“It is fascinating! I believe the GCRF START grant has laid a strong foundation for me to becoming an independent early career Structural Biologist. Now I am hands-on, a biochemist being chaperoned into the world of X-rays, electrons, neutrons, quantum mechanics and GPUs”
Dr Stanley Makumire, GCRF START Postdoctoral Research Fellow, University of Cape Town, South Africa.
My name is Stanley Makumire. I was born in Zimbabwe and have had a passion for Maths and Science for as long as I can remember. My desire is to gain an understanding of how disease works at the atomic level and thereby address important Sustainable Development Goals for health and wellbeing (SDG3). I had not encountered structural biology until I attended the Biophysics and Structural Biology at Synchrotrons workshop in Cape Town in early 2019 (17‐24 January), which was jointly funded by the GCRF START grant and the International Union of Pure and Applied Biophysics. At that meeting, I saw the cutting-edge work being done by people in the GCRF START programme and realised that understanding macromolecular structure was the key to understanding biochemistry, and this has inspired my research journey ever since. At the time I was completing my PhD at the University of Venda in the Limpopo province of South Africa, where none of the resources to do such work were available. Therefore, I was determined to collaborate with the GCRF START programme at the University of Cape Town (UCT).
Given the disease burden in Africa, my main career goal is to eliminate or minimise disease progression using molecular and structural biology tools, with proteins as targets using small molecules designed by rational processes as drugs. This knowledge has provided insights used to design medicines and vaccines. I am motivated by the rapid advance of biophysics that we have witnessed in response to the COVID-19 pandemic. This has clearly demonstrated the power of today’s visualisation technology and the field of Structural Biology in vaccine design.
Studying the mechanisms of enzymes of the nitrilase superfamily
I was motivated to join Prof. Bryan Trevor Sewell for my Postdoctoral Fellowship, which I was awarded through the GCRF START grant in 2020. Prof. Sewell is a GCRF START Co-investigator in the Structural Biology Research Unit at the University of Cape Town. I had applied to do postdoctoral studies on the mechanisms of enzymes of the nitrilase superfamily. These ubiquitous enzymes play a variety of roles in cellular processes, and many have found industrial roles in chemical synthesis and environmental protection. However, discovering how they work has been beset with difficulties.
It has been known for some time that three different amino acids play a pivotal role in their function: a cysteine, two glutamates and a lysine. Excellent clues have come from X-ray crystallographic studies (Fig.1), but the literature contains a multitude of different interpretations of the available evidence. The problem is that X-rays cause the cysteine to become oxidized and cannot image hydrogens (which are a key players) and electrons destroy the glutamates so that they are invisible in images obtained by electron microscopy. The tricks to circumvent these problems used by various investigators have introduced artifacts of their own and therefore a definitive mechanism has eluded humanity.
Overcoming the challenges with neutrons
Neutrons are known to be the least damaging of all atomic resolution imaging probes and furthermore, they enable the imaging of hydrogens (in fact, deuterium that has exchanged with the natural hydrogen). But imaging by neutron crystallography is also beset by difficulties, including the fact that the crystals required must be enormous making it necessary to prepare vast quantities of protein. To add to these difficulties, there are only six suitable neutron beams in the world, so access to an appropriate facility is very restricted. I have overcome these difficulties with the help of Zoë Fisher, who is the group Leader of the Deuteration and Macromolecular Crystallization (DEMAX) platform at the European Spallation Source, and Mathew Blakeley, instrument scientist at the Quasi-Laue diffractometer (LADI-III) at the Institut Laue-Langevin (ILL). I am in the process of collecting data and learning of the remarkable insights that can be obtained by using neutrons to study the enzyme mechanism. Determining a neutron structure of this amidase will form the basis of proposing a novel mechanism and I am excited since the preliminary results are very promising. This would be a game changer!
Opportunities, resources, and capacity building through the GCRF START grant
“GCRF START has provided me with opportunities and resources that I would never have believed were possible to access from the African continent. Participating in the START grant programme has been an extraordinary experience.”
During the first year of my GCRF START-funded Fellowship, I was able to collect, process and interpret X-ray data, process and interpret high resolution cryoEM data collected at the world-class Electron Bio-Imaging Centre (eBIC) at the UK’s national synchotron, Diamond Light Source, thereby solving the structure of the Plasmodium falciparum glutamine synthetase (deposited as EMDB entry ID EMD-12589). I used molecular mechanics software to explore the active site of amidases and interpret quantum mechanical models of the amidase active site, thus adding substantial value to the X-ray structures. I have participated in projects related to anti-malarial drug design and had the opportunity to reinterpret the literature on amidase mechanism.
I have met and interacted with leading scientists through my GCRF START Fellowship who have helped me to achieve my objectives. I have also met other early career scientists involved in START projects and collaborations, and I am amazed at how far they have progressed. I am excited that, because of the GCRF START grant, I am becoming one of the very small cohort of young people in Africa that have the knowledge to contribute to the field of Structural Biology.
Commenting on Stanley’s research progress and his involvement in multiple international collaborations, Prof. Sewell said,
“Stanley has maintained spectacular productivity in spite of the challenges caused by lockdown due to the Covid-19 pandemic. He has engaged with a remarkable array of science and technology at UCT’s Aaron Klug Centre for Imaging and Analysis and has built rapidly on the work of others to bring several projects to fruition. His enthusiasm and passion have been maintained by interaction with the GCRF START team and he has leveraged this network to make contact and collaborate with neutron crystallographers at ILL and DEMAX. This clearly demonstrates the process by which capacity has been built in Africa through the GCRF START grant.”
Find more information about the UN’s Sustainable Development Goals here
My name is Maria Hamunyela, and I am a second year PhD student in the structural biology research group at the University of Pretoria, South Africa. Born and raised in a small town in northern Namibia, I was inspired to pursue my studies in science by women scientists that I have come across. Women in science face extra challenges, having to balance their careers and personal lives. I was raised by strong black women, including my mother, from whom I draw my strength. My parents never had the same opportunities and therefore, on completion of my studies, I will be the first PhD holder in my family.
Although I work for the University of Namibia as a technologist, I chose to continue my studies at the University of Pretoria under the supervision of GCRF START Co-I, Prof Wolf-Dieter Schubert, due to limited research funding and the lack of structural biology facilities in my country. This has provided me with access to world-class equipment, such as the UK’s national synchrotron, Diamond Light Source (Diamond).
The impact of Escherichia coli (ETEC) and related diseases – the scale of the challenge
I am currently investigating the secreted EatA protein of enterotoxigenic Escherichia coli (ETEC) bacteria. ETEC commonly causes watery diarrhoea in children younger than five years old killing many children in this age group. ETEC also causes malnutrition and stunting in children. I decided to work on this project because ETEC affects young children in developing countries in regions with limited access to clean water and sanitation. This is true of many people in both Namibia and South Africa who are correspondingly severely affected by water and food borne pathogens such as ETEC and Shigella.
Globally, ETEC and Shigella are estimated by the World Health Organisation to cause ~400 million episodes of diarrhoea annually in children under five years of age (WHO 2009) causing moderate and severe stunting in ~2.6 and ~2 million children, respectively. Studying ETEC can help to develop vaccines and drugs against ETEC and related diseases.
Studying the functions and structure of the EatA protein passenger domain
The passenger domain of the EatA protein is required for the virulence of ETEC. It degrades Mucin 2, a protective protein secreted by, and covering the intestinal epithelium. Previous reports show that the EatA passenger domain is a potential vaccine candidate for ETEC and other enteric pathogens such as Shigella flexneri. However, the functional and structural properties of the EatA passenger domain have not been extensively studied. The full biological function of EatA passenger domain is therefore not well understood and might support infections in yet other ways. Studying the functions and the structure of EatA passenger domain will provide a better understanding of ETEC pathogenesis.
