Tag Archives: Evolution

Long-ignored antibiotic could help fight against multi-drug resistant bacteria

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“The end of modern medicine as we know it.” That’s how the then-director general of the World Health Organization characterized the creeping problem of antimicrobial resistance in 2012. Antimicrobial resistance is the tendency of bacteria, fungus and other disease-causing microbes to evolve strategies to evade the medications humans have discovered and developed to fight them. The evolution of these so-called “super bugs” is an inevitable natural phenomenon, accelerated by misuse of existing drugs and intensified by the lack of new ones in the development pipeline.

Without antibiotics to manage common bacterial infections, small injuries and minor infections become potentially fatal encounters. In 2019, more than 2.8 million antimicrobial-resistant infections occurred in the United States, and more than 35,000 people died as a result, according to the Centers for Disease Control and Prevention (CDC). In the same year, about 1.25 million people died globally. A report from the United Nations issued earlier this year warned that number could rise to ten million global deaths annually if nothing is done to combat antimicrobial resistance.

For nearly 25 years, James Kirby, MD, director of the Clinical Microbiology Laboratory at Beth Israel Deaconess Medical Center (BIDMC), has worked to advance the fight against infectious diseases by finding and developing new, potent antimicrobials, and by better understanding how disease-causing bacteria make us sick. In a recent paper published in PLOS Biology, Kirby and colleagues investigated a naturally occurring antimicrobial agent discovered more than 80 years ago.

Using leading-edge technology, Kirby’s team demonstrated that chemical variants of the antibiotic, called streptothricins, showed potency against several contemporary drug-resistant strains of bacteria. The researchers also revealed the unique mechanism by which streptothricin fights off bacterial infections. What’s more, they showed the antibiotic had a therapeutic effect in an animal model at non-toxic concentrations. Taken together, the findings suggest streptothricin deserves further pre-clinical exploration as a potential therapy for the treatment of multi-drug resistant bacteria.

We asked Dr. Kirby to tell us more about this long-ignored antibiotic and how it could help humans stave off the problems of antimicrobial resistance a little longer.

Q: Why is it important to look for new antimicrobials? Can’t we preserve the drugs we have through more judicious use of antibiotics?

Stewardship is extremely important, but once you’re infected with one of these drug-resistant organisms, you need the tools to address it.

Much of modern medicine is predicated on making patients temporarily — and sometimes for long periods of time — immunosuppressed. When these patients get colonized with these multidrug-resistant organisms, it’s very problematic. We need better antibiotics and more choices to address multidrug resistance.

We have to realize that this is a worldwide problem, and organisms know no borders. So, a management approach for using these therapies may work well in Boston but may not in other areas of the world where the resources aren’t available to do appropriate stewardship.

Q: Your team investigated an antimicrobial discovered more than 80 years ago. Why was so little still known about it?

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The first antibiotic, penicillin, was discovered in 1928 and mass produced for the market by the early 1940s. While a game-changing drug, it worked on only one of the two major classes of bacteria that infect people, what we call gram-positive bacteria. The gram-positive bacteria include staphylococcal infections and streptococcal infections which cause strep throat, skin infections and toxic shock. There still was not an antibiotic for the other half of bacteria that can cause human infections, known as gram-negative organisms.

In 1942, scientists discovered this antibiotic that they isolated from a soil bacterium called streptothricin, possibly addressing gram-negative organisms. A pharmaceutical company immediately licensed the rights to it, but the development program was dropped soon after when some patients developed renal or kidney toxicity. Part of the reason for not pursuing further research was that several additional antibiotics were identified soon thereafter which were also active against gram-negatives. So, streptothricin got shelved.

Q: What prompted you to look at streptothricin specifically now?

It was partly serendipity. My research laboratory is interested in finding new, or old and forgotten, solutions to treat highly drug-resistant gram-negative pathogens like E. coli or Klebsiella or Acinetobacter that we commonly see in hospitalized, immunocompromised patients. The problem is that they’re increasingly resistant to many if not all of the antibiotics that we have available.

Part of our research is to understand how these superbugs cause disease. To do that, we need a way to manipulate the genomes of these organisms. Commonly, the way that’s done is to create a change in the organism linked with the ability to resist a particular antibiotic that’s known as a selection agent. But for these super resistant gram-negative pathogens, there was really nothing we could use. These bugs were already resistant to everything.

We started searching around for drugs that we could use, and it turns out these super resistant bugs were highly susceptible to streptothricin, so we were able to use it as a selection agent to do these experiments.

As I read the literature on streptothricin and its history, I had the realization that it was not sufficiently explored. Here was this antibiotic with outstanding activity against gram-negative bacteria – and we confirmed that by testing it against a lot of different pathogens that we see in hospitals. That raised the question of whether we could get really good antibiotic activity at concentrations that are not going to cause damage to the animal or person in treatment.

Q: But it did cause kidney toxicity in people in 1942. What would be different now?

What scientists were isolating in 1942 was not as pure as what we are working with today. In fact, what was then called streptothricin is actually a mixture of several streptothricin variants. The natural mixture of different types of streptothricins is now referred to as nourseothricin.

In animal models, we tested whether we could kill the harmful microorganism without harming the host using a highly purified single streptothricin variant. We used a very famous strain of Klebsiella pneumoniae called the Nevada strain which was the first pan-drug-resistant, gram-negative organism isolated in the United States, an organism for which there was no treatment. A single dose cleared this organism from an infected animal model while avoiding any toxicity. It was really remarkable. We’re still in the very early stages of development, but I think we’ve validated that this is a compound that’s worth investing in further studies to find even better variants that eventually will meet the properties of a human therapeutic.

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Q. How does nourseothricin work to kill gram-negative bacteria?

That’s another really important part of our study. The mechanism hadn’t been figured out before and we showed that nourseothricin acts in a completely new way compared to any other type of antibiotic.

It works by inhibiting the ability of the organism to produce proteins in a very sneaky way. When a cell makes proteins, they make them off a blueprint or message that tells the cell what amino acids to link together to build the protein. Our studies help explain how this antibiotic confuses the machinery so that the message is read incorrectly, and it starts to put together gibberish. Essentially the cell gets poisoned because it’s producing all this junk.

In the absence of new classes of antibiotics, we’ve been good at taking existing drugs like penicillin for example and modifying them; we’ve been making variations on the same theme. The problem with that is that the resistance mechanisms against penicillin and other drugs already exist. There’s a huge environmental reservoir of resistance out there. Those existing mechanisms of resistance might not work perfectly well against your new variant of penicillin, but they will evolve very quickly to be able to conquer it.

So, there’s recognition that what we really want is new classes of antibiotics that act in a novel way. That’s why streptothricin’s action uncovered by our studies is so exciting. It works in a very unique way not seen with any other antibiotic, and that is very powerful because it means there’s not this huge environmental reservoir of potential resistance.

