31 August 2020. Dr Steed is at the Department of Plant Sciences, School of Biological Sciences. A PDF version of this Issue is available here.
Research focus: Circadian signal transduction in plants
I am currently working as a post-doctoral research associate looking at the role of the bZIP transcription factors in transducing sugar signals to the Arabidopsis circadian clock. In plants, the circadian clock is important for synchronising biochemical and physiological processes with the external light-dark cycle. This is important because the correct synchronisation of internal and external rhythms leads to an increase in yield traits. We know that the major product of photosynthesis, sucrose, relays metabolic timing information to the central circadian oscillator but we are unsure of the precise mechanism. The aim of my project is to fully elucidate this signalling pathway and to understand the role of the bZIPs. Our hope is that a better understanding of this pathway will allow us to identify potential breeding targets in crops and thus contribute towards an increase in yields which is desperately needed.
What made you decide to pursue research?
Prior to starting my PhD, I spent 4 years working as a secondary school science teacher. Whilst I thoroughly enjoyed being in a classroom, I missed the intellectual stimulation that comes from doing lab-based research. As an undergraduate studying at the University of Surrey, I was fortunate to have lectures specifically on the circadian clock which I found fascinating and when the opportunity came up to complete a PhD investigating the wheat circadian clock at Cambridge I jumped at the chance. I have continued onto a post-doc because I enjoy being in the lab and the problem solving that comes with research, things often don’t work!
What would be your advice to aspiring researchers?
I learnt that I enjoyed being in the lab during my undergraduate degree by spending my third year on industrial placement with a large pharmaceutical company. I think for any student thinking of a career in research if you get the opportunity to spend time doing a work placement do it because you will learn what you like and (almost more importantly) what you don’t like. When it comes to research it is important to follow your interests; when things aren’t working it’s the intrinsic interest in what you’re doing that keeps you going. Finally, don’t be afraid to get things wrong. Research can be super frustrating at times, you are doing something where you don’t know the answer and often you don’t even know how to get to the answer but that makes it all the more satisfying when you do get things right.
In a paper published today (27 Feb), researchers from the Institute of Astronomy revealed findings on the interior and atmospheric composition of exoplanet K2-18b, orbiting an M-dwarf (‘low-mass’) star in the habitable zone, only 124 lightyears away from Earth.
K2-18b’s density, between those of Earth and Neptune, suggested a hydrogen-rich outer envelope surrounding a rocky interior. Previous studies of similar planets proposed temperatures of around 250-300 Kelvin (-23 to 27 °C) – similar to those found on Earth. Given these properties, the authors detected the presence of water and the absence of methane and ammonia and did not find ‘strong evidence’ for clouds in the atmosphere.
The interior of the planet was modelled with an inner iron layer, an outer silicate layer, a water layer and a hydrogen/helium layer. Notice the similarities to Earth’s own structure: iron core, silicate mantle and crust, oceans, some sort of atmosphere. Consideration of variations on the model (i.e. different compositions and masses of different layers) resulted in three ‘representative classes’ defining K2-18b that include a ‘range of possible compositions’: rocky world, mini-Neptune and water world.
Life as we know it can survive in a huge range of harsh conditions, from pressures of ~1000 atmospheres and temperatures of ~400 K (127 °C). Whether or not K2-18b is habitable depends on the extent of the hydrogen/helium atmosphere. Many solutions to the data give water at the atmosphere-ocean boundary – the surface of the water layer – to be in the ‘supercritical’ phase, but some give water in the liquid or gas phases. The ‘water world class’ has liquid water approaching normal conditions (27 °C, 1-10 atmospheres) under a thin hydrogen/helium atmosphere, a description seemingly like that of Earth. Furthermore, chemical disequilibrium – the absence of methane and ammonia – indicates the possibility of biochemical processes, although other explanations exist. The authors argue that the search for biosignatures – signs of life – should not be limited to smaller rocky worlds as larger planets such as K2-18b have the potential to host life.
Najung Lee (Pembroke) & Ragavi Vijayakumar (Downing). April 20, 2020.
Social distancing
Social distancing means keeping space between yourself and other people outside of your home. The basic reproductive number (R0) is the expected number of cases directly generated by one case. The Signer Laboratory has made the following assumptions1 in order to mathematically model the effects of social distancing on R0:
Under normal conditions, each infected person is expected to infect 2.5 other people.
Infected people can transmit the disease for a five-day period while they are asymptomatic.
After five days a person will begin experiencing symptoms, quarantine and no longer infect others.
There is a direct linear correlation between social interaction and R0. For instance, R0 is reduced by 50% (R0=1.25) when social interactions are reduced by 50%.