A first step in studying the EatA passenger domain will be to introduce an affinity tag in the middle of the protein to simplify protein production and purification. This is non-trivial as both the N- and C-terminal ends are not available for the placement of such a tag and inserting it in the wrong place could affect the stability and the function of the protein. Once the protein has been produced and purified, the substrate specificity will be investigated by designing an enzyme activity assay. Observations on the optimal substrate will ideally allow the development of an inhibitor. Identifying other host proteins that interact with the target protein could provide information about additional functions. Structural and biophysical experiments will include thermal unfolding and refolding studies, co-crystallisation and finally X-ray diffraction to provide a fuller understanding of the role of EatA.
The WHO/UNICEF Integrated Global Action Plan for the Prevention and Control of Pneumonia and Diarrhoea (GAPPD) aims to reduce deaths from diarrhoea in children younger than five to less than 1 per 1000 live births by 2025 (WHO/UNICEF, 2013). Hopefully designing an inhibitor for EatA will be a fundamental step in achieving this goal
Collaborating with the GCRF START grant and next steps
It took more than a year of searching for opportunities before I came across Prof Wolf-Dieter Schubert and he accepted me to join his structural biology research group at the University of Pretoria. This is how the GCRF START programme afforded me the opportunity to study towards my PhD studies. The main benefit is that I now have access to Diamond, to world-class synchrotron techniques, and I have the reagents that I need to do my research. I am also getting scientific training, not only in the laboratory but through workshops connected to START. In addition, I am fortunate to be a part of a supportive research group.
As I am employed by the University of Namibia as a technologist, I will return to Windhoek (Namibia) in the future, and hopefully start my own academic research group in structural biology. If interesting opportunities arise, I would love to work for an international research facility or even the public sector. While the scientific industry in Namibia is still in its infancy, I may be able to bring my own knowledge to setting up a new company.
Read more about the UN’s Sustainable Development Goals here
As a biochemist/biophysicist working primarily with proteins, I am naturally drawn to the mechanisms of interactions of biological macromolecules. My name is Sylvia Fanucchi, and I am a senior Lecturer in the Protein Structure Function Research Unit (PSFRU) at the University of the Witwatersrand (Wits) in South Africa. I am interested in how things work at the molecular and atomic level, and how the structure of macromolecules leads to their function. This has inspired my research for the past six years which involves disentangling the neuromolecular networks involved in speech and language. With the GCRF START grant, the doors to collecting the detailed structural information we need through studying and obtaining crystal structures, have been opened for groups in Africa like ours. I have had multiple opportunities, thanks to the grant, to send crystals to the UK’s world class national synchrotron, Diamond Light Source (Diamond).
My research appeals so much to me because our ability to speak, to think, to read is fundamental to humankind. Indeed, my research question started with “what defines speech and language?” but has since expanded to include questions about cognition, reading, and a number of disorders associated with these such as Autism, Dyslexia, Epilepsy and Schizophrenia. Dyslexia, for example, occurs in at least one in 10 people world-wide, putting more than 700 million children and adults worldwide at risk of life-long illiteracy and social exclusion..
Globally, it is estimated that one in 160 children has an Autism Spectrum Disorder (ASD), although estimates vary significantly across studies, and between developed and developing countries. In Southern Africa, very little is known about the prevalence ASD and it is understood that many cases go undiagnosed. Because these disorders can be debilitating and impact on the quality of life of those living with these disorders, and because there is currently no known cure, it is of utmost importance that the complex neuromolecular mechanisms that define these disorders be explored and far better understood. It is hoped that through our research more robust forms of therapeutics could be developed.
Piecing together neuromolecular complexes and networks
In my work, I investigate protein-protein and protein-nucleic acid interactions and try to piece together the neuromolecular complexes and networks that form in both space and time to better understand the mechanism of their interaction and how this is associated with language and cognition, as well as how changes in these may lead to certain disorders. I use an array of biochemical and biophysical techniques to achieve this study and the most prominent of these include, fluorescence anisotropy, isothermal titration calorimetry, hydrogen exchange mass spectrometry and single molecule kinetics. These techniques are used to study binding kinetics and thermodynamics as well as the dynamics and motions of molecules and their interactions with each other, such as the interaction between a protein and DNA, or the interaction between two proteins. The work we have done has mostly been conducted at the PSFRU but I also have collaborations with Dr Previn Naicker and Dr Stoyan Stoychev at the CSIR in Pretoria who assist with mass spectroscopy, and Dr Carlos Penedo from the University of St Andrews in Scotland, UK, who assists with single molecule studies.
The promising biophysical studies conducted in this work will benefit greatly from detailed structural information, provided currently through access to Diamond with the GCRF START grant. Knowledge of the structures of macromolecular complexes allows us to fully understand our system at a level of detail that is otherwise unattainable. And this information, in addition to the dynamics/thermodynamics/kinetics data, will enable us to understand the complexity of these networks at atomic resolution. This will foster a deeper understanding of these mechanisms and enable detailed therapeutics to be designed that would help regulate these disorders, particularly if single strong contributing factors could be identified. Crystallography and solving the structures of the individual interacting partners, as well as of the complexes is therefore of fundamental importance in this project.
FOXP2 protein – the “the language gene”
The protein that sparked this investigation is a transcription factor (a protein that regulates the expression of genes) called FOXP2. FOXP2 was dubbed “the language gene” in the early 2000s when a mutation in this gene that severely impeded DNA binding was found to result in a form of verbal dyspraxia in a family of individuals in the UK. Because FOXP2 is a transcription factor, it is located in the nucleus of cells and its role is to bind to the promotor region of certain genes and facilitate/regulate their transcription to mRNA which ultimately results in the translation and thus expression of that particular protein. Therefore, the regulation of transcription (and hence translation) of any protein will have a direct effect on the functioning of that protein. Our focus is thus on transcriptional regulation because it is the process that initiates downstream effects and predicts which genes will be turned on or off and hence, crudely put, controls the way we function.
Over the past three years, this project therefore focused on the mechanism of DNA binding of FOXP2. Through this work we were able to meticulously describe what drives the interaction of the DNA-binding domain with cognate DNA. We identified electrostatic interactions that played a critical role, we studied binding sequences to gain insight into binding specificity and affinity, we outlined how a domain-swapped dimerisation event that is unique to this subfamily of FOX proteins was able to assist in the dynamics of the DNA binding event, and we described the thermodynamic and kinetic events that occur during binding. In essence, by describing how the transcription factor interacted with DNA, we were able to tell which sequences it preferred, which conditions were most favourable for transcription, and how the structure and fold of the protein was necessary for transcription to occur. Knowing this helps us understand what is necessary for certain genes to be turned on or turned off and how we could interfere with this process.
The focus of our work then moved from DNA binding to the complex network of neuromolecular protein-protein interactions and we began to piece together other interacting partners of FOXP2 and how these interactions affected transcriptional regulation. One specific interaction has yielded a very interesting link to Autism that we are currently exploring further. I have established a very fruitful collaboration with Dr Carlos Penedo from the University of St Andrews primarily through a Newton Fellowship from the Royal Society and the single molecule work done through this collaboration has helped to resolve intricate details about these interactions that I am very excited about.
Fast and remote access to diffraction and data collection with Diamond and the GCRF START grant
The opportunities to send crystals to Diamond with the assistance of the GCRF START grant have been revolutionary in enabling us to have fast and remote access to diffraction and data collection that would otherwise have been logistically far more difficult to achieve, and therefore far more sparsely accomplished. Unfortunately, up to now, crystallisation in this project has been a challenge and so far, we are yet to achieve the crystals we require. The fact that the proteins we are attempting to crystallise have not yet had their structures solved and published in the Global Protein Data Bank (PDB) attests to the challenge we knew we would face in obtaining good diffraction data. And while we have obtained some crystals successfully, none of the data we have obtained has been worthy of solving the structure. Nevertheless, the fact that we can obtain crystals is promising and I am determined to persevere with this work until we are successful.
