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Cambridge Biosciences DTP PhD Programme


Anna Yakovleva (3rd year, Pathology, IBBE)

Each year, an estimated 15 million deaths are caused by infectious diseases, of which 25% are considered ‘vaccine-preventable’. However, vaccination efforts in areas of the world with tropical climates and poor electrical infrastructure are costly and often not viable. This is due to the unstable nature of vaccines which are highly dependent on cold-chain environments to conserve efficacy during manufacture, delivery, and storage. Recent advances made by our team in the development of a novel protein stabilising technology, have enabled me to successfully engineer cold-chain independent vaccine and biologic candidates against several important human pathogens during my PhD.

Timothy Jenkins (4th year, Veterinary Medicine, World-Class Underpinning Bioscience)

Longitudinal changes in the gut microbiome of human volunteers with remitting-relapsing multiple sclerosis following experimental infection with the hookworm, Necator americanus

Numerous studies in humans and animal models have indicated a therapeutic effect of experimental infections by gastrointestinal (GI) nematode parasites on the clinical signs and pathology of a range of autoimmune and allergic inflammatory disorders, including Inflammatory Bowel and Coeliac Diseases. Whilst the immune-regulatory properties of parasite secreted/excreted products are thought to be primarily responsible for such effects, several recent studies have hypothesized that immune modulation might stem, partly, from qualitative and quantitative changes in the composition of the host gut microbiota that follows parasite infection and establishment. 

In the present MHRA approved study we investigated, for the first time, the changes in gut microbial profiles of human volunteers with remitting-relapsing multiple sclerosis (RRMS) prior to and following experimental infection with 25 hookworm L3 (Necator americanus; N+), and following administration of anthelmintic treatment, then compared the findings with data obtained from a cohort of RRMS patients subjected to placebo treatment (PBO). 

Bioinformatics analyses of bacterial 16S rRNA high-throughput sequencing data revealed significantly increased microbial alpha diversity in the gut microbiota of N+ compared to PBO subjects over the course of infection, which is indicative of a healthier gut environment. Furthermore, significant differences in the abundance of several bacterial taxa were observed between samples from N+ and PBO subjects. Most notably, Mollicutes, an immune-modulatory bacterial taxon hypothesised to be associated with the pathogenesis of autoimmune disorders, was significantly increased in N+ subjects compared to PBO. Overall, these data demonstrate a significant impact of N. americanus infection on the human gut microbiota and lend support to the hypothesis of a contributory role of parasite-associated changes in gut microbial composition to the therapeutic properties of hookworm parasites.

Anna Platoni (3rd year, Plant Science, Agriculture & Food Security)

Testing the ‘Pay-back’ hypothesis in the field:  Can bumblebee pollination ‘rescue’ seed production in CMV-infected tomato plants?

In lab experiments cucumber mosaic virus (CMV) causes plants to emit volatile chemicals that attract bumblebees. Bumblebees are important tomato pollinators but do not transmit this virus. For wild plants under natural conditions, helping host reproduction by encouraging bee visitation, pollination and increased host reproduction might represent a ‘payback’ by the virus to susceptible hosts. Fieldwork at RHS Garden Wisley in the summer of 2018 tested the ‘pay back’ hypothesis in a garden situation by comparing pollination rates and resulting seed set of CMV- and mock-inoculated tomato plants. Permitting pollinator access to both mock-inoculated and CMV-infected plants increased the number of seeds produced per g but CMV-infected plants benefited to a greater extent by being uncovered. This may be evidence of a ‘rescue effect’ with the virus ‘paying back’ its host by attracting pollinators.

Tom Reynolds (3rd year, NIAB, Agriculture & Food Security)

The genus Botrytis comprises over 30 species of necrotrophic fungi. These are plant pathogens infecting many important food crops. The genus is diverse in size of host range and ability to reproduce sexually. Some members are generalist pathogens, others are specialised to a small number of hosts. Many members of the genus are thought to reproduce exclusively clonally, whilst others are known to reproduce sexually. 