Q. You emphasize these are early steps in development. What are the next steps?

My lab is working very closely with colleagues at Northeastern University who figured out a way to synthesize streptothricin from scratch in a way that will allow us to cast many different variants. Then we can look for ones that have the ideal properties of high potency and reduced toxicity.

We are also continuing our collaboration with scientists at Case Western Reserve University Medical Center, diving more deeply to understand exactly how this antibiotic works. Then we can use that fundamental knowledge in our designs of future variants and be smarter about how we try to make the best antibiotic.

We have great collaborators that have allowed us to pursue a project that crosses multiple fields. This work is an example of collaborative science really at its best.

Co-authors included first author Christopher E. Morgan and Edward W. Yuof Case Western Reserve; Yoon-Suk Kang,Alex B. Green, Kenneth P. Smith, Lucius Chiaraviglio, Katherine A. Truelson, Katelyn E. Zulauf, Shade Rodriguez, and Anthony D. Kang of BIDMC; Matthew G. Dowgiallo,Brandon C. Miller, and Roman Manetsch of Northeastern University.

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Tiny Ocean Conquerors: How Ancestors of Prochlorococcus Microbes Mastered the Seas on Exoskeleton Rafts

A new study shows that carbon-capturing phytoplankton colonized the ocean by rafting on particles of chitin.

MIT researchers found that Prochlorococcus, a vital phytoplankton, likely used chitin from ancient exoskeletons as rafts to venture into open waters, evolving to absorb nearly as much CO2 as terrestrial forests and shaping Earth’s biosphere.

Throughout the ocean, billions upon billions of plant-like microbes make up an invisible floating forest. As they drift, the tiny organisms use sunlight to suck up carbon dioxide from the atmosphere. Collectively, these photosynthesizing plankton, or phytoplankton, absorb almost as much CO2 as the world’s terrestrial forests. A measurable fraction of their carbon-capturing muscle comes from Prochlorococcus — an emerald-tinged free-floater that is the most abundant phytoplankton in the oceans today.

But Prochlorococcus didn’t always inhabit open waters. Ancestors of the microbe likely stuck closer to the coasts, where nutrients were plentiful and organisms survived in communal microbial mats on the seafloor. How then did descendants of these coastal dwellers end up as the photosynthesizing powerhouses of the open oceans today?

MIT scientists believe that rafting was the key. In a new study they propose that ancestors of Prochlorococcus acquired an ability to latch onto chitin — the degraded particles of ancient exoskeletons. The microbes hitched a ride on passing flakes, using the particles as rafts to venture further out to sea. These chitin rafts may have also provided essential nutrients, fueling and sustaining the microbes along their journey.

Thus fortified, generations of microbes may have then had the opportunity to evolve new abilities to adapt to the open ocean. Eventually, they would have evolved to a point where they could jump ship and survive as the free-floating ocean dwellers that live today.

“If Prochlorococcus and other photosynthetic organisms had not colonized the ocean, we would be looking at a very different planet,” says Rogier Braakman, a research scientist in MIT’s Department of Earth, Atmospheric, and Planetary Sciences (EAPS). “It was the fact they were able to attach to these chitin rafts that enabled them to establish a foothold in an entirely new and massive part of the planet’s biosphere, in a way that changed the Earth forever.”

Braakman and his collaborators present their new “chitin raft” hypothesis, along with experiments and genetic analyses supporting the idea, in a study published on May 9 in PNAS.

MIT co-authors are Giovanna Capovilla, Greg Fournier, Julia Schwartzman, Xinda Lu, Alexis Yelton, Elaina Thomas, Jack Payette, Kurt Castro, Otto Cordero, and MIT Institute Professor Sallie (Penny) Chisholm, along with colleagues from multiple institutions including the Woods Hole Oceanographic Institution.

Prochlorococcus is one of two main groups belonging to a class known as picocyanobacteria, which are the smallest photosynthesizing organisms on the planet. The other group is Synechococcus, a closely related microbe that can be found abundantly in ocean and freshwater systems. Both organisms make a living through photosynthesis.

But it turns out that some strains of Prochlorococcus can adopt alternative lifestyles, particularly in low-lit regions where photosynthesis is difficult to maintain. These microbes are “mixotrophic,” using a mix of other carbon-capturing strategies to grow.

Researchers in Chisholm’s lab were looking for signs of mixotrophy when they stumbled on a common gene in several modern strains of Prochlorococcus. The gene encoded the ability to break down chitin, a carbon-rich material that comes from the sloughed-off shells of arthropods, such as insects and crustaceans.

“That was very strange,” says Capovilla, who decided to dig deeper into the finding when she joined the lab as a postdoc.

For the new study, Capovilla carried out experiments to see whether Prochlorococcus can in fact break down chitin in a useful way. Previous work in the lab showed that the chitin-degrading gene appeared in strains of Prochlorococcus that live in low-light conditions, and in Synechococcus. The gene was missing in Prochlorococcus inhabiting more sunlit regions.

In the lab, Capovilla introduced chitin particles into samples of low-light and high-light strains. She found that microbes containing the gene could degrade chitin, and of these, only low-light-adapted Prochlorococcus seemed to benefit from this breakdown, as they appeared to also grow faster as a result. The microbes could also stick to chitin flakes — a result that particularly interested Braakman, who studies the evolution of metabolic processes and the ways they have shaped the Earth’s ecology.

“People always ask me: How did these microbes colonize the early ocean?” he says. “And as Gio was doing these experiments, there was this ‘aha’ moment.”

Braakman wondered: Could this gene have been present in the ancestors of Prochlorococcus, in a way that allowed coastal microbes to attach to and feed on chitin, and ride the flakes out to sea?

To test this new “chitin raft” hypothesis, the team looked to Fournier, who specializes in tracing genes across species of microbes through history. In 2019, Fournier’s lab established an evolutionary tree for those microbes that exhibit the chitin-degrading gene. From this tree, they noticed a trend: Microbes start using chitin only after arthropods become abundant in a particular ecosystem.

For the chitin raft hypothesis to hold, the gene would have to be present in ancestors of Prochlorococcus soon after arthropods began to colonize marine environments.

The team looked to the fossil record and found that aquatic species of arthropods became abundant in the early Paleozoic, about half a billion years ago. According to Fournier’s evolutionary tree, that also happens to be around the time that the chitin-degrading gene appears in common ancestors of Prochlorococcus and Synecococchus.

“The timing is quite solid,” Fournier says. “Marine systems were becoming flooded with this new type of organic carbon in the form of chitin, just as genes for using this carbon spread across all different types of microbes. And the movement of these chitin particles suddenly opened up the opportunity for microbes to really make it out to the open ocean.”

The appearance of chitin may have been especially beneficial for microbes living in low-light conditions, such as along the coastal seafloor, where ancient picocyanobacteria are thought to have lived. To these microbes, chitin would have been a much-needed source of energy, as well as a way out of their communal, coastal niche.

