Codon Digest: Vaccine Printer Go Brrrrr!

Plus: Genome editing gets a boost & memes, memes, memes.

Good morning from my hometown on the banks of a sleepy river outside Chicago. I’m writing this newsletter to the sounds of falling rain, and trying to think up high-quality memes at the same time. Things are good. Also, last week’s digest had an error: The country that approved the malaria vaccine was Ghana.

Now let’s get into it!

🔥 Five Amazing Things

(That happened this week…)

1/ CRISPR Protein Penetrates Cells

Not one, but two new papers report a better way to deliver Cas9 or Cas12 gene-editing proteins into living cells. The key is to mix the proteins with cell-penetrating peptides that drag the enzymes into cells. In one study, this new method was used to edit genes in immune cells, harvested from both human and mice, with 98 percent efficiency (which is very good.)

How? Peptide-Assisted Genome Editing (PAGE) has two components: A cell-penetrating Cas9 (made by fusing the gene-editing protein to the TAT protein from HIV) and the peptides. The two are mixed together for 30 minutes, and then everything is incubated with human cells. The protein moves into the cells (no electricity or chemicals needed!) and edits the genes inside. This works for many different cell types, and the method can also be used to deliver several different gene editors at once.

So what? It’s an easier way to get CRISPR into cells! Other methods to deliver Cas9 (like with viruses) are way less efficient, and seem to vary wildly from one cell to the next.

Read more at Nature Biotechnology

(Similar paper at Nature Biomedical Engineering.)

How to make a cell-penetrating Cas9 protein, and then incubate it with peptides to edit human cells. From Zhang et al. in Nature Biotechnology.

2/ Live Long and Prosper, Lil’ Yeasty Boys

Yeast cells usually live for about one week. But now, their engineered brethren can live about 82 percent longer.

Yeast die for two reasons: Either their nucleolus (where the DNA is kept) degrades and dies, or their mitochondria whimpers out and they stop making energy. If you build a synthetic gene circuit that toggles between these two “age-related states,” back-and-forth, then it takes longer for the yeast to die from either one, and they live much longer.

How? Two important genes control the nucleolus and mitochondrial “aging states”: Sir2 and HAP. In this paper, these genes were connected together into a negative-feedback loop, and then yeast were studied in tiny channels with time-lapse photography. The levels of Sir2 went up and down throughout the yeasts’ lives.

The levels of Sir2 go up-and-down for days. From Zhou et al.

So what? If you just boost levels of Sir2 or HAP, yeast won’t live that much longer. But if you start to play with the times during which these genes are expressed, you can make cells age differently. Often, when we engineer a cell, we only mess with the magnitude of an effect; this study suggests that we should think more about the timing, too.

Read more at Science.

Engineered yeast live longer than their “normal” brethren. Zhou et al.

3/ I Swear I’m Not a Robot

Yeah, ChatGPT is cool and all, but can it write my poster abstract? Not yet.

AI-generated abstracts were classified as such 99.98% of the time, according to a new study. And when AI-generated abstracts were shown to “blinded human reviewers,” those reviewers correctly identified the fake ones 68% of the time (but also said that 14% of human-written abstracts were written by an AI. Is this proof that scientists really do write like robots?)

How? Science abstracts were pulled from five different medical journals and then fed into ChatGPT. The AI then generated a bunch more abstracts using similar verbiage. All the abstracts were mixed together and shown to humans, or fed into AI text detection algorithms.

So what? This study sheds light on how, exactly, AI-generated text differs from the real stuff, and how it could be used to (soon) write entire research papers. “ChatGPT writes believable scientific abstracts, though with completely generated data,” according to the study’s authors. The AI tool also created text that was “vaguer and more formulaic.”

Read more at npj Digital Medicine.

4/ Vaccine Printer Go Brrrrrrr

Instead of sticking a needle into someone’s arm, a new paper shows that you can load vaccines into a “microneedle patch” that slowly dissolves and immunizes people just as well (or better) than traditional methods. Also, the patches don’t need to be stored in the fridge, or be administered by a healthcare worker; you just slap it on.