My work focuses on Botrytis fabae, a specialised pathogen of faba bean. Field surveys in other countries have shown that this pathogen in clonal. My work has found that the UK population is not clonal. I have expanded this survey by genotyping a large collection of UK isolates over their mating-type loci, which has provided strong evidence that the UK population is sexually reproducing. 

This finding has implications for faba been breeding targets, and implies that controlling Botrytis in UK crops will be more difficult than previously imagined.

Yasmin Paterson (3rd year, Veterinary Medicine, Bioscience for Health)

Embryonic Stem Cell Derived Tendon Cells to Help Guide Therapies for Tendon Injuries in the Horse

Tendon injuries commonly occur in equine athletes, comprising up to 46% of sport-horse injuries. Adult tendon heals via the formation of biomechanically inferior scar tissue resulting in high re-injury rates. Fetal tendon injuries however undergo total scar-less regeneration. This study builds upon research into the use of equine embryonic stem cells (ESCs) to aid tendon regeneration. Using global RNA sequencing, we identified that ESC derived-tenocytes are more similar to fetal than adult tenocytes. Genes which were significantly upregulated in adult tenocytes were expressed at similar levels in fetal and ESC-tenocytes and were highly associated with responses to inflammation. Genes which were significantly upregulated in fetal tenocytes were even further upregulated in ESC-tenocytes and were associated with cell migration. To further study how adult and fetal tenocytes differ, scleraxis (SCX), a transcription factor which is upregulated following a tendon injury was knocked-down in fetal and adult tenocytes. RNA-sequencing confirmed that SCX knock-down had differential effects in adult and fetal tenocytes, highlighting that SCX has differing roles during tendon development. Future work will now delve into the regulatory differences between fetal, adult and ESC-derived tenocytes to uncover genes that are likely to play a key role in regulating tendon development and healing.

Maxime Couturier (4th year, Chemistry, IBBE)

Mutasynthesis of novel prodiginines derived from the antibiotic prodigiosin by exploiting substrate specificity of H2MAP oxidases PigB and HapB

The natural product, prodigiosin, caught researchers’ interest more than a century ago because of its bright red color. Today, interest in this tripyrrolic secondary metabolite remains strong due to its biological effects, including potent antibiotic activity against various Gram-positive bacteria. 

Further exploration of the potential of this class of molecules requires libraries of analogues. Yet, the total synthesis of prodigiosin-like compounds (prodiginines) proves challenging. This can be overcome by highjacking the bacterial biosynthetic machinery via mutasynthesis. Although a number of different bacteria produce prodigiosin, its biosynthetic pathway is well conserved. The final precursors, MAP and MBC, are always produced independently, before a terminal condensation reaction. 

Our work focuses on the last step of the formation of MAP: the oxidation of H2MAP. We were able to isolate and characterize HapB, the enzyme catalyzing this reaction in Hahella chejuensis. In addition, we showed that some modifications of alkyl substituents on the C2 and C3 positions of H2MAP did not alter HapB activity significantly. We then fed these analogues of H2MAP into Serratia ΔpigD, a mutant of Serratia ATCC sp.39006 which does not produce any endogenous H2MAP.  As expected from the in vitro testing, chain elongation past two carbons on the C2 position could not be accepted whereas all substrates with a modification on the C3 position restored pigmentation, leading to the formation of eight novel prodiginines.

Simon Chen (2nd year, Zoology, World-Class Underpinning Bioscience)

Control of silk production in caterpillars: a behavioural trade-off between attachment and resource availability

Many caterpillars feed externally on plants. The cost of losing attachment to host plants can be high, particularly for small herbivores, but attachment itself can also be costly. B. anynana caterpillars lay silk carpets to provide attachment points for their claws. However, as plant diets are low in nitrogen, producing protein-based silk may be expensive. We tested if caterpillars economize the use of silk. Do they prefer to attach without using silk? Do they produce silk only when it is necessary? Given the higher cost of detachment, do small caterpillars lay down more silk thread length relative to whole body movement?

