On-Demand Vaccines for Bacterial Infections: A new study, published in Science Advances, describes a method to produce conjugate vaccines—which are used to prevent some of the leading causes of vaccine-preventable deaths, according to the World Health Organization—using ground up, freeze-dried bacteria. E. coli bacteria were first engineered to produce an antigen for a pathogenic microbe of choice. Then, the researchers ripped open the cells and added in a piece of DNA encoding a carrier protein, which attaches to those antigens and helps display them to the immune system. The team turned the whole mixture into a powder that could be transported and stored at room temperature. Then, to make a dose of vaccine, they just add water. The freeze-dried tube produces the vaccine, on demand, in about one hour. As a proof of concept, the researchers manufactured vaccines that protected mice against a disease-causing bacteria, Francisella tularensis. The work was authored by researchers at Northwestern University in Evanston, Illinois.
Why It Matters: Most vaccines need to be stored at cold temperatures. This makes it difficult to transport them to parts of the world without a temperature-controlled supply chain. This study could help make vaccines accessible to a greater number of people. The technique is also very general; it can be used to make just about any conjugate vaccine that is on the market today. Conjugate vaccines are already used to prevent a lot of childhood diseases, including multiple types of bacterial meningitis, which killed an estimated 300,000 people in 2016. That’s according to a 2018 study30387-9/fulltext) in The Lancet Neurology.
Cas13a Treats SARS-CoV-2 and Flu: DNA targeting CRISPR enzymes, including Cas9 and Cas12a, can manipulate genomes with ease. But there are also CRISPR proteins that target RNA, including the Cas13 ‘family.’ Since influenza and SARS-CoV-2 are both RNA-based viruses, Cas13 can be used to target, and chop up, their genetic material. For a new study, published in Nature Biotechnology, researchers at the Georgia Institute of Technology and Emory University, in Atlanta, used Cas13a to cut specific regions of the influenza and SARS-CoV-2 viruses. They first searched for guide RNAs that could cut these viruses in a cell culture model. Then, they packaged up an mRNA sequence encoding Cas13a, together with its ‘guides,’ and delivered them into mouse airways with a nebulizer (a device that converts liquid into a fine mist). In the mice, “Cas13a degraded influenza RNA in lung tissue efficiently when delivered after infection, whereas in hamsters, Cas13a delivery reduced SARS-CoV-2 replication and reduced symptoms.”
Why It Matters: Vaccines are great for fending off diseases. But knocking out a respiratory infection—after it has already happened—is much more challenging. This study shows that a CRISPR-based system can be programmed to target viruses, and can be easily delivered into airways with a nebulizer. This approach could likely be used to target other types of respiratory infections in the future.
Glucose Sensor Upgrade: For a new study, published in Nature Communications, researchers at the University of Toronto merged engineered cells with a standard glucose meter, expanding the number of molecules that can be measured with these common devices. Glucose test strips are typically coated with an enzyme, called glucose oxidase, that senses sugar and converts that signal into electricity. The researchers built a genetic circuit that can sense a wider array of molecules—like an antigen from a pathogenic microbe—and produce a commensurate amount of sugar. Standard glucose test strips can then be used to measure the concentration of those ‘sensed’ molecules in about an hour. The genetic circuit + glucose sensor combo was used to measure small molecules and synthetic RNAs, including “RNA sequences for typhoid, paratyphoid A and B, and related drug resistance genes” at attomolar concentrations.
Why It Matters: The ongoing pandemic has highlighted the need for scalable, rapid testing. By leveraging a household technology—glucose sensors—to detect a wider range of molecules, perhaps this study could be an entryway for synthetic biology; a way to get engineered cells into the hands of more people.
Open the Genetic Floodgates: There are many ways to “turn on” a single gene, but few options to do the same for many genes at once. The Cas12a protein, though, is uniquely suited to this purpose. For a new preprint, which was posted to bioRxiv and has not been peer-reviewed, researchers at the University of Edinburgh used a Cas12a protein from the bacterium, Francisella novicida, to activate six genetic targets at once. They encoded six crRNAs—nucleotide sequences that direct Cas12a to a genetic target—in a single piece of DNA, and swapped around their order to study how their position impacts the efficiency of gene editing. They found that the crRNA in the last position was produced in the lowest amount.
Why It Matters: Researchers have been activating specific genes in cells for decades. But only recently—in the last few years—has ‘multiplexed’ activation become simple; routine even. This new preprint is important, in my opinion, because of the depth of its experiments. The team played with the order of crRNAs, as I’ve already written, but they also tested the synergism of crRNAs. In other words, can you turn a gene on at even higher levels if you target it with two crRNAs instead of one? (Yes.)
CRISPR Clocks: The Cas9 protein cuts DNA at a steady pace. Cut…cut…cut, like a wobbly metronome. For a new study00014-3), published in Cell, researchers at the Yonsei University College of Medicine, in Seoul, Korea, used this “CRISPR clock” to record the timing of cellular events. They figured out how long it takes Cas9 to cut DNA (every DNA sequence takes a different amount of time to cut) and then sequenced the DNA to figure out the amount of time that had elapsed. The “clocks” were tested in HEK293T, a type of human liver cell, and also in mice. The clocks could be turned “on” by inflammation or heat. In one experiment, the researchers put cells with these clocks into mice, and then injected the animals with fat molecules that cause inflammation. They sequenced the cells, and found that they could determine the elapsed time, from genetic sequencing alone, with a mean error of just 7.6 percent.
Why It Matters: Biological clocks are useful for many reasons. The researchers said that their CRISPR clocks could be used to record when a pre-cancerous cell is turned into a cancer cell, for example. Scientists could expose cells to toxins, for example, and then measure the amount of time that it takes for cancerous growth to begin. The CRISPR clocks could be used to study these effects inside of living cells.
More Studies

Special Issue: 20 Years of the Human Genome

• Science magazine’s issue, this week, was devoted to celebrating the “Human Genome at 20.” My recommendations: “Complicated legacies: The human genome at 20” and “Beyond DNA: The rest of the story.” Both are insightful. Link to Issue.

Biosensors

• (Review) Transcription factor-based biosensor for dynamic control in yeast for natural product synthesis. Frontiers in Bioengineering and Biotechnology. Open Access. Link
• A protein-based biosensor for detecting calcium by magnetic resonance imaging. bioRxiv. Open Access. Link

Fundamental Discoveries

• A genome-wide screen in the mouse liver reveals sex-specific and cell non-autonomous regulation of cell fitness. bioRxiv. Open Access. Link
• Photoactivatable CaMKII induces synaptic plasticity in single synapses. Nature Communications. Open Access. Link
• Resolving phylogenetic and biochemical barriers to functional expression of heterologous iron-sulphur cluster enzymes. bioRxiv. Open Access. Link
• Intercellular communication induces glycolytic synchronization waves between individually oscillating cells. PNAS. Open Access. Link
• A comprehensive phenotypic CRISPR-Cas9 screen of the ubiquitin pathway uncovers roles of ubiquitin ligases in mitosis. Molecular Cell. Link00014-9)

Genetic Circuits

• Ultrasensitive molecular controllers for quasi-integral feedback. Cell Systems. Link00035-1)

Genetic Engineering & Control

• Small-molecule inhibitors of histone deacetylase improve CRISPR-based adenine base editing. Nucleic Acids Research. Open Access. Link
• A piggyBac‐mediated transgenesis system for the temporary expression of CRISPCas9 in rice. Plant Biotechnology Journal. Link
• Expanding the SiMPl plasmid toolbox for use with spectinomycin/streptomycin. bioRxiv. Open Access. Link
• Joint universal modular plasmids (JUMP): a flexible vector platform for synthetic biology. Synthetic Biology. Open Access. Link

Medicine and Diagnostics

• Engineering advanced logic and distributed computing in human CAR immune cells. Nature Communications. Open Access. Link
• A thermostable, flexible RNA vaccine delivery platform for pandemic response. bioRxiv. Open Access. Link
• Toolkit for quickly generating and characterizing molecular probes specific for SARS-CoV-2 nucleocapsid as a primer for future coronavirus pandemic preparedness. ACS Synthetic Biology. Link

