Experience
- Over 15 years of experience in editorial management, including fact-checking, copyediting, proofreading, manuscript and review management.
- Extensive service on editorial boards, bringing experience in scientific and technical content editing.
- Skilled in distilling complex scientific concepts into accessible language for media, public engagements, and educational outreach.
- Proficient in desktop publishing, scientific visualization, and professional multimedia presentations using Adobe Creative Suite, Microsoft Office Suite, Google Suite, iWork Suite, WordPress, CSS, and HTML.
Philosophy
My editorial philosophy is centered on meticulous attention to detail, ensuring that every piece of content is accurate and well-structured, with compelling visualizations, resulting in impactful, readable outcomes. I believe that effective management of relationships with authors and reviewers is crucial; by fostering open communication and mutual respect, I strive to create a collaborative environment that enhances the quality of the work. My commitment to bringing contributions to timely publication is driven by a dedication to advancing knowledge while respecting the time and effort of all parties involved. This approach not only upholds the highest standards of editorial excellence but also ensures that valuable insights reach their intended audience without unnecessary delay.
The following text is (left on desktop, first on mobile device) from a first-draft manuscript written by a scientist who is not a native English speaker. It has been edited to correct typos (right on desktop, second on mobile device), grammatical errors, but more importantly, it was rewritten as needed. Comments are at the bottom of the right panel.
ORIGINAL: Generation of A Destabilized Form of EGFP
Introduction:
The green fluorescent protein (GFP) from the jellyfish Aequorea Victoria is one of the most useful reporters which has been widely applied in the study of gene expression and protein localization in vivo. This is because of its autofluorescent activity that does not require any substrate or cofactor (Chalfie et al., 1994; Marshall et al., 1995; Cubitt et al., 1995). A number of variants with mutations at the chromophore structure and with optimized human codons have been engineered, which enhanced the expression level and modified the fluorescence properties of GFP in mammalian cells. EGFP (enhanced GFP) is a such mutant with a 35-fold increase in fluorescence intensity (Cody et al., 1993). Its enhanced fluorescence intensity makes EGFP a very popular reporter in many applications. By fusion with other proteins, EGFP is widely used to monitor the expression and distribution of the target proteins in life cells (Kain et al., 1995). By linking with a promoter/enhancer element, expression of EGFP can be used to measure the promoter activity as well as to determine its regulation. By introducing EGFP into transgenic animals, EGFP can also been used to study the expression regulation of those stage dependent and spatially distributed genes.
The limitation of EGFP as a reporter in certain cases is due to its stability. Crystallographick structures of GFP and its S65T mutant reveal a compacted b barrel structure (Ormo et al., 1996). This structure presumably contributes to its unusual resistance to proteolysis and denaturation. The stability of EGFP means a slower turnover in vivo, which limits its applications in certain cases, such as being a reporter in transient transcription studies. The accurate measurement of changes in mRNA level requires a rapid turnover reporter. Therefore, creating a destabilized form of EGFP would significantly expand its application. By fusing a degradation domain of mouse ODC with EGFP, we generated the destabilized EGFP (dEGFP) which has a much shorter half-life. The application of dEGFP as a transcriptional reporter are discussed in the next two chapters.
Principle of method:
To generate the destabilized EGFP, a “degradation domain” from mouse ornithine decarboxylase (ODC) was fused to the C-terminus of EGFP. ODC is the key enzyme in the biosynthesis of polyamines. The protein is known to be one of the most short-lived proteins in mammalian cells (Bercovich et al., 1989). Its C terminus contains a PEST sequence that has been proposed to be a structural motif for short-lived protei. Removal of the C terminus of mouse ODC prevents its fast degradation, whereas addition of this domain to another stable protein trypanosome brucei ODC results a less stable fusion protein (Ghoda et al., 1990). In this chapter, we demonstrated that the addition of the degradation domain of ODC to EGFP shorten the half-life of EGFP. Protein stabilities of EGFP and its destabilized form (dEGFP) was determined in vivo by expressing them in CHO-tTA cells. After turning off the protein synthesis by ddition of cycloheximide (CHX), the half lives of EGFP and dEGFP were measured by Western Blots and FACS analysis. The destabilized EGFP has an apparent half life of 2 hours, which is much shorter than unmodified EGFP.
EDITED: Generation of A Destabilized Form of EGFP
Introduction:
Green fluorescent protein (GFP) from the jellyfish Aequorea victoria is one of the most useful and widely used reporter molecules in the study of gene expression and of protein localization[MES1]. Its autofluorescent activity does not require any substrate or cofactor (Chalfie et al., 1994; Marshall et al., 1995; Cubitt et al., 1995). A number of variants, like enhanced GFP (EGFP), have been engineered to improve expression in mammalian cells. Such enhancements include mutations affecting the chromophore structure and optimization of codons for translation. EGFP is a variant with a 35-fold increase in fluorescence intensity (Cody et al., 1993) making EGFP a popular reporter in a wide range of applications. In a protein fusion construct, [MES2] EGFP permits determination of the level of expression and distribution of target proteins in living cells and tissues (Kain et al., 1995). Constructs linking EGFP with promoter/enhancer elements allow spatial and temporal tracking of their activity and regulation (e.g., Beaulieu et al., 2010)[MES3]. Transgenic animals with EGFP constructs also have been used to study stage-specific expression and regulation of genes throughout developmental ontogeny (e.g., Xavier et al., 2015). [MES4]
One limitation of GFPs is that their stability results in lagging in vivo turnover. This delay of clearance limits their applications in certain cases like transient transcription studies. Crystallographic structures of GFPs reveal a compacted b barrel structure thought to contribute to their unusual resistance to proteolysis and denaturation (Ormö et al., 1996[MES5]). Since accurate measurement of changes in mRNA level requires a rapid turnover reporter construct, a destabilized form of EGFP would significantly broaden its utility. By including the degradation domain of mouse ornithine decarboxylase (ODC) in constructs with EGFP we generated just such a destabilized EGFP (dEGFP) with a much shorter half-life.
