Please tell us briefly about your current research. What do you find most exciting about it?
My overarching research goal is to identify more effective drug targets for cancer which can improve treatment outcomes. Towards this end, my current research is focused on finding new cancer-causing genes (known as “oncogenes” in scientific terms) in humans. We have developed an experimental system where we can test all genes in the human genome whose excessive activities can convert normal cells into tumor cells. Typically, we package all the known human genes into an efficient gene delivery vehicle derived from a special kind of virus, known as lentivirus, before expressing them in normal human cells. We then isolate cells with cancerous behavior and identify the causal genes. If we find such genes to be relevant in actual human cancers, we will further study their mechanistic details and therapeutic suitability.
Using such an approach, I was able to find a novel oncogene called MECP2, that was present in many copies inside the cells of significant subset of several human cancers including ovarian, uterine, lung and breast cancers. So, we are currently trying to better understand how exactly the excessive activities of this gene lead to cancer at cellular and molecular level, and we are also exploring whether we can use it as a therapeutic target in these cancers.
The most exciting and gratifying part of my research is its translational aspect. We do both basic science research and translational research in our group. This means any interesting discovery in the laboratory bench has the potential to be translated to patient’s bedside, and it is very satisfying when you find something that might possibly help to improve the lives of patients.
You started your studies as a veterinary student. Why were you interested in veterinary and what made you choose cancer research? Tell us a bit about your career journey starting from your early school days.
OK, let’s take a trip down memory lane…. Both my dad and uncle were faculties in Institute of Agriculture and Animal Science (IAAS) (part of Tribhuwan University then and Agriculture and Forestry University-AFU now). It was built in land-grant model and, back then, it had a very vibrant academic environment and impeccable reputation. I pretty much grew up inside livestock farm of the institute, interacting with and learning from the best minds; professors and scientists who had returned there after graduating from topmost universities around the globe.
At the beginning, I was equally interested in physical sciences and biological sciences. And, to be honest, even after finishing my Intermediate of Science (I.Sc.) degree (which is basically current +2 equivalent), I was not exactly sure at that point what I wanted to do with my career and life! I eventually decided to choose Veterinary Medicine, since I knew that this profession is uniquely positioned to contribute to both animal health and human health. I had several options to choose the career path from. I could have focused on one of the subspecialties: food animals, poultry, pets, wild-life and zoonotic diseases; similarly, I could have joined one of the workforces: private practice, government job, industry, public health, uniformed services, teaching, research… After graduating from vet school, I chose to be a lecturer in Himalayan College of Agricultural Sciences and Technology (HICAST) for about two years. I then wanted to dig deeper and explore the world of biomedical research. I started applying for graduate schools abroad, and got a full scholarship to pursue PhD in Comparative Medicine and Integrative Biology from Michigan State University in U.S.A. During my PhD, I studied bone cancers (known as “osteosarcoma”) using dog as a model system to understand human bone cancers. I became more and more interested in cutting-edge research and human cancers. I went on to conduct post-doctoral research at Dana-Farber Cancer Institute and Harvard Medical School, U.S.A. where I gained expertise in various aspects of Cancer Biology. I finally landed my current job of Assistant Professor in Sidney Kimmel Medical College of Thomas Jefferson University, U.S.A.
When we say ‘cancer research’, what are the various aspects of it? What are the recent/upcoming breakthroughs in the field of cancer research?
Indeed, the term ‘cancer research’ is pretty vague and generic. We address one or more of the following aspects in cancer research:
(i) Cancer Prevention: This includes research on prophylactic vaccines that would be effective for cancers caused by infectious agents, as well as chemoprevention research to find micronutrients and pharmaceuticals that might be helpful to prevent cancer.
(ii) Early Detection and Diagnosis: This includes finding new biomarkers and developing new diagnostic tests and imaging techniques to help in early diagnosis and catch the disease at an early stage.
(iii) Treatment: This includes finding novel drugs and biologicals that are more effective and less toxic and, repurposing existing drugs (that are being used to treat other diseases).
You can also view cancer research from another perspective:
(i) Basic science Research: This would generate new knowledge and ideas, and here cancer researchers will mostly focus their study at molecular or cellular level using biochemistry, molecular biology, and cell biology. Basic science researcher will identify new proteins, their 3-dimensional structure and signaling pathways that would promote or inhibit cell proliferation and develop mathematical models to predict evolution of tumor cells.