Metabolic Engineering

• An artificial self-assembling nanocompartment for organising metabolic pathways in yeast. bioRxiv. Open Access. Link
• Transport engineering for improving production and secretion of valuable alkaloids in Escherichia coli. bioRxiv. Open Access. Link
• Autophagy‐inducing peptide increases CHO cell monoclonal antibody production in batch and fed‐batch cultures. Biotechnology and Bioengineering. Link
• Quorum sensing-mediated protein degradation for dynamic metabolic pathway control in Saccharomyces cerevisiae. Metabolic Engineering. Link
• (Review) Synthetic biology approaches to enhance microalgal productivity. Trends in Biotechnology. Open Access. Link00004-4)
• A biological route to conjugated alkenes: Microbial production of hepta-1,3,5-triene. ACS Synthetic Biology. Open Access. Link
• (Review) Yeast-based biosynthesis of natural products from xylose. Frontiers in Bioengineering and Biotechnology. Open Access. Link

New Technology

• Synthetic protein quality control to enhance full-length translation in bacteria. Nature Chemical Biology. Link
• Scalable characterization of the PAM requirements of CRISPR–Cas enzymes using HT-PAMDA. Nature Protocols. Link
• A platform for post-translational spatiotemporal control of cellular proteins. Synthetic Biology. Open Access. Link
• An all-to-all approach to the identification of sequence-specific readers for epigenetic DNA modifications on cytosine. Nature Communications. Open Access. Link

Protein Engineering

• Computation-guided optimization of split protein systems. Nature Chemical Biology. Link
• Efficient Lewis acid catalysis of an abiological reaction in a de novo protein scaffold. Nature Chemistry. Link
• Periplasmic expression of SpyTagged antibody fragments enables rapid modular antibody assembly. Cell Chemical Biology. Link00011-8)

Systems Biology and Modelling

• A MATLAB toolbox for modeling genetic circuits in cell-free systems. Synthetic Biology. Open Access. Link
• Enzyme kinetics of CRISPR molecular diagnostics. bioRxiv. Open Access. Link
• Potential landscapes, bifurcations, and robustness of tristable networks. ACS Synthetic Biology. Link
• Modeling of copy number variability in Pichia pastoris. Biotechnology and Bioengineering. Link

Here is all the synthetic biology research this week. Hope you enjoy.
How to Engineer SARS-CoV-2: A new protocol, published in Nature Protocols, describes a reverse genetic system to create SARS-CoV-2 viruses with desired mutations. Creating the coronavirus—which is about 30,000 nucleotides in length—requires six basic steps, each of which could likely be completed by an undergraduate student in molecular biology. First, plasmids are prepared that complement each part of the virus, then those plasmids are cut and stitched together, before being converted to RNA and inserted into cells, which produce the viruses. The work was authored by researchers at the University of Texas Medical Branch, in Galveston, Texas.
Why It Matters: There are several SARS-CoV-2 variants circulating globally, according to the U.S. Centers for Disease Control and Prevention. To study new variants of the coronavirus—or variants that are likely to emerge—researchers can create them in the lab, and observe how specific mutations alter their properties. This protocol explains how to do that with a basic knowledge of molecular biology, and somewhat commonplace lab equipment, making it a potential biosecurity concern. Synthetic biologists expressed concern about the study on Twitter.
Microbial Communities: For a new study, published in Nature Communications, researchers used Bayesian statistics to find optimal combinations of bacteria to build microbial communities. The study focuses on two different methods to build microbial communities: quorum sensing (which are cellular signals based on small molecules) and bacteriocins, antimicrobial proteins that kill nearby bacteria and can be used to control their growth. The work was mathematical in nature, and the next step will be to test their predictions in the laboratory. The study was authored by researchers at University College London. To learn more about this study, read this article from the first author, Behzad Karkaria.
Why It Matters: By working together, bacterial organisms can perform tasks that, alone, would be impossible. For example, groups of different bacteria can work together to create complex molecules, or to share the “burden” of a particularly troublesome metabolic pathway. Unfortunately, it is hard to create microbial communities that can live, and work, together for a long time. A single type of bacteria in the mixture can dominate the others, destroying the community. In this study, the researchers “were able to derive the fundamental interactions that are most commonly associated with stable communities,” providing a framework to more easily, and efficiently, create synthetic microbial communities. This will help synthetic biologists expand their work from one organism to several.
More CRISPR Targets: For a new preprint, posted to bioRxiv, researchers showed that the amount of ‘AT’ or ‘GC’ nucleotides in a certain type of CRISPR array affects the performance of a Cas protein, called Cas12a. This study was authored by researchers at Stanford University.
Why It Matters: CRISPR is the gene-editing tool of choice, largely supplanting historical methods for manipulating DNA. The most commonly used protein to cut DNA, today, is probably the Cas9 protein taken from a bacterium called Streptococcus pyogenes. But there are other Cas proteins. One of them, called Cas12a, can even process its own guide RNA arrays, a feature that makes it well-suited to targeting—and cutting—many DNA targets at once. A study from 2019 showed that Cas12a can edit 25 genetic targets at once, and that its guide RNAs can be stored and expressed from a single piece of DNA. This new preprint demonstrates that the GC or AT content of spacer sequences between those guide RNAs affects how well they are expressed and, thus, how well Cas12a will work. This study could make “multiplexed” DNA editing—where many genes are targeted at once—more efficient.
Open-Source Research Software: In a paper published in Synthetic Biology, researchers at the University of Washington, in Seattle, present an open-source software, called Aquarium. The software can be used to manage experiments and laboratory inventory (think chemicals, pipette tips and gloves), and even store protocols and data.
Why It Matters: Many scientists use a hodgepodge of tools to manage their work. During my time in research labs, I used Benchling to take notes and design DNA sequences, Dropbox to store data files and Quartzy to manage lab inventories. Aquarium packs most of these features into one place. Experiments can be planned, in the software, through a graphical user interface, and then presented as a ‘workflow’ where each step, once completed, triggers the next step in the protocol. The software also seems pretty smart—it will warn you if there’s likely to be contamination in an experiment, or if you’re over budget for the month.
TALEN Beats CRISPR: In a new study, published in Nature Communications, researchers at the University of Illinois at Urbana−Champaign showed that TALEN, which stands for transcription activator-like effector nucleases, are more efficient at cutting DNA in tightly packed heterochromatin than the Cas9 protein. A TALEN is a type of protein that is made by fusing a TAL effector protein—which can bind to DNA—to a protein that can cut DNA. These proteins have been used to cut DNA since at least 1996.
Why It Matters: Cas9 is the de facto protein for cutting DNA. This new study, though, presents a better alternative to cut DNA inside of heterochromatin, which makes up an estimated “∼25% to 90% of multicellular eukaryotic genomes,” according to a 2018 review. To figure this out, the researchers used single-molecule imaging, in living cells, and found that Cas9 is not as good at cutting this type of DNA because it “becomes encumbered by local searches on non-specific sites,” unlike TALEN.

🧫 Other Studies Published This Week

Biosensors

• Genetically encoded formaldehyde sensors inspired by a protein intra-helical crosslinking reaction. Nature Communications. Open Access. Link
• A whole-cell biosensor for point-of-care detection of waterborne bacterial pathogens. ACS Synthetic Biology. Open Access. Link

Cell-Free Systems

• A Streptomyces venezuelae cell-free toolkit for synthetic biology. ACS Synthetic Biology. Open Access. Link

Directed Evolution

• ssDNA recombineering boosts in vivo evolution of nanobodies displayed on bacterial surfaces. bioRxiv. Open Access. Link

Fundamental Discoveries

• CRISPCas9-mediated genome engineering reveals the contribution of the 26S proteasome to the extremophilic nature of the yeast Debaryomyces hansenii. ACS Synthetic Biology. Link
• Genome-wide CRISPR-Cas9 screen identified KLF11 as a druggable suppressor for sarcoma cancer stem cells. Science Advances. Open Access. Link
• A biofoundry workflow for the identification of genetic determinants of microbial growth inhibition. Synthetic Biology. Open Access. Link
• A novel all-in-one conditional knockout system uncovered an essential role of DDX1 in ribosomal RNA processing. Nucleic Acids Research. Open Access. Link
• Integrated spatial genomics reveals global architecture of single nuclei. Nature. Link
• Global analysis of protein arginine methylation. bioRxiv. Open Access. Link

Genetic Circuits

• A synthetic mechanogenetic gene circuit for autonomous drug delivery in engineered tissues. Science Advances. Open Access. Link
• A synthetic switch based on orange carotenoid protein to control blue light responses in chloroplasts. bioRxiv. Open Access. Link

