1. Laberta, Valerie

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"Work is a large part of my life," said Uttiya Basu, PhD, a Research Scientist and Associate Professor of Microbiology and Immunology at Columbia University, New York, N.Y. "I am a scientist, my wife is a pediatric oncologist at Memorial Sloan Kettering, and we have a 7-year-old son. I'd like to say that I have lots of hobbies and a lot of time for fun things, but it would be a lie. Science is a tough business."

Uttiya Basu, PhD. Ut... - Click to enlarge in new windowUttiya Basu, PhD. Uttiya Basu, PhD

His dedication to research will hopefully allow others to have time for "fun" in the larger picture of life, as cancer eventually is limited in response to a greater understanding around non-coding RNAs (ncRNAs) and their role in gene regulation and function.


"This is a very new topic and has great academic interest," Basu explained. "Of greatest importance is the fact that this work has direct implications in understanding how the immune system works, how we make antibodies that combat many pathogens and viruses, and how this process of DNA recombination leading to antibody formation-when it does not occur properly-can lead to cancer." In particular, it can lead to cancer of the immune system, he noted.


Basu began building his area of research interest while working on RNA processing mechanisms at Albert Einstein College of Medicine in New York where he earned his PhD. He determined that he wanted to study DNA/RNA recombination mechanisms, "So I went to Boston to work with Frederick Alt, PhD, a pioneer in the field of DNA recombination mechanisms and the recognition that DNA breaks in the genome can lead to the generation of antibodies in B-cells, as well as cancer," Basu explained. "My experience in Boston was an important foundation to the work I am doing right now in a field that not only addresses questions guiding basic biological mechanisms, but also finds answers with direct implications to different genetically inherited diseases, cancers due to aberrant DNA rearrangements and somatic mutations, and pathophysiologies due to failure of the immune system."


Basu's work is indeed translational, a fact that allows him to attract essential funding and keep his lab up and running.


RNA Impact on Cells

While the concept of non-coding RNA expressed in the cells is known to most oncologists, their role in cellular physiology is, in Basu's words, "...a new and exciting discovery. We are busy answering the questions around how ncRNA in the cells help immune organization, antibody diversification, antibody generation, and prevention of cancer. That is very interesting and exciting for the field of oncology."


Basu said a big quest in the field of cancer is learning how to predict which people will eventually get cancer and which type(s) of cancer they are likely to get. "Right now oncologists only see people after they get cancer which has often progressed to a mature state. Sometimes the cancer is too aggressive and it is too late; treatment becomes a tentative survival process. Imagine the impact to doctors and their patients if we could identify likely cancer patients ahead of time, before they become sick."


According to Basu, the one vital clue to determining a person's propensity for cancer is found in understanding the epigenome of patients and their coding and non-coding RNA transcriptomes.


"The RNA profiles give clues way ahead of time and indicates a person will have cancer on one lineage or another before the disease becomes too aggressive," Basu explained. "We understand the major players in our physiology are proteins; they determine how a cell will develop different stages of differentiation and go from stage A to B to C. Sometimes in going from stage A to stage B, it goes through changes that can lead the cell to grow and double in an uncontrollable way, leading to cancer. Expression of proteins at stages A, B, and C keeps changing. The control of these proteins is regulated by two processes that are related: modifications on the histones on the DNA, and the expression of RNA that regulates elements on the DNA."


In short, the ncRNA expression pattern precedes expression of the protein, explained the India-born researcher. "It tells you, 'Here it comes.' It is what drives the protein expression but it comes first," Basu said. He further explained that it is not possible to predict cancer from expression of just one ncRNA of one protein. "A cell expresses thousands of ncRNAs. It is a combination of ncRNAs that will predict if a person has a tendency to develop cancer. Each cell has a fingerprint of ncRNA expression and a cell that is going to become malignant has a slightly altered fingerprint. The development of all the technologies of genomics-RNA sequencing, DNA sequencing, epigenomics mapping-has allowed us to detect these slight differences. Now we can find a set of RNAs that are expressed in a cell that is going to become malignant, a set that is not expressed in a normal cell."


Basu said one of his lab's recent studies has identified how the regulation of ncRNA expression at certain regions of the B cell genome determines occurrence of DNA mutagenesis/DNA double strand breaks and/or chromosomal translocation events, all of which can ultimately lead to fatal initiation of cancer of the immune system.


