Meeting people in-person is becoming a big challenge!

Every time I meet my fellow scientists during lunch hours in the canteen, I hear them talking about things that I am completely unaware of. In other words, I have no updates on anyone in the institute other than myself alone. Self centered? Yes I guess so. I consider not knowing about others a serious lapse on my part. On the other hand, I am not sure where people get the time to keep up with each other. I do the math in my head: Go to lab at 9.30 AM. Take few minutes to write down the jobs for the day. Next 3-4 hours “working” on bench, trouble shooting. 1-2 PM lunch break and socialize with my fellow colleagues over the lunch table. 2 PM onwards meeting with students discuss work/project. After 4 PM follow up on purchase/payment/vendor/funds/administration till 5 PM. Then continue with work till 7.30 PM. Meanwhile get interrupted numerous times by unsolicited visitors, phone calls, meetings etc. etc. Amidst all this, I never feel the urge to get up and go and meet someone unless work demands it. So, I am not sure how people do it. Over the phone? Possible. On the other hand, I find it very convenient to look at my computer screen browse and see who is posting what on social media like Twitter/Facebook. That way I reach out to more people and know many more people than I would if I were to go around and see them personally. Scientific social media like Researchgate.net, Academia.edu, Biomedexpert, Expertexchange, wiki, Mendeley, Scoopit, bloggers etc . I find Facebook pages of Nature, Biomedcentral, ASM, etc. incredibly useful since the first information on a great paper appears right on my screen without my searching for it. Twitter gives me much more information than I would ever need. If I knew Carl Zimmerman or Ed young personally, I would never have the amount of regard I have for them now through their writing prowess as scientific bloggers.

So what is the point? The point is no matter how much ever the wellness experts and social scientists abhor social media over normal human interactions; I hard sell social media alongside meeting people the natural way. I am a big fan of Facebooking, Blogging, Twittering over walking over to people and say hi. The reason why I am here in this blogsphere is because of social media. I would like to know what you guys think about it.

Myth 1: About Funding and setting up a lab in India.

What I thought: ‘I have to manage my show with my contingency for at least a year’.

I have had only 5 lakh per year as contingency and I thought I will buy 2 servers by paying 1.5 lakh each and hire a programmer for the remaining amount to start my computational work. I did not think of PCs and other items at that time! I did not know if the institute will give any start up money; the director also did not promise anything regarding this. In one of our informal conversations, he said you ask for money, but I will reduce it to half and give it to you. I did not think of getting any extramural funding from anywhere else at least for a year. So, my plans were to survive exclusively on the contingency for a year.

What it turned out to be: ‘Got the support that I never expected’.

I took chance and asked our director for some money for instruments and some for chemicals very gingerly. Tada.., he immediately granted the amount without any reduction. So, probably he expected that I will ask for lot more than that (I am still discovering that whatever I ask is actually the lowest that anyone asks here). So, now it gets me into thinking how much is too much or how little is too little. In USA, I have seen established researchers struggling for meager funds. So, probably I need to rekindle my thoughts and reset my lower limit. Also I have few grants lined up, although not funded yet, so there is still hope. So, money wise I would say I am pleasantly surprised here.

Myth 2:Starting wet lab is too difficult and people are un-co-operative…

What I thought: ‘I will not be able to set up any wet lab for atleast a year’.

I never thought of starting a wet lab for at-least few initial years here. When I would think about the things required for basic wet lab such as balance, pH meter, centrifuge, gel apparatus, chemicals, other consumables, culture facility and other countless number things, I have had cold sighs. I also never imagined that people (read scientists) can be co-operative in any way. About 7 months back I never thought of having my own small culture facility, culture collection, my own DNA/RNA extracting facility and small experimental facility.

What it turned out to be: ‘I am actually having a basic wet lab facility before completing one year’.