Figure 1. Simplified infographic on the impacts of social distancing1
The Future: Recurring global health threat and what do we need to learn
After the discovery of vaccines and antibiotics and with the improvement in hygiene, the number of deadly infectious diseases had rapidly declined. We were in hopes of eradicating them. Unfortunately, there have been new strains of infectious pathogens emerging from the 1970s and recently, the period between subsequent outbreaks has become shorter.
Why is this phenomenon happening despite the remarkable development of medical technology? The common feature shared by most of the diseases is that they are zoonotic viruses, which means they can infect both animals and humans. Researchers found out that more than 60% of emerging infectious diseases (EIDs), whose incidence has increased in the past 20 years, are caused by zoonotic pathogens2.
HIV came from many cross-species transmission from primates in Africa3. H1N1 is a type of swine influenza virus (SIV), which is a strain of the influenza family of viruses that circulate in pigs4. SARS-CoV, MERS-CoV, and SARS-CoV-2 are originally bat-borne coronaviruses. The noticeable point here is that the viruses have all crossed the species barrier from their natural host, and this phenomenon of cross-species transmission is called ‘Spillover’.
Figure 2. Schematic diagram of zoonotic transmission dynamics12.
70% of the zoonoses have originated from wildlife5 with most of them being of viral origin. Pathogens from livestock have already crossed the barrier during the formation of agrarian society, hence excluding them from the suspect of a novel disease outbreak.
There exist other factors, primarily the increase in the frequency of human and wildlife contact, which is accelerating the emergence of novel outbreaks6. Deforestation, rapid urbanisation, bushmeat hunting, and wet markets are forcing wild animals to move away from their natural habitats and to have greater contact with humans. This increases the risk of Spillover as there is a greater chance for the mutated virus within wild animals, which could infect another animal species, to be transmitted.
Most of the zoonotic infection cases also involve ‘intermediate hosts’ that connect between natural hosts – which are reservoirs of different viruses – and humans. The intermediate hosts can amplify the pathogen transmission and/ or introduce a genetic variation7. The ‘mixer vessels’ species, such as pigs, can recombine different viruses and produce a completely new recombinant strain of virus that gives greater biological variation; the swine flu pandemic in 2009 was caused by a novel influenza virus that has obtained the ability to spread between humans by genetic reassortment of avian, human and/or swine flu viruses in pigs8. There are also many reported endemic cases with the likely source of human transmission being infected livestock9. This is maybe warning us that we are opening Pandora’s box ourselves by allowing pathogens to overcome the cross-species barrier and infect intermediate hosts, which can essentially be any animals around us.
Furthermore, a massive increase in the frequency of air travel is providing an optimum environment for rapid transmission of infectious disease not only within certain communities but also across the globe6. Therefore, it is worth noting that any contagious disease in a single region is not the problem of a specific country or area; rather, the entire world needs to collaborate to achieve ‘One Health,’ which is an objective by the World Health Organization (WHO) to achieve better public health outcomes10. In such a globalised world, a complacent attitude towards an outbreak might result in failure in early prevention. In this process, WHO should also need to take an active step in constructing a global network to identify the regions with potential risks and to circulate up-to-date information transparently and promptly.
The vast majority of the world has been focusing on post-outbreak responses to a pandemic such as the development of vaccines and medical treatments. However, pre-outbreak measures are also vital to prevent initial mass infection, which can easily lead to uncontrollable situations. Early detection, surveillance, and mass testing are essential to block the inflow and nation-wide spread of the disease by improving preventive measures against epidemics to minimise considerable damage.
What can we, as in individual, do during the period of the outbreak? Along with individual protection measures such as wearing masks and washing hands frequently, having correct information and knowledge about the infectious disease is indeed very crucial. Fake news with incendiary titles instigates the public, triggering fear and panic. Such behaviour rather hinders the effort made by scientists and the government to control the situation. Hence, greater engagement of the public to the scientific background of infectious disease would make us better prepared for the unknown future.
Disease X
In 2018, WHO announced “Disease X” – representing a hypothetical, unknown pathogen that could cause a serious international epidemic11. Currently, COVID-19 fits the Disease X category. There is no guarantee that a pandemic like COVID-19 would not happen again soon; “Disease X” can appear in any form at any time. We need to learn from what has happened and thoroughly prepare so that future outbreaks would not lead to disastrous consequences.
The above article was written for the purposes of general public education about updates on the COVID-19 outbreak. It should not replace information provided by medical professionals and government officials.
Cantabrigian researchers have suggested that solar cells can have increased efficiency if their chemical compositions are less ordered.
The work, published in Nature Photonics, comes from an international team of scientists, led by Dr Samuel Stranks and Dr Felix Deschler, with members from the Cavendish Laboratory, Department of Material Sciences and Metallurgy, Department of Earth Sciences and the Department of Chemical Engineering and Biotechnology.
