Genome Institute of Singapore’s (GIS) Associate Director of Genomic Technologies, Dr Yijun RUAN, led a continuing study on the human genome spatial/structural configuration, revealing how genes interact/communicate and influence each other, even when they are located far away from each other. This discovery is crucial in understanding how human genes work together, and will re-write textbooks on how transcription regulation and coordination takes place in human cells.

The discovery was published in Cell, on 19 January 2012. The GIS is a research institute under the umbrella of the Agency for Science, Technology and Research (A*STAR).

Using a genomic technology invented by Dr Ruan and his team, called ChIA-PET, the Singapore-led international group, which is part of the ENCODE (ENCyclopedia Of DNA Elements) consortium, uncovered some of the fundamental mechanisms that regulate the gene expression in human cells.

“Scientists have always tried to understand how the large number of genes in an organism is regulated and coordinated to carry out the genetic programs encoded in the genome for cellular functions in our cells. It had been viewed that genes in higher organisms were individually expressed, while multiple related genes in low organisms like bacteria were arranged linearly together as operon [1] and transcribed in single unit,” Dr Ruan explained. “The new findings in this study revealed that although genes in human genomes are located far away from each other, related genes are in fact organised through long-range chromatin interactions and higher-order chromosomal conformations. This suggests a topological basis akin to the bacteria operon system for coordinated transcription regulation. This topological mechanism for transcription regulation and coordination also provides insights to understand genetic elements that are involved in human diseases.”

GIS’ executive director Prof Huck Hui NG said: “This is an important study that sheds light on the complex regulation of gene expression. Yijun’s team continues to use the novel method of Chromatin Interaction Analysis with Paired-End-Tag sequencing to probe the higher order interactions of chromatin to discover new regulatory interactions between genes.”

“This publication describes ground-breaking work by Dr Yijun Ruan and his team at Genome Institute o Singapore,” added Dr Edward Rubin, Director of the Joint Genome Institute in US. “They address the fundamental question of how communication occurs between genes and their on and off switches in the human genome. Using a long range DNA mapping technology called ChIA-PET, the study reveals in three dimensional space that genes separated linearly by enormous distances in the human genome can come to lie next to each other in the cell when it is time for them to become active. I expect this study to move rapidly from primary scientific literature to textbooks describing for future students the operating principles of the human genome. The ChIA-PET technology, that is the telescope used in this exploration of the human genome, is an innovative and powerful molecular technology invented by Dr Ruan and his collaborators.”

The ENCODE is an ongoing project which was awarded to Dr Ruan’s team by the National Human Genome Research Institute (NHGRI), an institute belonging to the National Institutes of Health (NIH, USA). The project was set up in 2003 with the aim of discovering all functional elements in the human genome to gain a deeper understanding of human biology and develop new strategies for preventing and treating diseases. So far Dr Ruan’s team has received over US$2 million towards this project.

The parasite that causes malaria is a genetic outlier, which has prevented scientists from discovering the functions of most of its genes. Researchers at National Jewish Health and Yale University School of Medicine have devised a technique to overcome the genetic oddity of Plasmodium falciparum, the major cause of human malaria. This new approach led them discover a new gene involved in lipid synthesis, and opens the door to further genetic discovery for the entire organism. This should foster a much greater understanding of the parasite, and facilitate discovery of new medications for a disease that infects more than 200 million people and kills nearly 700,000 every year.

“The malarial genome has been a black box. Our technique allows us to open that box, so that we can learn what genes in the most lethal human parasite actually do,” said Dennis Voelker, PhD, Professor of Medicine at National Jewish Health and senior author on the paper that appeared in the January 2, 2012 , issue of the Journal of Biological Chemistry. “This could prove tremendously valuable in the fight against a disease that has become increasingly drug-resistant.”

The genome of P. falciparum was sequenced in 2002, but the actual functions of many of the organism’s genes have remained elusive. One of the primary methods for discovering gene function is to copy a specific gene, insert it into a model organism that is easy to grow, often the yeast Saccharomyces cerevisiae, then draw on the incredible knowledge base about yeast and its abundant genetic variants to discover how that inserted gene changes the organism’s biology.

DNA is composed of building blocks with the shorthand designations A,T,C and G. The genome of P. falciparum is odd because it is particularly rich in A’s and T’s. Because of this A-T-rich nature, P. falciparum genes generally do not function when they are inserted into other organisms. As a result, scientists have been largely stymied when trying to understand the functions of P. falciparum‘s genes.