My students are all working on aspects of this project. They work on protein-protein interactions, crystallisation and structural biology, biophysics, and biochemistry. I am currently supervising 5 PhD students and 4 MSc students from diverse backgrounds, 8 of whom are females. I also have 2 postdoctoral Fellows – one from Lesotho and one from Kenya – that have worked under me for the past two years. In 2020, I graduated 2 PhD students and 2 MSc students. The students are given the autonomy to operate equipment, design experiments and analyse their data. Where possible, and covid-19 pandemic permitting, I encourage them to participate in international workshops and to visit other labs to gain experience and exposure.
Riyaadh Mayet is one of the early career MSc Students in my team.
“The GCRF START grant has enabled the African continent to foster development in synchrotron techniques through collaboration with the UK.” she says. “My MSc project deals with the structural biology of DNA-binding by the TBR1 T-box transcription factor implicated in Autism. The grant has enabled me to send my samples to the Diamond Light Source for diffraction, and without it, it would be very difficult if not impossible to obtain such data. It has also taught me how to better collaborate with fellow researchers, as well as given me the opportunity to learn how to diffract crystals to obtain atomic resolution data. Lastly, I have indirectly benefitted through learning about protein crystallography from fellow researchers who have used the START grant.”
Despite the challenges we have encountered with solving structures in this project, I am very grateful for the support received through the GCRF START grant and the support structures put in place – in particular, in bringing together a strong network of South African crystallographers. Knowing that I have this group of colleagues available across the country that forms a support structure is very reassuring. I am confident that the assistance and opportunities offered to me by this grant over the years is going to result in the ultimate success of my crystal structure dreams for this project and I am both grateful and excited for what the future holds.
Commenting on Sylvia’s research project and the access to infrastructure such as the Diamond synchrotron, Head of School of Molecular and Cell Biology (MCB), Prof Marianne J. Cronje, says,
“I am wholly in support of these research endeavours. Dr Sylvia Fanucchi is an incredibly talented researcher and her position within the school’s Protein Structure Function Research Unit strengthens her efforts by providing access to high-end research infrastructure to support her research in the school.”
Addressing disability is referenced in many of the UN’s Sustainable Development Goals (SDGs), namely health, education, economic growth and employment, inequality, accessibility of human settlements, and others. Read more about the SDGs here.
 In the USA~10% of school children struggle with dyslexia and ~1 of every 59 school children is diagnosed with ASD (Yuhang Lin et al Int. J. Environ. Res. Public Health 2020, 17, 7140). The number with ASD has increased over the years reflecting both an increase in awareness as well as a potential increase in environmental triggers although the disorder is currently believed to be predominantly genetically determined.
In a bid to design clinical drugs to improve health outcomes for people living with a particular strain of HIV and its mutants, scientists at the University of the Witwatersrand’s Protein Structure-Function Research Unit (PSFRU) in South Africa have embarked on a clinical drug discovery journey with promising results. The aim of the research, which receives funding from the GCRF START grant, is to develop a novel inhibitor specifically designed to target the South African HIV-1 subtype C protease (C-SA PR) and its mutants.
The purpose of developing an inhibitor is to stop C-SA PR’s activity by preventing the formation of mature copies of the human immunodeficiency virus (HIV). This would improve health outcomes in line with Sustainable Development goals across South Africa by increasing drug efficacy, reducing adverse side effects and drug resistance, as well as benefitting populations infected with the HIV subtype C in other sub-Saharan countries, India, China and Brazil.
There is no permanent cure for HIV/AIDS which has claimed the lives of an estimated 32.7 million people globally since the beginning of the HIV pandemic (UNAIDS, 2020). A number of drugs have been developed and approved by the USA’s Food and Drug Association (FDA) to increase the quality and duration of life in HIV infected individuals in some parts of the world. However, these are not specific to the HIV-1 protease subtype C which is dominant in South Africa – a country with approximately 20% of the global HIV infection rate and 10.44% of the global AIDS-related deaths (UNAIDS, 2020).
To date, the scientists at the PSFRU have screened ten drugs in the FDA approved and Zinc drug databases, with seven hits that show promise for optimisation as inhibitors. They have solved one protein structure through sophisticated computational modelling, and with high-resolution X-ray crystallography data collected on beamline i03 at the UK’s national synchrotron – Diamond Light Source (Diamond) – have solved the structure of the South African HIV-1 subtype C protease (C-SA PR), the results of which were deposited in the global Protein Data Bank (6I45.pdb) in 2018 (Fig.1).
The research involves characterising the structure and function of the South African HIV-1 subtype C protease (C-SA PR) and its mutants using state-of-the-art computational and experimental methods made possible by the GCRF START grant. The scientists want to understand what role amino acid insertions and mutations the HIV-1 protease may have on clinical drug binding so they can design an effective inhibitor.
This research builds on a previous study, in which a blood sample was taken from a drug naive infant born to an HIV positive mother. To prevent the transmission of the virus to her baby, the mother had received reverse transcript inhibitor treatment (but not protease inhibitors) prior to the birth. However, when the baby was born it was found to be HIV positive and a mutation was present rendering current drug therapy ineffective.
“It is the results like this of other research on the South African HIV-1 C-SA PR, and the impact of the disease on individual lives and livelihoods, which drives our motivation. The fact that the baby had developed drug resistance mutations is very rare in mother-to-child transmission but no less concerning,” says Professor Yasien Sayed, who heads up the PSFRU and leads the research on the HIV-1 C-SA PR, “and there is evidence that some adults are also failing drug therapies.We therefore need to develop treatments which work more effectively against the HIV-1 C-SA PR and its mutants if we are going to improve clinical outcomes for the large population of HIV positive adults and children in South Africa, and further afield.”
Some of the first steps in the team’s drug discovery journey have been computational involving Molecular Dynamics Simulation of the HIV wild type C-SA PR and its mutants. After this, drugs in various databases were screened. As a result, the scientists found a promising drug from the FDA database that binds with the HIV wild type C-SA PR and its mutant with best docking scores and energies.
“We modelled the homology structures of the HIV wild type protease and its mutants using the template South African wild type HIV-1 Subtype C Protease (PDB ID: 3U71),” explains Dr Pandian who is a Post-Doctoral Research Fellow funded by the GCRF START grant specialising in the computational aspects of the research. “The structure was solved at 2.72Å using the software packages: Swiss model/modeler/I-Tasser, followed by experimental validation of the modelled structures with in-house computer software. We are excited by the preliminary results, which are better than the current FDA approved drugs, although the computational results now have to be proved through wet lab experiments, along with the best results from the screened from the Zinc database.”
To conduct these studies, the PSFRU has its own computational and wet lab facilities for Molecular Dynamics simulation, docking studies, protein expression and purification. Screening of crystals is carried out using an Oryx8Protein Crystallization Robot (Douglas Instruments, UK) and testing of crystals using a home-source X-ray diffractometer. However, synchrotron facilities are not available on the African continent, so access to the Diamond Light Source synchrotron (Beamlines i03, i04, and also i04-1 and i24) is achieved remotely from the PSFRU lab in South Africa in order to characterise the structure and function of proteins at high resolution.
“Having access through the GCRF START grant to experimental synchrotron techniques like X-Ray crystallography at Diamond to obtain crystals and to solve the structures at high resolutions has been revolutionary for us,” reports Dr Pandian. “It is ultimately the combination of computational and experimental techniques that makes it possible to see how well the drugs are binding to optimise them for the South African HIV-1 subtype C protease (C-SA PR)” .
“During the wet lab experiments,” Dr Pandian continues, “we can’t screen the whole drug library for the target protein and it’s very costly to purchase the drugs for screening. The theoretical part of the drug discovery method is therefore useful for generating three dimensional structures for any proteins when the crystal structures are not available in the PDB databases, and for sorting out the best ligand / inhibitors for the protein target before starting protein characterisation wet lab experiments.”