How? Vaccines (basically little fat bubbles filled with mRNA and some dissolvable polymers) were physically printed onto microneedle patches using a robot. These patches can be stored at room temperature for at least 6 months.

The patches have little spikes that help push the vaccines through the skin. vander Straeten et al.

So what? I mean, come on. This is a much better way to administer vaccines, if it actually scales up. The vaccine printer can make lots of different types of vaccines, including protein, DNA, and mRNA ones, but I’m sure this is all quite expensive right now. But the printed vaccines are very good!

In one experiment, the microneedle patches were used to deliver a SARS-CoV-2 vaccine into mice, producing immune responses similar to a traditional injection. Printed vaccines caused mice to have a faster immune response.

If these printers were set up in resource-starved countries, where malaria and other diseases are endemic, they could make a world of difference.

Read more at Nature Biotechnology (some coverage in MIT News, too.)

This is what a vaccine printer looks like. It’s intimidating, but useful, and it could help roll out vaccines way faster than “conventional” approaches. vander Straeten et al.

5/ Lots O’ Gene Therapies

Not one, but two applications for sickle-cell gene therapies have been submitted to the F.D.A. If approved, these wouldn’t be the first gene therapies on the market, but they would be the first gene therapies for a disease that affects something like 100,000 Americans. The only cure for sickle-cell disease, right now, is to replace the patient’s abnormal stem cells, in their bone marrow, with healthy cells from a family member. But that comes with some serious risks, and often fails.

How? The latest F.D.A. application is from bluebird bio. The company uses a modified virus to deliver multiple copies of the correct form of the beta-globin gene into a patient’s blood-producing stem cells. A therapy that uses CRISPR gene-editing to treat sickle-cell disease was also submitted by Vertex & CRISPR Therapeutics in early April.

So what? These gene therapies would push genetic engineering to the forefront of the public psyche, and could have knock-on effects in terms of funding and awareness. Many gene therapies come with a massive price tag, though, so they will probably remain out of reach for most patients for a long time.

Read more at Biospace.

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🧪 From the Lab

• Tools to engineer plants just keep comin’! Now there’s a new type of protein (well, not really…it’s the third generation) called PrimeRoot editors that are optimized to work in plants. These enzymes can insert “up to 11.1 kilobases” of DNA into a plant genome. (My upcoming essay for Works in Progress will talk about some of this stuff.) Nature Biotechnology. Read

• A CRISPR-based assay can detect microRNAs associated with cancers in about 20 minutes. Nature Biomedical Engineering. Read

  • Another paper that used CRISPR to detect cancer signals in urine was published around the same time in Nature Nanotechnology. Read

• A tiny, battery-free device, implanted beneath the skin of mice, can record neural activity and body temperature at the same time. Nature Biomedical Engineering. Read

• A nanorobotic hand, made out of DNA, has “a palm and four bendable fingers” that can be used to pick up and move “gold nanoparticles…and SARS-CoV-2 virions.” WTF? bioRxiv. Read

  

• A protein with just 28 amino acids can fold around an iron atom and be used to transfer electrons in living cells. This man-made protein is the smallest yet to have a metal binding site. Nature Communications. Read

• It’s possible to design DNA sequences that respond differently to ultraviolet vs. blue light, and can thus be used to build molecular logic gates. JACS. Read

• Stem cells were induced to form insulin-secreting pancreas cells and then transplanted into diabetic mice, where they successfully restored glucose levels. Nature Cell Biology. Read

• Microbes in the wild ‘talk’ to their neighbors by emitting, and sensing, small chemicals. A new paper engineers a communication network between cells using DNA instead. Nature Communications. Read

• A new sequencing method, called CODEC, is up to 1,000-fold more accurate than traditional next-generation sequencing. “CODEC revealed mutation frequencies of 2.72 × 10⁻⁸ in sperm of a 39-year-old individual.” Nature Genetics. Read

• Wanna start a protein therapeutics company? This review is a good place to start. Nature Communications. Read

• This paper explains how synthetic biology is regulated in Europe. I like it because it focuses on specific examples, including an arsenic biosensor that was tested in Nepal and Bangladesh. Synthetic Biology. Read