Methods:[MES6]
To generate the dEGFP, the C-terminal degradation domain of mouse ODC was included in a fusion construct at the C-terminus of EGFP. A key enzyme in the biosynthesis of polyamines, ODC is one of the most short-lived proteins in mammalian cells (Bercovich et al., 1989). [EDITOR QUERY: It would be instructive here to note that the C-terminal domain of ODC targets the mature protein for degradation by proteasomes without the need for ubiquitination. The lack of a need for ubiquitin is key to the speed of degradation.] The C-terminus of ODC contains a PEST sequence that has been proposed as a general motif for short-lived proteins. For example, removal of the C-terminal domain of mouse ODC prevents its fast degradation, whereas addition of this domain to a stable Trypanosoma brucei protein results in the destabilization of the latter (Ghoda et al., 1990). In this chapter, we demonstrate that the addition of the C-terminal degradation domain of mouse ODC to EGFP shortens the half-life of the fusion protein.
Protein stabilities of EGFP and dEGFP were determined by expression in CHO-tTA cells. After extinguishing protein synthesis by the addition of cycloheximide (CHX), the half-lives of EGFP and dEGFP were measured by Western blot and flow cytometry (FACS). The destabilized EGFP [MES7] has an apparent half-life of 2 hr, which is much shorter than the [AUTHOR: insert hours here] hr of unmodified EGFP.
Additional references
Beaulieu AM, Rath P, Imhof M, Siddall ME, Roberts J, Schnappinger D, Nathan CF. 2010. Genome-wide screen for Mycobacterium tuberculosis genes that regulate host immunity. PLoS One. Dec 10;5(12):e15120. doi:10.1371/journal.pone.0015120
Xavier AL, Lima FR, Nedergaard M, Menezes JR. Ontogeny of CX3CR1-EGFP expressing cells unveil microglia as an integral component of the postnatal subventricular zone. Frontiers in cellular neuroscience. 2015 Feb 17;9:37.
Comments
[MES1]I deleted “in vivo” because (as the paragraph notes) it is used in vitro, in situ AND in vivo.
[MES2]Awkward: fusion proteins are not “fused” protein to protein. They result from concatenation of genetic code in a construct.
[MES3]Needed an example
[MES4]Needed an example.
[MES5]Please check References. E.g., Ormö not Ormo.
[MES6]Please check journal style. For many journals, what is written here in this section belongs in the Introduction, not the Methods. Is it “Methods”, or “Materials and Methods”?
[MES7]This is correct style, to spell out in full at the beginning of a sentence. Note to Copyeditor: please do not abbreviate to dEGFP here.
The first below (left on a desktop, top on mobile) is a submitted news piece concerning recent advances in the use of biotechnology to alter the human microbiome. It was obviously hastily written. It’s rife with spelling and grammatical errors. It also needed a “stand-first”. the second below is my edit. It’s not just a copy edit. The edited version (right on desktop, second on mobile device) adds context, embeds links, reorganizes some of the content, properly defines acronyms, and removes a section (about DART) that strayed off-topic toward the end.
In my letter to the author, I also wrote “I think there’s a missed opportunity to provide more background context. The utility of bacteriophage therapy goes back to Felix d’Herelle in 1917 and was abandoned with the discovery of penicillin in 1928. There’s also an established history of leveraging bacteriophages in the control of crop infections (see https://bmcmicrobiol.biomedcentral.com/articles/10.1186/s12866-021-02351-7). Even phage mediated delivery of CRISPR-cas systems has a prior history in the control of food-borne pathogens like Listeria. Can you cobble together a couple of paragraphs to add that credit-where-credit-is-due component? With my current edits you’re under 2,000 words, so lots of room. I don’t want to detract from the central human story though.”
ORIGINAL: Bacteriophage and CRISPR-Cas to modulate the microbiome
Stool transplants have been used since the 1950s to treat intractable bacterial infections like Clostridium difficile, through an infusion of beneficial, uncharacterised, bacteria, from healthy donors. But the future may lie in sequence-specific antimicrobials that use bacteriophage and CRISPR-Cas to hook and kill, harmful microbes, or to edit them to be beneficial.
Bacteria “play vital roles in the maintenance of health” says Eran Elinav, head of the systems immunology department at the Weizmann Institute of Science and director of the microbiome and cancer division and the German cancer research centre (DKFZ), but they are also the second biggest cause of death worldwide, according to a systematic analysis published in the Lancet in November.