Braakman says that once out at sea, the rafting microbes were sturdy enough to develop other ocean-dwelling adaptations. Millions of years later, the organisms were then ready to “take the plunge” and evolve into the free-floating, photosynthesizing Prochlorococcus that exist today.

“In the end, this is about ecosystems evolving together,” Braakman says. “With these chitin rafts, both arthropods and cyanobacteria were able to expand into the open ocean. Ultimately, this helped to seed the rise of modern marine ecosystems.”

Reference: “Chitin utilization by marine picocyanobacteria and the evolution of a planktonic lifestyle” by Giovanna Capovilla, Rogier Braakman, Gregory P. Fournier, Thomas Hackl, Julia Schwartzman, Xinda Lu, Alexis Yelton, Krista Longnecker, Melissa C. Kido Soule, Elaina Thomas, Gretchen Swarr, Alessandro Mongera, Jack G. Payette, Kurt G. Castro, Jacob R. Waldbauer, Elizabeth B. Kujawinski, Otto X. Cordero and Sallie W. Chisholm, 9 May 2023, Proceedings of the National Academy of Sciences.
DOI: 10.1073/pnas.2213271120

This research was supported by the Simons Foundation, the EMBO Long-Term Fellowship, and by the Human Frontier Science Program. This paper is a contribution from the Simons Collaboration on Ocean Processes and Ecology (SCOPE).

Study identifies key genetic mechanism of drug resistance in the deadliest malaria parasites

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An important genetic mechanism of drug resistance in one of the deadliest human malaria parasites has been identified in a new study published in Nature Microbiology.

A second key gene, pfaat1, responsible for encoding a protein that transports amino acids in the membrane of Plasmodium falciparum, is involved in its resistance to the major anti-malaria drug, chloroquine.

The findings may have implications for the ongoing battle against malaria, which infects an estimated 247 million people worldwide and kills more than 619,000 each year, most of which are young children.

Chloroquine is a major antimalaria drug, however in recent years, resistance has emerged in malaria parasites, first spreading through Southeast Asia and then through Africa in the 1970s and 1980s. Although alternative antimalarial drugs have been developed, resistance to chloroquine remains a big challenge.

Since its discovery in 2000, only one gene has been believed to have been responsible for resistance to chloroquine – the resistance transporter pfcrt which helps the malaria parasite transport the drug out of a key region in their cells, subsequently rendering it ineffective.

In this study, researchers from the Medical Research Council (MRC) Unit The Gambia at the London School of Hygiene & Tropical Medicine (LSHTM) analysed more than 600 genomes of P. falciparum that were collected in The Gambia over a period of 30 years. The team found that mutant variants of  a second gene, pfaat1, which encodes an amino acid transporter, increased in frequency from undetectable to very high levels between 1984 and 2014. Importantly, their genome-wide population analyses also indicated long term co-selection on this gene alongside the previously-known resistance gene pfcrt.

In the laboratory, a further team of researchers including from Texas Biomed, University of Notre Dame and Seattle Children’s Research Institute found that replacing these mutations in parasite genomes using CRISPR gene-editing technology impacted drug resistance. A team from Nottingham University also found that these mutations could impact the function of pfaat1 in yeast, resulting in drug resistance.

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Complementary analysis of malaria genome datasets additionally suggested that parasites from Africa and Asia may carry different mutations in pfaat1 which could help explain differences in the evolution of drug resistance across these continents.

Alfred Amambua-Ngwa, Professor of Genetic Epidemiology at MRC Unit The Gambia at LSHTM said: “This is a very clear example of natural selection in action – these mutations were preferred and passed on with extremely high frequency in a very short amount of time, suggesting they provide a significant survival advantage.

“The mutations in pfaat1 very closely mirror the increase of pfcrt mutations. This, and other genetic analyses in the paper demonstrate that the transporter AAT1 has a major role in chloroquine resistance.”

Grappling with drug resistance, for malaria and other pathogens, requires taking a holistic approach to both drug development and pathogen surveillance. We must be aware that different genes and molecules will be working together to survive treatments. That is why looking at whole genomes and whole populations is so critical.”

David Conway, Professor of Biology, LSHTM

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Journal reference:

Amambua-Ngwa, A., et al. (2023). Chloroquine resistance evolution in Plasmodium falciparum is mediated by the putative amino acid transporter AAT1. Nature Microbiology. doi.org/10.1038/s41564-023-01377-z.

Anticoronavirals: the development of COVID-19 therapies and the challenges that remain

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In a recent article published in Nature Microbiology, researchers highlighted the pace of development of coronavirus disease 2019 (COVID-19) therapies during the pandemic and the challenges that hinder the widespread availability of anticoronavirals.

Study: Therapeutics for COVID-19. Image Credit: Viacheslav Lopatin/Shutterstock.com
Study: Therapeutics for COVID-19. Image Credit: Viacheslav Lopatin/Shutterstock.com


COVID-19 is the third coronavirus disease in the past 20 years after severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). While the two predecessors caused severe mortality, they did not cause a pandemic. On the contrary, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered a pandemic, and by 21 February 2023, it had caused more than 757 million confirmed cases, including >6.8 million deaths worldwide.

Vaccines and monoclonal antibody (mAb) treatments for COVID-19 became available within a year of the pandemic. Yet, there is a substantial need for more effective therapeutics to treat unvaccinated and immunocompromised patients and those whose vaccine immunity waned over time.

About the study

In this study, the authors highlighted four stages of SARS-CoV-2 infection that require different therapeutic interventions as critical for identifying COVID-19 therapeutic targets. At stage 1, when viral replication begins inside the host, oral or intravenous administration of monoclonal antibodies and antiviral therapies are effective. However, an ideal time for prophylactic administration of vaccines is Stage 0 preceding the infection.

Clinical trials have established that mAbs and antivirals effectively combat COVID-19 when administered up to 10 days after symptom onset and within three to five days following the onset of symptoms, respectively. COVID-19 patients in stage 2 develop viral pneumonia, cough and fever, lung inflammation causing shortness of breath, and lung aberrations, such as ground glass opacities.

The most serious is stage 3 characterized by a hyperinflammatory state or acute respiratory distress syndrome (ARDS). Some patients might also develop coagulation disorders or shock or systemic inflammatory response syndrome (SIRS). Thus, at stage 3, a patient needs antiviral drugs and immunomodulatory therapy.

Stage 4 represents post-COVID-19 conditions when patients experience hyperinflammatory illnesses, e.g., multi-system inflammatory syndrome in children (MISC), following acute SARS-CoV-2 infection. Unfortunately, possible preventative measures and treatment for post-acute sequelae of SARS-CoV-2 (PASC) are not fully understood. It is a growing area of unmet medical need; thus, extensive research efforts are ongoing to classify PASC, which might be a conglomeration of several syndromes, and determine its cause(s).