(ii) Translational Research: This involves testing the findings of basic science research and determining whether they will be useful in clinical settings. In another words, the translational research involves testing the new biomarker or drug target identified by basic research scientists in living organisms and, then determining whether the candidate test or drug should be pursued further in clinical research. Translational researcher will test a new drug in relevant preclinical models such as mice genetically engineered to develop human cancers, or mice which carry human cancer cells or even pieces of human tumors. This will provide information on whether the new drug can indeed be useful for human patients before investing millions or even billions of dollars, and years of time in clinical trials.
(iii) Clinical Research: If the translational research identifies new drugs or diagnostic tests which hold promise to improve prevention, treatment, or diagnosis of cancer patients, they will be tested in clinical research. This entails determining the safety and efficacy of new drugs or diagnostic tests in clinical trials. Clinical researcher has to interact with patients and will use a lot of statistics and epidemiology.
The field of cancer research has become very competitive. However, only a very few cancers have been effectively ‘cured’ so far. There are a couple of major hurdles we need to overcome as a cancer research community. One is the lack of durable response to the therapy; a drug would work for a short period of time, and then the disease would relapse in more aggressive version. Another existing challenge is our inability to catch cancer in an earlier stage; by the time the disease is diagnosed, it would have already spread to several vital organs, making the effective treatment very difficult. Despite these challenges, we have seen some promising breakthrough lately. One of the breakthroughs which is worth mentioning is the finding that we can coax our body’s immune system to kill the cancer cells. Cancer cells are smart enough to stop our immune system from turning on against them. Now, scientists have found ways to prevent cancer cells from stopping our immune system so that our immune cells can seek and kill these tumor cells. This is the basis of the emerging field of immuno-oncology. I can envision a few breakthroughs in the near future. One will be the use of combination therapy to cure cancer. I think we will pay attention to the success story of tuberculosis where combination therapy had led to the cure and start adopting a similar approach to treat cancer. Another possible breakthrough will be the successful application of artificial intelligence and machine learning in the diagnosis and treatment of cancer.
Please tell us about a typical day of a cancer researcher?
Well, this depends on what stage of the career you have reached, which stage of the project you are currently working on, and what kind of cancer research you are doing (either basic, translational, or clinical). If you are in the early stages of your career ladder, you have to do benchwork, analyze data, write manuscript and grant proposals. If you are in a more advanced stage, you will do less bench work and more writing. Let me give you an example of early stage researcher doing basic and translational cancer research.
I think the most critical part is designing the right experiment which can address the question you want to ask. So, a thoughtful scientist will spend quality time in experimental design, making sure to include both positive controls and negative controls in the experiment. The next step, which is the most time-consuming stage, is assembling and/or preparing experimental tools and reagents necessary to execute the experiment. Then, the researcher will grow cancer cells derived from patients or experimentally-engineered cells, expose them to drug or other reagents of interest, harvest them, extract DNA, RNA, proteins, and analyze data as necessary. He or she will also work with animal models bearing tumors, treat them with reagents of interest (such as drugs), and see the effect on tumor growth.
Tell us about a time you made an exciting breakthrough — or any other highlight in your journey so far.
I would say this was probably when I was a postdoctoral fellow. After spending long hours in the laboratory for several years, I discovered a new cancer-causing gene, known as MECP2, which turned out to be involved in several different human cancers. It seems that we can help the patients whose tumors harbor excessive activities of this oncogene, by repurposing currently available drugs that are being used to treat other diseases. We are excited about this! This work was published in a high-profile journal, has been patented, and is the subject of a clinical trial in development.
Tell us about a time you had serious doubts about your own ability in the fields you chose. How did you overcome that?
Setback is very common in research. You spend several months carefully planning and executing the experiments, and you end-up getting no results at all or getting the exact opposite of what you had expected, thereby challenging your entire experimental rationale! That happens very often. You will get expected results only occasionally. Well… that’s the way how science works… There are so many times you doubt on your ideas and ability.
Remember what Nietzsche said: “What doesn’t kill you, makes you stronger”! You have to learn from failures, go back and carefully review those unexpected results or failed studies. If you have done everything correctly, it is entirely possible that you are on your way to find something great. When feeling low, I try to be resilient; keeping the big picture in mind, I try to find more effective alternative(s).
If you were in the admissions committee, what qualities would you look into a prospective graduate candidate in your field?
I would pick someone who has the following qualities:
(i) Passion for science and new knowledge.
(ii) Scholarly inquisitiveness and critical thinking skills that are necessary for graduate level work.
(iii) Intrinsic motivation.
(iv) Strong academic credentials.
The committee will assess those qualities, mainly on the basis of application materials submitted by the candidates. So, the letters of recommendation should be strong and credible. Even more important, the personal statement should be able to convince the committee why they should pick this candidate from the pool of applicants. This is a highly critical piece of writing, which I think is a one-time opportunity to show your thoughtfulness, creativity, and determination to the admissions committee. In addition, any research experience and undergraduate coursework in subjects relevant to cancer research such as molecular biology, biochemistry, cell biology, pathophysiology, and/or pharmacology will be a strong plus point.