Research from Elinav’s group, published in Cell in August, identified bacterial strains associated with inflammatory bowel disease and the bacteriophage that can kill them. Such research is a two-stage process: first identify the bacteria associated with disease – in this case specific strains of Klebsiella pneumoniae in IBD, a multi-factorial condition where bacteria are one of several risk factors. K. pneumoniae were also shown to induce gut inflammation in animal models. The team then hunted for naturally-occurring bacteriophage, viruses that infect specific bacteria and kill them through lysis. Five bacteriophage were identified, which could be safely given in a cocktail to healthy humans in a phase 1 clinical trial. “This opens up a whole opportunity to target other [bacterial] strains in other diseases” says Elinav, who co-founded Israel-based BiomX to commercialise bacteriophage applications. BiomX have a collaboration with Boehringer Ingelheim to identify microbial signatures in IBD, which could be used as biomarkers for this common, debilitating condition.
BiomX have identified naturally-occurring phage that kill Pseudomonas aeruginosa in the lungs of people with cystic fibrosis, a major cause of morbidity, which has been tested in two patients. California-based Armata Pharmaceuticals have taken a similar approach with an inhaled phage cocktail therapy, AP-PA02, also against Pseudomonas aeruginosa in CF patients, which is in phase 1b/2 clinical trials. Both BiomX and Armata have received up to $5 million equity investment from the CF Foundation to fund their clinical trials.
Armata were given FDA clearance in February for a phase 2 trial of AP-PA02 in Non-Cystic Fibrosis Bronchiectasis, a lung disease that affects 110,000 people in the US. Both BiomX and Armata have also identified phage that target Staphylococcus aureus on the skin, with clinical trials underway for each. “Our decision to focus on Pseudomonas aeruginosa and Staphylococcus aureus with our first two clinical programs reflects our commitment to introduce new solutions where patients most need improved outcomes,” said Mina Pastagia, Vice President of Clinical Development at Armata in a press release last year.
Cancer is also of interest to the phage therapy companies. BioMx have a phage cocktail targeting Fusobacterium nucleatum, which is associated with several human cancers. This phage therapy is engineered to express a payload to boost the immune system in colorectal cancer, using immunostimulatory cytokines, such as GM-CSF or interleukin-15. The goal is to engineer the bacteria, which are present within the tumour, to switch on the immune system – converting a cold tumour to hot.
Engineered bacteriophage have several applications. French biotech, Eligo, which was spun out of research at Rockefeller and MIT, use non-replicative phage engineered to express CRISPR-Cas. CRISPR is primarily a tool for killing bacteria, explains Xavier Duportet, CEO and co-founder at Eligo Bioscience. “When you deliver CRISPR to a bacterium the double stranded break caused by the CRISPR nuclease cannot be repaired and so the bacteria die.” The CRISPR-Cas provides an additional layer of targeting – a telescopic sight added to the bacteriophage sniper rifle. The bacteriophage will only infect certain microbial species and CRISPR-Cas will only target bacteria that express specific genes. CRISPR-Cas phage therapy “can kill the bacteria that contain toxin genes, or antimicrobial resistance genes, or pro-inflammatory genes, while leaving the rest of the strains from the same specific completely intact” says Duportet, so as not to disrupt the healthy microbiome.
Eligo’s most advanced research is in acne vulgaris, for which they were issued a US patent in November. Acne is caused by specific strains of Cutibacterium acnes and existing treatment is antibiotics, but this kills the beneficial C. acnes, as well as disease-associated strains that express pro-inflammatory cytokines. Non-replicative bacteriophage expressing CRISPR-Cas, designed to cut bacterial pro-inflammatory genes, will land harmlessly on most of the skin bacteria and only kill those that cause acne.
Eligo signed a $224 million deal with GSK in January 2021 that will fund pre-clinical research into EB005, their treatment for acne, with an option for licensing and further collaboration. Eligo, who have VC funding from Seventure and Khosla, hopes to start recruiting for human trials in moderate to severe acne in adolescents soon, with results expected in 2024. The company also received an orphan drug designation from the FDA in October for another bacteriophage therapy, EB003, which treats hemolytic uremic syndrome by cleaving the Shiga toxin gene in any bacteria that express it. Antibiotics do not work because killing the bacteria leads to over-expression of the toxin. Duportet says that they have shown efficacy in animal models and are now looking for a pharma partner to collaborate with on clinical trials.
As well as killing bacteria, CRISPR-Cas can be used to edit their genomes. “One of the ironies of CRISPR is that it was invented by bacteria, but has been used mainly to alter mammalian cells” reflects Peter Turnbaugh, Professor of Microbiology and Immunology at USCF and a Chan Zuckerberg Biohub Investigator. “Those of us that care about bacteria haven’t really benefited” from CRISPR technology, he says, until now.
CRISPR-Cas gene editing of the microbiome could allow the creation of microbial cell factories, engineered to produce specific metabolites in the skin or gut. “The microbiome can also be regarded as a huge biochemical factory which generates thousands of bioactive small molecules,” says Elinav. A pre-print in September showed that base editors and gene editors could be delivered to the mouse gut microbiome using Eligo’s non-replicative phage, with 99.7% of bacteria modified to express an antibiotic resistance gene after a couple of oral administrations. “We can transform the microbiome into a local drug factory” says Duportet.
Regulatory hurdles remain. “Genome editing of microbial communities is a big ask and we are currently lacking the regulatory infrastructure and guidelines” for this, says Jillian Banfield at UC Berkeley, who collaborated with CRISPR discoverer, Jennifer Doudna, to develop a transposon-based CRISPR-Cas gene editing tool called DART (DNA-editing All-in-one RNA-guided CRISPR Cas Transposase). Nevetheless, Banfield expects regulatory obstacles to gene editing of the microbiome to be overcome, with clinical trials likely within 5 years.