Genetic Engineering

• In-situ generation of large numbers of genetic combinations for metabolic reprogramming via CRISPR-guided base editing. Nature Communications. Open Access. Link
• Designing P. aeruginosa synthetic phages with reduced genomes. Scientific Reports. Open Access. Link
• (Review) Genetic toolkits to design and build mammalian synthetic systems. Trends in Biotechnology. Link30332-2)
• Guide-target mismatch effects on dCas9–sgRNA binding activity in living bacterial cells. Nucleic Acids Research. Open Access. Link
• Genetic code expansion of Vibrio natriegens. Frontiers in Bioengineering and Biotechnology. Link

Medicine and Diagnostics

• In vivo cytidine base editing of hepatocytes without detectable off-target mutations in RNA and DNA. Nature Biomedical Engineering. Link
• Direct control of CAR T cells through small molecule-regulated antibodies. Nature Communications. Open Access. Link
• A CRISPR-Cas autocatalysis-driven feedback amplification network for supersensitive DNA diagnostics. Science Advances. Open Access. Link
• Gene therapy via canalostomy approach preserves auditory and vestibular functions in a mouse model of Jervell and Lange-Nielsen syndrome type 2. Nature Communications. Open Access. Link

Metabolic Engineering

• Development of the high-productivity marine microalga, Picochlorum renovo, as a photosynthetic protein secretion platform. Algal Research. Link
• Engineering lithoheterotrophy in an obligate chemolithoautotrophic Fe(II) oxidizing bacterium. Scientific Reports. Open Access. Link
• (Review) Metabolic Engineering of Cupriavidus necator H16 for Sustainable Biofuels from CO2. Trends in Biotechnology. Open Access. Link00007-X)
• Transportome-wide engineering of Saccharomyces cerevisiae. Metabolic Engineering. Open Access. Link
• Extending the shikimate pathway for microbial production of maleate from glycerol in engineered E. coli. Biotechnology and Bioengineering. Link
• Fermentative production of L-2-Hydroxyglutarate by engineered Corynebacterium glutamicum via pathway extension of L-lysine biosynthesis. Frontiers in Bioengineering and Biotechnology. Open Access. Link
• Efficient production of oxidized terpenoids via engineering fusion proteins of terpene synthase and cytochrome P450. Metabolic Engineering. Link

New Technology

• Expansion sequencing: Spatially precise in situ transcriptomics in intact biological systems. Science. Link
• A synthetic BRET-based optogenetic device for pulsatile transgene expression enabling glucose homeostasis in mice. Nature Communications. Link
• Light-controllable RNA-protein devices for translational regulation of synthetic mRNAs in mammalian cells. Cell Chemical Biology. Link00002-7)
• Norovirus detection in water samples at the level of single virus copies per microliter using a smartphone-based fluorescence microscope. Nature Protocols. Link
• The loopometer: a quantitative in vivo assay for DNA-looping proteins. Nucleic Acids Research. Open Access. Link
• Single cell epigenetic visualization assay. Nucleic Acids Research. Open Access. Link
• Low-cost, scalable, and automated fluid sampling for fluidics applications. bioRxiv. Open Access. Link

Protein Engineering

• De novo design of modular and tunable protein biosensors. Nature. Open Access. Link
• Orthogonal translation enables heterologous ribosome engineering in E. coli. Nature Communications. Open Access. Link
• DutaFabs are engineered therapeutic Fab fragments that can bind two targets simultaneously. Nature Communications. Open Access. Link
• Cell-free directed evolution of a protease in microdroplets at ultrahigh throughput. ACS Synthetic Biology. Open Access. Link
• Pore structure controls stability and molecular flux in engineered protein cages. bioRxiv. Open Access. Link
• Posttranslational chemical installation of azoles into translated peptides. Nature Communications. Open Access. Link

Systems Biology and Modelling

• Benchmarking of numerical integration methods for ODE models of biological systems. Scientific Reports. Open Access. Link
• Dynamical modeling of optogenetic circuits in yeast for metabolic engineering applications. ACS Synthetic Biology. Link
• Probability-based mechanisms in biological networks with parameter uncertainty. bioRxiv. Open Access. Link
• Generating novel protein sequences using Gibbs sampling of masked language models. bioRxiv. Open Access. Link

I took a week off, but I'm back! Hope you enjoy the newsletter.

The Crystal Jelly Unveils Its Brightest Protein Yet

Aequorea victoria, the crystal jelly, hovers in the waters off the coast of California. Decades ago, Osamu Shimomura noticed that these jellies emit a faint, green light. So he took pieces from one of them, did some experiments, and found the protein responsible for the glow. That protein—GFP—is now used in thousands of labs to light up the insides of microscopic cells. Shimomura shared the 2008 Nobel Prize for that work, along with Martin Chalfie and Roger Tsien, who died in 2016.
Now, it looks like the crystal jelly hasn’t given up all of its secrets just yet.
In a new study, nine previously unstudied proteins, also from Aequorea victoria and a related species, were reported. Several of the new fluorescent proteins have quirky characteristics, too. One of them is “the brightest GFP homolog yet characterized”, while another protein can respond to both UV and blue light. The scientists even found a couple of purple and blue-pigmented chromoproteins. The findings are further evidence that, in the darkness of the oceans, scores of mysteries remain to be discovered. This work was published Nov. 2 in the open-access journal PLoS Biology. Link

Will DNA Replace Grocery Store Barcodes?

A standard barcode—think grocery store rectangle, with black-and-white lines—contains 11 digits. Mixing up those digits in every possible way gives about 100 billion possible combinations. That’s a lot, but it’s not nearly as many combinations as what a barcode made from DNA could provide.
A new study, published in Nature Communications, reports a molecular, DNA tagging system that could become the future of barcodes. The DNA was dehydrated, which made it more stable, and the sequences were read out in just a few seconds with an Oxford Nanopore MinION, a small, portable DNA sequencer. To facilitate that speed, the authors came up with some clever ways to avoid complex, computational analysis of the DNA signals; they were able to read the barcodes directly from the raw sequence data. This study was published Nov. 3 and is open access. Link

Bacteria Produce Tyrian Purple Dye (From Sea Snails!)

As early as 1570 BC, the Phoenicians were dying fabrics with Tyrian purple. To make the dye required a process so intensive as to be nonsensical; as many as 250,000 sea snails (Bolinus brandaris) had to be smashed into goop to make just one ounce of dye. It was a color reserved for royalty, and literally worth more than its weight in gold.
Thank goodness, no more snails need to be smooshed to make Tyrian purple dye. Engineered E. coli bacteria can now make the dye’s predominant chemical, called 6,6'-dibromoindigo. To achieve this, scientists from Seoul National University added several genes to the bacteria; a tryptophan 6-halogenase gene, a tryptophanase gene and a flavin-containing monooxygenase. That’s a mouth garbling sentence, but I promise the result is easier to understand: the cells were able to produce 315 mg of 6,6'-dibromoindigo per liter in flasks, using tryptophan—an animo acid—as the chemical precursor. This work was published Nov. 2 in Nature Chemical Biology. Link

79 Different Cas9 Proteins Were Tested. Some Are Wicked Cool

Cas9 is maybe the most famous protein on earth. It’s like, the Kim Kardashian of the protein world. If there was a magazine for proteins, Cas9 would be on its cover. Oh wait, that already happened.
There’s a lot of different Cas9 proteins, but not all of them have been characterized. In a new study, scientists identified, and tested, 79 different Cas9 orthologs—proteins taken from different species, but that have the same function—and figured out how they recognize and cut DNA. Intriguingly, some of the Cas9 proteins only worked at specific temperatures; Cme2 Cas9, for example, “was only robustly active from ~30 °C to 55 °C suggesting the possibility of temperature-controlled DNA search and modification.” This study was published Nov. 2 in Nature Communications, and is open access. Link

CRISPR Shuts Down Fertilized Eggs

I didn’t know about the birds and the bees until my parents sat me down and told me. But if you’re wondering, a typical pregnancy starts like this: a fertilized egg latches on to the endometrium in the uterus. That activates a flood of genes to turn “on”, including one called leukemia inhibitory factor, or LIF. A new study has figured out a way to cut off fertility—with CRISPR—by targeting LIF and switching it “off”. The reason this is cool is because, well, the CRISPR-Cas9 system is photoactivatable, meaning it can be switched on with an LED.
The scientists, from Keio University in Tokyo, think that their work could prove useful in basic science research that probes the molecular signals underpinning this process. The study was published Nov. 2 in the journal PNAS, and is open access. Link