 By recording locomotion, silk production behaviour, and attachment forces in B. anynana caterpillars, we found that: (1) caterpillars prefer higher-traction coarse-rough substrates to slippery micro-rough ones; (2) caterpillars rapidly increase silk production on steeper and micro-rough substrates, and conversely reduce it on horizontal or coarse-rough substrates; (3) caterpillars detect substrate roughness using both their thoracic legs and abdominal prolegs; (4) second-instar caterpillars lay more silk thread length per whole body movement distance than final-instar caterpillars; (5) this ratio correlates with food nitrogen content.

In contrast to B. anynana, caterpillars of the closely related species Heteropsis iboina migrate daily up and down their host plant. We found that H. iboina exploit plant geometry for attachment more often, and produce less silk than B. anynana. Our results suggest the trade-off between substrate attachment and nitrogen availability is a key factor determining the use of silk by caterpillars.

Josie Gaynord (3rd year, Chemistry, Bioscience for Health)

Antimicrobial Stapled Peptide-Drug Conjugates

Driven by the global threat of antibiotic resistance, antimicrobial peptides (AMPs) are gathering increased interest as alternative antibacterial agents. One class of AMPs have a membrane-disrupting mechanism of action due their amphipathic and cationic nature. There have been several examples of stapled AMPs (STAMPs) reported in literature, which have increased alpha-helicity, improved physico-chemical properties and higher stability comparted to their unstapled counterparts. These STAMPs have all relied on one-component stapling, where the macrocyle is formed by intramolecular cyclisation between two amino acid chains. Herein, we report the first approach towards the development of two-component STAMPs (cyclisation with a bis-functionalised linker) using a novel two-component cysteine-divinylpyrimidine stapling method which has been developed in our group. Exploiting the ease of functionalisation that is possible with two-component stapling, we have designed a peptide-drug conjugate where a STAMP is conjugated to a small-molecule antibiotic via a linker bearing a beta-lactamase cleavable moiety. The conjugated drug is only released upon beta-lactamase-mediated cleavage, resulting in selective delivery of the small-molecule antibiotic. This yields a therapeutic agent with two distinct mechanisms of action, thus reducing the possibility of the emergence of antimicrobial resistance. A variety of peptides, staples and linkers are described, along with their biological activity, in the hope that an agent will be identified displaying exquisite antibacterial activity, a wide therapeutic safety index and improved physico-chemical properties compared to conventional AMPs and small molecule antimicrobial agents.

Matthew Harris (4th year, Pharmacology, Bioscience for Health)

Allosteric Modulation of the Gastric Inhibitory Polypeptide Receptor

G protein-coupled receptors (GPCRs) are targets for ~30% of marketed drugs. It is therefore important to understand their signalling. Family B GPCRs are a group of 15 receptors that are therapeutic targets for a wide range of diseases. Gastric inhibitory polypeptide receptor (GIPR) and glucagon-like peptide-1 (GLP-1R) are prototypical class B GPCRs. Their cognate ligands, GIP and GLP-1, are incretin hormones released postprandially from the small intestine to potentiate glucose-stimulated insulin secretion (GSIS) from pancreatic beta-cells – a process which is significantly reduced in Type 2 diabetic patients. This has led to considerable research aimed at enhancing incretin action as a diabetic therapy. Peptide-based incretin mimetics (e.g. Byetta) have shown some success but are limited by poor oral bioavailability. Orally active incretin-targeted small molecules are far more attractive therapeutics. Indeed, small molecule GLP-1R positive allosteric modulators (PAMs) have been developed that modulate GLP-1R activity to promote insulin secretion. Using in-silico docking we have identified the “first-in-class” GIPR PAM. Pharmacological characterisation of this molecule has revealed that it potently increases cAMP accumulation and intracellular calcium release. Importantly, it also enhances GIP potentiation of GSIS from isolated human pancreatic islets and may therefore have therapeutic benefits for patients with Type 2 diabetes.

Rebecca Martin (3rd year, Pathology, Agriculture & Food Security)

Classical MHC allele diversity and distribution in chicken populations worldwide

Chickens are becoming an increasingly important source of global dietary protein, and an increasingly dangerous reservoir for zoonotic pathogens. Thus, understanding their responses to pathogens is crucial. 