DART uses non-targeted transposon insertion to sequence undefined bacterial species in the environment (which could be the human gut, or soil in a field), followed by CRISPR-Cas gene editing of those newly-identified bacteria. “One of the real drivers for developing genome editing of [microbial] communities is to be able to access the genomes of organisms that cannot be grown in pure culture,” – which is most of them, says Banfield.
DART is also a tool for bioremediation, where bacteria are induced to remove chemicals like uranium from groundwater. “It’s affordable, doable, and uncontroversial” says Banfield of bioremediation. “From those [bacterial] genomes you can predict protein function and then you may be able to deduce that certain organisms use a specific substrate” like organic carbon, which promotes the growth of uranium-reducing bacteria in groundwater.
Bacteriophage and CRISPR-Cas are invaluable tools to remove individual bacteria from a given microbiome, and thereby understand the role of that species in the ecosystem. “In the microbiome field we really lack the equivalent of a knock-out mouse” says Turnbaugh – until now. “This is the way that the rest of biology works.” Techniques are improving, agrees Banfield. “Microbial communities are incredibly complex and dynamic and the methods to understand them have been developing.”
Studying new bacterial species provides hope that researchers will hit the biotechnology jackpot. CRISPR-Cas was itself discovered in bacteria, somewhat ironically as part of their immune system against bacteriophage, and many new genes and pathways with unknown applications are surely awaiting discovery. “There could be innumerable other examples of systems just as potentially valuable and important as CRISPR-Cas that just haven’t been accessed to date” says Banfield.
Microbiome researchers and bacteriophage companies have a willingness and excitement to try new approaches and experiment. “The field is slowly maturing to identify therapeutic targets” says Elinav. “The companies who are moving forward most quickly in the field are putting forward very different-looking therapies,” agrees Fischbach, which shows that there is no consensus as to what approach will work. “We should expect more messiness before the cleanliness comes.”
EDITED: Pioneering microbiome makeovers with CRISPR-Cas and bacteriophages
Bacteriophage and CRISPR-Cas systems hold promise for targeted killing and gene editing of pathological microbes. The diversity of applications implies a need for regulatory guidelines to catch up.
Stool transplants, the infusion of beneficial, uncharacterized bacteria from healthy donors, have been used since the 1950s to treat intractable bacterial infections like Clostridium difficile. But the future may lie in sequence-specific antimicrobials that deploy bacteriophages, some with CRISPR-Cas systems, to target and kill harmful microbes, or even edit them to be beneficial.
Bacteria “play vital roles in the maintenance of health,” says Eran Elinav, who heads the Weizmann Institute of Science’s Department of Systems Immunology and is Director of the Division of Microbiome and Cancer at the German Cancer Research Centre (DKFZ). Still, and according to a systematic analysis published in The Lancet in November 2022, bacterial infections remain the second leading cause of death worldwide.
In addition to identifying bacterial strains associated with inflammatory bowel disease (IBD), research published in Cell by Elinav’s group characterized the bacteriophages that can kill the microbes through a multi-step process. Specific strains of Klebsiella pneumoniae are known to be one of several risk factors associated with IBD. First, clinical isolates of K. pneumoniae from patients with IBD that induce gut inflammation in mice were isolated. The team then hunted for naturally occurring bacteriophage viruses that specifically infect and kill pathogenic strains of K. pneumoniae through lysis. Ultimately, five bacteriophage types specific to K. pneumoniae were identifiedthat could be safely given as a cocktail to healthy humans in a phase 1 clinical trial. “This opens up a whole opportunity to target other [bacterial] strains in other diseases,” said Elinav, who co-founded the Israel-based BiomX to commercialise such bacteriophage applications. BiomX also has a collaboration with Boehringer Ingelheim to identify other microbial signatures of IBD that could be used as biomarkers for this common and debilitating condition.
Researchers at BiomX also have identified naturally occurring bacteriophages that kill Pseudomonas aeruginosa, testing them in the lungs of two patients with cystic fibrosis (CF), a major cause of pulmonary insufficiency in children of European descent. California-based Armata Pharmaceuticals has taken a similar approach against Pseudomonas aeruginosa in CF patients with an inhaled phage cocktail therapy (AP-PA02) in phase 1b/2 clinical trials. Both BiomX and Armata have received up to $5 million equity investment from the Cystic Fibrosis Foundation to fund these programs. Armata received FDA clearance in February for a phase 2 trial of AP-PA02 in non-cystic fibrosis bronchiectasis, a lung disease that affects 110,000 people in the US alone.
With clinical trials underway, each of BiomX and Armata also has identified bacteriophages that target Staphylococcus aureus on the skin. “Our decision to focus on Pseudomonas aeruginosa and Staphylococcus aureus with our first two clinical programs reflects our commitment to introduce new solutions where patients most need improved outcomes,” said Mina Pastagia, Chief Medical Officer at Armata.
Cancer is also of interest to bacteriophage therapy start-ups. BioMx has developed a phage cocktail targeting Fusobacterium nucleatum that is associated with poor prognosis when present in colorectal, pancreatic and esophageal tumors. The goal is to use bacteriophages to edit bacterial genomes, switch on the immune system, and convert an immunologically “cold” tumour to “hot” one. Their phage therapy is engineered to insert a payload to boost immunostimulatory cytokines like GM-CSF or interleukin-15 into any F. nucleatum present in colorectal cancer.
