South African scientists show ‘gene-kissing’ impacts gene activation

 

In a ground-breaking discovery that will have a major impact on our understanding of the regulation and function of our genes and DNA – our genetic blueprint – a group of scientists in South Africa is the first to show that when genes interact in three dimensions, or engage in so-called ‘gene kissing’, this has a major impact on how genes are switched on inside the cell. This landmark finding appears in the 24 October 2013 issue of the journal Cell, one of the world’s most prestigious research publications.

This is only the fifth South African-affiliated article that has ever been published in Cell, and one of just two articles in three decades to feature an all-South African-based cast.

A long-standing question in biology is whether ‘gene kissing’ is a cause – or simply correlated – with gene activation. This question was finally answered when a team led by Dr Musa Mhlanga, CSIR gene expression and biophysics research group leader, together with a collaborator at the University of the Witwatersrand faculty of Health Sciences, performed ground-breaking experiments to show that ‘gene kissing’ can switch genes on. The discovery sheds light on how genes change from inactive to active states, and how different genes can coordinate their activity simultaneously.

Within each of our cells lies an incredible 1.2 metres of tightly coiled DNA, shrunk to a size one fiftieth that of a grain of sand. These genes encode our physical traits, such as eye colour or blood type. However, DNA also codes for genes that function constantly to keep us alive. These need to be switched ‘on’ and ‘off’ by the cell as needed. How gene activity is regulated has been the subject of intense study for many years, and scientists have suspected for some time that the physical contact between genes, or ‘gene kissing’ could play a role.

“DNA is coiled and tangled like spaghetti inside the cell,” explains Prof Marc Weinberg from the University of the Witwatersrand and co-author of the study. “So, there are many places where the DNA touches and intersects. These interactions could be crucial to how the information in the DNA is read and interpreted by the cell, but this had never been shown before.”

State-of-the-art microscopes, which were custom-built in South Africa by Dr Mhlanga’s group, were an important tool in being able to achieve single-molecule resolution in imaging this gene activity by peering deep into the nucleus of cells. These tools enabled them to see the activity of even a single gene, among the 30 000 human genes. Then, using DNA nucleases – nicknamed ‘molecular scissors’ – they were able to cut DNA at precise locations to prevent genes from making contact.

According to lead author and Claude Leon postdoctoral fellow, Dr Stephanie Fanucchi, “being able to alter the genetic code in this manner is the ‘holy grail’ of molecular biology, but has only recently been made possible”. In this way, some genes were shown to ‘kiss’ in order to be switched ‘on’ and surprisingly in this instance, one gene acts as a master gene to orchestrate the activity of other genes. Co-author and Claude Leon postdoctoral fellow, Dr Youtaro Shibayama, remarks, “We jumped on the technology of producing efficient ‘molecular scissors’ as soon as it became available last year, and our integrated expertise in microscopy and molecular biology, combined with creative thinking, gave us a unique advantage over our peers in conducting this study.”

The group is focusing some of its efforts on what this work could mean for human health. In late 2011, Dr Mhlanga’s laboratory at the CSIR was the first in Africa to generate induced pluripotent stem cells, a type of stem cells which could hold the key to growing new tissue to replace that which is diseased – and can even be used to create disease models ‘in a dish’. This occurred several years after the initial breakthrough in this respect in Japan. Combined with the knowledge to alter the genetic code and control gene activity, exciting novel experiments and therapeutic avenues can be envisaged for the future. Scientists will gain a deeper understanding of cancer, chronic diseases such as diabetes, allergy responses and a host of other diseases and important cellular processes. This important research, which has now been published, gives scientists across the globe new knowledge and tools about how genes behave and how to direct them, paving the way for future discoveries.

Senior author, Dr Mhlanga, is passionate about what this discovery means, globally and to South Africa: “This work germinated from a desire to answer a fundamental long-standing question in gene regulation. Our goal is that scientists in Africa should not simply be consumers of fundamental scientific discoveries; rather they should be active contributors and producers to this body of basic scientific knowledge. We would like to train the next generation of scientists in Africa to become excellent scientists who routinely produce ground-breaking work. In this endeavour, we are very grateful for the continued support we receive from the Department of Science and Technology Emerging Research Area programme for several aspects of this work over the last few years.”