Classical class I and II molecules of the Major Histocompatibility Complex (MHC) play a key role in the adaptive immune response, presenting antigenic peptides to T lymphocytes. In contrast to mammals, unusually strong genetic associations exist between MHC haplotype and responses to infection in chickens. These associations, at least in part, seem to be due to the expression of a single classical MHC class I and II molecule in most tissues. Some of these molecules have wide peptide binding repertoires and seem to protect from a range of pathogens (‘promiscuous generalists’) while others have a much narrower range (‘fastidious specialists’).

This study aimed to begin the most complete and exhaustive analysis of global MHC population genetics outside of humans. Illumina MiSeq was used to perform multiplexed amplicon sequencing of exons 2 and 3 from all classical class I and class II loci. Samples were obtained from all major commercial breeders, ‘fancy’ breeds and free-range local chickens from Ethiopia, Nigeria, Tanzania and Ghana.

We have shown that, globally, there is huge diversity in chicken MHC alleles. Commercial flocks, in contrast to most healthy populations, have extremely low MHC diversity, but are enriched in apparently promiscuous haplotypes.  Previously unreported MHC alleles in African populations will now be investigated in the light of associated geographical and phenotypic data.

Samuel Kidman (4th year, Sanger Institute, Bioscience for Health)

Comparative genomics of Pseudomonas aeruginosa infections in cystic fibrosis

Pseudomonas aeruginosa is an opportunistic pathogen which invades and colonises the lung in people with cystic fibrosis. In this project, 4,200 isolates from 9 patients with cystic fibrosis have been whole-genome sequenced in order to better understand phenotypic and genetic diversity and adaptation within the cystic fibrosis lung. This project has confirmed the current understanding of cystic fibrosis infections through deep sequencing of hundreds of isolates from each patient. Throughout this project, we have identified very little genomic diversity within individual patients, though there is genomic diversity between the patients. However, phenotypic diversity is varied. Together with data for 12 phenotypes for all 4,200 isolates, we have attempted to correlate phenotype with genotype through genome-wide association studies to better understand the complex cystic fibrosis lung. 

Maya Petek (4th year, Biochemistry, IBBE)

Exploring insertions and deletions for directed evolution

Fitness landscapes attempt to describe the relationship between sequence changes and protein functions, usually by measuring the effect of a number of amino acid substitutions, which are widely used in protein engineering. In contrast, small insertions and deletions alter the protein backbone and have the potential for larger beneficial changes, but their effect is less well understood. So far, no fitness landscape for insertions or deletions has been experimentally recorded.

Here we use protein mutant libraries in GFP and the enzyme phosphotriesterase with up to 9 nucleotide insertions, deletions or 3 nucleotide subsitutions, sort them according to fluorescence and sequence each fraction with Illumina MiSeq. We extract mutations counts from sequencing and compare them to describe the effect of hundreds of mutations. We shows that these rarely-used mutations are surprisingly well tolerated and may be interesting to anyone working in protein engineering.

Diljeet Gill (3rd year, Babraham, World-Class Underpinning Bioscience)

Examining the DNA methylation age reset that occurs during iPSC reprogramming

DNA methylation is an epigenetic modification with repressive properties. As we age, the pattern of DNA methylation changes with some sites gaining and some sites losing this mark. These changes are relatively consistent between individuals and as a result, they can be used to predict age. These predictors (such as the Horvath epigenetic clock) produce a value called DNA methylation age, which is thought to represent the biological age of an individual. As a result, lifestyle factors that affect the ageing rate (e.g. diet) also affect DNA methylation age.

 During the process of iPSC (induced pluripotent stem cell) reprogramming, where somatic cells are converted into pluripotent stem cells, DNA methylation age is reset to 0 years old (regardless of the initial donor age). Here, we are investigating how and when this DNA methylation age reset occurs. We have found that DNA methylation age is reduced by day 15 of the 50 day process but only in cells that are successfully reprogramming. We are now investigating if partial reprogramming followed by recovery is sufficient to reduce epigenetic age using novel in vitro and in vivo approaches. These approaches could help us to understand the significance and mechanism of the epigenetic clock.