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The National Institutes of Health (NIH) Treatment Guidelines Panel makes recommendations for the treatment and prevention of COVID-19. Early in the pandemic, clinicians used azithromycin and hydroxychloroquine as a possible COVID-19 treatment for hospitalized patients based on in vitro evidence of their synergistic effect on SARS-CoV-2 infection. Later, clinical trials found this combination ineffective. Similarly, the NIH panel did not specify recommendations for empirical antimicrobials.

The NIH rejected giving vitamin/mineral supplements, e.g., zinc, for hospitalized COVID-19 patients. On the contrary, they recommended prompt use of supplemental oxygenation and high-flow nasal cannula in patients with ARDS. In the absence of effective treatments, clinical recommendations by NIH continue to change and evolve.

Early drug repurposing efforts targeted nucleotide prodrugs, e.g., remdesivir (or GS-5734), AT-527, favipiravir, and molnupiravir (or MK-4482). However, only three antivirals received full Emergency Use Authorization (EUA) approval from the United States Food and Drug Administration (US-FDA), remdesivir, molnupiravir, and nirmatrelvir.

Pre-clinical characterization of remdesivir for other coronaviruses, pharmacokinetic and safety evaluation in humans in a failed clinical trial for Ebola virus, all acquired before the beginning of the COVID-19 pandemic, enabled rapid progression of remdesivir.

A phase 3 study conducted among patients in outpatient facilities and nursing facilities showed that remdesevir administration within seven days of symptom onset decreased hospitalization risk by 87%. Thus, its approval extended to high-risk non-hospitalized patients as well. Currently, phase 1b/2a study for inhaled remdesivir, and pre-clinical evaluation of an oral prodrug based on remdesivir is ongoing.

Another randomized phase III trial evaluated ivermectin, metformin, and fluvoxamine, all repurposed drug candidates, for early COVID-19 treatment of overweight or obese adults. Earlier pivotal efficacy and clinical studies found that molnupiravir provided no clinical benefit in hospitalized COVID-19 patients.

Conversely, the MOVe-OUT outpatient study demonstrated that treatment initiated within five days of symptom onset reduced the hospitalization risk or death. Accordingly, molnupiravir attained an EUA in the US on in late 2021 for treatment of mild-to-moderately ill COVID-19 patients at high risk of progression to severe disease. However, an outpatient study suggested that molnupiravir might augment SARS-CoV-2 evolution in immunocompromised individuals.

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In the USA, multiple initiatives have been undertaken to identify candidate agents that may be repurposed as COVID-19 drugs. For instance, the Bill and Melinda Gates Foundation launched the Therapeutics Accelerator in March 2020, wherein they adopted a three-way approach to test approved drugs, screen drug repositories, and evaluate novel small molecules, including mAbs against SARS-CoV-2.

Encouragingly, apilimod, a PIKfyve kinase inhibitor developed for treating autoimmune diseases, is being tested for COVID-19 in clinical studies. Likewise, multiple clinical trials are ongoing for camostat mesilate, an inhibitor of transmembrane protease serine 2 (TMPRSS2), an approved chronic pancreatitis treatment in Japan.

Among anti-inflammatory and immunomodulating drugs, dexamethasone, a corticosteroid, baricitinib, a Janus kinase (JAK) inhibitor, and tocilizumab have received FDA approval. Among mAb therapies, casirivimab with imdevimab and bamlanivimab with etesevimab, Sotrovimab, Bebtelovimab, Tixagevimab–cilgavimab have received FDA approval. However, as SARS-CoV-2 continues to evolve, changes in the spike protein led to EUAs being withdrawn for all mAb therapies due to loss of efficacy.


There is a vast knowledge gap regarding COVID-19 pathogenesis. Despite the absence of a viral reservoir, severe disease persists for weeks or even months after COVID-19 recovery. Another intriguing area of investigation is why autoantibodies increase over time during COVID-19. In February 2022, the government of the United States of America (USA) started a flagship program, RECOVER, to understand, prevent and treat COVID-19-related long-term health effects.

Amid decreasing vaccine uptake and waning efficacy of mAbs as SARS-CoV-2 mutates, there is a need for new, safe, and effective COVID-19 therapies for population-level deployment and the potential to reduce resistance development. Researchers need to accelerate research targeting small molecule candidates that would mechanistically target the conserved region of SARS-CoV-2 and not become ineffective across mutant strains.

To be prepared for another pandemic, a large repository of small molecules that have already progressed through early pre-clinical and clinical evaluation is needed to develop drugs, like remdesivir, developed in a short span of two years.

More importantly, research efforts should continue to advance the development of antivirals for other pathogens, including coronaviruses, in preparation for the next pandemic.

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Journal reference:

How the COVID pandemic has improved genomics

insights from industryDavide CacciharelliMolecular Biology and Genomics ProfessorUniversity of Naples

In this interview, Davide Cacchiarelli, Molecular Biology and Genomics Professor at the University of Naples talks to NewsMed about how the COVID pandemic has highlighted the vital role of genomic surveillance and improved genomics.

Please introduce yourself and what inspired your career in molecular biology and genomics?

My name is Davide Cacchiarelli, and I am a molecular biology and genomics professor at the University of Naples. I was inspired by the fact that genomics is classed as an effective tool to improve human health, dissect the molecular events happening in the cell and nucleus, and better understand how cells and organisms work.

Image Credit: ShutterStock/pinkeyes

In The Telethon Institute of Genetics and Medicine, you combine various disciplines with cell biology, molecular biology, and genomics. Why is having a multidisciplinary approach useful when making discoveries, particularly surrounding infectious diseases such as COVID?

The majority of the time, a single omic, measuring only gene expression by RNA sequencing, measuring only epigenetics, or measuring only phenotype, is insufficient to understand how a cell works.

The best solution is to combine all efforts to understand how these events happen, from the nucleus to the cell’s exterior. COVID, in particular, has been a case where acquiring one single omic or a single view of how the system works is ineffective in understanding how COVID behaviors occur in the population or clinically hospitalized patients.

We, therefore, try to combine the general information and patient outcome to get the best result regarding COVID infection.

Davide Cacciarelli at ICG17 – How the COVID pandemic has improved genomics

On what research areas are you and your team at TIGEM currently focusing?

Our group aims to answer various questions, from basic microbiology to developmental biology. Then we can re-engineer it for real regenerative medicine purposes. We also look at how we can effectively use genomics as a medical instrument that can be used to impact the healthcare of patients in our healthcare system.

You have recently co-authored a paper, “Improved SARS-CoV-2 sequencing surveillance allows the identification of new variants and signatures in infected patients.” Can you expand on that?

One of the significant issues in Italy regarding SARS-CoV-2 genome sequencing was the cost. Sequencing the COVID genome was also a tedious and elaborate procedure.