The Minister of Science and Technology, Mr Derek Hanekom says this achievement makes the country proud.

“We are proud of this achievement made through the pioneering research of the CSIR and its partners. We are confident that this important finding will shed light on and give scientists and researchers greater understanding of the treatment of a number of diseases, as well as insight into important cellular processes,” says Hanekom.

The paper is titled, Chromosomal Contact Permits Transcription between Coregulated Genes, and is authored by Stephanie Fanucchi, Youtaro Shibayama, Shaun Burd, Marc S Weinberg, and Musa M Mhlanga.

Story by: T. Tsedu, CSIR media release, October 2013

Researchers unite to stop malaria transmission

 

Experts at the CSIR and the universities of Pretoria (UP) and Witwatersrand (Wits) are pooling their skills in a new project to find compounds for drugs that can block malaria transmission between humans and mosquitoes.

Malaria is preventable and treatable. Yet, it infects millions and kills hundreds of thousands of people every year, while increasing drug resistance might soon limit our treatment options. Researchers have realised that, if they want to eradicate this disease, they need to look beyond treatment to drugs to block transmission between humans and mosquitoes.

Dr Dalu Mancama, who heads the CSIRs biomedical technologies research group, says the aim of the Gauteng Gametocyte Consortium is to focus on specific stages in the life cycle of Plasmodium falciparum, the malaria-causing parasite which is transmitted from mosquitoes to people and vice versa.

The parasite has a complicated lifecycle. When a mosquito bites, the parasite is passed into the human and develops in the liver for some weeks. Initially there are no symptoms to indicate that the person has been infected. The parasite is then released into the blood stream where it multiplies quickly and the symptoms of malaria become obvious, hydroxyzine belongs to the class of medications called antihistamines. it is used to relieve itching and other symptoms caused by allergic conditions.says Mancama.

These parasites are called gametocytes when they are circulating in the blood stream at their sexual reproductive stage, ready to be picked up by the Anopheles mosquito when the infected person is once again bitten. They then reproduce in the mosquito and the life cycle of new parasites commences.

The consortium has established local capacity to test,  in advanced infection models, compounds which researchers hope could disrupt the parasites life cycle and block transmission in future. Over the next two years they will test thousands of compounds provided by local South African researchers as well as libraries of compounds obtained from pharmaceutical companies.

We have developed a model in vitro which allows us to rapidly identify drugs that have the most potential for further development. The idea is to develop drugs that work on different metabolic or biological processes in the gametocyte, to minimise the potential for future drug resistance.

In South East Asia there is already resistance to artemisinin-combination therapy, the newest and now standard anti-malarial drug on the market, and the fear is that this resistance can spread.

There are several stages during drug development. During the early development stage, researchers get rapid baseline information about the viability of a compound. The consortium has established a knowledge base in Gauteng consisting of molecular biologists, entomologists, analysts, chemists, biochemists and laboratory infrastructure.

In future, instead of referring parts of the testing to different countries, much of this can be done locally in Gauteng. We grow the parasites in flasks and once they reach the stage of maturity needed for testing, we split them into 96-well plates and expose the parasites to the different compounds. We then add various reagents to allow us to establish whether the parasites have survived the exposure or not, Mancama explains.

For the gametocyte stage, we use dyes which mimic a substrate which is normally found in parasites. After administering the drug, we expose the gametocytes to the dye. The parasites take it up and process it as if it were a normal endogenous substrate. During the processing, the gametocytes produce a metabolite which we can pick up fluorescently. The metabolite fluoresces at a certain wavelength.

Higher florescence indicates higher parasite activity and vice versa. It is a way to figure out if the parasite is alive or dead.

The group will also collaborate with researchers who look at other life stages of the parasite, for example when it develops in the mosquito just before being transmitted to humans.

The consortium is funded by the Medical Research Council and the Medicines for Malaria Venture (MMV). The latter focuses on developing and delivering new drugs against malaria.

Mancama says the researchers have done preliminary work and the testing of compounds is about to start. He leads the project along with Prof Lyn-Marie Birkholtz from UP and Prof Theresa Coetzer from Wits who specialise in gametocyte biology and advanced assays. They work in close collaboration with researchers at the NICD, and various leading groups and organisations abroad.