Although not an easy job to set up a wet lab as pointed by one of my senior, but nevertheless I already have one! I now have a culture collection. We have standardized growing BGAs, extracting DNA and RNA from them. We have also sequenced two genomes in house!! That is stupendous for me considering what I had thought before and the slow pace of everything else here. We also just walk across the corridor and get help from the neighboring lab for anything else. So, people are much nicer than I imagined them to be…

Myth 3:I will not have adequate computational facility here…

What I thought: ‘Althoughcomputers exist, but the power will be inadequate’.

After leaving Virginia Tech, I thought the computational resources I will have is going to be meager and I will not be able to do much until I buy my own big servers. At VT, I worked with machines with 16 GB memory and a max of 16 cores. Of course there were clusters but they were shared by a number of people. So, getting to the front of the queue was just as good as waiting for a month.

What it turned out to be: ‘Much superior computers exist here’.

Not only do we have superior computational facilities here, but also access to Indias superfast computing facilities. We have a HPC cluster in our institute shared by 2 groups, out of which one group already owns several such HPC clusters, so really don’t need to share it with us. I have my 3 linux servers on NFS with most of the bioinformatics pipelines installed. I have exceptional help in bioinformatics from Applied Biosystems. This is something I never expected.

Myth 4: I have to run my own sequencing here…

What I thought: I thought I have to do my own sequencing here by myself! Since it is a govt. lab, I thought they just have machines and no one to operate (that is what people think about govt. run labs).

What it turned out to be: My senior colleagues who bought the machine are much smarter than I could have imagined!! They negotiated with the company to station their dedicated personnel to take care of our sequencing initiatives. Thankfully I can do sequencing here without being hassled by unwanted details of running reactions and all…

So, far all my expectations have been turned into fair amount of pleasantries. I also have a number of other myths turning out to be pleasant surprises such as getting students with fellowships, getting smart programmers as project assistants and getting experienced women scientists in my lab. In total I have been overwhelmed by the benefits that we get here.

But there are few cultural barriers that I had to overcome and few things that I learnt the hard way

I will share some of my experiences here:

1. Dont accept objects you did not intend to order or never open a pack:
Some of our lab purchases has been excellent, some were OK and some were awful. Among the awful stuff I there were few that did not work too well which I could not return. The bills could not be paid on time and finally I had to pay it off of my contingency.

2. When processing bills, if you give a file to someone keep a copy or keep an evidence of it.
Here in govt. run lab, when the bills are processed, it passes through a string of processes. I still dont understand why it has to be that way. For me purchase should be straight forward. You choose the company that sells a particular product, then procure it and send the bill to account section for final payment. To top it all money has a cycle and it goes back by March. That is very tough to adjust.

3. Follow up:
Here nothing happens without following up. You may tell one thing one time, but the other person does not take it seriously till you tell it N number of times. That is true in every aspect of life here. So follow up on each and everything. Buy a tape recorder if necessary and play it multiple number of times.

4. Have infinite memory:
Since you have to follow up on each and everything, you need to have infinite amount of memory. If you already did not have it, buy an external hard drive :)

During the golden days of Indian Generics – India (as per the patent act of 1970) did not recognize patents in areas considered vital to human life - food and health. Therefore none of the pharmaceutical patents were valid in India, allowing Indian companies to manufacture generic medicines without licensing to the originators as long as the process used for manufacturing was different from that used by the original company. The Indian pharmaceuticals became experts in reverse engineering. This allowed Indian generics to compete in the world market most importantly by providing medicines at an affordable prize to areas of the world that badly needed them. The best example for this are the antiviral drugs manufactured by Cipla. These generics were made available in Africa as well as South America. The availability of these generics at an affordable prize no doubt had a great effect on curtailing the spread of the HIV epidemic.

In 1994 India became a part of the World Trade Organization (WTO) and signed the agreement on trade-related aspects of intellectual property rights (TRIPS) and as part of that, it was required to recognize all international patents including those within the food and health. Compulsory licensing is a provision provided under TRIPS, though it has hardly ever been implemented in any of the western countries especially for pharmaceuticals.

The compulsory license was granted to NATCO under Section 84 of the patents act. The law details are available in the above blog. This section allows any one who feels that the product covered under the patent is 1) Not available to the public at a reasonable cost 2) does not meet the requirements of the public, or 3) is not sufficiently worked in India, can appeal for compulsory license.