Scientific results are not the only progress being made by the PSFRU team in their research which is meeting the UN’s Sustainable Development Goals for health (SDG 3); great strides have also been made in the PSFRU in terms of education and capacity building in structural biology (SDG 4) with more than 30 postgraduate students involved in the collaboration with the GCRF START grant since 2019. This includes Dr Ramesh Pandian, and Ms Mpho Setshedi who is a MSc. candidate working on the wet lab studies of the HIV-1 C-SA PR and its mutants.
“The research is meaningful,” says Ms Setshedi, “I feel like we are doing a good job and doing something to solve a challenge that impacts South Africa. I hope it contributes something big – an effective HIV inhibitor. In terms of what I am learning, there are challenges in this field but once you get the hang of the techniques you just need to persevere. Getting funding is a struggle in my field generally and there aren’t a lot of women doing this work. There have also been challenges caused by the COVID-19 lockdown in 2020 – but I haven’t let anything discourage me.”
Read more about the UN’s Sustainable Development Goals here
The Molecular Dynamics (MD) simulations of validated structures were performed under physiological conditions for 100ns using GROMACS software packages. The MD simulated structures were analysed thoroughly and extracted the energy minimised structure for further analysis. Important parameters such as root mean square deviation (RMSD), root mean square fluctuation (RMSF), radiation of gyration (Rg) and hydrogen bonding analysis were carried out.
The energy minimised structures of HIV wild type and its mutants were used for the screening of drugs from different data bases such as the Zinc database and FDA approved drugs database.
The results of the binding pocket analysis of the protease complex form obtained by the docking studies with best ligand directed the scientists to modify the side chain with the combination of different R group of the drug to improve the binding affinity.
The effects of human activity on climate change are evident in accelerated changes to global climatic conditions. As a result, there have been efforts to decrease human impact on the environment. This includes sustainable and environmentally friendly waste management systems, bioremediation of damaged ecosystems and biocatalysis as a replacement for conventional chemical synthesis in industries in line with the UN’s Sustainable Development Goals.
One way to address these challenges is through the use of enzyme biotechnology in which proteins (enzymes) are used as industrial catalysts. Nitrilases are widely used enzymes with potential in the production of high-value fine chemicals including medicines, bioremediation and waste management. A problem with using enzymes in environmental remediation is that naturally occurring enzymes are susceptible to degradation and inactivation under harsh conditions. They can, however, be engineered to make them more tolerant of these conditions. Nitrilases have intrinsically robust, spiral structures that suggest that substantial improvements in stability are possible.
My name is Lenye Dlamini and my PhD study in the Structural Biology Research group at the University of Cape Town (UCT) concerns the engineering of a cyanide-degrading nitrilase enzyme that can be used to remediate cyanide waste in the textile, electroplating and gold-mining industries. In particular, cyanide is used in huge quantities in these industries and spills or unsafe disposal results in environmental degradation and causes harm (and occasionally death) to humans and livestock.
My study will use predictive biophysical methods based on structural knowledge of cyanide degrading nitrilases to measurably improve their tolerance of non-optimal temperature ranges and enhance the operational stability of the enzyme so that they can be routinely used for safe and cheap disposal of cyanide waste. The project builds on the work of Dr Andani Mulelu,2 and several of Prof Michael Benedik’s students at Texas A&M University who used directed evolution, a technique in which random amino acid mutations are introduced throughout the protein, to increase protein stability and ultimately led to the first structure of an enzyme of this type. My goal is to use this structure to identify specific amino acid changes that will lead to increased stability.
I am working from Prof Trevor Sewell’s (GCRF START Co-I) laboratory at UCT and the Electron Microscope Unit at the Aaron Klug Centre for Imaging and Analysis. My work is a component of the work on nitrilases being done by a large team of local and international collaborators (my first experience of collaborating with scientists outside of South Africa) that includes in South Africa: Dr Jeremy Woodward (GCRF START Co-I), Dr Gerhard Venter and Prof Roger Hunter at UCT, Prof Dean Brady at the University of the Witwatersrand, Dr Nishal Pharbhoo at UNISA; in Germany: Prof Andreas Stolz and Mr Erik Eppinger at the University of Stuttgart, Prof Markus Piotrowski of the Ruhr University at Bochum, and Prof Achilleas Frangakis at Goethe-University, Frankfurt.
While the direct impact of my research project is environmental, it has broader implications in a variety of industries. There is growing demand for biological agents and processes that will replace conventional processes of managing waste and chemical synthesis. Enzymes, including the nitrilases, have taken centre-stage in this regard and present not just an environmentally benign alternative but one that produces better reaction products (they are highly specific in the enantiomers and regions on compounds that they bind to, leading to more specific reaction products).
It is critical that we understand and can adapt enzymes for these new uses. Nitrile-containing compounds are widespread in nature and are also utilised in industries including agriculture, mining, pharmaceuticals and the plastics and paper industry. Most nitrile-containing compounds are toxic, mutagenic, and carcinogenic. We are trying to design a way that will result in the use of harmful compounds as substrates for the catalysis of useful compounds in a sustainable and environmentally benign manner.
In my research on nitrilases, I am building on previous research skills I gained through my MSc. project which also benefitted from access to the UK’s national synchrotron, Diamond Light Source (Diamond). Through supporting research, workshops, mentoring and supervision, and other aspects of these labs, the GCRF START grant has also, by extension, supported the development of my research career. In addition, workshops presented by structural biologists from Diamond in South Africa, have enabled me to acquire skills that include molecular biology techniques, protein crystallography, electron microscopy and data collection at synchrotrons.
My Master’s research was in rational drug design against Mycobacterium tuberculosis using molecular and structural biology techniques. One of the main outcomes of my study was the crystal structure of thiamine monophosphate kinase from Mycobacterium tuberculosis, solved at a resolution of 2.19 Å, with data collected using the i04 beamline at Diamond with access through the GCRF START grant.
Commenting on the research outlined above, Prof Trevor Sewell, Lenye’s supervisor, said,
“The work of the last 30 years has provided a wealth of knowledge about the structures, occurrence and chemistry of members of the ubiquitous nitrilase superfamily of enzymes. This has led to their widespread use as industrial enzymes and a recognition that some superfamily members are potential drug targets. Even so, our understanding of their mechanism and our ability to introduce desirable properties through design is very limited. Lenye’s work seeks to surmount the barriers, leading to the ability to enhance at least one property of the cyanide degrading nitrilases, the thermostability, by design and then verify that the desired goal has been achieved experimentally using CryoEM and differential scanning calorimetry.”
Find out more about the UN’s Sustainable Development Goals here
About Lenye Dlamini
Lenye Dlamini was born and raised in Mbabane, the capital city of Swaziland, which is also where she received her primary and high school education. Lenye was inspired into science at high school through her biology and chemistry teacher who, Lenye says, saw the potential in her and motivated her to work extra hard. Prior to embarking on her PhD studies, Lenye’s tertiary education was at the University of Pretoria in the laboratory of GCRF START Co-I, Prof Wolf-Dieter Schubert. Lenye is currently a PhD candidate in Medical Biochemistry in the Structural Biology Research group, Department of Integrative Biomedical Sciences, Faculty of Health Sciences at the University of Cape Town, South Africa.
From medicinal chemist to protein crystallographer, Dr Anton Hamann has made remarkable strides in structural biology despite many challenges. These achievements he attributes to new doors of opportunity which have opened as a result of GCRF START grant funding for his role as a Post-doctoral Research Fellow at Stellenbosch University, South Africa – a role which has changed his life and career in many ways. Although possessing “no previous experience” (as he puts it) in the particular techniques and skills required, Anton has not only retrained into a new field of science in a short space of time, but he has also learnt world-class techniques scarce in Africa, and now develops small and novel molecule inhibitors to combat diseases. Here is his inspiring story in his own words….
