ValitaCHO: Faster and cheaper manufacturing of biopharmaceuticals using next generation “super” CHO cell lines generated using a novel directed evolution and synthetic biology strategy

The biopharmaceutical industry is rapidly growing and is crucial to the well-being of global citizens. Biotherapeutics offer significant advantages and we now have the theoretical toolkit to treat almost all diseases. Significant challenges exist in transferring it to a viable solution.

Currently over 70% of the commercial biotherapeutics are manufactured using Chinese Hamster Ovary (CHO) cells, but it is widely acknowledged that in their current format this is unlikely to continue. As the complexity increases, the economics of current CHO based biomanufacturing further deteriorates and, as we prepare for more futuristic applications, the CHO expression system needs to be significantly improved or to be completely replaced.

The key objective of this project is to generate “super” CHO cell lines for improved biopharmaceutical production. Herein, we describe an approach to utilise all of the knowledge generated to date on CHO cells and to evolve this to develop a cell line more fit for purpose, in terms of both cost and production capacity.

Contact details:
Deepak Balaji TG PhD (KU Leuven Belgium)
Marie Curie Global Individual Fellow (2020-2023)
ERA Leader Synthetic Biology
Centre Manager – CSIR Synthetic Biology and Precision Medicine Centre
CSIR NextGeneration Health
Pretoria, South Africa
email:

 

 

Drug repurposing for Cancer Precision medicine: High-Throughput Drug Screening as an integrative precision medicine platform in drug repurposing for South African cancer patient cohort.

Optimizing Drug discovery and Translation is one of the key tracks in Global Challenges Annual meeting 2019 and is the critical factor in achieving UN Sustainable Development Goals 3 Good Health and Well Being. WHO reports Cancer is the second leading cause of death globally with the estimated 9.6 million deaths in 2018 (1 in 6 death is due to cancer). In additional, 70% of mortality from cancer occur in low- and middle-income countries such as South Africa.

Relevance to the low- or middle-income country setting and Grand Challenges: Recent report from Discovery Medical Schemes states that cancer causes more death in South Africa than HIV, Tuberculosis and Malaria. Leukaemia is one of the top ten most common cancer in South Africa. In addition, leukaemia is the most common childhood cancer (25.4% of all cancers) in South Africa, which is similar to rates in other countries.

Currently, there is drive at South Africa by DSI, CSIR and MRC to establish a precision medicine program that would address the needs of South African Patient cohort. Our functional precision medicine strategy is designed to directly identify tailored drug regimens that target individual patient´s cancer cells and give benefit to the same donors by supporting clinical decision-making.

We aim for this project to serve as a proof of concept to showcase whether individually designed high throughput drug sensitivity screening along with microfluidics based single cell drug screening can provide patient benefit with limited material available and to build competence on existing drug sensitivity screening at CSIR using newly developed platform technologies such as microfluidics based single cell drug screening. The proposed project is therefore well aligned with the strategy of present drive of South African Precision Medicine initiative.

Contact details:
Deepak Balaji TG PhD (KU Leuven Belgium)
Marie Curie Global Individual Fellow (2020-2023)
ERA Leader Synthetic Biology
Centre Manager – CSIR Synthetic Biology and Precision Medicine Centre
CSIR NextGeneration Health

Rural school children to benefit from comprehensive nanotechnology water purification, leading to an energy-efficient commercial solution as part of an NRF flagship project

From 2014 to 2016, nanotechnology researchers led by Prof Sabelo Mhlanga from the Department of Applied Chemistry at the University of Johannesburg (UJ) will be developing a sustainable water purification solution for rural schools to help combat ilness in local inhabitants and school chidren due to untreated drinking water. This project forms part of the National Research Foundation’s Nanotechnology Flagship awarded to Prof Mhlanga, titled ‘Energy efficient nanofiltration water purification technologies for rural communities in South Africa.’

The project aims to install a nanotechnology water filtration system at each of five school identified in Mphumalanga. These sites were selected as they rely entirely on borehole water in summer. In winter the borehole water sometimes runs dry. The five schools selected, represent areas at risk of water-borne diseases and will be used as case studies for the the NRF Flagship. The filtration system provides water into a completely new storage tank.The treated water will be free of heavy metal contamination, viruses, bacteria and organic pollutants. It should be completely safe to drink and wash hands with. Tanks and filtration material will be designed to function autonomously and if needs be, solar powered systems may be developed to insure that electricity is not required to power the fitration process.