How can prospective graduate students prepare themselves for being a part of cutting edge research labs in your field?
Because of the improvement in communication, transportation and technology in general, the world is shrinking. I would say the world is at their fingertips for prospective graduate students these days. You can sit in front of your laptop sipping your coffee while attending online courses from MIT for free! So, start digging deeper and build a solid knowledge-base in your area of interest. Make a list of research labs you are interested to work in and, then visit their webpages and go through a few recent publications from those labs. This will give you an idea of what these labs are currently working on and what kind of research techniques do they routinely use.
There are a few emerging biotech companies and research-based labs in Nepal these days. I would strongly recommend contacting them and see whether you can volunteer there and learn some of the basic molecular techniques they use. This will make your application portfolio stronger. I would also suggest talking to your professors and senior colleagues within Nepal who might have ongoing collaborations (or past collaborations) with researchers abroad. Always remember that networking is a key for success in every aspect of your life!
Can you recommend 3 resources for people looking to get into your field (these can be job portals, networking groups, listservs, magazines, colleges — anything)?
I would recommend the following 3 resources:
(i) American Academy for Cancer Research (AACR)> Resources for students
(ii) National Cancer Institute (NCI)> Information for cancer research community
(iii) One can also look at the following online coursework on Cancer from Coursera
What are your observations about the research scenario in Nepal? How can we make our education system more conducive to innovation and research?
The biomedical research in Nepal is still in primitive stage. Although some efforts have been made by a few colleges, institutes, and universities, they are still struggling with resources-both financial resource and manpower resource. However, I must say that there are a few start-ups in the private sector which have made substantial progress in their area of focus. But we are already lagging far behind the rest of the world and, unless the government allocates resources to establish a solid research platform at the national level, we cannot generate competent research manpower anytime soon.
In my opinion, our education system needs to be revamped. It still puts too much emphasis on fact-oriented rote memorization rather than encouraging the students to properly understand the concept. We should put more emphasis on attributes such as critical thinking, problem-solving, creativity and innovation. We should also introduce a research component into our curriculum from earlier semesters at the undergraduate level.
Tell us about the role of mentorship in your professional life.
Mentoring is a critical component in the professional development of anyone, no matter how far you have progressed in your career. I feel fortunate to have wonderful mentors throughout my career so far. I have received invaluable support, guidance, advice and inputs from my mentors. Once you develop a strong mentor-mentee relationship, you can seek honest feedback on any aspect of your professional life from the mentor. My mentors have not only taught me how to do good science but also have shared their wisdom, perspective, and professional network with me. They have always been my resource personnel, and I regularly reach out to them whenever I hit a road-block. The ride of mentoring relationship has been a tremendously rewarding experience.
What is the best career advice you have ever received?
One of my mentors used to say: “Don’t lose sight of the forest for the trees”. I think this is probably the best career advice I have ever received. It is easy for us to become so engrossed in small details of a particular project that we occasionally lose sight of the big picture. We should not forget why we are doing research. So, every once in awhile you should step back to stop and smell the roses!
The career advice you wished you received in your twenties.
In retrospect, it may seem obvious, but I wish someone had made me realize earlier that “you can’t have everything and the sooner you start to focus on doing a few things really well, the better it will be.”
Please share your experiences on opportunities and responsibilities of being at the forefront of cutting edge research as a Nepali national.
On the one hand, Nepal is lagging far behind the rest of the world in scientific research. On the other hand, quite a few of rigorously-trained and highly-skilled Nepalese scientists have been working around the globe, doing top-notch research. I think it is the right time to contribute our motherland in whatsoever manner we can. It might sound too risky to go back physically and start working over there, but I think if someone wants to take this risk and help in laying the foundations of cutting-edge research in Nepal, the risk premium will definitely compound over the years both in terms of professional growth and personal gratification. We have our own circumstances and all of us cannot be there in person, but I don’t think that is even necessary as long as we have a sense of indebtedness to Nepal. We can help in the transfer of technology by setting up a collaboration with institutes/universities in Nepal. Similarly, we can host informative webinars to cultivate research culture and to educate interested groups of people about ongoing scientific activities in our research institutes.
Your final words of advice for someone who wants to get into your field.
I want to say a couple of things. First of all, there are a lot of smart people out there, so avoid the crowded area and try to carve a niche for yourself. Another important thing: since you are setting yourself up for a marathon, not a sprint, you should work on building resilience; grit matters the most!