According to the World Health Organization an estimated 219 million malaria cases occurred globally in 2010. The disease killed about 660 000 people, most of them children under five years of age.

Story by: D. Mancama, CSIR News, October 2013

Proteomics Bioinformatics Workshop facilitated by world renowned expert

 

 

As part of the ACGT’s drive to build a sense of community among national proteomics stakeholders and address training needs in the field, a Proteomics Bioinformatics Workshop was recently held at the University of Pretoria’s Bioinformatics and Computational Biology Unit (BCBU).

The three-day workshop was facilitated by Prof Lennart Martens, a world-renowned bioinformatics expert, who is affiliated to the Flemish Institute for Biotechnology (VIB) and Ghent University, Belgium. The Workshop was a logical continuation of training hosted by the ACGT, and linked very well to the national workshop facilitated by Prof Kathryn Lilley, of Cambridge University, hosted in the two-week period preceding.

The workshop covered a range of topics, which included the principles of mass spectrometry and proteomics. This was an excellent introduction for those who are in the initial stages of their proteomics experiments. These principles were also important for considering different statistical approaches to data analysis; which were covered in detail later in the workshop.

The workshop included daily practical sessions following introduction of different proteomics principles and considerations in the lecture sessions. Course participants were also introduced to open source software developed by Prof Martens and his team.

Feedback from participants was extremely positive. Some of the participants had this to say about the workshop:

          “The workshop was of a very high quality and was very professionally organised and presented.”

          Prof Lennart Martens is a true expert in Proteomics-Bioinformatics field. For someone like myself without a lot of background in the field, to be able to follow and understand his lectures says it all.”

          “It was an excellent experience to attend this workshop. I really appreciate efforts put by ACGT and CSIR to bring researchers together to attend these workshops. Thank you very much.”

The participants included students as well as principal investigators who have been active in the field for some time. With the ACGT’s efforts of trying to reach the proteomics community at a national level, the participants included delegates from the ACGT partner institutions as well as other institutes such as the University of the Western Cape and the University of Fort Hare. 

The ACGT is currently planning the proteomics workshops and training events for 2014. For more information on all proteomics related events, please contact Mr Thabo Khoza at .

Please also visit (and join) the LinkedIn page: Proteomics SA.

 

Proteomics Bioinformatics Workshop facilitated by world renowned expert

As part of the ACGT’s drive to build a sense of community among national proteomics stakeholders and address training needs in the field, a Proteomics Bioinformatics Workshop was recently held at the University of Pretoria’s Bioinformatics and Computational Biology Unit (BCBU).

The three-day workshop was facilitated by Prof Lennart Martens, a world-renowned bioinformatics expert, who is affiliated to the Flemish Institute for Biotechnology (VIB) and Ghent University, Belgium. The Workshop was a logical continuation of training hosted by the ACGT, and linked very well to the national workshop facilitated by Prof Kathryn Lilley, of Cambridge University, hosted in the two-week period preceding.

The workshop covered a range of topics, which included the principles of mass spectrometry and proteomics. This was an excellent introduction for those who are in the initial stages of their proteomics experiments. These principles were also important for considering different statistical approaches to data analysis; which were covered in detail later in the workshop.

The workshop included daily practical sessions following introduction of different proteomics principles and considerations in the lecture sessions. Course participants were also introduced to open source software developed by Prof Martens and his team.

Feedback from participants was extremely positive. Some of the participants had this to say about the workshop:
– “The workshop was of a very high quality and was very professionally organised and presented.”
– “Prof Lennart Martens is a true expert in Proteomics-Bioinformatics field. For someone like myself without a lot of background in the field, to be able to follow and understand his lectures says it all.”
– “It was an excellent experience to attend this workshop. I really appreciate efforts put by ACGT and CSIR to bring researchers together to attend these workshops. Thank you very much.”
The participants included students as well as principal investigators who have been active in the field for some time. With the ACGT’s efforts of trying to reach the proteomics community at a national level, the participants included delegates from the ACGT partner institutions as well as other institutes such as the University of the Western Cape and the University of Fort Hare.

The ACGT is currently planning the proteomics workshops and training events for 2014. For more information on all proteomics related events, please contact Mr Thabo Khoza at .

Please also visit (and join) the LinkedIn page: Proteomics SA.