• Ribosomes are able to build proteins because they contain a strand of RNA that imbues them with their catalytic power. Now, the ribosome’s peptidyl transfer center has been comprehensively mutated and mapped to better understand how it works, and how it can be engineered to make ribosomes build entirely new materials. Science Advances. Read

• Synthetic carboxysomes (which improve CO2 absorption) were engineered into tobacco plants to enhance photosynthesis and potentially boost crop yields. Nature Communications. Read

• A comprehensive map of how genes interact in fruit flies, followed by the prediction of gene functions using a machine learning tool. Cell Systems. Read

• An automated platform to make riboswitches (RNA strands that bind to small molecules and then quickly switch their structure) that can sense specific proteins. This could be very important for building low-cost medical diagnostics in the near future. Nature Communications. Read

💾 Hack Biology (Software 🤝 Cells)

• General language models were used to evolve antibodies that are already used in the clinic. The AI model suggested mutations to the antibody proteins that increased some of their binding strengths to Ebola or SARS-CoV-2 up to 160-fold. Nature Biotechnology. Read

• Prime editing is a really cool gene-editing method that can make small substitutions or deletions in the genome. Now, deep learning models have been trained on data from nearly 339,000 guide RNAs to create DeepPrime, an algorithm that predicts gene-editing outcomes. Cell. Read

• PASSer is an online tool that predicts allosteric sites in proteins, which are where molecules bind to switch a protein ‘on’ or ‘off’. Just download a protein file (from the Protein Data Bank) and upload it to the free web tool! Nucleic Acids Research. Read

• Create, edit, and annotate plasmids (circular loops of DNA) in the browser. Nucleic Acids Research. Read

  • A similar tool was also recently released, but for entire genomes! PLOS Computational Biology. Read

• Another browser-based tool, except this one lets you draw RNA strands much like you would paint on a canvas. “RNAcanvas automatically arranges residues into strictly shaped stems and loops while providing robust interactive editing features, including click-and-drag layout adjustment.” Nucleic Acids Research. Read

• AI tools designed proteins that bind to other proteins, including the SARS-CoV-2 spike. Nature. Read

• Genome sequences from more than 1,000 microbes were collected, and then AlphaFold was used to predict structures for more than 200,000 of their proteins. Nature Communications. Read

📰 News

• Newly unveiled archival letters from Rosalind Franklin suggest that the brilliant King’s x-ray crystallographer “was relaxed” about her data being share with James Watson. “We found no evidence that she felt robbed—and this letter suggests that she did not feel this way.” In other words, Rosalind Franklin was open and honest with her data; a virtue that few scientists possess in our modern, hyper-competitive landscape. Nature. Read (Also see a summary on Twitter by one of the authors.)

• A few months ago, one participant in a clinical trial for a CRISPR-based gene therapy for Duchenne muscular dystrophy suddenly died. New details suggest that the man, 27-year-old Terry Hogan, did not die from CRISPR gene-editing. Jason Mast for STAT. Read

• The reason we have lagers today (apparently) is because yeasts for a white ale and brown beer “mixed in a cellar of the original Munich Hofbräuhaus….sometime between 1602 and 1615.” How did scientists make this ultra-niche, yeasty discovery? Why, by studying the “genetic histories of yeast,” of course. Ann Gibbons for Science. Read

• Elizabeth Holmes, the ousted founder of Theranos, was convicted of fraud and sentenced to 11 years in prison. But she’ll stave off jail time for a bit longer after appealing an earlier denial of bail. Beth Mole for Ars Technica. Read

• The first children conceived using a sperm-injected robot (which is controlled with a PS5 controller) have now been born. Startups are popping up like flies on spoiled meat. Antonio Regalado for MIT Technology Review. Read

• Some Illumina sequencer softwares had a cybersecurity vulnerability that enabled unauthorized users to take over the devices remotely, alter “data on the instrument” or change “genomic data results in the instruments intended for clinical diagnosis.” Whoops. FDA.gov. Read