In addition, some of the schools have land which they could use to grow vegetables and supplement their feeding schemes. One of the projects will investigate recovering  nutrients from urine by precipitation of K-struvite as well as water by the use of solar domes using solar energy only. The recovered water can be used for irrigation. A fertilizer will be produced from the recovered nutrients

Prof Mhlanga plans plan to demonstrate a system that can be commercialised within the NRF flagship project. To do that Mhlanga has called on international experts in developing nanotechnology for water purification and commercialisation of such systems in developing countries. Professor Arne Verliefde from Ghent University will form part of the multi institutional team. Prof Verliefde brings with him, expertise in both the biosciences and engineering. Four of his Masters students will travel to UJ on an exchange basis until May 2014. Prof Verliefde will be traveling to SA a few times during the project. In addition Prof Mhlanga has also engaged Professor Thalappil Pradeep, who is a professor of Chemistry from the Indian Institute of Technology in Madras. Prof Pradeep will be taking up a chair in Nanotechnology and Water Research and has expertise is in developing nanotechnology filtration systems for areas affected by heavy metal pollution. He has a company mass-producing these systems.

Local researchers on the project include Prof Titus Msagati, Prof Catherine Ngila and Dr Edward Nxumalo. Prof Msagati and Prof Ngila from the Department of Applied Chemistry at UJ will carry out the water characterisations and method development of the nanotechnology filtration materials.  Dr Edward Nxumalo will work on the composition of the materials in the nanofilter.

Other collaborators on the project the DST/Mintek Nanotechnology Innovation Centre -Water Research Platform and the newly established Institute for Nanotechnology and Water Research established at UJ.

Contact information:

Professor Sabelo Mhlanga

Associate Professor

Director: DST/Mintek Nanotechnology Innovation Centre – Water Node

Department of Applied Chemistry

University of Johannesburg

Tel: +27 11 559 6187; Fax: +27 11 559 6425

Novel antibiotics by rational drug design

The discovery of new antibiotic drugs is based on the isolation of compounds that are screened for bacteriocidal or bacteriostatic activity. These compounds may either be chemically synthesised or isolated from nature. An additional route to drug discovery is rational drug design.

Protein structural analysis, active site modification and reaction mechanism studies performed at the CSIR have identified an enzyme as a potential new drug target for the disease. Structural analysis of reaction intermediates has identified novel molecules as potential drug candidates with application to tuberculosis, as well as other bacterially induced diseases.

The innovative research and development phase of the project will comprise further structural analysis and molecular modelling of the drug candidates and enzyme, synthesis of the potential drug analogs followed by in vitro enzymatic analysis of efficacy. An analysis of efficacy against growth and the infection process of the pathogen responsible for the disease (Mycobacterium tuberculosis) will also be undertaken.

This project is being undertaken in collaboration with a number of partners in South Africa, with funding from the Innovation Fund.

For more information, contact:
Dr Colin Kenyon, Tel: +27 11 605 2702, Fax: +27 11 608 3020 or
Prof Jan Verschoor, Tel: +27 12 420 2477 Fax: +27 12 362 5302

In 1994 Prof Jan Verschoor of the University of Pretoria (UP), partnered by Adcock Ingram Limited, initiated the tuberculosis (TB) research programme in the Department of Biochemistry at the University. The South African Medical Research Council, THRIP and the National Research Foundation support this tuberculosis research programme.

In 2001, in collaboration with the Heinrich Heine University in Düsseldorf, Germany, a research paper appeared describing the purification of lipid cell wall antigens from the tuberculosis organism and the effects these have on cells of the human immune system.

In 2000 Dr Annemieke ten Bokum, a post-doctoral fellow from the EUR, joined the project, contributing towards understanding the arthritis-type auto-immunity associated with tuberculosis. Dr ten Bokum is also a co-inventor, with Prof Verschoor, of a new approach to the therapy of multi-drug resistant tuberculosis, especially with concurrent HIV infection. The University of Pretoria has filed a provisional patent for this in South Africa, while Dr Chris Parkinson of the CSIR in South Africa has synthetised a first prototype version of the patented principle, which is currently undergoing laboratory testing at UP. Work is currently underway to prove the basic concepts of the patent. This patent is the fourth emanating from this project with the UP tuberculosis research team members as inventors and co-inventors. The previous three patents have been filed internationally in the name of Adcock Ingram Limited.