It turns out, however, that P. falciparum has a close cousin, P. knowlesi, which shares almost all its genes with P. falciparum, but with fewer A’s and T’s. As a result, P. knowlesi genes function well when inserted into yeast. Scientists can now insert P. knowlesi genes into yeast, discover their function, and then match them to corresponding genes in P. falciparum, which reveals the function of the malarial parasite’s genes.

“This technique could lead to an explosion in knowledge about malaria and the parasite that causes it.” said Dr. Voelker.

The researchers used the technique to discover a new gene involved in the synthesis of lipids in cell membranes of P. falciparum. The gene, phosphatidylserine decarboxylase, directs the formation of a protein unique to malarial parasites and is a potential therapeutic target. For example, selective disruption of lipid synthesis in P. falciparum, would prevent the organism from making new cell membranes, growing and reproducing in human hosts.

Concern over access to essential medicines has dominated international health policy debates over the last two decades. Much of this debate has focused on the role of intellectual property rights in either restricting or enabling developing countries to address persistent and emerging medical challenges. Much of this debate has focused on African countries which have borne higher disease burdens due in part to their low income levels.

These arguments and the associated policy prescriptions are guided by the view that Africa will remain a marginal player in the world of health innovation and will continue to rely on imported solutions. This collection of original papers provides a different prognosis. They reveal an emergent “health innovation system” in Africa that is driven by a combination of local research, entrepreneurship and institutional adaptations.

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First results from ongoing Phase III trial show malaria vaccine candidate, RTS,S* reduces the risk of malaria by half in African children aged 5 to 17 months

Seattle, 18 October 2011 — First results from a large-scale Phase III trial of RTS,S, published online today in the New England Journal of Medicine (NEJM), show the malaria vaccine candidate to provide young African children with significant protection against clinical and severe malaria with an acceptable safety and tolerability profile. The results were announced today at the Malaria Forum hosted by the Bill & Melinda Gates Foundation in Seattle, Washington.

5 to 17 month-old children

The trial, conducted at 11 trial sites in seven countries across sub-Saharan Africa, showed that three doses of RTS,S reduced the risk of children experiencing clinical malaria and severe malaria by 56% and 47%, respectively. This analysis was performed on data from the first 6,000 children aged 5 to 17 months, over a 12-month period following vaccination. Clinical malaria results in high fevers and chills. It can rapidly develop into severe malaria, typified by serious effects on the blood, brain, or kidneys that can prove fatal. These first Phase III results are in line with those from previous Phase II studies.

The widespread coverage of insecticide-treated bed nets (75%) in this study indicated that RTS,S can provide protection in addition to that already offered by existing malaria control interventions.

6 to 12 week-old infants

The trial is ongoing and efficacy and safety results in 6 to 12 week-old infants are expected by the end of 2012. These data will provide an understanding of the efficacy profile of the RTS,S malaria vaccine candidate in this age group, for both clinical and severe malaria.

Combined data in 6 to 12 week-old infants and 5 to 17 month-old children

An analysis of severe malaria episodes so far reported in all 15,460 infants and children enrolled in the trial at 6 weeks to 17 months of age has been performed. This analysis showed 35% efficacy over a follow-up period ranging between 0 and 22 months (average 11.5 months).

Long-term efficacy

The RTS,S malaria vaccine candidate is still under development. Further information about the longer-term protective effects of the vaccine, 30 months after the third dose, should be available by the end of 2014. This will provide evidence for national public health and regulatory authorities, as well as international public health organisations, to evaluate the benefits and risks of RTS,S.

Safety

The overall incidence of serious adverse events (SAEs)** in this trial was comparable between the RTS,S candidate vaccine (18%) recipients and those receiving a control vaccine (22 %).

Differences in rates of SAEs were observed between the vaccines groups for specific events, such as seizures and meningitis, and were higher in the malaria vaccine group. Seizures were considered to be related to fever and meningitis was considered unlikely to be vaccine-related. These events will continue to be monitored and additional information about the safety profile of the RTS,S malaria vaccine candidate will become available over the next three years.

Tsiri Agbenyega, a principal investigator of the trial and Chair of the Clinical Trials Partnership Committee, said: ”The publication of the first results in children aged 5 to 17 months marks an important milestone in the development of RTS,S. These results confirm findings from previous Phase II studies and support ongoing efforts to advance the development of this malaria vaccine candidate. Having worked in malaria research for more than 25 years, I can attest to how difficult making progress against this disease has been. Sadly, many have resigned themselves to malaria being a fact of life in Africa. This need not be the case. Renewed interest in malaria by the international community, and scientific evidence such as that we are reporting today, should bring new hope that malaria can be controlled.”