My love for science and medicine
My name is Anton Hamann and I grew up on the outskirts of Cape Town, in the Western Cape of South Africa. I was diagnosed with severe hearing loss in both ears with no possibility of recovering the loss. Despite this, from a very young age, I enjoyed science and building contraptions. I was also a bookworm and always enjoyed visiting the local library. My high school science teacher was extremely passionate in chemistry and motivated me to pursue a degree in chemistry. As a result, I decided to pursue a career in science, starting with a BSc degree in Chemical Biology at the University of Stellenbosch. After that, I started with my postgraduate studies (BSc Honours, MSc and PhD) with organic chemistry as my discipline.
I was always fascinated in medicine and how it affects our bodies and staves off diseases. It was questions like – What molecules are involved and how do these molecules change the biology in our bodies? How can we use these molecules to combat diseases? Can we cure these diseases with better molecules? What are these molecules? – that intrigued me.
This prompted me to do research in the field of medicinal chemistry which is a multi-functional field with various applications in drug discovery, drug design, synthetic chemistry, and protein molecular modelling. During my MSc and PhD, I focused on developing drugs with better medicinal properties for the treatment of malaria and Alzheimer’s disease. Over the course of time, I have synthesised several molecules that have the potential to be further developed into medicinal drugs for malaria and Alzheimer’s disease. This has resulted in two publications for my work in malaria (South African Journal of Chemistry, 2013, 66, 231-236 and Bioorganic & Medicinal Chemistry Letters, 2014, 24, 5466-5469) and we are currently in the process of publishing the Alzheimer’s disease results in a peer reviewed journal.
Re-training as a protein crystallographer
After my PhD, I decided to carry on with my research in the field of medicinal chemistry but was looking for a new challenge. This is when I joined Prof. Erick Strauss’ research team as a post-doc to explore the possibilities of developing novel antibiotics for Staphylococcus aureus. This is also where I heard about the GCRF START grant for the first time.
Although GCRF START’s life sciences focus is mainly structural biology, a field in which I possessed no previous experience, I was determined to learn as much as possible and be retrained as a protein crystallographer. This is where the START grant made a significant impact on me, not only fully funding my role as a post-doc but also giving me opportunities to attend conferences and workshops in South Africa and UK, and to hone my skills as a protein crystallographer. As I’ve progressed during my post-doc, I have become a better medicinal chemist with the new skills that I have developed in the field of structural biology thanks to the opportunities provided by the GCRF START grant.
The GCRF START grant has given me an incredible opportunity to visit XChem twice for two weeks in total at the UK’s national synchrotron, Diamond Light Source (Diamond), to carry out X-ray crystallographic fragment screening experiments. I’ve gained valuable experiences from Dr Romain Talon and Dr Alice Douangamath and these visits also introduced me to a new field of high-throughput screening where the workflow is almost fully automated. I’ve had access to Diamond’s state-of-the-art equipment including the I04-1 beamline. During this time, I’ve had the opportunity to soak my protein crystals with hundreds of different fragments to identify potential small molecules that bind to the enzyme. These molecules can then be expanded into larger molecules with higher potency and act as antibiotics for Staphylococcus aureus.
To date I’ve used the I03, I04 and I04-1 beamlines at Diamond to obtain diffraction data of my Staphylococcus aureus protein crystals which was extremely valuable to my research. I have also attended a CCP4 (Collaborative Computational Project Number 4) workshop in York in the UK, where I learned how to process the diffraction data to solve the crystal structures. GCRF START is one of the CCP4 workshop partners.
Another benefit of the GCRF START grant has been the fruitful collaborations and relationships that I have built with other South African and British structural biologists who have significantly aided my career progression. In addition, I have learned valuable tips and skills from Romain and Alice at Diamond. They gave me insights on how to achieve optimal crystals and what to do if your proteins do not crystallise. They have been incredible in assisting me with the XChem project.
Commenting on Anton’s achievements and the support of the GCRF START grant, Prof. Erick Strauss said,
“I’ve always personally been of the opinion – and this is especially relevant in the South African context – that a scientist with multiple skill sets and the ability to transition easily between fields is more likely to make a deep impact. It was with this in mind that I was really happy to welcome Anton into my group: as a skilled synthetic chemist I was certain that he would be more than able to take on protein crystallography to bridge the chemistry/biology divide. And without the GCRF START grant, this would not have been possible – we are extremely thankful for this support.”
I would like to thank Prof. Erick Strauss, who is a GCRF START Co-Investigator, for taking a gamble on someone like me who is an organic chemist and not a biochemist! The effort he was willing to put into me and this project is highly appreciated. I couldn’t have asked for a more invested supervisor. I am also grateful to my lab mates, Dr Blake Balcomb (GCRF START-funded Post-doctoral Research Fellow) and Konrad Mostert, for teaching me the nuts and bolts of protein chemistry. I am also thankful to Dr Carmien Tolmie (previously a GCRF START-funded Post-doctoral Research Fellow) and the other GCRF START Co-Investigators, Prof. Trevor Sewell, and Prof. Wolf-Dieter Schubert for their work behind the screen to keep things running smoothly. Lastly, a big thank you to the people at Diamond for making this a reality.
Read about the UN’s Sustainable Development Goals for Health and Wellbeing here.
On International Women’s Day (today – 8th March), we highlight the achievements of Melissa Marx, an MSc medical biochemistry student in the University of Cape Town’s (UCT) Faculty of Health Sciences (FHS), who is conducting ground-breaking research in the field of cervical human papillomavirus (HPV) with the assistance of the GCRF START grant. HPV is the cause of most cervical cancer cases amongst women worldwide. Melissa’s research into HPV, which forms part of a larger departmental programme, was funded by the GCRF START grantwhich provided access to the UK’s world class national synchrotron, Diamond Light Source.
Marx’s research focused on visualising the effect of an enzyme found within the reproductive tract on the structure of the virus, as it occurs during the infection process. To achieve this, she and fellow researchers studied HPV pseudoviruses (non-infectious and synthetic viruses) using laboratory-based techniques, structural biology and computational work.
Melissa hopes that her findings will set a strong foundation as scientists work towards discovering preventative and therapeutic options for HPV infection to decrease the high burden of HPV infection in South Africa, on the continent and around globe. Cervical cancer is the fourth most common cancer among women worldwide.
“Without the help of the GCRF START grant, much of my research would not have been possible. The grant enabled me to apply cutting-edge structural biology techniques to gain insights into the structure of HPV,” she said.
“I was also incredibly fortunate to have collected data at the Electron Bio-Imaging Centre at Diamond Light Source in the United Kingdom. This was only possible with funding from the GCRF START grant.”
“Our collaboration with the GCRF START grant has allowed us to gain new skills and experience that has fast-tracked our research programme in antimicrobial drug discovery. It played an integral part in Blake’s development as a scientist too, through the visits to the UK’s national synchrotron, Diamond Light Source and XChem, and this investment is already paying forward as new students are being trained.”
Professor Erick Strauss, Strauss Laboratory, Stellenbosch University, South Africa
My name is Blake Howard Balcomb, and I am a Post-doctoral Research Fellow funded by the GCRF START grant in the Department of Biochemistry at Stellenbosch University in South Africa. My research degrees, throughout the years, have centered on tackling the global and local challenges of human health and disease, motivated by my experiences growing up on a small farm in rural KwaZulu-Natal, South Africa. During those times and since, I have seen the stark impact that health epidemics such as HIV/AIDS and Tuberculosis (TB) have on society, as well as the effects on family livelihoods. And so, from a young age, it was only natural that I had a strong inclination to try and help my local communities where I could. Originally, I had an interest to pursue a medical degree; however, after seeing the wonderful world of microorganisms under a microscope I was set on a science career. I was also very fortunate to have several terrific mentors and supervisors during all my research degrees that have played a big role in the scientist I am today, enabling me to share my experience with my colleagues.