Nexavar priced at 280,000 per month is obviously not available to the public at a reasonable cost and neither is it available to all patients who need the drug. NATCO will now manufacture and sell the same drug at Rs 8800 per month and will also pay a royalty of 6% of its sales to Baylor. The Judgment against Novartis drug Glivec tackled a completely different aspect of the drug industry. Patents give exclusive rights to the companies to manufacture and sell a particular product. Often times, the pharma industry change their patented drug slightly by converting it to a salt, adding a ester or ether, making an isomer that does not in any way alter the efficacy or biosorbtion of the drug. This new form of the same chemical is now patented. This process called evergreening is exploited by pharma companies to hold exclusive rights to manufacturing the drug several years after the original patent has expired.

When India signed the WTO agreement and modified its patent law, it made a provision called 3(d) which supposedly addressed evergreening by prohibiting the patenting of new forms of existing pharmaceutical substances that do not demonstrate significantly enhanced "efficacy (). This provision is unique to India without precedence elsewhere. Details of section 3(d) are dealt within both the Frontline issue as well as the blogs on SpicyIP. If interested in the entire provisions within the section read the article.

Patents were an incentive for Pharma companies to invest in drug development. Drug development is an expensive venture that requires millions of dollars being spent without returns. When a miracle drug is finally produced, patenting and exclusive manufacturing rights allow these companies to make sufficient profits to justify their previous investments, as well as to invest in future innovations. So a big debate now is if such decisions (viewed as) against Baylor and Novartis, hamper the process of innovation in drug development? Do they discourage pharma companies from investing in innovation? Based on the literature and studies done, I doubt these have any impact on the profits that these giant pharmaceuticals make. Prof. Chien’s article clearly shows that granting of compulsory licenses does not/has not hurt innovation.

Moreover, as the well-known IP lawyer Shamnad Basheer points out in his interview to Frontline, the generics tap into a market that is not catered to by these giants – the middle and low income group. This group of the population cannot afford the patented drugs at their exorbitant prices and have to rely only on generics. By licensing to generic producing companies the pharmaceuticals can not only increase the reach of their drug but can also make sufficient profits (through royalties).

Secondly, in cases of epidemics and life threatening situations availability of a drug is solely humanitarian and it should be implemented as such. Whatever the loss incurred by the company might be, it cannot be worse than the loss of lives due to unaffordability of the life saving drugs . For example – anti-retroviral drugs manufactured by Cipla proved to be a boon for HIV patients in Africa. The availability of generics in this case has obviously not had an effect on the viability or profits of the pharmaceuticals. So why is there such a big hue and cry over incentives for innovation, protecting the interest of the pharma companies? Maybe it is time to turn around and protect the people for whom the drugs are actually manufactured rather than the profits (which seems to be the only direction companies are heading in).

In between long hours of coaxing finicky mice to ‘behave’, I spent many days last summer avidly following the Rotavac vaccine story. While the press coverage was undeniably deserved for the successful results in the clinical trials, the story started long back, in the 1980s, with thousands of hours of research in India and US. Rotavac can be considered a thumping endorsement for translational research and ‘India Shining’. World over, significant time, effort and resources are being devoted to what is broadly called translational research. Translational research is nothing new and previously existed silently under the alias of applied research. Now, the lines between basic and applied research are getting blurred and what was once a linear relationship more has now evolved into a circular one.

Translational science is the process by which basic research findings are transformed into viable and usable applications for improving health or solving other ecological and biological problems. While we celebrate the triumphs of a handful of success stories, there are a lot of failures and unfinished work, so one should consider the investment, limits and timescales involved before going down this road. To do that we need to understand what translational research is, how one goes about it, the challenges and payoffs, and most importantly how excited we should be by the high volumes of related research being published in major journals these days. Being engaged in it to some degree, I think of it usually as a multi-dimensional relay race with lots of hits and misses. While a lot is written on the trials and tribulations of human clinical testing, I’d like to focus on the stage in which the baton is still firmly outside human arena. Consider this a generalized ‘how to’ guide on embarking, conducting and presenting translational work as a bench warrior before handing it over to the experts in industry. There is no one superhit formula and the approaches should be tailored to the needs of each situation.