This resulted in a PhD and MSc at the Universities of Brussels and Gent in Belgium for Dr (MD) Anton Stoltz and Hannelie Korf respectively. They discovered unique morphological and functional changes that the cell wall biolipids of the tuberculosis bacillus brings about in the macrophage target cells of experimental animals. Prof Verschoor, Dr Gilbert Siko and Mr Pieter Vrey visited the Department of Immunology at the Erasmus University Rotterdam (EUR) in The Netherlands to make the resonant mirror biosensor technology applicable to the measurement of biolipids-antibody interaction in tuberculosis.

The purchase in 2001 of a resonant mirror biosensor and multi-well fluorimeter, equally funded by the CSIR and UP, equipped the Department of Biochemistry with access to the latest technology to study quantitative molecular binding interactions in bio-medical research. This instrument proved to be essential to understand the peculiar interaction of patient antibodies to lipid antigens of the tuberculosis bacillus. This work may provide the solution to serodiagnosis of tuberculosis patients, which would contribute hugely to the management of the tuberculosis epidemic.

In 2002 Miss Yvonne Vermaak, a MSc student at UP, and Dr Gunther Schleicher, collaborator and post-graduate medical student from the WITS Medical School in South Africa, published their noteworthy results on the study of tuberculosis patient antibodies against cell wall biolipids as possible surrogate markers for tuberculosis infection.

For more information, contact Prof Jan Verschoor, Tel: +27 12 420 2477, Fax: +27 12 362 5302

Malaria is endemic to large parts of Africa, and is common in the Northern and Eastern parts of South Africa. It is estimated that worldwide, malaria causes up to 500 million clinical cases and an about three million deaths each year, mostly amongst children under five years of age. The direct and indirect costs of malaria in sub-Saharan Africa, according to the 1997 estimates of the World Health Organisation, exceed $US 2 000 million per annum.

Almost all deaths and severe disease incidents of malaria are caused by Plasmodium falciparum.

This species is becoming increasingly resistant to the current anti-malarial drugs and it is unlikely that a vaccine will be available in the near future. In order to counteract a disease of this magnitude, a multi-faceted strategy is required. The application of structural and functional genomics will open up new prospects for the development of novel, more effective drugs.

A major aim of the malaria research programme is to establish a core expertise in anti-malaria drug development and discovery, which includes:

• Bioinformatic and computational analyses of parasitic traits and properties.
• Recombinant expression of native or E coli codon-adapted synthetic genes of malaria proteins.
• Purification and biochemical characterisation of expressed proteins.
• Comparative structural modelling of selected targets (folate and polyamine pathways).
• Drug discovery either by:
• In silico screening of chemical libraries of small molecules (knowledge-based drug design);
• In silico redesign of existing, but less organism-specific drugs used as templates or
• Screening of isolated plant compounds on malaria cultures (novel chemical scaffolds).
• Rationalisation of the mode of action of drug-leads by gene expression profiling experiments.
• Identification and characterisation of new drug targets.

For more information, contact
Prof Braam Louw, Tel: +27 12 420 2480, Fax: +27 12 362-5302 or
Dr Lyn-Marie Birkholtz, Tel: +27 12 420 2479, Fax: +27 12 362 5302

Acquired Immune Deficiency Syndrome (AIDS) is the leading cause of death in humans in the age group 25 to 44.

The causative agent of AIDS is the HI virus, which is a retrovirus consisting of two types – the more pathogenic and widespread HIV-1, and HIV-2, which occurs mainly in West Africa.

According to estimates by the Joint United Nations Programme on AIDS, HIV continues to spread globally and has now been reported in every country in the world. It is estimated that there are 16,000 new HIV-1 infections daily, and 90% of those occur in developing countries. Sub-Saharan Africa had an estimated 22.5 million HIV infected people in 1999. Predicted are that this disease will have a major impact on the economies of developing countries.

The development of an effective treatment regime and a vaccine has been hindered by the extensive variability of the virus. It is this genetic diversity that forms the basis of the subtyping of the virus. Of note is that the strains occurring in the USA and Europe are primarily of subtype A and B, and those of sub-Saharan Africa are mainly of subtype C.

Vaccines developed to date have mainly focused on subtypes A and B, as the majority of work has been carried out in the USA and Europe. Little to no work has been carried out on vaccine development for subtype C, as this is largely a Third World problem. It is believed that any vaccine developed against subtypes A and B would not be effective against subtype C, thereby necessitating the independent development of vaccines for subtype C.

The current project makes use of protein homology modelling, testing of peptide inhibitors, NMR structural analysis, phage display, and a number of other techniques for the development of novel vaccine candidates.

For more information, contact:
Dr Colin Kenyon, Tel: +27 11 605 2702, Fax: +27 11 608 3020