Image Credit: ShutterStock/Kateryna Kon

The main objective was first to make this approach economically affordable and create a proof of printing pulled by which this approach could become a cost-effective method for anyone and any country.

Our second approach, therefore, included integrating the genome information and the transcriptomic profiling of the patient airway epithelia. This helps us to understand how the genome evolves and allows us to track its evolution, in addition to seeing the response of the host respiratory epithelium. Finally, we implemented new ways to classify viral variants based on different characteristics using this approach.

What are the advantages of better identifying new cells, or two variants, for healthcare centers and patients?

The European Center for Disease Control has issued several requirements for next year focused on tracking respiratory viruses. One of these is tracking emerging variants as soon as possible, which we have done with COVID-19. We now know that new, specific variants can emerge in a short timeframe, so immediate tracking is crucial to help contain or at least delay the spreading of possible pathogenic variants.

MGI offers a variety of tools and technology surrounding genomics. Can you tell us more about some of the products used during your research and your experience with them?

At MGI, we have typically applied the COVID and whole genome solutions. We also have the freedom to test the stereo-seq they have in production this month. MGI can offer alternative solutions for various genome sequencing needs.

Image Credit: ShutterStock/peterschreiber.media

At present many sequencing genomic companies are coming up with different solutions. At MGI, we understand that the best genomic solution is the one that better fits your needs. With our experience, for example, with COVID, MGI had the right solution at the right moment.

How important is selecting the right sequencing technology for your research? When undertaking new research, what do you look for in a product/sequencer?

When the primary focus is not on identifying genes or mapping gene expression but on identifying or qualifying gene variants, there must be no issues in the sequencing, as the sequencing issue might be an error in the sequencing and misinterpreted data.

The error rate of MGI technology on DNB sequencing is extremely low, which offers significant benefits. Users can confidently rely on the data at the level of leaders in the field, which is what we look for when we start COVID genome sequencing.

You have often collaborated with other researchers throughout your research projects, especially concerning COVID. How vital have these collaborations been in accelerating your research?

Like many scientists who faced the COVID pandemic, I had much to learn. We used our knowledge in medical genetics and variant interpretation, and the crosstalk we had with virologists, MGI scientists, and genomic specialists was a step towards acquiring the best solution and the best effort to try to get those results as soon as possible, which is crucial for COVID sequencing.

Surprisingly, some scientists who had no interest in healthcare possessed knowledge valuable in tackling COVID issues. The circumstances and contingencies around the event forced them to think outside the box.

Do you believe that if we can understand SARS-CoV-2 better, we could better use this knowledge to prepare ourselves for future pandemics better? What advantages would this have for global health?

COVID did not give us any significant advantages for healthcare, but it may have for science. It highlighted how vital advanced genomics is to track diseases which influenced decisions at the governmental level.

Image Credit: ShutterStock/CKA

Today, several diseases require advanced genome sequencing, such as cancer diagnostics and medical genetics. Given that the issues with this problem affect a small population, you do not feel the urgency to improve specific knowledge or tests.

Therefore, the COVID pandemic has highlighted the vital role of genomic surveillance and improved genomics. Today, we have laboratories that, until two years ago, thought they could never afford to set up a genomic workflow; the pandemic forced them to enter the genomics field. Our mission as genomic scientists is to help them implement this solution in their lab because improving genomics in any lab is the best for healthcare in the future.

There is a saying, “omics for all.” As a scientist, what does that mean to you?

‘Omics for all’ has to be understood in two ways. It is critical to give everybody the chance to have access to omics. However, we need to remember that it is still a medical procedure. Thus, the omics flow offers everybody access to high-quality omics profiling of their genome, but under medical supervision.

Finally, what is the future for you in your research?

I will continue my basic research in my lab: studying how pluripotent cells and stem cells can be manipulated and organized for medical purposes. We also want to use the knowledge accumulated in the COVID pandemic to apply fast, cost-effective, and reliable genome sequencing to other types of screening.

Image Credit: ShutterStock/Anusorn Nakdee

With this in mind, we hope to screen for several hereditary cancers, for example, breast cancer inheritance. Therefore, we can effectively use the COVID strategies we set up for COVID sequencing as proof of principle to apply the sequencing to human and human disease-driving genes.

About MGI

MGI Tech Co., Ltd. (referred to as MGI) is committed to building core tools and technology to lead life science through intelligent innovation. MGI focuses on R&D, production, and sales of DNA sequencing instruments, reagents, and related products to support life science research, agriculture, precision medicine, and healthcare. MGI is a leading producer of clinical high-throughput gene sequencers, and its multi-omics platforms include genetic sequencing, mass spectrometry, medical imaging, and laboratory automation.

Founded in 2016, MGI has more than 1000 employees, nearly half of whom are R&D personnel. MGI operates in 39 countries and regions and has established multiple research and production bases around the world. Providing real-time, comprehensive, life-long solutions, its vision is to enable effective and affordable healthcare solutions for all.

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Genomic study reveals Babesia duncani’s pathogenicity and virulence

‘Tis the season for hiking now that spring has arrived and temperatures are on the upswing. But with hikes come insect bites and on the increase in North America is babesiosis, a malaria-like disease spread especially between May and October by a tick.

Indeed, recent research suggests an increase in the incidence of diseases transmitted by ticks around the world, not just the United States and Canada, due likely to climate change and other environmental factors. Among the tick-borne pathogens, Babesia parasites, which infect and destroy red blood cells, are considered a serious threat to humans and animals. All cases of human babesiosis reported in the United States have been linked to either Babesia microti, B. duncani, or a B. divergens-like species.

Now a research team led by scientists at the University of California, Riverside, and Yale University reports the first high-quality nuclear genome sequence and assembly of the pathogen B. duncani. The team also determined the 3D genome structure of this pathogen that resembles Plasmodium falciparum, the malaria-causing parasite.

“Our data analysis revealed that the parasite has evolved new classes of multigene families, allowing the parasite to avoid the host immune response,” said Karine Le Roch, a professor of molecular, cell and systems biology at UC Riverside, who co-led the study with Choukri Ben Mamoun, a professor of medicine at Yale University.

According to Le Roch, who directs the UCR Center for Infectious Disease Vector Research, the study, published today in Nature Microbiology, not only identifies the molecular mechanism most likely leading to the parasite’s pathogenicity and virulence, but also provides leads for the development of more effective therapies.

By mining the genome and developing in vitro drug efficacy studies, we identified excellent inhibitors of the development of this parasite -; a pipeline of small molecules, such as pyrimethamine, that could be developed as effective therapies for treating and better managing human babesiosis. Far more scientific and medical attention has been paid to B. microti. The genome structure of B. duncani, a neglected species until now, will provide scientists with important insights into the biology, evolution, and drug susceptibility of the pathogen.”