Engineered bacteriophages have diverse applications. French biotech Eligo Bioscience, which was spun out of research at Rockefeller and MIT, uses non-replicative bacteriophages engineered to express CRISPR-Cas systems, primarily as a tool for killing bacteria. “When you deliver CRISPR to a bacterium the double stranded break caused by the CRISPR nuclease cannot be repaired and so the bacteria die,” explains Xavier Duportet, CEO and co-founder at Eligo. CRISPR-Cas systems provide an additional layer of targeting, like a telescopic sight added to a sniper rifle. Inasmuch as a particular bacteriophage will only infect certain microbial species, the CRISPR-Cas payload will only target bacteria that are armed with specific genes so as not to disrupt the healthy microbiome. CRISPR-Cas phage therapy “can kill the bacteria that contain toxin genes, or antimicrobial resistance genes, or pro-inflammatory genes, while leaving the rest of the strains from the same species completely intact,” says Duportet.
Eligo’s research that is furthest along, and for which they were issued a US patent in October 2022, concerns their treatment for acne vulgaris, EB005. Acne is caused by pro-inflammatory strains of Cutibacterium (previously Propionibacterium) acnes.Existing topical antibiotic treatments non-specifically alter beneficial bacterial communities of the skin, including beneficial strains of C. acnes. Non-replicative bacteriophages expressing a CRISPR-Cas system are designed to kill only bacteria with pro-inflammatory genes. Landing harmlessly on most skin bacteria, they kill only those strains of C. acnes that cause acne. Eligo signed a $224 million deal with GlaxoSmithKline in January 2021 to fund pre-clinical research into EB005, with an option for licensing and further collaboration. With VC funding from Seventure and Khosla, and results expected in 2024, Eligo hopes soon to start recruiting adolescents for trials targeting moderate to severe acne.
Eligo also received an orphan drug designation from the FDA in October for EB003. This bacteriophage therapy treats hemolytic uremic syndrome (HUS) caused by Shiga toxin-producing Escherichia coli (STEC) through cleavage of the Shiga toxin gene only in bacteria that possess it. Antibiotic therapy for HUS is controversial, having been found to enhance or even induce HUS through over-expression of Shiga toxin by stressing E. coli. Duportet says that they have shown efficacy in animal models and are now looking for a commercial pharmaceutical partner with which to collaborate on clinical trials.
In addition to killing bacteria, CRISPR-Cas systems can be used to precisely target any genome for editing, including microbial genomes. “One of the ironies of CRISPR is that it was invented by bacteria, but has been used mainly to alter mammalian cells,” reflects Peter Turnbaugh, Professor of Microbiology and Immunology and Chan Zuckerberg Biohub Investigator at UCSF. “In the microbiome field we really lack the equivalent of a knock-out mouse,” said Turnbaugh, noting that targeted deletion of one species from a given microbiome allows understanding the role of that species in the ecosystem. “Those of us that care about bacteria haven’t really benefited,” from CRISPR technology until now, he added.
Gene editing of a microbiome by CRISPR-Cas systems also could allow the creation of in situ bioreactors engineered to produce specific metabolites in the skin or gut. “The microbiome can also be regarded as a huge biochemical factory which generates thousands of bioactive small molecules,” says Elinav. “We can transform the microbiome into a local drug factory,” agreed Eligo’s Duportet. In a September 2022 pre-print in BioRciv, an Eligo Bioscience team showed that base editors and gene editors could be delivered to the mouse gut microbiome using one of Eligo’s non-replicative bacteriophages. The result was 99.7% of bacteria modified to express an antibiotic resistance gene after just 3 days of oral administration.
Microbiome researchers and bacteriophage companies have a willingness and are eager to try new approaches and to experiment. “The field is slowly maturing to identify therapeutic targets,” says Elinav. Yet regulatory hurdles remain. Jillian Banfield at UC Berkeley, who collaborated with (CRISPR discoverer) Jennifer Doudna to develop a transposon-based CRISPR-Cas genome editing tool, noted that “Genome editing of microbial communities is a big ask, and we are currently lacking the regulatory infrastructure and guidelines.” However, she expects that regulatory obstacles to microbiome gene editing will be overcome and anticipates clinical trials to commence within 5 years.
This was a portion of a public exhibition “Power of Poison” in which the highlight was pharmaceutical uses of naturally occurring toxins. In effect, the other edge of the double-edged sword.
My edits are marked as [DEL:][INS:] and {} for comments to the writer. It’s a mixture of content editing, copyediting, and fact-checking.
POISON FOR GOOD
“Poison” [DEL: is a scary word, evoking] [INS: evokes] peril and pain. But[DEL: poisons are not always harmful. When][INS:, when] used in certain, careful ways, poisons can be beneficial. Plant toxins and animal venoms have been used [DEL:in] [INS: as] treatments for medical conditions ranging from coughing{Other than alliteration, why coughing? And is this referring to opium? Is that wise? I think “diabetes” is more appropriate here} to cancer. And the search for new medicines made from natural toxins has barely begun {That will come as a surprise to the many researchers who have been doing it for a long time. Maybe say “is an active area of scientific research”}. Thousands of toxins are now being studied, providing a wealth of potential new drugs. [DEL: Such research] Toxicology has led to medical breakthroughs in other ways[DEL:, too]. Studying how [DEL: poisons][INS: toxins] affect human cells helps scientists [DEL: figure out how to protect, repair and heal them] [INS: understand how they function properly and when they don’t].