🧫 Rapid-Fire Highlights

More research & reviews worth your time

• Antibodies can be targeted to the Receptor Binding Domain of SARS-CoV-2, the virus that causes COVID-19, to block the virus from entering cells. But antibodies are hard to make. A new preprint describes a cell-free platform—internal ‘goo’ extracted from cells—that can be used to quickly produce antibodies. The method was eventually used to identify more than 800 “predicted binder families”, or antibody structures that might be able to bind to, and inhibit, the coronavirus. bioRxiv (Open Access). Link
• A new review discusses the tools available to design and create ‘designer’ proteins. The title of the article has a weird, political uprising vibe: “Arming Yourself for The In Silico Protein Design Revolution.” Trends in Biotechnology. Link30267-5)
• It turns out that S. cerevisiae—Baker’s yeast—have metabolic pathways that can be used to metabolize methanol. Those findings emerged from a new study that used laboratory evolution (in which scientists selectively passage cells, over time) and carbon-13 to trace metabolites through yeast cells. Nature Communications (Open Access). Link
• A beautiful review takes a deeper look at how molecular signals can be used to create synthetic, multicellular systems. The authors also discuss feedback loops, chemical messaging systems, and other fun synthetic biology topics. Current Opinion in Systems Biology (Open Access). Link
• New tools to perform “multiplex” genome editing—in which multiple genes are targeted, and modified, at once—have been reported for wheat. If anyone uses this on wheat, and bakes a loaf of bread, please send me your recipe (and a sample). Plant Biotechnology Journal. Link
• By mixing Cas9 with Cre-lox (a classic gene editing system, which has long been used to create engineered mice for medical studies), many different bacterial species can be precisely engineered. In this study, authors used the system to engineer four different species. PLoS One (Open Access). Link
• A new gene drive for Anopheles stephensi mosquitoes was reported by the James lab. This one targets and disrupts a mosquito gene required for survival, as well as a gene involved in eye color. Read the writeup from the lead author, which describes it far better than I could do in ~100 words. Nature Communications (Open Access). Link
• Engineered cells are stressed out, and for good reason. Some scientist, towering over a bench, has introduced all this foreign DNA and said, “Go on, take this! And make something with it.” The cell is, understandably, placed in a precarious position, teetering between a normal existence and a call to manufacture some new, foreign protein. Now, a new study helps alleviate that stress. By using quorum sensing signals and genetic circuits, scientists were able to redistribute cellular resources in a pathway agnostic way. The method could prove useful for all sorts of metabolic engineering projects. Nature Communications (Open Access). Link
• A genetic circuit—containing just 7,700 bases of DNA—was delivered, by virus, to bladder cells. The circuit can differentiate cancer cells from non-cancer cells, using a “miniaturized” genetic logic gate. Nature Communications (Open Access). Link
• Working in a lab means collecting reams of data. Notebooks, computer files, and printouts of PCR experiments. That disorganized data, applied to something that requires a lot of troubleshooting (like building a genetic circuit that works as expected), slows down progress. Now, a new data management system can help organize all that data. bioRxiv (Open Access). Link
• To keep a genetically-modified organism (GMOs—gasp!) from leaving the lab, some labs have been hard at-work developing “biocontainment” systems; molecular checks and balances that can make a cell’s life outside of its flask untenable. A new study uses fluoride to keep engineered yeast in check. Without fluoride around, the engineered yeast behave identically to their non-engineered cousins. But when fluoride is present in the environment, the “biocontained” yeasts slow their growth. That means that, were a yeast to escape down the drain, it may swiftly meet its demise in the public water system. Nature Communications (Open Access). Link
• By decoupling a cell’s normal processes from its engineered functions—like producing a recombinant protein—noncanonical amino acids can be incorporated into proteins at higher yields. ACS Synthetic Biology. Link
• A new study has reported a coupled pair of engineered bacterial strains (E. coli) that repress each other; that “mutual inhibition”, alone, was enough to “produce stable domains of gene expression in response to dynamic morphogen gradients”. Nature Communications (Open Access). Link
• All mammals—and yeasts and worms, too—have something called an “unfolded protein response” that kicks on when a cell gets stressed out, and triggers a response that moves around resources in the cell to manage that stress. A new study reports several different biosensors that can detect and measure the unfolded protein response, including one genetic biosensor that is just 98 bases in length. Using that sensor, the authors “demonstrate its ability to accurately discriminate between cells expressing different heterologous proteins and at varying production levels.” bioRxiv (Open Access). Link

#SynBio in the News

• I wrote an article, with Suzy Beeler, about our published work in eLife, and how our group at Caltech is working to “decipher the language of genomes”. Check it out. Caltech Letters. Link
• A gene therapy trial for Angelman syndrome, “a rare genetic condition related to autism”, was halted after two participants temporarily became unable to walk. Spectrum. Link
• Academic outlooks look increasingly bleak for many scientists. That’s why some researchers are carving out their own self-employed niches. Bioeconomy.xyz. Link
• London-based LabGenius, a company that uses robots and AI to design new materials and drugs, was featured in an article by Jeremy Kahn. Fortune. Link
• Henrietta Lacks’ cells, taken during an operation without her or her family’s knowledge, have been used to develop cancer treatments and make vaccines. Only now are giant corporations atoning for the ethical violations that enabled that work. Future Human. Link
• Basic science alert: Spider silk is cool, and scientists continue to unravel its “gloopy” secrets. Learn how silk gets made inside of a spider’s glands. New York Times. Link
• Ginkgo Bioworks released their second edition of “Grow”, a magazine that focuses on synthetic biology. This issue is all about Beauty. Grow By Ginkgo. Link
• A weekly news roundup, focused on “everything bringing humans closer to a food-secure future”, highlights a company that is making synthetic honey, and a seed bank for CRISPR-modified seeds. Future Human. Link
• CRISPR may not be ready—in some scenarios—for editing human embryos. Emily Mullin reports on two recent preprints; in one, which aimed “to fix a mutation in a gene called EYS”, an entire chromosome was inadvertently deleted. Future Human. Link
• Guide RNAs come in many different flavors. A new technology feature, by Vivien Marx, explains. Nature Methods. Link
• An article featuring companies like Octarine Bio and Hyasynth explores synthetic biology for cannabinoids. Labiotech.eu. Link
• PerkinElmer bought Horizon Discovery, one of the leading CRISPR therapy companies, for $383 million. Fierce Biotech. Link

Hey, Reddit. I'll imminently be getting my master's in biomedical science, and have started tossing PhD applications into various dustbins across the country. Unfortunately I recently made the classic mistake of getting excited about a particular position, and want this cover letter to be PERFECT. And to actually, you know, have a chance at success.
But although I'm pretty good at doing jobs, I've always been crap at getting them. So I'm turning to strangers for help! Realistically my background (clinical studies and antibiotic resistance) is only a tangential fit to the programme (pathogen transcriptomics and effects of the microbiome), and my footprint in academia is extremely limited, so I'm trying to take the approach of enthusiasm, flexibility, and honesty instead.
If anyone would like to take a few minutes and give their thoughts on whether my letter will be a help or hindrance, and whether my strategies were misguided at all... well, you'd have the profound gratitude of an internet stranger, for whatever it's worth.

Dear sir or madam,

[It's an advertised position with an application portal and all that. I didn't find any specific names for the committee, and since I'm technically applying for two positions at once it seemed like a bad idea to address the specific professor I'm aiming for.]

Good day! As an imminent graduate in biomedical science, please accept my interest in joining the [PROGRAMME] excellence cluster as a doctoral researcher.

[Standard opening, but I wanted to inject a little friendliness so it sounds less robotic.]

This cluster sparked particular interest, as microbial interactions play a significant role in antibiotic resistance, my own primary interest. Though my own relationship with microbes does tend to be on the antagonistic side – it was the specific phrases ‘microbial communities in human hosts’, ‘infectious diseases on the microbiome level’, and ‘developing strategies for remediation by targeted interventions’ that seized my attention – my ecological and clinical backgrounds both emphasise the importance of environmental factors.

[Did a BSc in ecology before being pivoted into medical research by lack of ecological work. Never actually got a job in that field, but I'm trying to leverage the degree into a bridge between my more medically-focussed experience and the microbiome focus of this research group.]