Solar cells are traditionally made of crystalline silicon, but perovskite solar cells have recently emerged as promising alternatives, with efficiencies of above 25%. The lead or tin-based materials are easier to source and manufacture than their silicon predecessors, thus reducing costs and increasing the feasibility of solar cells as an energy source.
Less structurally refined products were found to be further increasing the efficiency of perovskite solar cells by creating pockets which can localise charge, created by either sunlight in a solar cell or electrical currents in an LED. It is then easier to extract that energy from the material.
The localisation of the charge is stabilised by chosen cations in the surrounding material, so next steps for the team involve improving performance through identifying ideal cations, as well as finding the right conditions for taming the ‘chaos’ that lends augmented efficiency. Furthermore, if perovskite solar cells are to become widespread in the future, they will need to reduce their sensitivity to water, a trait for which silicon still holds the advantage.
Ragavi Vijayakumar (Downing) & Najung Lee (Pembroke). April 13, 2020.
Current treatments
As of now, there is no vaccine against SARS-CoV-2 – the virus strain that causes COVID-19. Researchers are currently working on creating a vaccine specifically for this virus, as well as potential treatments for COVID-19. Antibiotics are ineffective because COVID-19 is a viral infection, not bacterial.
There is some evidence that certain medications may have the potential to be effective in treating the symptoms of COVID-19. However, researchers need to perform properly randomized controlled trials in humans before these medications become available as a treatment method for COVID-191. It is also important to realise the fact that the efficacy and side effects of the drug can differ from person to person.
Here is a treatment option that is currently being investigated for protection against SARS-CoV-2 and treatment of COVID-19 symptoms.
Remdesivir
Remdesivir was initially developed by Gilead Sciences. It has a similar structure to adenosine, so it shuts down viral replication by inhibiting a key viral enzyme, RNA polymerase2,3. Researchers did testing with Remdesivir in the past during the Ebola outbreak, however, it did not show any promising improvement.
Remdesivir was given a chance to shine again. In the United States, a COVID-19 patient was given Remdesivir when his condition worsened; his symptoms showed improvements the next day, according to a case report in The New England Journal of Medicine (NEJM).
Such evidence from individual cases is not sufficient to prove a drug’s safety and efficacy, however. Still further testing on humans is required to make a safe conclusion before its global usage as a COVID-19 treatment.
APN01 – Apeiron Biologics
Apeiron is a privately-held European biotech company based in Vienna, Austria, focused on the discovery and development of novel cancer immunotherapies. It has recently secured approvals from regulatory agencies in Austria, Germany and Denmark to conduct a Phase II clinical trial of APN01 for the treatment of COVID-1915.
APN01 is a recombinant form of human angiotensin-converting enzyme 2 (ACE2). It was previously tested in phase I and II trials for acute lung injury (ALI) and pulmonary artery hypertension (PAH) involving 89 patients14.
The drug has been hypothesised to work against SARS-CoV-2 in two ways. Firstly, since it is a recombinant form of ACE 2, the virus binds to soluble APN01, instead of ACE2 on the cell surface, which means that the virus can no longer infect the cells.
At the same time, it reduces harmful inflammatory reactions in the lungs that occur in some patients with COVID-19 and lead to ALI and acute respiratory distress syndrome (ARDS).
Vaccines
What is a Vaccine?
Figure 1. Simplified graphic on how vaccinations work4
A vaccine is typically a biological agent made from weakened or killed forms of the microbe, its toxins, or one of its surface proteins. It provides active acquired immunity to a particular infectious disease. It is important that the attenuation is done in a way that makes the pathogens incapable of causing an infection, but still able to induce an immune response to confer resistance4,5.
Vaccines encourage our adaptive immune systems to produce highly specific antibodies and immunological memory against potential future infection. Essentially, vaccines work by introducing protection without having to risk the initial exposure of the wild-type pathogen.
How is a Vaccine produced?
The Centre for Disease Control has stated that there are six stages to vaccine development: Exploratory, Pre-Clinical, Clinical Development, Regulatory Review and Approval, Manufacturing and Quality Control. On average, developing and manufacturing a vaccine takes about 8 to 12 years in total.
Figure 2. Simplified graphic on the phases of vaccine development6
Exploratory: This phase is to characterize the pathogen and identify potential antigens that might help treat or prevent a disease6.
Pre-clinical: This phase is to determine if the potential antigen has the ability to produce immunity, while not causing harm through animal testing.
Clinical development: An application for an Investigational New Drug (IND) to the U.S. Food and Drug Administration (FDA) is made. This application basically summarizes all the pre-clinical findings to date and also describes how the drug will be tested and created.
Once the proposal has been approved, the vaccine must pass three trial stages of human testing:
Phase I: administers the candidate vaccine to a small group (less than 100 people) with the goal of determining whether the candidate vaccine is safe and to learn more about the responses it provokes among test subjects.
