Shaping the key to unlocking cancer

| Posted by Andre DP Encarnacion

It could hold the key to unlocking cancer’s secrets, and the Philippines could soon help in shaping that key.

Ten years ago, Francis Collins and Anna Barker, at that time from the National Human Genome Research Institute and the National Cancer Institute, respectively, wrote an article for Scientific American celebrating the launch of a milestone project in science and health research. Today, aspects of that research can be undertaken here at the University of the Philippines.

The project so loudly lauded by the pair was The Cancer Genome Atlas (note the acronym, TCGA) of the US National Institutes of Health.

Building on the technological and collaborative breakthroughs accomplished by the Human Genome Project, TCGA is a massive collection of multi-dimensional maps of notable genomic changes found in at least 33 types of cancers.

All 2.5 petabytes (1 PB=1,000,000 GB) of data on these cancers from 11,000 patients are now publicly available, thanks to the efforts of a vast network of research and technology teams. Researchers have established that cancer is primarily caused by mutations in specific genes to create a catalog of genetic mutations that, for instance, cause normal cells to turn malignant.

Through this analysis of each cancer cell’s complete set of genes, its genome, and how these changes within them interact on a broader scale, scientists attempt to improve cancer prevention, detection, and treatment.

An interdisciplinary environment

One key dimension that Collins and Barker revealed in their work is the highly multidisciplinary environment in genomics and cancer research, an environment of which the TCGA is both a promoter and a product.

Such global and eclectic projects naturally encourage players from traditionally distinct research areas to capture the complexity of biological phenomena using a unique set of scientific tools.

Increasingly, therefore, biologists and clinicians who had long manned the front lines of cancer and health research are finding themselves shoulder to shoulder with a different sort of ally.

Armed with algorithms, software, and statistical modeling techniques, this new class of researcher allows initiatives like the TCGA to share and make better sense of the hundreds of terabytes of genomics data being produced globally. These data sets, many believe, hide important secrets to preserving human health and to uncovering deep truths about the origins and future of life on the planet.

Enter the Filipino scientist. To take advantage of these exciting developments, the UP Board of Regents approved the creation of the Computational Genomics and Systems Biology (CGSB) research program at the Philippine Genome Center (PGC) in January 2017.

Marrying two fields

The reorganization of the PGC allowed its researchers to group genomics and systems biology—normally considered distinct areas of study—into a single R&D program. PGC Executive Director Baltazar D. Aguda, himself a systems biologist and cancer expert, explained what holds these different parts firmly together.

“Genomics is all about genomes,” Aguda said, referring to the genetic material of an organism, made up of DNA (deoxyribonucleic acid) that some call the blueprint for creating an organism. Information in DNA is encoded in a sequence of four letters or bases, the aforementioned T, C, G, and A which stand for thymine, cytosine, guanine, and adenine.

Sequences of these letters run along every DNA strand in different arrangements and permutations, totaling around 3 billion for each person. The primary challenge of genomics lies in interpreting the meaning behind these four-letter sequences. Some of these sequences, less than 2% of them, are called genes, which contain the code for the creation of molecules called proteins.

And the rest? “What does the bulk of our DNA do?” asked Aguda. This, he said, was an open question, one that the men and women of the PGC are trying their hand at answering. Using next-generation sequencing (NGS) technologies, PGC researchers are sequencing the DNA of a wide variety of organisms, from plants like coconuts to microorganisms like infectious bacteria.

While genomics attempts to uncover the secrets behind the fundamental units of life, systems biology views the components and space-time scales of organisms as one integrated and holistic system.

“If DNA sequences are not complex enough for you,” Aguda said, “think of networks of interactions among genes, proteins, cells and organs.” These networks and interactions are the fertile ground that systems biologists till for scientific insights.

Modeling and predicting 

Unlike its “wet laboratory” counterparts, the CGSB is, as its name implies, an initiative built around computation. The language of life is read by these scholars via the Rosetta Stone of equations and computer models.

More specifically, computational genomics researchers use advanced mathematics and computer algorithms to decipher the meaning behind huge linear arrays of the T, C, G, and A found in DNA. Computational systems biologists, on the other hand, generate models to simulate how genes affect the development and behavior of biological systems (e.g., a particular organism).

When combined, the results of these models and analyses are then used to make scientific predictions that can then be verified by experimentation.

What would a research effort from the CGSB look like? Aguda mentioned the example of cancer genomics coupled with a systems biology modeling approach to predict combinations of cancer drug targets.

Recently, the PGC entered into a partnership with a local biotech company, Geosmart, to work with FIZ, a German genetics company. The members of this partnership are preparing to carry out a massive profiling of Philippine cancer patients.

CGSB will be involved in the analysis of gene expression (i.e. the process by which genetic instructions are used to synthesize gene products) data to discover modules of gene interactions, and predict which of these modules are strongly associated with tumor growth and development.

Once this is done, a systems biology approach can be taken to link these gene modules to molecular pathways, roughly a series of interactions among components in a cell that lead to certain products or changes. Dynamical models can then be created that simulate perturbations or changes that lead to cancer.

Ultimately, these steps will lead to suggestions of protein targets for new and more specific anti-cancer drugs.

Busiest of them all 

While the CGSB may be a very young program, its members, led by its founding director, Jan Michael Yap of the UP Department of Computer Science, are all prepared to face the important challenges that they were trained to address.

According to Aguda, they have already pinpointed several computational genomicists and systems biologists around the country whom the group are planning to collaborate with.

These developments, when combined with the output emerging from massive mega-sequencing projects developing globally (like the TCGA and the Beijing Genomics Institute’s bid to sequence 10 million human genomes), as well as the huge sequence data-sets produced daily by the PGC itself, promise to keep the team busy for years to come.

Aguda and his colleagues look at these future challenges with excitement and optimism.

The predictions produced by the CGSB to guide the laboratory work are expected to cut down on discovery times dramatically. Moreover, Aguda envisions the CGSB to contribute several innovative algorithms and software for use by the global scientific community.

These are exciting times for genomics research in the country, and this project promises to be at the forefront of it all.

More importantly, however, this peculiar combination of “computer scientists, mathematicians, physicists, statisticians and engineers” will facilitate the PGC’s mission of helping our citizens face the challenges of the 21st century. From producing more sophisticated predictions of health risks to creating innovative food security solutions, these modelers of life’s basic functions are raring to make the act of living a safer and more fruitful experience for Filipinos everywhere.

For more information about the CGSB, as well as other programs of the PGC, please visit: http://www.philippinegenomecenter.org/