Soil bacteria, for example, have been identified as a reservoir for tetracycline destructases, and thus play a role in the proliferation of resistance to front-line drugs. And although my master’s thesis focussed on the killing of Pseudomonas aeruginosa when under stationary-phase conditions, the fact is that any in-vivo infection will be complicated by quorum-sensing and biofilm formation, expression of virulence-affecting regulators like RpoS, interspecific effects, and countless other factors. Medicine is becoming increasingly individualised, and supplanting the brute-force techniques of the past will require a more thorough comprehension of bacterial evolution.

[This paragraph was an attempt to reference the cluster itself, and to justify how a focus on antibiotic resistance is applicable to them; their group deals with environmental microbes, the specific position will focus on a gram-negative pathogen grown under varying conditions, and the professor in question has previously published on RpoS. It's also supposed to show that I'm mentally flexible and don't have my head stuck up my arse, but I have no idea if it is actually a good idea to spend a paragraph essentially undermining the value of my own master's thesis.]

Apart from this, it would also be remiss to pretend that [CITY] itself holds no special appeal in its own right; the reputation for scientific renown and progressive philosophy, the cosy population density, and of course the nearby [NICE PLACE], together paint an enticing picture for any country Kiwi.

[Look guys, I'm not just a beep-boop robot! And researched the wider area and stuff! I don't know. It's actually true, though, the location seems fucking amazing and is like half of why I'm so excited.]

Regarding my own background, this interest in combatting human pathogens reaches back into the mists of 2017; raised to become an engineer, I instead pursued an ecologically-focussed biology degree and then swerved into the realm of clinical trials. There I uncovered a buried passion, and by the expiration of my two-year working holiday visa, had served with distinction in three departments and gained a relative wealth of skills. But with only a bachelor’s I then found my further research opportunities sharply limited; the attempt to rectify this took me to [MASTER'S] and hopefully will lead next to [CITY] and the [INSTITUTE] University.

[The details are in my CV, but I want to emphasise them, because I have no presence in academia, while my work history (although spread across the IT and biomedical sectors) is legit pretty impressive for my age. It's my best shot; can't afford for it to get overlooked.]

Although the fact is that my academic research experience does remain limited, life has taught me to embrace challenge; I am eager for the chance to further grow, to add to the biomedical corpus, and with luck to earn a place in the nation that has proven so remarkably welcoming. Between my academic, clinical, and technical backgrounds, today I am confident that I can rise to meet any occasion, and – should you have me – will prove a useful and dedicated addition to your team.

[All completely true; the last ~6 years have been a fucking whirlwind and academia now seems thoroughly unintimidating. I also enjoy life here and am super enthusiastic about not getting deported. Unfortunately it all sounds painfully generic when written out...]

Please do not hesitate to contact me with any questions. Otherwise, I await your reply with hope and bated breath. Many thanks for your time, and for your consideration.
With best regards,
-[KP6]

​
If anyone actually read to this point, then again, a thousand thanks for your thoughts. Be brutal, and if something feels like a bad idea that just really should not be attempted, then please don't hesitate to set it straight.

Good day, CoverLetters! Should have occurred to me earlier that there would be a sub for this.
If anyone would be willing to give feedback on a cover letter for a PhD candidate position that I unwisely got myself emotionally invested in, I'd much appreciate it. Please be brutal, letting killer mistakes slip by unfixed will hurt far worse than a few harsh words.
I'm going to provide a certain amount of essential context, but otherwise refrain from explaining my exact thought processes - am curious whether the points I wanted to make come across or not.
​

Dear sir or madam,

It's a publicly-posted position with its own application form; couldn't find anyone specific to address.

Good day. As an imminent graduate in biomedical science, please accept my interest in joining the [GROUP] excellence cluster as a doctoral researcher.
This cluster sparked particular interest, as microbial interactions play a significant role in antibiotic resistance, my own primary interest. Though my own relationship with microbes does tend to be on the antagonistic side – it was the specific phrases ‘microbial communities in… human hosts’, ‘infectious diseases on the microbiome level’, and ‘develop strategies for remediation by targeted interventions’ that initially seized my attention – my ecological and clinical backgrounds both demand due consideration of environmental factors.

Did a bachelor's in ecology, worked in drug testing, then did a thesis on antibiotic resistance. The group I'm applying for focusses more on the microbial community.

Soil bacteria, for example, have been identified as a reservoir for tetracycline destructases, and thus play a role in the proliferation of resistance to front-line drugs. And while my thesis work specifically focussed on the killing of Pseudomonas aeruginosa when under stationary-phase conditions, one would be hard-pressed to find a medical scientist who denies the importance of factors such as quorum-sensing and biofilm formation, expression of virulence-affecting regulators like RpoS, or the presence of other species and strains. Modern medicine is ever-increasingly personalised, and supplanting the brute-force techniques of the past requires thorough comprehension of bacterial evolution – basically, to better beat the bugs, we need to know what they do and how they do it.

Shameless pandering. The group focusses on multiple environments, the position will work with a different gram-neg species grown under variable conditions, the prof has previously published on RpoS, and they are interested in inter-species interactions. Finally, an effort to associate my focus on killing bacteria with their own mission of understanding them.

Apart from this, it would also be remiss to pretend that location plays no role in my interest. Even discounting its noted excellence in the natural sciences, [INSTITUTE] stands among the top institutions in [COUNTRY], which itself is one of the most competitive nations in [REGION]. The surrounding city of [CITY], with a reputation for innovation and progressivism, a comfortably triple-digit population density, and the nearby [TOURIST HOTSPOT], is but icing on the proverbial cake.
Regarding my own background, this interest in combatting human pathogens reaches back into the mists of 2017; raised to become an engineer, I instead pursued an ecologically-focussed biology degree and then sidestepped into the realm of clinical trials. There I uncovered a buried passion and, by the expiration of my two-year working holiday visa, had served with distinction in three departments and gained a relative wealth of skills. But with only a bachelor’s I then found my further research opportunities sharply limited; the attempt to rectify this took me to the University of [MASTER'S DEGREE], and hopefully will lead next to [INSTITUTE].

Details alluded to here are in an attached CV.

Although the fact is that I still have far to come in academia, life has taught me to embrace challenge; I am eager for the chance to further grow, to add to the biomedical corpus, and with luck to earn a place in the nation that has proven so remarkably welcoming. Between my academic, clinical, and technical backgrounds, today I am confident that I can rise to meet any occasion, and – should you have me – will prove a useful and dedicated addition to your team.
Please do not hesitate to contact me with any questions. Otherwise, I await your reply with hope and bated breath. Many thanks for your time, and for your consideration.
With best regards,
-[KIWIPHOENIX6]

​
If you read all the way down to the bottom, then a thousand thanks for your time, and for any thoughts you may have. Cheers. :)

A few days ago I reposted a list of questions that you can answer during a graduate school interview. This is my response to the ones that were particularly useful for me. Im applying to a biomedical engineering master's degree with a molecular biology background, in case that's relevant. My interview will be tomorrow so wish me luck!!
​
Tell us a little about yourself
​

• I graduated from my bachelors last year in molecular biology with a specific interest in genetics and biochemistry. Its aligned with the subjects I was most interested in as a kid; the world of microscopic machines and DNA.
• Research is something I definitely want in my future. Throughout my undergraduate years I took a special liking to the hours i spent at the lab. I liked it so much that i decided to build my rudimentary lab at home. I want to understand the fundamentals of Biology and the Chemistry within us and apply it to technology in a way that I believe is quite lacking in todays academic literature.

​
What motivated you to apply to grad school:
​

• My fascination with synthetic biology and biomedical engineering lead me to get in contact with prominent researchers at the pasteur institute and max plank society to ask for guidance on how to go about realizing that dream.
• They advised me that biomedical engineering degrees are a good way to learn interdisciplinary science and to be able to apply it is a huge plus

​
Why specifically X?
​

• I find the way the program is structured is interesting with a first semester purely theoretical section and a second semester internship option. In this structure it allows me to gain much more practical knowledge than if it was kept for the fourth semester like most other schools
• I find that the program is well suited and structured for individuals who are interested in pursuing a PhD and this is something ive wanted to do for a long time and eventually have my own lab someday.
• I have been in contact with both professors, research institutions and alumni at the university to ask questions about the program and hear their opinion on it
• The responses were overwhelmingly positive, which cant be a bad sign.
• Ive also been in touch with influential researchers like Ceers Bekker and Kate Adamala and I sent them a list of programs they could review. They advised me to apply to X in particular as the opportunities at the collaborative universities are quite vast and the research going on in my field of interest is quite pronounced here.