For me, the beauty of science and research is that one can ask difficult questions and sometimes come across new unexpected answers or perspectives. I relish the idea that a basic scientific discovery has the potential to lead onto bigger things that could contribute towards combating a debilitating disease. This is where the GCRF START grant has provided me with some important opportunities: from learning new skills through training and mentoring, to participating in new international collaborations and building on the experience of my early post-graduate studies. These skills I have been able to pass on to my peers and so contribute to capacity building efforts here in Africa.
During my Master’s degree (2011-2014), before GCRF START came into being, I got my first taste of international collaboration whilst on a Fulbright scholarship in the USA, working with talented enzymologist, Prof Audrey Lamb. In the Lamb laboratory I was introduced to the wonderful world of protein X-ray crystallography. This technique allows one to use powerful scientific instruments to bombard the sample of interest with X-rays and compile a zoomed-in three-dimensional picture (more than ~1,000,000 times the zoom power of a regular laboratory microscope) of a protein and gain insight into its structure, which is important in understanding the chemical reactions that it might entail. These details can help one understand some of the broader biological complexities that occur in healthy, as well as diseased cells. I think in many ways this was a major eye-opener as to the multiple opportunities that one has access to, if one takes the time and effort to make contact with a leading expert in the field, and it can certainly open many doors. And this for me was a great parallel to South Africa in that although we are a developing country, we have an immense pool of talented young scientists that I am confident will solve many of the global health pandemics and challenges we face in society today – from drug resistance, HIV vaccines and Tuberculosis (TB), to anti-malarial drugs and even cancers.
Following the completion of my PhD in 2019, at Stellenbosch University in the Department of Biochemistry, I was introduced to the GCRF START grant through my supervisor, Prof Erick Strauss, who is a GCRF START Co-I and the Group Leader of the Strauss Laboratory. This has certainly been one of my highlights in my research career, not only as a highlight for the cutting-edge science capabilities I experienced first-hand when I visited Diamond Light Source (Diamond) in the UK, but equally importantly, for the genuine interest, support, and encouragement that the GCRF START team provides. Many of the beamline scientists at Diamond have freely shared their scientific expertise and hands-on experience in assisting me to get the most out of the experiments that I conducted at Diamond, and I am enjoying passing these skills on to other researchers here in South Africa.
The Strauss Laboratory primarily relies on outsourcing many of the structural biology related aspects of the projects that we work on. Therefore, through the GCRF START grant, it has been very gratifying using the training that I received during my Master’s degree on my Fulbright scholarship in the USA together with the new skills I am gaining as a START Post-doc, to help develop our own structural biology capabilities within our department at Stellenbosch University. This, of course, has led to multiple opportunities for training the next generation of structural biologists, as well as opening the opportunity to collaborate with colleagues within our department and hopefully in the future, colleagues across the African continent. Being one of the more senior researchers in the Strauss Laboratory I have had the opportunity to train several junior and senior members in our laboratory such as Master’s student, Karli Bothma, in our research group.
Being formally trained in structural biology, I have also been able to assist and team up with another GCRF START PDRA, Dr Anton Hamann. Anton originally trained as an organic chemist (now retrained in the art of protein X-ray crystallography), and so it has been very rewarding training and learning together with a fellow colleague funded by GCRF START. It is these networking connections with other researchers that often lead to career-long collaborations.
The GCRF START grant has allowed us to initiate exciting new collaborations on my projects, as well as visit and use Diamond Light Source for the first time. Through Diamond’s X-ray structure-accelerated, synthesis-aligned fragment medicinal chemistry (XChem) facility, under guidance from GCRF START Co-I, Prof Frank von Delft, we have been able to fast track the identification of novel compounds that we are currently pursuing further as promising antimicrobials against Staphylococcus aureus. In South Africa, more than 50% of bacterial infections isolated in hospital settings are S. aureus strains. S. aureus infections range from mild to life threatening, and the bacteria are notoriously known for their resistance against many of the first-line antibiotics.
The GCRF START grant has in addition enabled us to initiate another new collaboration with Dr Nir London at the Weizmann Institute of Science to develop compounds that target this protein covalently (form an irreversible attachment to proteins). This approach is also based on a high-throughput setup that screens several fragments which contain specific reactive groups. The results of the most reactive fragments are then again fed back into the XChem workflow, whereby one would be able to visualise the compound – protein complex. All these findings help aid the development of potent and specific compounds that could be assessed further in the drug discovery pipeline, and in turn, the discovery of novel antimicrobials to tackle disease challenges both here in Africa and beyond.
It is indeed very exciting — as an African scientist — to have the opportunity to receive training on these cutting-edge techniques, not only in the pursuit of identifying promising antimicrobial compounds but also from a capacity skills development aspect. Learning these particular techniques is very valuable in that it allows me to train and impart the knowledge I have gained to the next generation of scientists in South Africa involved in drug discovery initiatives on the African continent. For example, one of the post-graduate students I passed these new skills to is Nicholas Herbert, who is now an MSc. student at the Africa Health Research Institute (AHRI) in Durban (in KwaZulu-Natal). Nick reports on the impact of this ‘peer-training’ below,
“Being trained on X-ray crystallography has opened my eyes to its very diverse and useful application. Finally seeing the atomic structure of our protein, after the riveting experience of collecting data remotely from our laboratories in South Africa, was an incredibly rewarding experience and I am grateful to have been taught such a technique by Dr Balcomb. I will eagerly be looking for the next opportunity to gain further experience in X-ray crystallography.”
We are thrilled too that – through the GCRF START Grant – these new collaborations and preliminary data have allowed us to submit a grant application (2nd Drug Discovery Call – Grand Challenges Africa Round 10). This program is a partnership between the African Academy of Sciences (AAS), the Bill & Melinda Gates Foundation (BMGF), Medicines for Malaria Venture (MMV), and the University of Cape Town (UCT) Drug Discovery and Development Centre (H3D)) – so watch this space!
Commenting on the impact over the course of the collaboration with the GCRF START grant, Professor Erick Strauss, Group Leader at Stellenbosch University’s Strauss Laboratory, said,
“We are extremely thankful for the opportunities we’ve already had as part of the GCRF START grant and are looking forward to what it will unlock in the future.”
Read about the UN’s Sustainable Development Goals for Health and Wellbeing here.
 Int J Infect Dis. 2018 Aug; 73:78-84. doi: 10.1016/j.ijid.2018.06.004
And why collaborating with young female scientists in Africa is reaping great results.
Timed to coincide with UN International Day of Women and Girls in Science on 11 Feb, and to inspire more female students to study and work in science, the GCRF START grant has announced the results of its three year project launched in March 2019. To date it has directly collaborated with nearly 50 young African research students and given access to almost 100 synchrotron beamline sessions. Over half of START’s students are female scientists who are demonstrably changing perceptions and increasing the possibilities for women choosing long term STEM research careers.
“Globally UNESCO figures show that only 30% of researchers are female and they occupy only 20% of STEM leadership positions. These figures are even lower in many countries in Africa underlining how important it is to challenge women’s under-representation. Young female African scientists are vital both for their research and as role models and mentors for the next generation. So we are really delighted to see many of the young women we collaborate with through the START grant, making great strides and achieving some incredible results in the fields of structural biology and energy materials”
Prof. Chris Nicklin, Science Group Leader and Principal Investigator (PI) in the GCRF START (Synchrotron Techniques for African Research and Technology) grant programme.
GCRF START is an innovative collaboration between Diamond Light Source, the UK’s national synchrotron, and higher education and research partners in the UK and Africa. It is funded by the Science and Technology Facilities Council under the UK government Global Challenge Research Fund programme. It is enabling and inspiring researchers from this, and the next generation of Africans to choose careers in science and find African and joint UK-African solutions to some of the world’s most pressing health and environmental challenges. A key goal is to challenge the under-representation of women in science by providing access to world-class scientific facilities, funding, training, mentoring, and unique international collaborations. Great results have been achieved in a relatively short space of time because START scientists get access to specialist technologies and facilities not available on the African continent – like beamtime on the Diamond synchrotron.