Andrew Witty, CEO, GSK, said: ”These data bring us to the cusp of having the world’s first malaria vaccine, which has the potential to significantly improve the outlook for children living in malaria endemic regions across Africa. The addition of a malaria vaccine to existing control interventions such as bed nets and insecticide spraying could potentially help prevent millions of cases of this debilitating disease. It could also reduce the burden on hospital services, freeing up much needed beds to treat other patients who often live in remote villages, with little or no access to healthcare. Today’s results are a testament to the dedication and tenacity of many scientists, led at GSK by Jean Stéphenne and his vaccine team, including Joe Cohen, the co-inventor of RTS,S, in partnership with many others from across the world. Development is however only half the task, but GSK remains committed to further research into malaria and most importantly, to ensuring that this vaccine will reach those who need it.”

Christopher Elias, president and CEO of PATH , said: ”This trial represents a powerful example of the high-quality science that is moving us toward controlling and someday potentially eliminating malaria. The results made public today are encouraging and certainly something to feel good about, but let’s also remember the human dimension. The PATH Malaria Vaccine Initiative’s mission is to deliver a vaccine to the children of Africa so that instead of carrying near lifeless babies to crowded pediatric wards, mothers will carry their infants past noisy school playgrounds to bustling immunization clinics. Today, we are an important step closer to realizing that vision, and we look forward to continuing our drive, together with our partners, to bring this vaccine home to the children of Africa.”

Bill Gates, co-chair of the Bill & Melinda Gates Foundation, said: ”A vaccine is the simplest, most cost-effective way to save lives. These results demonstrate the power of working with partners to create a malaria vaccine that has the potential to protect millions of children from this devastating disease.”

The vaccine is being developed in partnership by GSK and the PATH Malaria Vaccine Initiative (MVI), together with prominent African research centers. The partners are all represented on the Clinical Trials Partnership Committee, which is responsible for the conduct of the trial. Major funding for clinical development comes from a grant by the Bill & Melinda Gates Foundation to MVI. An extended team of organisations continues to work on RTS,S, including scientists from across Europe, North America and Africa. Should it be approved by regulatory authorities and recommended by the World Health Organisation (WHO), it will be used for African children, who are most at risk from the disease. Successful development of an effective vaccine to be used alongside other measures such as bed nets and anti-malarial medicines would represent a decisive step toward sustained malaria control.

The impact of the RTS,S Phase III trial extends beyond the vaccine being researched. The trial has made a considerable contribution to many of the African communities that host the trial sites through improved healthcare and hospital facilities. Research capacity at many of the research centres has been strengthened through the training of staff, provision of state-of-the-art laboratories, equipment, and construction of new facilities. This enhanced capacity bodes well for the centres to expand further their leadership in developing remedies for malaria and other infectious diseases for years to come.

Looking ahead

GSK and MVI are committed to making this vaccine available to those who need it most, should it be approved and recommended for use. In January 2010, GSK announced that the eventual price of RTS,S will cover the cost of manufacturing the vaccine together with a small return that will be reinvested in research and development for second-generation malaria vaccines or vaccines against other neglected tropical diseases.

If the required public health information, including safety and efficacy data from the Phase III programme, is deemed satisfactory, the WHO has indicated that a policy recommendation for the RTS,S malaria vaccine candidate is possible as early as 2015, paving the way for decisions by African nations regarding large scale implementation of the vaccine through their national immunisation programmes.

Innovative collaboration between researchers in Kampala and Seattle furthers specialized study and effective treatment of infection-related cancers

SEATTLE and KAMPALA, Uganda – A pioneering international collaboration forged by Fred Hutchinson Cancer Research Center in Seattle, Wash., USA, together with the Uganda Cancer Institute in Kampala, Uganda, has broken ground for the future construction of a state-of-the-art cancer training and outpatient treatment facility in Kampala. The building will be the first comprehensive cancer center jointly constructed by U.S. and African cancer institutions in sub-Saharan Africa.

“Through the collaboration between the Hutchinson Center and the Uganda Cancer Institute, we hope to develop new, low-cost prevention and treatment strategies that will not only stem the rising burden of cancer in sub-Saharan Africa but will benefit millions of people worldwide,” said Lawrence Corey, M.D., president and director of the Hutchinson Center.