Karine Le Roch, professor of molecular, cell and systems biology at UC Riverside

Human babesiosis caused by Babesia duncani is an emerging infectious disease in the U.S. and is often undetected because healthy individuals do not usually show symptoms. It has, however, been associated with high parasite burden, severe pathology, and death in multiple cases. Despite the highly virulent properties of B. duncani, little was known about its biology, evolution, and mechanism of virulence, and recommended treatments for human babesiosis against B. duncani are largely ineffective.

A strong immune system is required to fight the pathogen. A compromised immune system could lead to flu-like illness. The tick that spreads babesiosis is mostly found in wooded or grassy areas and is the same tick that transmits bacteria responsible for Lyme disease. As a result, around 20% of patients with babesiosis are co-infected with Lyme disease.

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B. duncani mostly infects deer, which serve as the reservoir host during the pathogen’s asexual development. The parasite’s sexual cycle occurs in the tick after the tick bites the infected deer. When this tick bites humans, infection begins. The full life cycle of Babesia parasites has not yet been determined. The tick that spreads babesiosis, called Dermacentor albipictus, lives longer than mosquitoes and could facilitate a long life cycle for B. duncani.

Even though scientists are discovering more Babesia species, diagnostics are mostly developed for B. microti. Le Roch is already working with Stefano Lonardi, a professor of computer science and engineering at UCR and co-first author of the study, on new Babesia strains that have evolved.

“The Babesia genomes are not very long,” said Lonardi, who assembled the B. duncani strain. “But they are challenging to assemble due to their highly repetitive content and can require years of research. Once the genome is assembled and annotated, it can provide valuable information, such as how the genes are organized, which genes are transcribed during infection, and how the pathogen avoids the host’s immune system.”

In older and immunocompromised people, if B. duncani is left unattended, babesiosis could worsen and lead to death. Once the pathogen enters the body and red blood cells start to get destroyed, fever, headache, and nausea can follow. People who get bitten by the ticks often don’t feel the bite, which complicates diagnosis. Skin manifestations of babesiosis are rare, Lonardi said, and difficult to separate from Lyme disease.

Le Roch and Lonardi urge people to be mindful of ticks when they go hiking.

“Check yourself for tick bites,” Le Roch said. “When you see your physician don’t forget to let them know you go hiking. Most physicians are aware of Lyme disease but not of babesiosis.”

Next the team plans to study how B. duncani survives in the tick and find novel vector control strategies to kill the parasite in the tick.

Le Roch, Mamoun, and Lonardi were joined in the study by colleagues at UCR, Yale School of Medicine, Université de Montpellier (France), Instituto de Salud Carlos III (Spain), Universidad Nacional Autónoma de México, and University of Pennsylvania. Pallavi Singh at Yale and Lonardi contributed equally to the study. The B. duncani genome, epigenome, and transcriptome were sequenced at UCR and Yale.

The study was supported by grants from the National Institutes of Health, Steven and Alexandra Cohen Foundation, Global Lyme Alliance, National Science Foundation, UCR, and Health Institute Carlos III.

Journal reference:

Singh, P., et al. (2023). Babesia duncani multi-omics identifies virulence factors and drug targets. Nature Microbiology. doi.org/10.1038/s41564-023-01360-8.

Simple but revolutionary modular organoids

A team led by Masaya Hagiwara of RIKEN national science institute in Japan has developed an ingenious device, using layers of hydrogels in a cube-like structure, that allows researchers to construct complex 3D organoids without using elaborate techniques. The group also recently demonstrated the ability to use the device to build organoids that faithfully reproduce the asymmetric genetic expression that characterizes the actual development of organisms. The device has the potential to revolutionize the way we test drugs, and could also provide insights into how tissues develop and lead to better techniques for growing artificial organs.

Scientists have long struggled to create organoids — organ-like tissues grown in the laboratory — to replicate actual biological development. Creating organoids that function similarly to real tissues is important for developing medicines, since it is necessary to understand how drugs move through various tissues. Organoids also help us gain insights into the process of development itself, and are a stepping stone on the way to growing whole organs that can help patients.

However, creating life-like organoids has proven difficult. In nature, tissues develop through an elaborate dance that involves chemical gradients and physical scaffolds that guide cells into certain 3D patterns. In contrast, lab-grown organoids typically develop either by letting the cells grow in homogeneous conditions — creating simple balls of similar cells — or by using 3D printing or microfluidic technologies, which both require sophisticated equipment and technical skills.

But now, in an initial paper published in Advanced Materials Technologies, the group from the RIKEN Cluster for Pioneering Research announced the development of a new, innovative technique that allows them to spatially control the environment around groups of cells based on cubes, using nothing more elaborate than a pipette.

The method involves confining layers of hydrogels — substances made up mostly of water — with different physical and chemical properties inside a cube-shaped culture vessel. In the study, different hydrogels were inserted into the scaffold using a pipette, and were held in place based on surface tension. Cells could be inserted into the cubes either within the individual hydrogels or as pellets that could move into the different layers, thus making it possible to create a range of tissue types.

In a second paper, published in Communications Biology, the group also demonstrated the ability to recreate what is known as body-axis patterning. Essentially, when vertebrates develop there is a head/rear and back/stomach patterning of cell differentiation. Though important for the creation of organoids that faithfully recreate what happens in actual organisms, this has been very difficult to achieve in the laboratory.

In this work, using the cube-based system, the group was able to recreate this patterning, using a mold cap to precisely seed a group of induced pluripotent stem cells (iPSCs) within a cube, and then allowing the cells to be exposed to a gradient of two different growth factors. They even went as far as to “recruit” a lab assistant and a junior high school student to successfully perform the work, showing that the seeding of the cells would not require a high level of expertise. The team also demonstrated that the resulting tissues could be sectioned for imaging and still maintain the information about the gradient orientation.

According to Hagiwara, “We are very excited by these achievements, as the new system will make it possible for researchers to quickly, and without difficult technical hurdles, recreate organoids that more closely resemble the way that organs develop in actual organisms. We hope that a range of researchers will use our method to create various new organoids and contribute to research on different organ systems. Eventually, we hope that it will also contribute to understanding how we can build actual artificial organs that can help patients.”

Hagiwara joined RIKEN in 2019 as a RIKEN Hakubi Fellow, a program that encourages talented young researchers to establish their own laboratories. His specific focus is on the development of lungs, but he emphasizes that the technology could be used for the creation of other types of organoids as well.

  • Isabel Koh, Masaya Hagiwara. Gradient to sectioning CUBE workflow for the generation and imaging of organoids with localized differentiation. Communications Biology, 2023; 6 (1) DOI: 10.1038/s42003-023-04694-5

    Highly complementary, biologically relevant protein-protein interactions can evolve entirely by chance

    Proteins are the key players for virtually all molecular processes within the cell. To fulfil their diverse functions, they have to interact with other proteins. Such protein-protein interactions are mediated by highly complementary surfaces, which typically involve many amino acids that are positioned precisely to produce a tight, specific fit between two proteins. However, comparatively little is known about how such interactions are created during evolution.