​
Why do you feel prepared to start graduate school?
​

• I have finally been able to pinpoint exactly what I want to dedicate my life to. During my undergraduate years I often speculated what kind of molecular biology research I wanted to conduct specifically.
• It was during my senior year that I moved away from theoretical molecular biology to more applied molecular biology in the shape of nanotechnology and biomedical engineering
• I also showed myself that I am able to handle a large amount of stress during my final year of undergrad without giving up which. I believe is a beneficial attribute to have going into graduate school and to be a successful student, and researcher in the future.

​
Biggest strengths and weaknesses
​

• Im a detail oriented person, which is a blessing in terms of getting things done on time and with the highest quality possible. That said I find that ive needed to work on seeing the bigger picture of things this past year. Its still something im working on but i feel like ive made alot of progress in that regard
• Academic achievement and learning has always been a priority for me and like most things in life, the downside to that is I find myself to be too self critical. This is also something i work on addressing, how to balance becoming more flexible while still maintaining a commitment to achieve my goals.
• Right now im focusing more on my family. This is why at least once every couple of days I call my parents and siblings. I believe a cornerstone of the graduate experience is to be deeply involved and passionate in my research project . A key factor to succeeding I would say would be to have a strong protective structure such as having a proper support system. Thats something ive been doing recently and has been incredibly fulfilling

​
Research Interests
​

• This is a question with a two part answer, every goal has a certain path but goals often have multiple paths in order to reach it.

​

1. First, my ultimate goal has always been, and probably will always be to increase the productive natural lifespan of a human being

• The fact that we only have 80 years of life is pretty unfortunate in my point of view.
• If i can learn enough about aging, senescence and its molecular mechanisms then I hope to be able to advance the knowledge in this field in the future.

​

1. Secondly, the path towards my goal has been fluctuating somewhat throughout my academic life. I base my changes on the utility it can have to the public. Currently, the way I see is best to achieve my goal is through nanobiotechnology.

• As I see it right now, the first step towards that is to create nanoscale autonomous biosensors that imitate the quorum sensing capability in bacteria and report back to an artificial intelligence able to process the data in real time
• During my masters degree at X id like to develop this idea into a testable research project

​
Development of the field
​

• Currently synthetic biology is used to create high value molecules
• In 2018 a joint team from MIT and Harvard actually produced several molecules like pyrrolnitrin within a remarkable short period of time
• Research is ongoing to eventually be able to predictably engineer novel metabolic pathways, genes or even entire organisms from scratch.
• There is a lot of research into producing theranostic cell lines that can sense a diseases state and trigger an appropriate response but our metabolomic research isnt good enough to produce a disease fingerprint yet
• A lot of research is currently going into microfluidic systems and lab-on-chip development along with biosensors and biomaterial development and it seems most funding goes to these areas

​
Most significant accomplishment

• There are two but they are interlinked with each other

​

• The first one is actually my homemade lab.
• Ive managed to create machine that cost hundreds of thousands of dollars such as the Nanodrop machine for a fraction of the cost
• The nanodrop machine cost me less than 100 dollars in supplies
• It showed me that I dont need to rely solely on asking people for permission when it comes to doing things that I like
• I no longer needed to wait for my lab days to be in the lab, I could just open a door and id be there
• It also gave me experience in asking questions to a more independent degree that I did before I started building it
• When designing your own experiments out of pocket you have to optimize every process in order to cut costs and work as effectively as possible
• In this way, I learned a lot of methodology planning and general scientific procedures to reach a conclusion

​

• Second is that I proved to myself that I could handle an immense amount of stress and mental discomfort by pulling myself out of my head after my kidnapping with the help of others
• Since then Ive learned that a large part of getting the places you want to get is largely dependent on yourself individually but the support network you have around you can help significantly in doing so
• Those two points laid the groundwork for who I am today and will likely be responsible for my future accomplishments

​
Long term career goals
​

• If there is anywhere I want to be in the next 5 years, its in a lab of my interest.
• Theres a few in particular that i would like to explore if i am admitted to the program, for instance:

​

1. Pasteur Institute

• David Bikards Synthethic biology team
• Charles Bariouds microfluidics and bioengineering team
• Pierre Lafayes Antibody Engineering team

​

1. Curie Institute

The Multiscale Physics-Biology-Chemistry and Cancer department

• They are experts in the interdisciplinary field of synthetic biology and nanobiotechnology and the research they have produced is remarkable papers
• For example they detailed a method where they used click chemistry to label and visualize a large range of dynamic small molecules in vivo
• This is of great interest to me and my biosensor research interest

​

1. University of Paris

Microsystems and Nanobiofluidics lab in the center for nanoscience and nanotechnology

• They have great team headed by Pierre-Yves Jourbert that deal with issues that are relevant to my research topic
• Their biodevices and nanobiofluidics especially.
• Their research on microswimmers prompted me to actually send an email to Joubert asking if he would be willing to allow me to shadow their team if I am admitted to the program

Functional and adaptive biology department

• They have a very relevant team for degenerative processes and aging that interests me
• Their research involve the pathology of aging and it would be incredible to get to learn under a team with such a vision

​
What else should we know about you / What sets you apart from other candidates

• Yes, I dont believe we talked about it but I have quite a lot of experience in programming with different languages. I currently know 4 computer languages and plan to dive deeper into computer science by learning about computer architecture, neural networks, and artificial intelligence.
• I believe these skills will come to good use when if I am admitted and something that sets me apart from other candidates

A few days ago I reposted a list of questions that you can answer during a graduate school interview. This is my response to the ones that were particularly useful for me. Im applying to a biomedical engineering master's degree with a molecular biology background, in case that's relevant. Hope someone somewhere gets some use for this. My interview will be tomorrow so wish me luck!!
​
Tell us a little about yourself
​

• I graduated from my bachelors last year in molecular biology with a specific interest in genetics and biochemistry. Its aligned with the subjects I was most interested in as a kid; the world of microscopic machines and DNA.
• Research is something I definitely want in my future. Throughout my undergraduate years I took a special liking to the hours i spent at the lab. I liked it so much that i decided to build my rudimentary lab at home. I want to understand the fundamentals of Biology and the Chemistry within us and apply it to technology in a way that I believe is quite lacking in todays academic literature.

​
What motivated you to apply to grad school:
​

• My fascination with synthetic biology and biomedical engineering lead me to get in contact with prominent researchers at the pasteur institute and max plank society to ask for guidance on how to go about realizing that dream.
• They advised me that biomedical engineering degrees are a good way to learn interdisciplinary science and to be able to apply it is a huge plus

​
Why specifically X?
​

• I find the way the program is structured is interesting with a first semester purely theoretical section and a second semester internship option. In this structure it allows me to gain much more practical knowledge than if it was kept for the fourth semester like most other schools
• I find that the program is well suited and structured for individuals who are interested in pursuing a PhD and this is something ive wanted to do for a long time and eventually have my own lab someday.
• I have been in contact with both professors, research institutions and alumni at the university to ask questions about the program and hear their opinion on it
• The responses were overwhelmingly positive, which cant be a bad sign.
• Ive also been in touch with influential researchers like Ceers Bekker and Kate Adamala and I sent them a list of programs they could review. They advised me to apply to X in particular as the opportunities at the collaborative universities are quite vast and the research going on in my field of interest is quite pronounced here.

​
Why do you feel prepared to start graduate school?
​

• I have finally been able to pinpoint exactly what I want to dedicate my life to. During my undergraduate years I often speculated what kind of molecular biology research I wanted to conduct specifically.
• It was during my senior year that I moved away from theoretical molecular biology to more applied molecular biology in the shape of nanotechnology and biomedical engineering
• I also showed myself that I am able to handle a large amount of stress during my final year of undergrad without giving up which. I believe is a beneficial attribute to have going into graduate school and to be a successful student, and researcher in the future.