Once completed, the Uganda Cancer Institute/Fred Hutchinson Cancer Research Center Clinic and Training Institute will extend patient access to cancer diagnosis and research-based treatment while furthering study on the links between infectious diseases, such as HIV and Epstein-Barr virus, and cancers such as Kaposi sarcoma and the most common life-threatening malignancy among Ugandan children, Burkitt lymphoma.

Ugandan Vice President Edward Ssekandi led the Oct. 4 groundbreaking ceremony and was joined by Harold Varmus, M.D., Ph.D., Nobel laureate and director of the U.S. National Cancer Institute, Ugandan Minister of Health Christine Ondoa and other government officials, international dignitaries, global health experts and community leaders.

“We are gathered here today to celebrate a great example of a partnership between two institutions dedicated to saving lives – the Uganda Cancer Institute in Uganda and Fred Hutchinson Cancer Research Center in Seattle, Washington. I offer my congratulations to the two institutions who have come together, dedicated to improving the health and well being of people in Uganda and worldwide,” Ssekandi said.

“Cancer is being increasingly recognized as an enormously important global health problem that kills more people worldwide than HIV, tuberculosis and malaria combined, and nearly two-thirds of these deaths are in the developing world,” Corey said. “Sub-Saharan Africa has among the highest cancer rates in the world, and these rates appear to be increasing in association with the HIV epidemic. Through the collaboration between the Hutchinson Center and the Uganda Cancer Institute, we hope to develop new, low-cost prevention and treatment strategies that will not only stem the rising burden of cancer in sub-Saharan Africa but will benefit millions of people worldwide.”

Nearly 25 percent of cancers cases worldwide are infection related, and 50 percent of these cancer deaths occur in sub-Saharan Africa, explained Corey Casper, M.D., M.P.H., an associate member of the Hutchinson Center’s Vaccine and Infectious Disease Division and co-scientific director of the UCI/Hutchinson Center Cancer Alliance, which is the name of the collaboration between the Hutchinson Center and the Uganda Cancer Institute. “Our commitment in Uganda is to increase survival rates for common infection-caused cancers from 10 percent to 90 percent over the next three years while pursuing a unique research opportunity to find new ways to prevent infection-associated cancers, which will benefit cancer patients both in resource-poor and resource-rich regions,” he said.

The planned new facility that will enable these lifesaving advances will be three stories and total approximately 5,600 square feet. The building will include adult and pediatric cancer care clinics, including exam rooms, procedure suites, pharmacies and an infusion suite. It also will be equipped with specialized diagnostic laboratories. The facility is funded in part by two grants totaling $1.4 million from the United States Agency for International Development’s American Schools and Hospitals Abroad program and a $900,000 investment from the Hutchinson Center.

The Hutchinson Center’s relationship with the Uganda Cancer Institute dates back to 2004 and the UCI/Hutchinson Center Cancer Alliance was established formally in 2008. The program builds on the Hutchinson Center’s innovative research approach, which is to draw data from a setting where the disease burden is exceptionally high, while reinforcing the organization’s commitment to reduce cancer-related suffering and death.

In 2008, Uganda had just one oncologist who treated more than 10,000 patients annually. In response, the Hutchinson Center spearheaded an extensive medical training program that has increased the number of practicing oncologists in Uganda fivefold.

More than 1.2 million Ugandans are living with HIV/AIDS. According to the U.S. National Cancer Institute, people infected with HIV are several thousand times more likely than uninfected people to be diagnosed with Kaposi sarcoma and at least 70 times more likely to be diagnosed with non-Hodgkin lymphoma. Kaposi sarcoma is the most common cancer in adult Ugandan men; human herpesvirus 8, also a cause of Kaposi sarcoma, is the most common cancer-related infection in women. According to UCI/Hutchinson Center Cancer Alliance researchers, nearly 75 percent of these cases can be treated for less than $800.

Ugandan children are also vulnerable to infection-related malignancies that are not HIV-associated. “Cancer, especially childhood cancer, is a growing threat to Uganda’s next generation and must be addressed with equal vigor as HIV/AIDS,” stated Jackson Orem, M.D., director of the Uganda Cancer Institute and co-scientific director of the UCI/Hutchinson Center Cancer Alliance.

