Qiagen : Cracking the code - how RNA may hold the answer

Dr. John Martignetti is Associate Professor at the Icahn School of Medicine at Mount Sinai Hospital in New York City and Network Director of the Laboratory for Translational Research at the Western Connecticut Health Network Biomedical Research Institute. Dr. Martignetti is also a code breaker, and his success in deciphering these codes promises to benefit the health of mankind. Specializing in Genetics and Genomic Sciences, one of Dr. Martignetti's missions is to unravel the mysteries of ribonucleic acid (RNA), currently one of the most exciting areas of clinical research. His insights bring the possibility of transforming the diagnosis, treatment, and survival of life-threatening conditions, including several cancers.

For decades, scientists trying to better understand genetics and molecular biology focused almost exclusively on DNA; RNA was the forgotten relation. However, following clarification of the genetic code in the 1970s, it became clear that RNA plays important roles in mediating cell mechanisms, gene expression and helping control cell function. It is now a promising area of research in its own right.

Dark Matter That Really Matters

Dr. Martignetti is excited by the prospect of revealing its secrets. 'Think about the genetic material present in a cell or organism. Only a small fraction of it, around 2 - 3 percent, codes for protein. The balance is non-coding RNA,' he explains. 'This has function, but precisely what that function is, we don't yet know. It's part of what we are exploring.'

Increasingly, researchers believe that this non-coding RNA - known as 'dark matter' - may be the key to unlocking the nature of disease. In some cases, it may even be the source of inherited disease itself. Future RNA research will target the precise location of disease traits within the human genome. It sounds simple, but in reality, Dr. Martignetti and his team are looking for - and finding - needles in a haystack.

'RNA is a key to understanding how we will diagnose and treat many different diseases in the future, but it will also be vital in understanding normal physiology and health.'

Dr. John Martignetti, Associate Professor, Icahn School of Medicine at Mount Sinai Hospital, and Network Director, Laboratory for Translational Research, Western Connecticut Health Network Biomedical Research Institute.

Game-Changing Research

This is not only due to the constantly evolving nature of the 'RNA world.' 'The biggest challenge is the large amount of data generated by our experiments and how to make sense of it,' explains Dr. Martignetti. 'We need bioinformatic tools, which analyze data generated by, for example, coding RNA, messenger RNA, small nuclear RNA, so that we can see patterns and understand relationships across data sets.'

This can be a challenging yet extremely rewarding task. In one instance, Dr. Martignetti's team used RNA to understand how cancer cells responded to a specific treatment, a novel class of chemotherapeutic recently entered into Phase II clinical trials. Using cancer cell lines derived from patients with ovarian cancer, the researchers examined their transcriptomes to determine which pathways were affected by the novel drug. This enabled the team to identify signatures associated with patients likely to respond to the proposed treatment, and those who were not likely to respond. The ultimate goal: a precision medicine approach of giving this novel agent specifically to patients whose tumors will be sensitive and respond, while not giving it to those patients whose tumors are unlikely to respond.

In another study, the scientists looked for the cause of an inherited form of bone cancer across a number of families from around the world. 'By analyzing these families, we identified that a single mutation resulted in the showering of new hybrid RNA molecules that change the function of a critical metabolic enzyme,' explained Dr. Martignetti.

Breakthroughs from bioinformatics

According to Dr. Martignetti, breakthroughs like these would be virtually impossible without advanced bioinformatics tools. 'It's a bioinformatics issue. We need software that helps us to make sense of the data in a meaningful way, and the QIAGEN software products we're using are very powerful analytical tools.'

In his research, Dr. Martignetti primarily turns to QIAGEN's Ingenuity Pathway Analysis (IPA) software. IPA allows him and his team to analyze complex genomic data in real time - within days rather than weeks - without depending on other bioinformaticians for help. 'It's not something we could do manually. We would not see these kinds of relationships we've seen in our previous studies without IPA,' Dr. Martignetti explains.

Dr. Martignetti believes that his area of research is only now beginning to realize its immense promise; so far, it has only scratched the surface. He predicts major advances in using RNA to improve the understanding, diagnosis, and treatment of disease. There is the prospect of a virtuous circle, with new insights leading to increasing opportunities to harness RNA in furthering research and improving healthcare.

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