• If we want the “biorevolution” to be as disruptive as the “Industrial Revolution,” then we will need a “pop-culture moment” that vaults biotechnology to the forefront of society. This is something I think about a lot, and I’m not sure how to make it happen. More memes and jokes in this newsletter might be a start! Cecilia Manduca on Medium. Read

• Remember all the new weight loss drugs, like tirzepatide, that celebrities are going crazy for? Well, more data is out, and people who took the drug for 72 weeks “lost up to 15.7% of body weight.” Read

• A company called Dalan Animal Health is making “a vaccine for honeybees.” Willow Shah-Neville for Labiotech. Read

• Last week, I wrote about how Ghana became the first African country to approve a new, highly effective malaria vaccine. But there are many other vaccines under development, too! Roohi Mariam Peter for Labiotech. Read

• An easier (and cheaper) way to do single-cell RNA sequencing? Derek Lowe for Science. Read

• Soon, companies will want to sequence the microbes in your poop and then recommend diets. Jessica Hamzelou for MIT Technology Review. Read

• The F.D.A. has authorized Biogen to sell their drug, called Qalsody, “for a rare genetic form of the neurological disorder A.L.S.” These treatments typically cost about $150,000 per year. Qalsody targets a mutation in a specific gene that is only “present in about 2 percent of the roughly 6,000 cases of A.L.S. diagnosed in the United States each year.” Rebecca Robbins for The New York Times. Read

🧠 Musings & Memes

• Cyborg Goldfish, anyone? Kate Golembiewski for The New York Times. Read

• Robots learn to play soccer. (They use their hands a lot!) Tuomas Haarnoja on ArXiv. Read

• A nice article from Aatish Bhatia about how A.I. tools, like ChatGPT, learn to “speak.” The New York Times. Read

• When I was a kid, one of my favorite books was about Balto, the sled dog that ran hundreds of miles to deliver diphtheria antitoxin to Nome, Alaska in 1925. Now, DNA sequencing shows that “Balto was just part Siberian husky, and, contrary to popular legend, he was not part wolf.” Jennifer Ouellette for Ars Technica. Read

• A massive ant farm, housing 500,000 leafcutter ants, will be unveiled at the American Museum of Natural History on May 4th. It is truly a work-of-art. Emily Anthes for The New York Times. Read

📈 Companies

• Vedanta Biosciences, a company in Cambridge, MA that uses “bacterial consortia therapeutics” to treat disease, raised $106.5 million. It’s gonna be used for phase 3 trials of a C. difficile therapy. Read

• Orbital Therapeutics, a company in Cambridge, MA that is making RNA therapeutics using lots of automation and machine learning, raised $270 million in a Series A (the largest so far this year.) Read

• Chunk Foods, an Israeli alt-food company, raised $15 million in seed funding last November and is nearing completion of a factory that can produce millions of plant-based steaks each year, at a cost of about $5 each. “The company develops whole cuts of alternative proteins using fermentation technology and food-grade microorganisms to turn soy and wheat into its proteins.” Read

• Adcentrx Therapeutics, a company in San Diego that fuses proteins together to build cancer therapies, raised $38 million in a Series A. Read

• Calico, the Google-backed biotech company in San Francisco that is studying “the biology of aging and healthspan,” has dosed its first patient in a phase I trial for an ultra-rare disease that causes the brain’s white matter to break down over time. Read

• Seres Therapeutics has become just the second company to get F.D.A. approval for a microbiome therapy. Seres’ drug, called Vowst, is a living microbe that treats C. difficile infections. Allison DeAngelis for STAT. Read

• A beauty company just bought out a Boston-based biotech company that uses AI to discover molecules for $76 million. Read

• Boston-based Life Biosciences says that their gene therapy for NAION (a somewhat rare, age-related disease that causes vision loss) restored sight in primates. Read

• Asimov, a Boston-based company that uses software and a large library of genetic parts to design living cells, published a white paper that explains their technology in more detail. (Note: I’m employed by the company and a co-author on the paper.) Read

That’s it for today! See you next week. In the meantime, find me on the imploding nightmare that is Twitter (@NikoMcCarty), where I haven’t posted in like two weeks, and promise not to clutter up your timeline. That’s a win.

— Niko

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.