[panel for central model of yew tree]
TREATMENT FROM A TREE
A toxin to treat cancer
This yew tree (Taxus baccata) is so poisonous that eating a handful of needles [DEL:can kill a person]{perhaps “a child” — The minimum lethal dose is 1 g yew leaves/kg body weight. So 30 grams for a 10 yr old, but 80 grams for an adult.} [INS:can badly affect your heart]. [INS: Yews have a variety of alkaloid compounds called taxanes. Taxane B can stop your heart, but a different one, paclitaxel,][DEL:Yet a chemical found in yew bark] has proven to be an effective anti-cancer medicine. Demand for this drug, known as [DEL:paclitaxel, or] Taxol {I don’t think we should be mentioning brand names. Taxol is only one of several paclitaxel drugs. I suppose we could use “e.g.,”}, became so high that in the 1990s[DEL:,][INS: that] several species of yew trees were threatened from overharvesting. Today, chemists make the medicine from other, more abundant [DEl:chemicals in][INS:taxanes produced by] yew trees, or from [INS: plant] cells grown in vats of liquid, sparing the trees. These methods [DEL: all harness the power of nature to grow chemicals][INS: harness the plants’ own biosynthetic pathways to produce compounds] that would be nearly impossible to make from scratch in a lab.
POISON PROFILE
What [DEL:is it][INS: are they]: Yew trees contain a mixture of toxic alkaloids called [DEL:taxoids] [INS:taxanes]
What [DEL: does it][INS: do they] do: [DEL:Protects tree][INS: Protection] from being eaten by browsing animals; In humans, causes dizziness, nausea, vomiting, pain, muscle weakness, heart failure, death
How it works as a drug: [DEL:One taxoid,][INS:The taxane] called paclitaxel[DEL:,] (Taxol) {I don’t think we should be mentioning brand names. Taxol is only one of several paclitaxel drugs. I suppose we could use “e.g.,”} prevents cells from dividing and multiplying. Since cancer cells divide and multiply very quickly, the drug stops them from growing and spreading. (Unfortunately, hair and stomach cells also multiply quickly, so cancer drugs often cause hair loss and nausea as well.) {Why is that in parentheses?}
By the numbers
It takes more than 1 ton of yew bark to extract just 10 grams of medicine. That’s why paclitaxel is now made in the lab. {This is misleading. It’s not just the bark. They take the tops off of yew trees, which can continue to grow, and then semisynthesis involves several steps of increasing purity. see Ganem and Franke 2007 doi:10.1021/jo070129s}
Image of paclitaxel molecule
WHY MEDICINES FROM PLANTS?
Plants can’t run away from predators {? AWK – “predators” eat animals, not plants – why is this not “herbivores”?} But many of them can produce toxins that stop animals from eating them. Plant toxins can be quite potent—millions of years of evolution have left behind many useful compounds, while weeding out less successful varieties. Synthesizing a complex molecule like paclitaxel (above) from scratch [DEL: would be][INS: has proven to be] very difficult and time consuming. Letting a tree do the work saves a lot of time and energy {and money, no?}.
Mini-photos of sample plants?
MEDICINES FROM PLANTS
Many plants have evolved toxic defenses that protect them from hungry insects and other animals. From these plant toxins, chemists have extracted many useful drugs.
Photo:
Sweet wormwood (Artemisia annua) is the source of [INS: artemisinin] a widely used malaria treatment. {Worth mentioning that Yu got a Nobel Prize for it!}
Photo:
Foxglove (Digitalis lanata) [DEL:has led to] [INS:provides digoxin] a treatment for irregular heartbeat.
Photo:
The opium poppy (Papaver somniferum) has yielded potent medicines for pain relief, including codeine and morphine.
Photo:
Wintergreen (Gaultheria [DEL:sp.][INS: spp.]) is the source of the popular pain reliever aspirin.{This is untrue. salicylic acid was isolated first from willow bark and then from meadowsweet}
photo, if room: Immense yew in cemetery, and/or Voldemort’s wand (perhaps inset?)
TREE OF DEATH
Many legends have arisen about yew trees, perhaps because their needles and berries {Untrue: the red flesh of the berries are not toxic} contain deadly poison. Yews have traditionally been grown in cemeteries in Europe, and in the Harry Potter books, the evil Lord Voldemort’s wand is made of yew. {MISLEADING: Yew trees were long associated with immortality becauae they can live for thousands of years. THAT is why they are in cemeteries and THAT too is the association with Voldemort, the fact that he wanted to live forever. Nothing to do with being toxic.}
[live animal/model wall sub-intro]
MEDICAL MARVELS
[DEL:Poisons can come from almost any species—and so can new medicines {untrue}]. Studying venoms and toxins has led researchers to many promising new drugs. From spiders to snails, trees to tarantulas, [DEL:foxgloves][INS:foxglove] to fungi, new medicines can come from almost any branch on the tree of life {AWK: I don’t know of any medicines that come from tapeworms, birds, primates, I think you see my point.}. The examples shown here are just the beginning; thousands more species are being studied right now in search of life-saving new drugs.
MEDICINES FROM MICROBES
BOTOX® from bacteria {Why are we using the registered trademark symbol here and not for Taxol?}
Botulinum toxin is one of the deadliest known substances: a millionth of a gram can kill an adult. This highly dangerous [DEL:substance][INS: protein] is produced by a tiny microbe, Clostridium botulinum [INS: . These] bacteria produce the toxin as part of their ongoing chemical warfare against other microbes. Scientists have harnessed these toxins to treat [DEL: a] medical conditions ranging from [DEL:infections{<- This cannot be true}] [INS:migraines] to muscle spasms.