Burkitt lymphoma, both potentially fatal and disfiguring, is the most common cancer diagnosis among Ugandan children and is caused by the Epstein-Barr virus. Burkitt lymphoma has particular connections with Uganda; it first was identified there in 1958 by Sir Denis Burkitt. The first use of combination chemotherapy in the world was used to treat Burkitt lymphoma and initiated by Uganda Cancer Institute physicians in conjunction with the National Cancer Institute at the U.S. National Institutes of Health. This approach is now the most widely utilized therapy for cancer.

Each year in Uganda, 600 new Burkitt cases present for medical attention and the average age at diagnosis is 5. Currently, the five-year survival rate is less than 40 percent, but it is estimated that 85 percent of these children could be cured for less than $600 a case.

When completed, the Uganda Cancer Institute/Fred Hutchinson Cancer Research Center Clinic and Training Institute will be an incubator of research that will dramatically alter the course of cancer diagnosis, treatment and care. The building will serve as a state-of-the-art venue for gathering data and conducting studies to further the prevention and treatment of cancer-related infectious diseases, with far-reaching implications for global health.

Boosting patient access to diagnostic technology and significantly increasing the number of patients who can be treated, the new facility will enhance integration of HIV treatment into cancer care and enable Hutchinson Center experts to devise a model of effective cancer care that could be deployed in other resource-limited areas.

To date, the Hutchinson Center has trained more than 100 individuals in both the United States and Uganda. Of the more than 70 Ugandan trainees, interns and fellows, 15 have traveled to Seattle to study at the Hutchinson Center. Twelve of the 25 Americans have trained in Uganda. The program offers training in a variety of disciplines —hematology, oncology, epidemiology, global health and HIV-associated malignancies, among others. Trainees include postgraduate and postdoctorate fellows, laboratory technicians, medical officers, study nurses and administrators.

Modified vaccine shows promise in preventing malaria

Vaccine uses immune-stimulating gene

EAST LANSING, Mich. — Continuing a global effort to prevent malaria infections, Michigan State University researchers have created a new malaria vaccine – one that combines the use of a disabled cold virus with an immune system-stimulating gene – that appears to increase the immune response against the parasite that causes the deadly disease.

At the same time, the group led by Andrea Amalfitano of the College of Osteopathic Medicine also discovered another immune-system stimulating agent – created at MSU and which has been successful in improving immune responses in vaccines for diseases such as HIV – paradoxically made for a less effective malaria vaccine.

Both of the findings will help researchers develop more effective vaccine platforms in general, and malaria vaccines specifically, hopefully leading to human clinical trials soon, Amalfitano said. The research is published in the current edition of PLoS ONE.

“Researchers across the globe are working on ways to prevent people from becoming infected with malaria,” said Amalfitano of the disease that kills up to a million people each year, mainly in sub-Saharan Africa. “Some vaccines are showing promise, but they are not as effective as they need to be for any mass distribution.”

Amalfitano and his research team are focusing on one such vaccine platform, spearheaded by the U.S. Army, that targets a certain gene on the malaria parasite, a protein called Circumsporozoite Protein, or CSP.

That protein is thought to play a key role in creating an immune response to the malaria parasite; past research shows people infected by malaria multiple times will begin creating an immune response to this protein, suggesting at some level it could be protective.

“What we are looking to do is improve the ability of the vaccine to induce immune responses to that protein,” Amalfitano said. “We are adding genes to the vaccine to try and stimulate the immune system.”

Those genetic agents, similar to chemical adjuvants, are stimulants that improve the ability of vaccines to induce beneficial.

In mouse models, the researchers used two such “gene-adjuvants”: rEA and EAT-2, both of which aimed to illicit improved immune responses to the malaria CSP gene. Surprisingly, the rEA agent – which was developed at MSU in part by the late Barnett Rosenberg – did not produce the desired result and in fact seemed to worsen the animal’s ability to generate an immune response to CSP.

However, the EAT-2 gene-adjuvant stimulated the immune system in a different way, and Amalfitano and his team were able to increase the ability of the immune system to respond to CSP to a level that surpassed currently available malaria vaccine systems.

“The results were surprising, but we were able to hit our goal eventually,” he said. “This research will help us as we create a viable vaccine. While the way that rEA is trying to stimulate the immune system may not be the best way for malaria, we did come up with an alternative adjuvant to effectively target the parasite.”

Amalfitano said the next step is to see if researchers can prevent malaria in animal models using the EAT-2 gene-adjuvant: “Then we can take the lessons learned and really go forward and do what’s necessary to feel confident to begin human trials.”