    Classical evolutionary theory suggests that any new biological feature involving many components (like the amino acids that enable an interaction between proteins) evolves in a stepwise manner. According to this concept, each tiny functional improvement is driven by the power of natural selection because there is some benefit associated with the feature. However, whether protein-protein interactions also always follow this trajectory was not entirely known.

    Using a highly interdisciplinary approach, an international team led by Max Planck researcher Georg Hochberg from the Terrestrial Microbiology in Marburg have now shed new light on this question. Their study provides definitive evidence that highly complementary and biologically relevant protein-protein interactions can evolve entirely by chance.

    Proteins cooperate in a photoprotection system

    The research team made their discovery in a biochemical system that microbes use to adapt to stressful light conditions. Cyanobacteria use sunlight to produce their own food through photosynthesis. Since much light damages the cell, cyanobacteria have evolved a mechanism known as photoprotection: if light intensities become dangerously high, a light intensity sensor named Orange Carotenoid Protein (OCP) changes its shape. In this activated form, OCP protects the cell by converting excess light energy into harmless heat. In order to return into its original state, some OCPs depend on a second protein: The Fluorescence Recovery Protein (FRP) binds to activated OCP1 and strongly accelerates its recovery.

    ‘Our question was: Is it possible that the surfaces that allow these two proteins to form a complex evolved entirely by accident, rather than through direct natural selection?’ says Georg Hochberg. ‘The difficulty is that the end result of both processes looks the same, so we usually cannot tell why the amino acids required for some interaction evolved – through natural selection for the interaction or by chance. To tell them apart, we would need a time machine to witness the exact moment in history these mutations occurred, ‘Georg Hochberg explains.

    Luckily, recent breakthroughs in molecular and computational biology has equipped Georg Hochberg and his team with a laboratory kind of time machine: ancestral sequence reconstruction. In addition, the light protection system of cyanobacteria, which is under study in the group of Thomas Friedrich from Technische Universität Berlin since many years, is ideal for studying the evolutionary encounter of two protein components. Early cyanobacteria acquired the FRP proteins from a proteobacterium by horizontal gene transfer. The latter had no photosynthetic capacity itself and did not possess the OCP protein.

    To work out how the interaction between OCP1 and FRP evolved, graduate student Niklas Steube inferred the sequences of ancient OCPs and FRPs that existed billions of years ago in the past, and then resurrected these in the laboratory. After translation of the amino acid sequences into DNA he produced them using E. coli bacterial cells in order to be able to study their molecular properties.

    A fortunate coincidence

    The Berlin team then tested whether ancient molecules could form an interaction. This way the scientists could retrace how both protein partners got to know each other. ‘Surprisingly, the FRP from the proteobacteria already matched the ancestral OCP of the cyanobacteria, before gene transfer had even taken place. The mutual compatibility of FRP and OCP has thus evolved completely independently of each other in different species, says Thomas Friedrich. This allowed the team to prove that their ability to interact must have been a happy accident: selection could not plausibly have shaped the two proteins’ surfaces to enable an interaction if they had never met each other. This finally proved that such interactions can evolve entirely without direct selective pressure.

    ‘This may seem like an extraordinary coincidence,’ Niklas Steube says. ‘Imagine an alien spaceship landed on earth and we found that it contained plug-shaped objects that perfectly fit into human-made sockets. But despite the perceived improbability, such coincidences could be relatively common. But in fact, proteins often encounter a large number of new potential interaction partners when localization or expression patterns change within the cell, or when new proteins enter the cell through horizontal gene transfer.’ Georg Hochberg adds, ‘Even if only a small fraction of such encounters ends up being productive, fortuitous compatibility may be the basis of a significant fraction of all interactions we see inside cells today. Thus, as in human partnerships, a good evolutionary match could be the result of a chance meeting of two already compatible partners.’

    Journal reference:

    Steube, N., et al. (2023). Fortuitously compatible protein surfaces primed allosteric control in cyanobacterial photoprotection. Nature Ecology & Evolution. doi.org/10.1038/s41559-023-02018-8.

    Research opens the door to new approaches for tackling antibiotic-resistant TB

    University of Otago researchers have discovered new ways to treat antibiotic-resistant strains of tuberculosis (TB), opening the door to new approaches for tackling the disease that kills about 4,000 people a day.

    Led by PhD candidate Natalie Waller and Senior Author Dr Matthew McNeil, of the Department of Microbiology and Immunology, researchers were able to identify antibiotics that could rapidly kill drug resistant strains of TB and when combined could stop drug resistance from occurring altogether.

    TB is a major global cause of infectious disease morbidity and mortality, second only to COVID-19 and is one of the hardest infections to treat. Ten million people develop the disease every year and it kills about 4,000 people a day. About 300 cases of TB are diagnosed in New Zealand each year.

    Adding to the challenge, is that drug-resistant strains of the disease – that are very hard to treat and have limited treatment options – are spreading at an “alarming rate”.

    We need not only new drugs, but better drug combinations that can improve treatment success and prevent the further spread of antibiotic resistance.”

    Dr Matthew McNeil, of the Department of Microbiology and Immunology, University of Otago

    Typically, antibiotic resistance leads to reduced sensitivity, but in some cases becoming resistant to one antibiotic can make a pathogen more sensitive to other completely unrelated antibiotics, he says. However, this phenomenon – collateral sensitivity – has largely been unexplored in TB, until now.

    “It is very hardy, resilient and hard to study in the lab because it is a dangerous pathogen that grows extremely slowly.

    “To overcome this, our study used a weakened non-virulent strain of Mycobacterium tuberculosis that cannot cause disease or survive outside of the lab to generate strains that were resistant to different antibiotics,” he says.

    Researchers then determined if the drug-resistant strains of the bacterium had either increased or reduced sensitivity to other antibiotics.

    “We wanted the results of our work to have the greatest chance for clinical impact. For this reason, our study placed an emphasis on drugs that are either clinically approved or in pre-clinical development,” Dr McNeil says.

    “Excitingly this work identified a number of instances in which a particular drug-resistant strain was more sensitive to antibiotics that targeted a completely unrelated pathway. We then showed we could use these specific drugs to rapidly kill drug-resistant strains as well as design unique drug combinations that prevented the emergence of drug resistance.

    “Put simply, this work demonstrates that drug-resistant strains of M. tuberculosis have unique weaknesses, that if we can identify them, can be targeted to greatly reduce treatment times and prevent the emergence of drug resistance.”

    Dr McNeil says work will now need to focus on further extending these findings into in animal studies.

    “There is still work to do, but this is certainly a significant step in the fight again anti-microbial resistance.”

    The research was funded through the Royal Society of New Zealand Marsden Fund and the Maurice Wilkins Centre.