​
Biggest strengths and weaknesses
​

• Im a detail oriented person, which is a blessing in terms of getting things done on time and with the highest quality possible. That said I find that ive needed to work on seeing the bigger picture of things this past year. Its still something im working on but i feel like ive made alot of progress in that regard
• Academic achievement and learning has always been a priority for me and like most things in life, the downside to that is I find myself to be too self critical. This is also something i work on addressing, how to balance becoming more flexible while still maintaining a commitment to achieve my goals.
• Right now im focusing more on my family. This is why at least once every couple of days I call my parents and siblings. I believe a cornerstone of the graduate experience is to be deeply involved and passionate in my research project . A key factor to succeeding I would say would be to have a strong protective structure such as having a proper support system. Thats something ive been doing recently and has been incredibly fulfilling

​
Research Interests
​

• This is a question with a two part answer, every goal has a certain path but goals often have multiple paths in order to reach it.

​

1. First, my ultimate goal has always been, and probably will always be to increase the productive natural lifespan of a human being

• The fact that we only have 80 years of life is pretty unfortunate in my point of view.
• If i can learn enough about aging, senescence and its molecular mechanisms then I hope to be able to advance the knowledge in this field in the future.

​

1. Secondly, the path towards my goal has been fluctuating somewhat throughout my academic life. I base my changes on the utility it can have to the public. Currently, the way I see is best to achieve my goal is through nanobiotechnology.

• As I see it right now, the first step towards that is to create nanoscale autonomous biosensors that imitate the quorum sensing capability in bacteria and report back to an artificial intelligence able to process the data in real time
• During my masters degree at X id like to develop this idea into a testable research project

​
Development of the field
​

• Currently synthetic biology is used to create high value molecules
• In 2018 a joint team from MIT and Harvard actually produced several molecules like pyrrolnitrin within a remarkable short period of time
• Research is ongoing to eventually be able to predictably engineer novel metabolic pathways, genes or even entire organisms from scratch.
• There is a lot of research into producing theranostic cell lines that can sense a diseases state and trigger an appropriate response but our metabolomic research isnt good enough to produce a disease fingerprint yet
• A lot of research is currently going into microfluidic systems and lab-on-chip development along with biosensors and biomaterial development and it seems most funding goes to these areas

​
Most significant accomplishment
​

• There are two but they are interlinked with each other

​
The first one is actually my homemade lab.

• Ive managed to create machine that cost hundreds of thousands of dollars such as the Nanodrop machine for a fraction of the cost
• The nanodrop machine cost me less than 100 dollars in supplies
• It showed me that I dont need to rely solely on asking people for permission when it comes to doing things that I like
• I no longer needed to wait for my lab days to be in the lab, I could just open a door and id be there
• It also gave me experience in asking questions to a more independent degree that I did before I started building it
• When designing your own experiments out of pocket you have to optimize every process in order to cut costs and work as effectively as possible
• In this way, I learned a lot of methodology planning and general scientific procedures to reach a conclusion

​
Second is that I proved to myself that I could handle an immense amount of stress and mental discomfort by pulling myself out of my head after my kidnapping with the help of others

• Since then Ive learned that a large part of getting the places you want to get is largely dependent on yourself individually but the support network you have around you can help significantly in doing so
• Those two points laid the groundwork for who I am today and will likely be responsible for my future accomplishments

​
Long term career goals
​

• If there is anywhere I want to be in the next 5 years, its in a lab of my interest.
• Theres a few in particular that i would like to explore if i am admitted to the program, for instance:

​

1. Pasteur Institute

• David Bikards Synthethic biology team
• Charles Bariouds microfluidics and bioengineering team
• Pierre Lafayes Antibody Engineering team

​

1. Curie Institute

The Multiscale Physics-Biology-Chemistry and Cancer department

• They are experts in the interdisciplinary field of synthetic biology and nanobiotechnology and the research they have produced is remarkable papers
• For example they detailed a method where they used click chemistry to label and visualize a large range of dynamic small molecules in vivo
• This is of great interest to me and my biosensor research interest

​

1. University of Paris

Microsystems and Nanobiofluidics lab in the center for nanoscience and nanotechnology

• They have great team headed by Pierre-Yves Jourbert that deal with issues that are relevant to my research topic
• Their biodevices and nanobiofluidics especially.
• Their research on microswimmers prompted me to actually send an email to Joubert asking if he would be willing to allow me to shadow their team if I am admitted to the program

Functional and adaptive biology department

• They have a very relevant team for degenerative processes and aging that interests me
• Their research involve the pathology of aging and it would be incredible to get to learn under a team with such a vision

​
What else should we know about you / What sets you apart from other candidates
​

• Yes, I dont believe we talked about it but I have quite a lot of experience in programming with different languages. I currently know 4 computer languages and plan to dive deeper into computer science by learning about computer architecture, neural networks, and artificial intelligence.
• I believe these skills will come to good use when if I am admitted and something that sets me apart from other candidates

Full text via https://www.biorxiv.org/content/10.1101/494179v1.full
> Small microbial proteins also take part in communication and warfare between cells. For example, quorum sensing, a communication mechanism that influences sporulation, competence, antibiotic production, biofilm formation and virulence is mediated by small proteins (Moreno-Gámez et al., 2017).
> In addition, some of the antimicrobial peptides produced by bacteria against other microorganisms are small proteins (Cotter et al., 2013).
> Our analysis reveals 4,539 small protein families encoded by human-associated microbes.
> We expose small proteins that are potentially involved in the crosstalk with the host or with other microbial cells; we find small proteins that are likely subject to horizontal gene transfer and highlight small protein families that could be related to defense against phage or against other bacteria;
> Altogether, our data suggests that among the small protein families there are families that may be important for the adaptation of the bacteria to a specific body niche and are probably not essential in other body niches. Contigs originating from human gut samples are dominated by Bacteroidaceae and Ruminococcacea families.
> Small protein families with a potential role in bacterial defense against phage

So, I discussed on this subreddit my attempts at making moral decisions, and I’ve found it lacking. There is a Harvard online survey that asked the usual ethical conundrums (railroad spur / fat man problem). After taking it, I felt many of the choices were correct but profoundly disturbing. After reading Richard Dawkins and Daniel Dennett and Sam Harris; I have a better feeling of where I’ve gone wrong and where I made some progress. I disagree with the authors primarily on the deterministic nature of the universe. Either way, here is my slightly different take that is less human centric and allows for more diversity of morality. In some sense it definitely trends towards an evolutionary Gaia theory of morality, but allows for respect for alien or artificial intelligent beings. Hopefully, in reading this you could find logical flaws and worst case scenarios that I can rectify and ameliorate.
I propose the purpose of humanity is to protect and propagate the entirety of this living biome to another planet, then another, then another. I base this assumption on the evolution of the Earth’s living inhabitants and their biome. Therefore we need a moral code to carry out this purpose. Rating things that achieve this goal as higher in moral importance. Humans are of high importance not because of some innate god-given superiority, but because of their unique ability to propagate all life to another planet. From this theory of purpose I am trying to come up with a hierarchy of morals that would help guide us towards that goal with the least harm and most positive outcome.
Life by my definition is the end of the random epoch of the universe and the beginning of free will. Why is this non-random complexity found in free will important to me? I hold free will above all else because otherwise the universe is just fluctuations in entropy. Life stacks the odds in favor of itself. Out of this odds stacking more preferential outcomes occur. Free will is the evolution of degrees of freedom. A bacteria has a freedom of movement and signaling potentials. A ant has freedom of movement, signaling potentials and behavioral action programs (instincts). A human has all those freedoms and the ability to plan for the future and learn from the past. All of this life is interconnected and an imbalance for one species can create negative consequences for all.
Hierarchies
W.I.P. Hierarchy of Moral Importance based on feelings/pain-suffering/intelligence-complexity/communal intelligence-communal complexity/scarcity/value to life on Earth overall? A feeling is a physical/chemical response to outside stimuli that triggers upper level cognitive conscious response. A negative stimuli detrimental to the survival of the being can in some instances create a negative emotional response and the reverse is true. Pain is the realization and physiological reaction to destructive forces that hinder growth and survival. Suffering is an emotional reaction to negative forces both physical and psychological. Intelligence is the whole of programs/thoughts/instincts/planning associated with growth and survival. Communal intelligence/ability is the computational complexity of groups. Complexity is the sum and depth of intelligence+feeling+value to life on Earth. Scarcity is the probability that a particular phylum/genus/species is in danger of being completely eliminated. Value to life on Earth overall is a method to include those organisms who are weighted low on the intelligence+scarcity scales, but contribute greatly to the other organisms survival.

