This week, IBM Research and the KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH) said that they have signed a collaborative agreement to use computational tools developed by IBM to research new and improved treatment options for tuberculosis.
The partners are using IBM's analytics applications to analyze bacterial sequences and data from drug susceptibility tests to better understand the genomic mechanisms that lead to antibiotic resistance and to find new and more effective medicines and diagnostic approaches for the disease.
It's a partnership that gives K-RITH researchers access to IBM's expertise in bioinformatics and machine learning. Additionally, it "will allow us to analyze data in new and imaginative ways and it holds the promise of giving us better insight into the mechanisms of drug resistance, leading to better diagnostic tests," Alex Pym, an associate investigator at the South African research institute, said in a statement. IBM's expertise, he continued, will enable K-RITH researchers to "map which antibiotic treatments are successful for which TB strains. And then, by finding the associations between the genetic markers and the correct antibiotic treatment, we can improve treatment protocols."
Specifically, the researchers are using components of a broader portfolio of internally developed IBM applications for clinical genomic analysis called Bioclinical Data Analysis (BDA), Michal Rosen-Zvi, senior manager of analytics at IBM's Research Lab in Haifa, Israel, told BioInform.
Applications in the BDA suite are based on similar technological concepts. When projects come up that involve clinical or genomic data or both, IBM researchers tailor components from the suite to provide the capabilities that the clients in question need. BDA is not currently for sale, although the company has used its components in some commercial engagements, according to Rosen-Zvi. For example, last year it worked with UCB, a Belgian pharmaceutical company, using parts of BDA to work on creating improved treatments for epilepsy patients. She said that IBM is mulling several commercialization options, including possibly providing a cloud-based version of the suite but it is not disclosing specific plans on this point at the moment.
Aside from commercial projects, the IBM Research team has also put the system to work in non-commercial settings. For example, it built a version of the system for a cancer project in 2012 that was done in collaboration with researchers at Italy's Fondazione IRCCS National Cancer Institute. Hospitals there used the tool to analyze data from patients with sarcoma and head and neck cancers.
Another project that's used BDA components explored treatment responses in HIV cases. Here, IBM worked with the EuResist network, an international effort to build a database of HIV genomic and clinical data that would be used to predict patients' response to treatment. For that project, IBM researchers used components from the BDA suite to develop a tool that modeled how HIV strains would respond if the person was treated with a particular drug cocktail.
That freely available system, which came online in 2008, has the world's largest database of clinical and genomic information from HIV, according to IBM. It was also through its work with the HIV consortium that IBM was introduced to TBresist and came to partner with the group. Now working alongside its TB collaborators, IBM intends to build a similar repository for tuberculosis that holds data collected in the course of studying the different strains of drug-resistant tuberculosis (DRTB), Rosen-Zvi said.
They are also adapting BDA components to fit TB data. TB genomes are more complex and larger than their viral counterparts, making the data generation step more challenging, she noted. The small size of the HIV genome — just about 10 genes — makes it relatively easy and cheaper to use PCR techniques to obtain information about variants in the genome, Rosen-Ziv told BioInform. The longer genome of TB makes generating data a more complex process, she said, which is why the researchers are using next-generation sequencing for the task. The Broad Institute is handling the sequencing step for the South African study, but it's a more expensive technology and the higher cost has imposed some limits on the amount of data that the researchers can generate. For now, the researchers are only sequencing the TB strains but not the hosts' genomes.
There are also challenges with the measures used to gauge treatment response in TB versus HIV. "For HIV, technology can look at the difference in viral load before and after treatment, and use that to understand whether the treatment was a success," Rosen-Zvi explained. "But in TB, there is no single measure that defines the status of the disease." As a result, "we will need to develop multiple ways to label the treatment outcomes and new methods to indicate whether a treatment was effective."
So far in the K-RITH partnership, the collaborators have analyzed a number of bacterial strains in conjunction with drug data and identified some strains that respond better to certain beta-lactam antibiotics and others that quickly develop resistance, Rosen-Zvi said. They believe that they have some indication of how the genome affects antibiotic effectiveness and that they could come up with more effective treatments. But it's still early days and there is a lot of work that needs to be done including incorporating clinical data into the mix, she said.
The partnership is part of a much larger research effort dubbed TBResist, a global consortium that's focused on collecting and sequencing the complete genomes of multiple strains of DRTB collected from different geographical locations with an eye toward better understanding the disease and associated co-morbidities and developing better methods and tools for disease control.
Participants in this international coalition, which launched officially in 2008, include members of industry, non-profit organizations, government entities, as well as academia.
That list includes the US National Institutes of Health, the Broad Institute, and IBM, as well as academic institutions based in China, Russia, South Africa, Sweden, Romania, and Belarus. They came together with the goal of "dramatically chang[ing the] diagnosis as well as treatment" of DRTB "not only with respect to having new drugs but [being] able to get patients on the right drugs at the right time and as soon as possible," Gail Cassell, a senior lecturer in Harvard University's global health and social medicine department and a senior scientist at the Brigham and Women's Hospital, told BioInform.
Furthermore, with genome sequencing now more "practical from an expense standpoint and feasible from a technology standpoint to do high-throughput sequencing on large numbers of organisms, it became apparent that it might be possible to have a predictive analytic to diagnose patients and also to identify new drug targets," she said. "We not only want to have the results from whole-genome sequencing of drug-resistant strains but you have to look at a large number from different geographies."
Teams at TBResist partner sites have begun gathering and sequencing TB isolates from the four countries that have the highest number of cases of DRTB in the world. These are South Africa, China, Russia, and India. But initial research efforts have focused on South Africa because of the urgency of the DRTB situation in that country.
South Africa has the world's third-highest TB burden with the province of KwaZulu-Natal having the highest number of cases — over 100,000 are reported every year from this province alone. Furthermore, about 60 percent of individuals with TB are also affected with HIV, and a lack of integration between HIV and TB treatments, as well as challenges with healthcare delivery, are contributing factors to the scale of the TB problem in the country. K-RITH, which is based at the University of Kwazulu-Natal's School of Medicine, is an independent research institute that was established in 2009 to research TB and HIV with an eye toward developing new tools to curb the spread of these diseases.
"In 2006, there was an outbreak of expensively drug-resistant TB that was reported" in South Africa with a large number of cases and rapid spread from person to person, Cassell said. The country has "probably the most urgent need in terms of better understanding the epidemic," so focusing their research efforts there first made the most sense.
So far, the TBResist group has sequenced over 1,000 DRTB strains from around the globe with more to come, Cassell told BioInform. They're also collecting drug susceptibility and clinical outcomes data from the patients, as well, in order to explore correlations between genes, drug response, and clinical outcomes. "We are looking at potentially thousands of different sequences and running some analyses on the cloud to look at the genetic relationships individually with the outcome and or drug resistance but also how the genes and clinical and other variables are interacting together," Gil Alterovitz, an assistant professor at Harvard Medical School and the HMS Center for Biomedical Informatics, told BioInform.
Besides the Broad, researchers at the Russian Academy of Sciences and the Chinese Academy of Sciences are sequencing isolates collected from Russia and China, respectively. They hope at some point to be able to sequence the genomes of the human hosts and make that data available as well, Cassell said.