    Journal reference:

    Waller, N. J. E., et al. (2023). The evolution of antibiotic resistance is associated with collateral drug phenotypes in Mycobacterium tuberculosis. Nature Communications. doi.org/10.1038/s41467-023-37184-7.

    Designing more useful bacteria

    In a step forward for genetic engineering and synthetic biology, researchers have modified a strain of Escherichia coli bacteria to be immune to natural viral infections while also minimizing the potential for the bacteria or their modified genes to escape into the wild.

    The work promises to reduce the threats of viral contamination when harnessing bacteria to produce medicines such as insulin as well as other useful substances, such as biofuels. Currently, viruses that infect vats of bacteria can halt production, compromise drug safety, and cost millions of dollars.

    Results are published March 15 in Nature.

    “We believe we have developed the first technology to design an organism that can’t be infected by any known virus,” said the study’s first author, Akos Nyerges, research fellow in genetics in the lab of George Church in the Blavatnik Institute at Harvard Medical School and the Wyss Institute for Biologically Inspired Engineering.

    “We can’t say it’s fully virus-resistant, but so far, based on extensive laboratory experiments and computational analysis, we haven’t found a virus that can break it,” Nyerges said.

    The work also provides the first built-in safety measure that prevents modified genetic material from being incorporated into natural cells, he said.

    The authors said their work suggests a general method for making any organism immune to viruses and preventing gene flow into and out of genetically modified organisms (GMOs). Such biocontainment strategies are of increasing interest as groups explore the safe deployment of GMOs for growing crops, reducing disease spread, generating biofuels, and removing pollutants from open environments.

    Building on what came before

    The findings build on earlier efforts by genetic engineers to achieve a helpful, safe, virus-resistant bacterium.

    In 2022, a group from the University of Cambridge thought they’d made an E. coli strain immune to viruses. But then Nyerges teamed up with research fellow Siân Owen and graduate student Eleanor Rand in the lab of co-author Michael Baym, assistant professor of biomedical informatics in the Blavatnik Institute at HMS. When they sampled local sites rife with E. coli, including chicken sheds, rat nests, sewage, and the Muddy River down the street from the HMS campus, they discovered viruses that could still infect the modified bacteria.

    Discovering that the bacteria weren’t fully virus-resistant “was a bummer,” Nyerges said.

    The initial method had involved genetically reprogramming E. coli to make all their life-sustaining proteins from 61 sets of genetic building blocks, or codons, instead of the naturally occurring 64. The idea was that viruses wouldn’t be able to hijack the cells because they couldn’t replicate without the missing codons.

    The HMS team, however, figured out that deleting codons wasn’t enough. Some viruses were bringing in their own equipment to get around the missing pieces.

    So, Nyerges and colleagues developed a way to change what those codons tell an organism to make — something scientists hadn’t done to this extent in living cells.

    Lost in translation

    The key lay in transfer RNAs, or tRNAs.

    Each tRNA’s role is to recognize a specific codon and add the corresponding amino acid to a protein that’s being built. For instance, the codon TCG tells its matching tRNA to attach the amino acid serine.

    In this case, the Cambridge team had deleted TCG along with sister codon TCA, which also calls for serine. The team had also removed the corresponding tRNAs.

    The HMS team now added new, trickster tRNAs in their place. When these tRNAs see TCG or TCA, they add leucine instead of serine.

    “Leucine is about as different from serine as you can get, physically and chemically,” said Nyerges.

    When an invading virus injects its own genetic code full of TCG and TCA and tries to tell the E. coli to make viral proteins, these tRNAs mess up the virus’s instructions.

    Inserting the wrong amino acids results in misfolded, nonfunctional viral proteins. That means the virus can’t replicate and go on to infect more cells.

    Viruses, however, also come equipped with their own tRNAs. These can still accurately turn TCG and TCA into serine. But Nyerges and colleagues provided evidence that the trickster tRNAs they introduced are so good at their jobs that they overpower their viral counterparts.

    “It was very challenging and a big achievement to demonstrate that it’s possible to swap an organism’s genetic code,” said Nyerges, “and that it only works if we do it this way.”

    The work may have cleared the last hurdle in rendering a bacterium immune to all viruses, although there’s still a chance something will appear that can break the protection, the authors said.

    The team takes confidence in knowing that overcoming the swapped codons would require a virus to develop dozens of specific mutations at the same time.

    “That’s very, very unlikely for natural evolution,” Nyerges said.

    Safety measures

    The work incorporates two separate safeguards.

    The first protects against horizontal gene transfer, a constantly occurring phenomenon in which snippets of genetic code and their accompanying traits, such as antibiotic resistance, get transferred from one organism to another.

    Nyerges and colleagues short-circuited this outcome by making substitutions throughout genes in the modified E. coli cells so that all codons that call for leucine got replaced with TCG or TCA — the codons that in an unmodified organism would call for serine. The bacteria still correctly made leucine in those places because of their trickster tRNAs.

    If another organism were to incorporate any of the modified snippets into its own genome, though, the organism’s natural tRNAs would interpret TCG and TCA as serine and end up with junk proteins that don’t convey any evolutionary advantage.

    “The genetic information will be gibberish,” said Nyerges.

    Similarly, the team showed that if one of the E. coli‘s trickster tRNAs gets transferred to another organism, its misreading of serine codons as leucine codons damages or kills the cell, preventing further spread.

    “Any modified tRNAs that escape won’t get far because they are toxic to natural organisms,” said Nyerges.

    The work represents the first technology that prevents horizontal gene transfer from genetically modified organisms into natural organisms, he said.

    For the second fail-safe, the team designed the bacteria themselves to be unable to live outside a controlled environment.

    The team used an existing technology developed by the Church lab to make the E. coli reliant on a lab-made amino acid that doesn’t exist in the wild. Workers cultivating these E. coli to produce insulin, for instance, would feed them the unnatural amino acid. But if any bacteria escaped, they would lose access to that amino acid and die.

    Therefore, no humans or other creatures are at risk of getting infected by “superbacteria,” Nyerges emphasized.

    Nyerges looks forward to exploring codon reprogramming as a tool for coaxing bacteria to produce medically useful synthetic materials that would otherwise require expensive chemistry. Other doors have yet to be opened.

    “Who knows what else?” he mused. “We’ve just started exploring.”

  • Akos Nyerges, Svenja Vinke, Regan Flynn, Siân V. Owen, Eleanor A. Rand, Bogdan Budnik, Eric Keen, Kamesh Narasimhan, Jorge A. Marchand, Maximilien Baas-Thomas, Min Liu, Kangming Chen, Anush Chiappino-Pepe, Fangxiang Hu, Michael Baym, George M. Church. A swapped genetic code prevents viral infections and gene transfer. Nature, 2023; DOI: 10.1038/s41586-023-05824-z
  • Harvard Medical School