POISON PROFILE
Substance: Botulinum
Source: Produced by Clostridium botulinum bacteria
Effects in humans: Muscle paralysis; causes death by suffocation {Is “respiratory arrest” too technical? How about “stopping your lungs from breathing”?}
How it works as a drug: By carefully paralyzing specific muscles, doctors can stop unwanted muscle spasms, crossed eyes, jaw clenching and other disorders; most commonly used cosmetically (under the commercial name BOTOX®) to [INS: temporarily] reduce wrinkles [DEL:temporarily].
WHY MEDICINE FROM MICROBES?
It is no coincidence that most antibiotics—medicines that kill [DEL:microbes][INS: bacterial infections]—come from [INS:other] microbes. Microbes are tiny living things that include bacteria, fungi, molds {AWK: molds are fungi} and otherI single-celled organisms {AWK: filamentous fungi, from which we get cephalosporins are multicellular, not single-celled}. They live everywhere. With multiple species competing for space [DEL:at all times][INS: in the natural environment], many microbes evolved the ability to produce poisons that kill off competitors. Some of these toxins are now used to kill microbes {Not just microbes. The cure for river blindness caused by a nematode worm, ivermectin, also came from a microbe, Streptomyces avermitilis} that make people sick.
Mini Photos of magnified bacteria and fungi
MEDICINES FROM MICROBES
If you’re suffering from a bacterial infection, how do you kill the bacteria that are making you ill, without harming your own cells? One solution is to use the toxins that microbes use against each other; this is how antibiotics were discovered.
Photo: Penicillium chrysogenum mold
The first antibiotic drug, penicillin, came from Penicillium molds. Penicillin kills bacteria that the mold competes with; scientists found it also could be used to kill bacteria that cause disease.
Photo: Bacillus brevis bacteria are the source of the antibiotics gramicidin and tyrocidine.
Photo:
Streptomyces cattleya bacteria are the source of potent antibiotics called carbapenems, which are often used when other antibiotics fail.
Photo:
The fungus Acrimonium ([DEL:also][INS: previously] known as Cephalosporium) is the source the antibiotics called cephalosporins.
Botulism, a type of food poisoning caused by Clostridium botulinum bacteria, can be prevented by canning food, which involves sterilizing food in sealed, heated containers. The French emperor Napolean Bonaparte is considered the father of canning because he offered a prize to anyone who figured out how to keep his army’s food from spoiling. The winner earned 12,000 francs.
REPTILE REMEDIES
Help from a gila monster
Gila monsters (Heloderma suspectum) move slowly but have a dangerous bite. When these predators attack their prey, venom travels down grooves in their teeth into their [DEL:victims][INS:quarry]. Scientists found that one component of the venom, exendin-4 {Why are we not using the brand name Exenatide here when we used Taxol and BOTOX above?}, lowers blood sugar, and used it to make a drug to treat type II diabetes; patients have used the medication successfully since 2005. Medical researchers are investigating other venoms[DEL, too]: Several other drugs derived from snake venoms, designed to treat ailments ranging from high blood pressure to bleeding, are already in use or in development.
POISON PROFILE
What it is: Gila monster venom; contains a peptide that lowers blood sugar
What it does: may help gila monsters immobilize prey or ward off predators; may also slow digestion, making infrequent meals last longer. In humans, gila monster venom causes extreme pain, swelling and reduced blood pressure; can cause internal bleeding
How it works as a drug: Exendin-4, one component of the venom, stimulates insulin production and lowers blood sugar levels. The drug exanatide, based on {is it based on, or is it} exendin-4, helps regulate blood sugar in people with type II diabetes, whose blood sugar becomes dangerously high, while also reducing appetite and obesity.
MEDICINES FROM VENOM
Snake venom components are being studied to create drugs to reduce blood pressure, block pain, lower blood sugar, prevent clots, strokes and heart attacks, stop bleeding and even fight cancer.
Photo:
Blood-pressure regulating drugs called ACE inhibitors [INS: like Captopril], in use since 1975, were developed by studying the venom of the Brazilian pit viper (Bothrops jararaca).
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Used in India for thousands of years to treat arthritis , the venom of the Indian [DEL:monocellate][INS: spitting] cobra (Naja kaouthia) is now being tested [DEL: by doctors for use against][INS: to treat] arthritis, with encouraging results. {I am pretty sure this has only been demonstrated in rodents. I do not believe there have been human trials.}
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The venom of the Malayan pit viper (Calloselasma rhodostoma) contains [DEL:chemicals][INS: toxins] that prevent blood from clotting, leading researchers to drugs that protect humans from dangerous blood clots. {This is ancrod and trade name Viprinex. Should be mentioned.}
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Black Mamba (Dendroaspis polylepis) venom may lead researchers to new pain medications, because it blocks nerve function.
Photo of vampire bat
VAMPIRE BATS
The vampire bat (Desmodus rotundus) drinks blood from other animals—and may lead researchers to a life-saving drug for stroke patients. The bat’s saliva contains compounds that prevent clotting and keep [DEL:the victim’s][INS: a cow’s] blood flowing while the bat drinks. In humans, blood clots in the brain can cause strokes and brain damage. The vampire bat’s anticlotting agent, known as Draculin, could potentially dissolve these clots more safely than current drugs. Similar drugs [DEL:are also being][INS:, like hirudin, have been] developed from leeches.