One indicator of the success of the programme is how the tiny community of structural biologists in Africa has grown across South Africa including a whole new generation of women. Similarly, in energy materials, the gender factor has traditionally been a barrier, so having young women entering materials science is great progress. Additionally, all these women participate in outreach and act as role models to inspire girls to choose STEM careers. Female START successes include:
Priscilla Masamba has solved the partial structure of a protein from Schistosoma mansoni, a parasite responsible for the debilitating disease Schistosomiasis (Bilharzia) which is endemic in more than 78 countries, with an estimated 4 million people infected in South Africa alone. Her work will contribute to drug discovery efforts and is notable because she was the first student from the University of Zululand, South Africa, to use the Diamond synchrotron, which she did remotely from a lab in South Africa learning many scientific techniques for the first time;
Thandeka Moyo is part of a leading South African team working on HIV/AIDS vaccine research and is currently researching Covid-19; Originally from Zimbabwe, Thandeka mentors early career female scientists and is a role model for school children;
Gugulethu Nkalais investigating new generation renewable energy storage systems in South Africa to help close the energy poverty gap; she is active in inspiring girls into STEM;
Lizelle Lubbe is a GCRF START grant-funded Postdoctoral Research Fellow in Structural Biology (a scarce skill in Africa). Lizelle is one of only a handful of scientists in Africa as a whole trained in single particle cryo-EM – a cutting-edge technique for determining the structure of proteins;
Michelle Nyoni is studying energy materials to improve the performance of Lithium-ion batteries for portable electronics and renewable energy sources to make them affordable and improve their environmental footprint to tackle climate change. Michelle is also a chemistry lecturer in Zimbabwe.
“The GCRF START grant has been a game-changer for young African scientists, particularly from under-represented groups such as female, and black scientists, enabling them to enter the fields of Structural Biology and Energy Materials and thrive.”
GCRF START Co-Investigator, Prof. Edward D. Sturrock from the University of Cape Town, South Africa.
One young scientist working with START, Gugulethu Nkala, is an Energy Materials PhD student from South Africa. The eldest of three daughters and first in her family to go to university, she remarks; “Seeing a black girl in science, makes girls see that there is someone, just like them, who has gone this far. We are breaking barriers that makes science seem unattainable, by being the link between science and society, made possible by funding bodies like the GCRF START grant.”
Access to inclusive quality education and lifelong learning opportunities is a distant dream for many young people across Africa, especially women. Few have the opportunity to finish school, let alone reach university to study world-class science, be mentored by experts or continue to postdoctoral studies. This can be due to lack of access to resources at home institutions, insufficient grant writing experience, lack of mentors or supervisors, inadequacy of facilities, and poor postdoctoral pay.
“It is important to support and mentor young women in science especially since women are largely under-represented, particularly in the case of the physical sciences, the field in which we work. I found that having access to synchrotrons and also building international collaborations through the GCRF START grant programme has not only allowed the young women that I work with to gain better skills but they also grow in confidence about their abilities”
Professor Caren Billing, Energy Materials Research Group Co-Principal Investigator (Co-PI), Lecturer and Associate Professor in the School of Chemistry at the University of the Witwatersrand, South Africa.
The GCRF START grant supports young scientists working on key Climate, Energy, Health, and Education challenges in line with the UN’s Sustainable Development Goalsby building partnerships between world leading scientists in Africa and the UK and enabling them to work together on research using synchrotron science. The project focuses on developing and characterising new energy materials, for example in the development of solar cells or improving energy efficiency through novel catalysts, and structural biology to understand diseases and develop drug targets for better treatments and potential vaccines. The START programme is grant-funded through the UK’s Global Challenges Research Fund (GCRF) and delivered by UK Research and Innovation (UKRI) through the Science and Technology Facilities Council (STFC) and the UK’s national synchrotron facility, Diamond Light Source.
“Science is a collaborative discipline. Yet science is being held back by a gender gap. Girls and boys perform equally well in science and mathematics – but only a fraction of female students in higher education choose to study sciences. To rise to the challenges of the 21st century, we need to harness our full potential. That requires dismantling gender stereotypes. It means supporting the careers of women scientists and researchers.” United Nations, Secretary General, Antonio Guterras, United Nations International Day of Women and Girls in Science – 11 February
“Hard work, dedication and endless opportunities, I can now say I am on the path to previously unimaginable goals. A dream come true! We are breaking the barriers that make Science seem unattainable, by being the link between Science and society, made possible by funding bodies like the GCRF START grant.”
Gugulethu Nkala, PhD student in the Energy Materials Research Group at the University of the Witwatersrand, South Africa.
Gugulethu Charmaine Nkala is a PhD student at the School of Chemistry in the Energy Materials Research Group at the University of the Witwatersrand (Wits), South Africa. From Roodepoort, west of Johannesburg, she is the eldest of three daughters, descending, she says, “from a line of great women, whose circumstances did not allow them to proceed to higher education”. Gugu’s great grandmother had to leave school at grade 7 (after she finished primary school) because as a woman it was only seen necessary to be able to write and read letters; Gugu’s maternal gogo (grandmother) was a domestic worker, and her parents were not able to study beyond high school. Gugu says, therefore, “It is with this in my heart, that I have been encouraged to go forth and reach places that their hopes and dreams could not take them. I have a story to tell, a story to finish.” Gugu is determined to share her story and be a role model to motivate women and girls to take up science.
Gugu’s research focuses on improving renewable energy storage systems to make them more efficient, affordable, safe and environmentally friendly in order to address the energy poverty gap in Africa, in line with the UN’s Sustainable Development Goals. Under the PhD supervision of GCRF START grant Co-I, Professor Dave Billing, Prof Caren Billing and Dr Roy Forbes, her particular interest is: ‘The Use of Fused Bimetal Phosphate-based Ceramics for Solid-State Electrolyte Applications’, through which she investigates batteries as energy storage devices for applications such as phones and tablets, with the aim of fabricating a solid-state electrolyte that can be used in an all-solid-state battery (a battery in which the electrodes and electrolyte are solid).
It is with the GCRF START grant, that Gugu has been able to visit the UK’s national synchrotron, Diamond Light Source (Diamond), and has also attended START related workshops and meetings which have furthered her research knowledge and skills, introducing her to international collaborations and research networks overseas and in Africa – experiences Gugu describes as “beyond invaluable in my studies” and a “privilege”. In the next few weeks, some of Gugu’s research materials are set for analysis using X-ray Absorption Spectroscopy (XAS) techniques on the B18 beamline at Diamond as part of a Beamtime Allocation Group (BAG).
Gugu is the first in her family to go to university, an achievement she attributes to the culture of her school and the support of her parents who invested in their children’s school education, leading her to become one of the top pupils in her school and developing her love of STEM.
“My grandmother encouraged my father to enable the education of the ‘girl-children’ in our family,” Gugu explains, “and I was interested in the physical sciences in particular – physics, chemistry, biology – subjects not many girls go for. From an early age I was inquisitive, and my parents nurtured that side and were engaging and supportive. This was formative, coupled with the school I went to which instilled discipline, resilience and, above all else, ‘the spirit of chasing one’s greatness’.”
Gugu’s aunt assisted with university fees in Gugu’s first year when Gugu’s father was retrenched as a machine minder in 2012, and what followed is a journey of tenacity and resilience into the world of energy materials science – an unusual career-path for a woman in Africa. Through bursaries and working hard in her vacations to fund her studies, despite various setbacks, Gugu has been able to accomplish her dreams and achieve great things. Testament to her hard work, she has received various awards and is now studying for her PhD, receiving mentorship from her supervisors and mentors, Prof. Caren Billing and Prof. Dave Billing and funded by a bursary.
“I was sold at an early stage on material science – I fell in love with it! Being part of Prof Dave Billing’s group helped me to look at things from different perspectives,” Gugu enthuses.
