formylcytidine — to guide RNAs changes how they fold and bind to targets during gene-editing. It’s another lever to control CRISPR. JACS. Read
A chikungunya vaccine induced high levels of neutralizing antibodies in a phase II trial. Science Translational Medicine. Read
A new protocol explains how to encapsulate proteins and make them more stable for biomanufacturing. Nature Protocols. Read
A wearable device helps amputees feel heat in their "phantom” hands. Science. Read
GWAS, CRISPR, and single-cell sequencing were merged to link noncoding genetic variants to blood traits. The study found target genes in 134 regulatory elements across 254 loci. Science. Read
An intensive study engineered P. putida bacteria to eat D-xylose, a sugar common in plant biomass. bioRxiv. Read
Prime editing was used to modulate neural circuits and change a mouse’s behaviors. bioRxiv. Read
💾 Computers x Bio
Papers from the worlds of AI & programming. (* = Recommended)
*DeepBE is a deep learning tool to predict gene-editing efficiencies for base editors and Cas9 proteins. It is 20-fold better than some other models. Nature Biotechnology. Read
*“How I became myself after merging with a computer.” Brain Stimulation. Read
AlphaFold can predict protein structures with astonishing accuracy, but we still need actual crystal structures. bioRxiv. Read
Graphinity, an AI model, predicts the binding efficiency of therapeutic antibodies — with a little help from 1 million synthetic data points. bioRxiv. Read | Thread
A deep learning tool calculates how mutations in a protein will affect its thermostability. eLife. Read
Monte Carlo x deep learning were used to design synthetic DNA with specific expression levels. bioRxiv. Read
A mathematical model controls when, and how much, sugar should be released into a tube of microbes to control their growth rates. bioRxiv. Read
htFuncLib can design proteins with mutated active sites. It was used to design >16,000 green fluorescent proteins. Nature Communications. Read
Introme: A machine learning tool to predict gene splicing from coding and noncoding sequences. Genome Biology. Read
ESP is a machine-learning model to predict enzyme-substrate pairs. Nature Communications. Read
An open-source workflow to run -omics assays on model organisms. npj Systems Biology and Applications. Read
📈 Data Brief
One chart about biology and our world.
We make a lot of concrete. This is bad.
Between 2011-2013, China made more concrete than America did in the entire 20th century. Today, there are two trucks’ worth of concrete made each year for every man, woman, and child on the planet. Cement production accounts for about 8% of all carbon dioxide emissions. One paper estimates that the entirety of human-created mass (half of which is concrete) probably reached the total weight of Earth’s entire biomass — every tree, bacterium, virus, and whale — in 2020.
If you want to make an impact with biotechnology, materials are a great place to start.
📤 In the News
Rapid-fire news items you might have missed.
The FDA approved a rub-on gene therapy for dystrophic epidermolysis bullosa, a genetic condition that causes sensitive, fragile skin. MIT Technology Review. Read
It costs $24,250 per vial, and patients need about 26 vials per year. That’s $631,000 per year. Read
For the last two months, Zuzalu has brought together people who think “we have a moral duty to find ways to slow or reverse aging.” They have been living together in Montenegro. It actually sounds great and I hope they do it again. MIT Technology Review. Read
Scientists are making plants that can effectively clone themselves, which could one day displace the power of monopolistic seed companies. It’s called synthetic apomixis and I’ll have much more to say about it tomorrow. Science. Read
This is a nice article about the multiplexed genome editing efforts underway in George Church’s lab. The Scientist. Read
CRISPR was not responsible for the death of 27-year-old Terry Horgan in a recent gene therapy trial for Duchenne muscular dystrophy. STAT. Read
A CRISPR tool that adds methyl groups to DNA — called an epigenome editor — effectively silenced the PCSK9 gene in monkeys and lowered their cholesterol levels. An important proof-of-concept for human trials. STAT. Read
A neurotechnology company, Paradromics, will get expedited reviews from the F.D.A. and also closed $33 million in funding. Their device is designed to help paralyzed people communicate. Another company, Synchron, is already in advanced clinical trials. Fierce Biotech. Read
Fun stuff that has little to do with biotech.
A crystal cooled to near absolute zero has the minimum amount of possible vibration: one phonon. It is the quietest sound in the universe. WIRED. Read
Fermented coffee apparently tastes like raspberries. Ars Technica. Read
The earliest recorded kiss dates back 4,500 years, to a Mesopotamian clay tablet. The Guardian. Read
⚒️ In the Ether
Education, resources, and events.
Bio x AI Hackathon kicks off on May 26 and runs to June 4. Open to all. Event
Synthace is hosting a free event at MIT on June 21. Come say hi! Event
Spira, a company that uses engineered algae to manufacture pigments, is having a free demo in San Francisco on Thursday, May 25th. Event
The 2023 International Mammalian Synthetic Biology Workshop is on June 22-23 in San Jose. It’s $100 for students. Event
👀 Meme of the Week
See you next week! In the meantime, find me on Twitter or LinkedIn.
Disclosure: The views expressed in this blog are entirely my own and do not represent the views of any company or university with which I am affiliated.