WHY MEDICINES FROM VENOM?
Snake venoms contain an astounding variety of [DEL:chemicals][INS:compounds] that affect the human body in different ways. Even when venoms contain no beneficial ingredients, studying them can still be helpful. Uncovering how venoms do their damage can help scientists learn how the human body works. For instance, some of the most important blood-pressure medications are called ACE inhibitors. These drugs are not made from snake venom, but were discovered by studying how snake venom works. {This is redundant with the content above}
AID FROM ARACHNIDS
Toxic Tarantulas
Spiders like this Chilean rose tarantula (Grammostola rosea) can frighten animals much larger than themselves, including people—and for good reason. Their bites deliver toxic venom. Even so, spiders have long been used in traditional medicine, from the ancient Chinese to the Mayans of what is now Mexico. Today, scientists are studying exactly how these venoms work to help them make safe and effective medicines. Research on spider and scorpion venom may soon help doctors treat conditions ranging from pain to heart disease.
POISON PROFILE
Substance: Rose tarantula venom
Effects in prey: Painful bites deters predators; toxins [DEL:may also help] immobilize and digest prey
Effects in humans: Bites are painful but do not cause serious damage
How it works as a drug:
An extract from tarantula venom called GsMtx-4 appears to help regulate heartbeats. In diseased or damaged hearts, calcium enters heart cells through openings called ion channels, triggering random, uncoordinated spasms of the heart called fibrillations. The spider drug blocks these ion channels , causing the heart to beat more steadily. The substance may also help fight pain and muscular dystrophy.
MEDICINES FROM ARACHNIDS
Several spider and scorpion venoms are now being studied for medical use, though they are still in the research stage.
Photo of deathstalker scorpion.
The deathstalker scorpion (Leiurus quinquestriatus) produces a neurotoxin called chlorotoxin, which is currently being studied for potential medical uses. Possible applications include treatments for [INS: brain] cancer [DEL:and diabetes].
Photo of Fraser Island funnel web spider:
Australian funnel web spiders are among the most deadly to humans. Scientists are studying up to 300 different molecules from their lethal venoms in search of potential treatments for pain, cancer and other maladies.
Photo of Macrothele raveni
Lab research suggests the venom of the Macrothele raveni spider could help fight lung cancer and leukemia.
OCEAN ALLIES
Medicines from Marine Invertebrates
This aquarium may look pretty, but almost everything in it is toxic. The anemones, tunicates and snails you see here use poison to kill small animals, which provide them with food, or to ward off predators. The oceans teem with poisonous creatures; toxins are especially common among species that can’t swim around. Thousands of marine invertebrate toxins could provide a rich source of potential medicines to treat problems from pain to Parkinson’s disease.
WHY MEDICINES FROM MARINE INVERTEBRATES?
Like plants, many sea creatures are rooted in place and use chemical defenses to deter predators. But unlike plants, which survive on water and sunlight, many of these organisms kill and eat other animals. While some filter food from the surrounding seawater, others kill their victims with venom. These marine toxins could be a rich source of future drugs.
Photo of living Conus purpurascens
KILLER CONE SNAILS
These cone snails (Conus purpurascens) produce a [DEL:nerve poison][INS: neurotoxin] so powerful it can rapidly paralyze a large fish—or kill an unwary person. Yet toxins from cone snails have already yielded a useful pain drug [INS: Ziconotide (Prialt)]; future medicines could [DEL:potentially] be used to fight epilepsy, Alzheimer’s disease and Parkinson’s disease .
Two photos with shared caption
DEADLY BEAUTY
The flower-like anemones in this tank are no shrinking violets—they are predatory animals that kill their prey with [DEL:poison][INS:toxins]. Their venoms are currently being studied for potential use against cancer (Entacmaea quadricolor) and to treat multiple sclerosis (Stichodactyla helianthus).
Stichodactyla helianthus
Entacmaea quadricolor
Photo of Ecteinascidia turbinata, mangrove tunicate
CHEMICAL DEFENSES
The lovely mangrove tunicate (Ecteinascidia turbinata) eats by filtering tiny creatures called plankton and other bits of food from the water. It is harmless to larger animals—unless they try to eat it. Like many marine invertebrates, it creates toxins as a defense. A tunicate toxin called trabectedin [INS:(Yondelis)] is already being used as a cancer drug in Europe and Asia.
Magnified image of cone snail barb, inset with cone snail photo
POISONED HARPOON
Cone snails inject their prey with a barbed harpoon (magnified image) covered in deadly venom. The cone snail’s venom is so toxic it can quickly paralyze a large fish by blocking nerve transmissions to muscles. Snail toxins can also block pain signals from reaching the brain, yielding pain relievers more powerful than morphine.
Clownfish photo caption
WHY AREN’T THESE CLOWNFISH DEAD?
Most fish and shrimp stay away from anemones, which kill and eat small animals. But certain species, like clownfish, are specifically adapted to live among their [DEL:poisonous][INS:venomous] tentacles—the fish have a thick layer of mucus that protects them from anemone venom. Both organisms benefit from this partnership. The fish clean off parasites and may chase away the anemone’s enemies; in return, they get to eat some of the small animals killed by the anemone, and gain protection from predators[DEL:, which][INS:that] avoid anemones.