Gugu loves working with the Energy Research Group at Wits and collaborating with the GCRF START grant because she is encouraged to dream big and believe what some might seem is impossible to achieve for a young woman in Africa.
“Earlier in my academic career, I dreamed of being the head of a Research and Development department in South Africa. However, being in my research group with the teachings and mentoring of my supervisors has shown me that I can aim higher, dream the once impossible,” she explains.
Closing the energy poverty gap in sub-Saharan Africa
Gugu’s motivation behind her research project comes from the desire to find solutions to energy challenges in sub-Saharan Africa, starting in South Africa where a large population, especially in the rural areas, is still without access to basic commodities such as electricity, sanitation and health care, something that particularly impacts women. In these parts, firewood is still the most used source of energy for cooking, as well as paraffin lamps and candles for lighting. Approximately 80% of South Africa’s electricity relies on coal, with the resulting environmental challenges that this brings. Shifting the focus towards improving renewable storage systems (such as solar, wind, hydrology, and others) would be beneficial, not only to the planet but to the health and livelihoods of human populations.
In order to bring renewable energy sources into the energy mix, the focus of scientific research needs to be moved towards improving renewable storage systems such as batteries. The most widely used rechargeable batteries contain toxic electrolytes such as sulfuric acid in lead acid batteries and lithium perchlorate in lithium-ion (Li-ion) batteries. The drawbacks of current Li-ion batteries are, amongst others, their costs and reliability concerns, which are attributed to the deterioration of battery devices over relatively short periods of time. The constant replacement of these materials has a negative impact on the environment.
Commercial batteries use an organic liquid as an electrolyte and these organics compromise the safety of the battery. Increasingly, alternative electrolyte materials have received great attention, more specifically solid-state electrolytes. The use of solid-state electrolytes would eliminate the need for a separator, avoiding the use of organic electrolytes and therefore the use of safer batteries that do not pose any leakage risks.
In Gugu’s studies, she is working on a material based on the sodium (Na) superionic conductor (NASICON) structure type, namely lithium titanium phosphate LiTi2(PO4)3 (LTP). This involves investigating its properties as a potential material for a solid-state electrolyte in Li-ion batteries to address the challenges that arise from current batteries. Gugu’s research includes understanding the Li-ion conductivity of the class of materials being studied under different environmental conditions such as temperature, and how the materials behave in different atmospheres, specifically air and nitrogen, an inert atmosphere. The research also involves exploring ways in which lower cost batteries can be synthesised.
Breaking down barriers and giving back to the community – being a role model
Gugu’s involvement in university science outreach projects to schools has focussed on educating learners and teachers from different backgrounds about the importance of renewable energies. Organised through the Energy Materials Group, Gugu is enthusiastic about motivating and assisting young people from disadvantaged backgrounds to fulfil their dreams in the way she herself was encouraged from a young age to fulfil her goals. This is also a way for Gugu to give back to the community, as well as learn about community-based perspectives and how the Group’s research might impact everyday lives.
“Most of these children come from impoverished backgrounds and do not have role models in their society who they can look up to, to enable them to see that their dreams are not so far out of reach, and that their circumstances do not have to be a tight leash that keep them away from dreaming bigger,” Gugu explains. “Seeing a black girl in science, makes them see that there is someone, just like them, who has gone this far. We are breaking barriers that makes science seem unattainable, by being the link between science and society, made possible by funding bodies like the GCRF START grant.”
One of the outreach science demonstrations was a solar panel station where people could charge their phones. This enabled the scientists to explain the science behind solar panels, as Gugu describes below,
“The students were excited and astonished by the fact that one can use the sun to power their devices. Seeing their reactions and being part of something so special made me come back with the understanding of just how deep our impact in society could be, educating one child at a time.”
Attending ANSDAC workshops in Africa and visiting Diamond Light Source in the UK
In 2018, Gugu attended the first African Neutron and Synchrotron Data Analysis Competency workshop (ANSDAC), where the GCRF START grant is amongst the funding bodies. This workshop focuses on teaching African scientists about synchrotron techniques and how to analyse the results obtained, bringing in experts in different field techniques to ensure the best teaching possible. The students not only learn about synchrotron science but also how to analyse the data. Gugu also took an online course through Brookhaven Laboratory in the USA, which, she says, “forced us to push ourselves and the boundaries of science, making the best of whatever resources we had.”
From the 10-12 March 2020, just before the Covid-19 pandemic lockdown, Gugu was one of the attendees of the XAS workshop hosted and taught at Diamond on the Harwell Campus, the UK’s world-class innovation hub.
“Visiting Diamond in the UK was a life changing opportunity,” Gugu enthuses. “It took me from a position of remotely learning about synchrotrons and taking virtual tours, to experiencing this first-hand.”
“You read about it in textbooks,” she continues “and then I was standing in front of it and there was a glorious opportunity to take a tour inside the facility. One of the topics we covered at the ANSDAC workshop was XAS, so I already had a good basis for the workshop at Diamond. This background knowledge allowed me to learn more about the technique and the data analysis, starting from a position of knowledge, once again, enabled by the GCRF START grant. It was wonderful to consult the beamline scientists and do hands on tutorials; to be in the same room as the people one looks up to.”
Not only has the GCRF START grant enabled Gugu to visit the synchrotron of her dreams, but it has also fundamentally impacted her skills and abilities, and her perspectives on her future career path. Visiting Diamond, Gugu says, has shown her new horizons of learning which she wants to bring back to the science community in Africa.
“The GCRF START grant has enabled me to move forward from attending online courses by Brookhaven National Laboratories (Applications of Synchrotron and Electron-Based Techniques 2018) to actually running X-ray diffraction (XRD) – an analytical method used to determine the nature of crystalline materials – and atomic Pair Distribution Function experiments – an X-ray scattering technique that can be used to study the local structure of materials at the atomic scale,” explains Gugu. “This brings results that take us students closer to answering the fundamental questions in our projects, sharpening our focus and skills to work out what steps to take next in the future.”
Another goal achieved, she says, would be the opportunity to take up a postdoctoral position and work alongside beamline scientists at Diamond on X-ray Absorption Spectroscopy.
“Achieving this goal,” Gugu says, “would be the completion, or the start of my story, of my grandmothers’ stories. The story of Black Girl Magic!”
With the ongoing Covid-19 pandemic in 2020 and 2021, Gugu and her peers are thankful for the support of their supervisors, despite the challenges and delays that lockdowns and restrictions have brought, such as restricted access to campus to undertake experiments and having to book precious time slots to use laboratories.
“Our supervisors have been checking in on us regularly, encouraging us and helping us not to panic. They have been going above and beyond to try to ensure we have the software to process our data. This has been pretty amazing support,” Gugu reports.
Commenting on Gugu’s progress and ambitions, Prof Caren Billing says, “Gugu got back from attending an XAS training workshop at Diamond Light Source the week before our airports were closed due to the Covid-19 pandemic (March 2020). The visit to Diamond through the GCRF START grant has raised her expectations of herself and her work to new levels. She has been presenting talks at our group meetings to inform others of what she has learnt and brought a great amount of enthusiasm with her.”
 Prof Dave Billing is Professor in the School of Chemistry and Co-PI of the Energy Materials Research Group at the University of the Witwatersrand (Wits), South Africa, and also Assistant Dean in the Faculty of Science at Wits.
 Prof Caren Billing is Associate Professor in the School of Chemistry at the University of the Witwatersrand, South Africa
 The support of the DST-NRF Centre of Excellence in Strong Materials (CoE- SM) towards this research is hereby acknowledged. Opinions expressed and conclusions arrived at, are those of the author and are not necessarily to be attributed to the CoE- SM.
Luo, X., Wang, J., Dooner, M. and Clarke, J., 2015. Overview of current development in electrical energy storage technologies and the application potential in power system operation. Applied Energy, 137, pp.511-536.