W.I.P. Weighting Importance: Scarcity
The probability that a particular phylum/genus/species that is in danger of being completely eliminated is an important consideration. An individual shrimp is less morally important than an individual octopus. The shrimp has a simple nervous system, and neuronal synapses. It does not feel pain the way a human does, nor does it have feelings as humans experience them. A octopus has a very complex nervous system. It experiences pain, has relatively high functioning problem solving skills, and possibly feelings. A shrimp that is one of the last of it’s genus/species is more morally important though than a common individual octopus. Efforts need to be made to protect that shimp over the octopus in those instances based on scarcity. A species loss in a habitat has ripple effects that is always microscopic and sometimes macroscopic.

W.I.P. Weighting Importance: Overall value to life on Earth
Value to life on Earth overall is a way to include those organisms who are weighted low on the complexity scales, but contribute greatly to the other organisms survival. Bacteria are a perfect example. Atmospheric oxygen, all carbon fuel, digestive capabilities, viral defenders, dangerous waste removal, soil health, and plant growth. Without bacteria, life on Planet Earth would barely move to multi-cellular life let alone human civilization. Eradicating a species of bacteria simply because it kills some humans is shortsighted and potentially a danger to all humanity.
W.I.P. Weighting Importance: Pain/Suffering - A negative state for life
There are two types of pain to consider. Physical pain and emotional pain(suffering). Ability to react to physical pain is objectively the least important consideration in the moral landscape in evaluating a being. Physical reactions to injury can be found in nearly all living beings. From single-celled bacteria to plants to beetles. It is a baseline for life. Conversely, certain humans cannot feel physical pain, yet are just as morally important as those who do. Emotional pain is much higher on the scale as it indicates the intellectual complexity of an organism. Emotional and physical pain also indicates an understanding the past, present, and future. An elephant can show consideration of dead relatives for years. Rats can be conditioned to avoid certain areas based on shocks they receive, but have shown fewer indicators of emotional pain. In conclusion, pain is a way to indicate the level of awareness of a being.
(Therefore, injuring an eye of a rat is less morally reprehensible than injuring an elephant's eye, and is less than a human’s eye based on emotional pain if the physical pain is nearly identical. - Maybe?)
Logic Problem: humans with low emotional pain Are humans deemed sociopathic/psychopathic lesser on the Hierarchy based on their diminished emotional pain? Initial thought, Yes. How much lower? Less than all other humans? Less than all other intelligent beings? The potential for damage is much greater given the intellect and capabilities. Higher threat to humanity, and the biome of Earth.
W.I.P. Weighting Importance: Intelligence - A higher order of free will
In order of complexity, a bacterial colony, slime molds, jellyfish(simple nervous system), flatworms(simple brain), frogs(limbic system), ant colonies, mice(neocortex), Octopus,elephants, whales, chimpanzees, and humans are all intelligent beings. Evaluations regarding them use a scale of complexity. A being that can simulate the functions and complexity of this computational system would necessarily be alive and a thinking being. Artificially created beings or human created beings would have the same standing as “naturally occurring beings. A human hybrid lab created creature to be super-intelligent would command respect based on it’s own merits. A machine general intelligence born of computer chips would also stand on it’s own merits.
(Therefore, beings with more intelligence (free will) should be treated with more respect and deference than lower beings of intelligence in a broad categorical sense.)
*This would explain why some humans feel less guilt eating fish than eating horses.
W.I.P Weighting Importance: Communal intelligence - Free will on a larger scale
Case in point a colony of bacteria does not have a limbic system, but it does have a communication system involving quorum sensing in the form of chemical signaling. A hive of ants is orders of magnitude more complex than a solitary ant. Through scent trails and scent signaling ants are found on six continents and make up a large percentage of insects the world over. Therefore a hive of ants is more important than a solitary ant. A pod of Dolphins can capture for more fish than a lone dolphin. An elephant matriarch can guide the herd to water. A solitary human is orders of magnitude less capable than a community. The pyramids of egypt would never have been built without a well functioning society.
W.I.P. Weighting Importance: Feelings (other than pain)
Other feelings have become emergent through evolutionary pressures of group survival. Positive feeling engender a path to recreate the experiences that produce them. A virtuous cycle is created when positive feelings create positive actions and more often positive outcomes. Negative feelings engender a path to avoid or confront. Surprise, disgust, fear, shame, confidence, joy, anger, and harmony all serve to communicate and guide a communal grouping of beings. A chimpanzee will altruistically feed another member of its tribe and feel good about doing so. This good feeling leads to positive actions that help strengthen the group as a whole. A matriarchal elephant will prevent injury of a young elephant by a Bull through a sense of harmony. Sadness is displayed in intelligent communal animals. Whales, dogs, elephants all have shown traits associated with remembering a death in the group.
*Logic Problem: Some human activities that create positive feelings produce negative actions. Chasing a heroin high leads to theft, and leads to a worse physical and mental state.
Obviously, all of this pre-supposes the non-existence of a god or god-like creator. The problem with Atheism as it currently stands is that it doesn’t offer as much in terms of goals. (A fulfilling life possibly?) A better freer society where people are treated fairly is a completely worthwhile goal, but it does not compete with an infinite life of pure happiness or your own planet. On a similar note our negative consequences are significantly less intrusive. Jail, fines and low standing in society versus everlasting pain, grief and suffering in a personal hell. Getting Earth’s biome to another planet or at least some small part might be enough to compete with the religions of today.
So that's my start. No numerical values or charts and graphs. A simple beginning.
Thank you for your time.

The big chunks of knowledge I learn at school, even when they are part of the same theme/subject, do not all feel connected in my mind. It feels like I have these seperated islands of knowledge, which are waiting to be connected to each other. For example, I might know what the cellular membrane is composed of and also additionally that cells can (somehow) communicate with each other but still lack the connection between them. However something I read the other day made me realise how the two subjects can be related: Some bacteria send out certain substances out of their cells so that these substances stick to other bacteria's receptors, thus allowing any bacterium around to get a feel of how many other bacteria there are around. I believe this was called quorum sensing or something similar.
Anyway, the example might have been elementary but reading that bit from yesterday really helped me form a picture how the two subjects are connected and it felt good. Does anyone know whether there are books that might help with my problem described above (not necessarily textbooks)?
I am a last year high school student if that is going to help.

So, i know i have been out for a little while. Sometimes its healthy to take a break from reddit every now and then. But im back. During my little vaykay i kept learning, though. Somehow, i began reading up on amoebas and protozoans and then on to pathological bacterium. Somewhere down the line, i came across Quorum Sensing.

Quorum sensing is a system of stimulae and response correlated to population density. Many species of bacteria use quorum sensing to coordinate gene expression according to the density of their local population.

Essentially, most bacteria produce a certain chemical (AI-2) that they also have certain receptors for. Once enough of their receptors are triggered, then it causes a certain chain of reactions, and it begins to go through different phenotypical expressions. But no individual bacteria actually produces enough of this AI-2 to trigger itself. Instead, it requires a certain level of population density wherein it resides (this brought me down an hour long tangent concerning biofilms, aka Extracellular Polymeric Substances, neat shit).
Once the colony or population reaches that threshold limit, the entire group then goes through changes of gene expression that changes it pathogenicity. All of a sudden, the group acts as one; Swarming Motility, production of Biofilms, virulence, and cell aggregation, all things bacteria do together. No single bacteria does it alone.
For example, a certain bioluminescent bacteria -- i forgot the name -- produces a chemical called luciferase. However, it does np good if one bacteria produces it, as the amount one individual makes is very small. It would be a waste of energy. So, through Quorum Sensing, each individual waits for his group to get big enough, once they reach threshold, they all start producing at the same time, and now in much much greater quantities.
Insects do these things too. The way worker ants and bees go out ajd find a new nest is amazing. Thete is no centralized decision making, yet, by their tactics of quorum sensing is nothing short of ingenious. (This brought me down another hour long tangent concerning swarm intelligence and other stuff).
Anyhow, the whole time im reading up on all of this stuff, i coupdnt help but to think about how quorum sensing affects humans. Do humans do it too?
I began to think about how we started to settle certain areas. Once a few found a great spot, more people came, more people talked about how great tha lt town site was, more people came, more people talked, etc etc.
Once Threshold was met, they named it New York City. And Philadelphia. (Or further back in time, Alexandria, Egypt, or even Sumer, or Babylon).
Urban Crawl would be another example, imo.
Anyways, i brought this up to see if you guys can come up with any other kinds of quorum sensing that us humans do. Id like to see what an intelligent swarm such as yourselfs can produce =-)