"We found that at certain regions of the B cell genome a subclass of noncoding RNAs known as 'antisense RNAs' ('antisense' meaning the opposite of the sense messenger RNA that makes proteins) is transiently expressed. Antisense RNAs need to be rapidly removed from the cells via transcription termination-coupled and post transcriptional degradation-coupled mechanisms," Basu explained. "Identification of antisense RNAs-for example expressed inside famous oncogenes like c-Myc-unravels a new mechanism involved in genomic stability and organization. The hope is that these antisense RNAs could be used as molecular beacons, whose expression levels may provide insights into the cells' susceptibility to cancer."


Basu noted that research in his laboratory has now expanded into other avenues of cancer biology, beyond the understanding of cancer of the immune system. For example, in collaboration with neuro-oncologists and systems biologists at Columbia University, researchers in his lab are now working toward a better understanding of a brain cancer called glioblastoma. "The lessons we learned from studying the immune system-related cancers are now being used to better understand cancer of the human brain," he added.


From Research to Clinical Practice

While this information resides in the realm of research right now, Basu said the ultimate goal is to see it utilized in clinical practice. "If we can consistently see that expression of cell ncRNAs precede a disease state, we will be able to test people for the expression of these ncRNAs."


Then what? Basu used the example of blood cancers to explain how things might change once this research becomes actionable. "Consider cancer of the blood-leukemias and lymphomas. The origin of these cells is our bone marrow. Today when someone has a blood cancer, treatment includes the depletion of lymphocytes; depletion of all the bone marrow cells by radiation allows new, normal cells to come in. In the future we hope to be able to react to a patient with a strong leaning toward cancer. People who have a different fingerprint on non-coding transcriptomes will be more closely monitored," Basu detailed. "Secondly, if we know what cell type will have a problem-for example, lymphocytes in B or T cells that cause blood cancers, we could replace those cells in therapy ahead of time. With the recent ability to manipulate people's genomes, one can actually do such cell therapy. So if a person is susceptible to a cancer, we could fix that mutation and put it back together again. That is a goal, generally aspired to by many in the scientific community. Another possibility is we could attack cells that are potentially likely to become cancerous by immunotherapy and model or change the immune system in such a way that they could recognize these cancerous cells and remove them from the body."


How will healthcare find those people with aberrant non-coding RNA patterns to take advantage of the evolving understanding brought forth by this research? The answer likely starts with transcriptome analysis and DNA/RNA sequencing for individual patients-an idea whose time has come.


"The concept of routine genome sequencing is not that far away," agreed Basu. "I think it will become part of regular checkups in the near future. But that doesn't totally answer this question. However, if the technology around sequencing comes that far, I believe the technology of transcriptome analyses will be right behind it. And that can answer some very important questions." Basu also noted that another, more obvious, strategy is to look at people's family history; people who are more susceptible to a particular type of cancer may elect to have the cells of the cancer lineage sequenced.


Cost Effectiveness of Progress

Asked if the cost of routine sequencing of genomes, and later transcriptomes, might be a barrier to progress, Basu assured to the contrary. "Normal transcriptome sequencing is going to become a part of life and healthcare, because not doing it would exact an enormous expense," he explained. "Treating cancer patients with progressed disease is extremely expensive. We must change our medical perspective from one of treatment to one of prediction and early intervention.


"My message to clinicians is they must embrace the importance of prediction," said Basu earnestly. "Yet all the recent milestones are focused on cancer therapy, such as immunotherapy through checkpoint blockades, mutations brought in to kill tumor cells, etc., all in the context of aggressive cancer. Oncologists are still in the business of treating cancer, not in the business of predicting cancer."


So will predictability put oncologists out of business? "No way," said Basu. "When prediction becomes reality, the doctors will like it. It is painful to deal with patients; too many people die. Oncologists take that stress home with them every day. Clearly, cancer is a part of our human physiology. We age, something goes wrong in some area of the body, and disease takes over. Cancer is not a disease that is going away. It is simply a question of how much we can limit it and address the problems arising well ahead of time and to our satisfaction."


Basu added that even though there has been a great deal of research in cancer biology in the last 50 years, success in the clinic has not been proportional. "Biologists as clinical scientists know that cancer cells are too strong and too powerful to be treated in most cases," Basu claimed. "Attacking at the earliest stage is the solution. The remaining question is who is going to be in on this revolution? How do you identify it? How do you implement it in the clinics? How do you convince the government and insurance companies to pay for checking genomes and transcriptomes?


"The advance of science cannot be seen as a threat to the health industry. But advancing this research to something practical is the biggest challenge," he concluded. "I want this research to be used in my lifetime. And I do think that will happen-in the next 10 years or so."


Valerie Laberta is a contributing writer.


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