Phase II: which includes hundreds of human test subjects, aims to deliver more information about safety, immunogenicity, immunization schedule and dose size.
Phase III: which can include thousands or tens of thousands of test subjects, continues to measure the safety (rare side effects sometimes don’t appear in smaller groups) and effectiveness of the candidate vaccine.
Regulatory review and approval: A Biologics License Application (BLA) has to be made to the FDA.
Manufacturing: Drug manufacturers provide the necessary support to create mass quantities of vaccines.
Quality control: Stakeholders – healthcare system and providers, academic researchers, vaccine manufacturers, etc. – involved must adhere to procedures that allow them to monitor whether the vaccine is performing as well as anticipated. Multiple systems are designed to keep track of its performance, safety and effectiveness of an approved vaccine7.
mRNA Vaccines
What is an mRNA vaccine?
Instead of standard vaccines where viral proteins are used to immunize, an mRNA vaccine provides a synthetic viral mRNA, which the host body uses to produce viral proteins. This will allow the host body to produce necessary antibodies and immunological memory against a potential future infection8.
Figure 3. Diagram of Central Dogma Smith, J. (2020, April 1). Analysis: Could mRNA Vaccines Fulfill Their Potential Against Coronavirus? Retrieved from https://www.labiotech.eu/medical/coronavirus-mrna-curevac-etherna/.
Advantages of mRNA vaccine
mRNA vaccines:
are much safer than killed or attenuated viruses since it is non-infectious and non-integrating. There is close to no risk of infection or insertional mutagenesis
can be administered repeatedly
have the potential for rapid, inexpensive and scalable manufacturing, mainly owing to the high yields of in vitro transcription reactions. It bypasses the process of producing and purifying viral proteins for vaccines, saving time for production.
Why have mRNA vaccines not been used before?
mRNA molecules are highly unstable since they are susceptible to degradation in the cytoplasm after a short period of time. They also have high innate immunogenicity which needs to be downregulated for the safety of the vaccine. Finally, in vivo delivery of mRNA molecules is inefficient making it a bad candidate for vaccines9.
How can these problems be overcome?
mRNA degradation can be regulated using various chemical modifications:
addition of 5’ CAP,
adding an optimal length of poly(A) tail,
replacing rare codons with frequently used synonymous codons that have abundant cognate tRNA in the cytosol.
This will increase protein production and reduce mRNA degradation.
Immunogenicity of the mRNA can be down-modulated to further increase the safety profile.
The efficiency of in vivo delivery can be increased through the insertion of mRNA into carrier molecules – liquid nanoparticles, so that mRNA is in an injectable form – will allow rapid uptake and expression in the cytoplasm.
Moderna, Inc. – Developing an mRNA vaccine (mRNA-1273)
Moderna, Inc. is a Cambridge, Massachusetts-based biotechnology company that is focused on drug discovery and drug development based on messenger RNA. Moderna is in the process of developing an mRNA vaccine, mRNA-1273, which encodes for the SARS-CoV-2 spike protein. The first participant of the mRNA-1273 was dosed on the 16th March 2020 (Phase I trials). There’s still Phase II and III to overcome, but if every stage of the vaccine development goes smoothly, mass production of the SARS-CoV-2 vaccine could start in about a year or a year and a half, at the earliest10,11.
Another concept? RNA-based Antibodies
Moderna Inc. is also working on mRNA vaccines which encodes an antibody protein known to attack the virus. Effective antibodies can be identified from those who have gotten immunity through infection and recovery of COVID-19. Specific antibodies against SARS-CoV-2 can be isolated and can be sequenced, such that the mRNA sequences for the antibody is identified. These mRNA, if injected into an individual, will be translated into antibody against proteins on the virus itself, conferring immunity to the disease12.
CanSino Biologics, Inc. – Developing a Viral Vector-Based Vaccine (Ad5-nCoV)
CanSino Biologics Inc. is a global vaccine company based in China. CanSino Biologics is in the process of developing a recombinant SARS-CoV-2 vaccine (adenovirus type 5 vector) candidate. In preclinical animal studies of Ad5-nCoV, the vaccine candidate was able to trigger a strong immune response and a satisfactory safety profile. It has recently received Chinese regulatory approval to start human trials13.
Figure 4. Diagram of Vector-Based Vaccine D., D. (2017, August 8). Virally vectored vaccine delivery: medical needs, mechanisms, advantages and challenges. Retrieved from https://smw.ch/article/doi/smw.2017.14465.
This article has touched on some of the major discoveries by some companies/research groups around the world to prevent and fight COVID-19. It is just an overview, however, and the actual progress is far beyond what this article is able to cover.
The above article was written for the purposes of general public education about updates on the COVID-19 outbreak. It should not replace information provided by medical professionals and government officials.
Najung Lee (Pembroke) & Ragavi Vijayakumar (Downing). April 20, 2020.