We have come a long way from just relying on serendipity to discover our next drugs and instead build on years of work to understand a disease process. So, one of the starting points of a typical translational medicine story could just be the next interesting finding from your cell culture or in vitro experiment. At this stage, hypothesis and proof of concept are firmly in the arena of basic research. The idea is speculative and requires a lot of evidence to validate. At this point it is prudent to consider how you want to proceed with developing therapeutics based on this exciting new concept. For instance, if your previous study relies on modulating gene expression at the level of DNA, broad spectrum HDAC inhibitors may be great to prove the concept, but they are not suitable for therapy in human beings.

The lack of viable experimental agents that recapitulate your basic research is a major stalling point. The choice of the agent is critical since it has to be something that is specific enough to engage the cellular process you want to target, yet be amenable enough to be given to a whole animal via intra-peritoneal, oral or other routes. The other questions to consider can range from—will it be a small chemical molecule or a DNA based therapy? Does it need a delivery agent like nanoparticles? Are the compounds available or need to be invented? This search can be surprisingly short or may need many years; but once you have zeroed in on the potential candidate, another set of challenges set in—for example, the approach that worked in a cell culture dish may need some modifications to pass beyond the liver or blood brain barrier in a whole organism. Many compounds are given directly to site of action in the body, but one needs to evaluate toxicity upon spreading, tolerance over time etc. Hence, pre-clinical validation is an intense process and is a delicate mix of pharmacokinetics, biochemistry and whole organism assays. Finally, you must also consider what experiments you will conduct on the whole animal to test your candidate therapeutic. For example, for cancers the metric usually is decrease in tumor size or related parameters, however for neurologic diseases, picking the right behavioral tests to test your candidate molecule is critical.

In parallel, before embarking on the project, it is worthwhile for the researcher to spend some time understanding the disease not in its biological avatar, but its clinical face and the life of a person with the condition. This gives a fresh perspective, and brings home the responsibility of finding a therapy. It also helps design your pre-clinical validation experiments. For example, spending two hours a week in a clinic with patients with disease ‘A’ may help you decide that a therapy may well be worthwhile if it rescues epilepsy associated with the condition rather all the symptoms at one go. Across the world, numerous fellowships, meetings and workshops are being conducted to enable bench-experienced scientists to get exposure to clinic-based doctors and patients to talk and work together to find a solution.

The other major shift that a bench-based scientist needs to appreciate is that the performance of a chemical agent will likely have off-target side effects that have to be documented and reported. This is not something we bench warriors are comfortable doing, largely because there is no incentive to do so when publishing manuscripts in mainstream journals, where usually, only the perfect story is rewarded. However, given the complexity of the whole body, it is unlikely that your candidate therapy will be ideal in every way. This need is being increasingly addressed in specialized translational journals like Science Translational Medicine, Journal of Translational Medicine, Clinical and Translational Science where reports of adverse events and how they were managed are being encouraged and published. So researchers would better serve their science and the disease community by considering where they publish their findings. One also hopes that the review process in mainstream journals becomes increasingly open to sharing and discussing negative results.

Safeguarding your intellectual property before handing over the baton to experts that herd in the next stage is also important. While some PIs opt to start companies that will develop the compound further with external funding, others choose to tie up with a consortium made up of doctors and pharma support. The final phase is dealing with the publicity of a well worked out project that has culminated in a good publication. Usually press releases from the university or institute are cautious, and present the study in the most realistic light. Popular press has the duty to report findings realistically and not sensationalize a finding to make it news worthy.

Do things work differently in India? As with most things, translational research in India has recently got much encouragement and support. Hopefully we should have takers for all these opportunities and should see results in due course. At the academia end, two new biotech clusters have emerged—NCR and Bangalore. Institutes like Translational Health Science Institute, Institute for Molecular Medicine, Tata Translational Research Center, InStem and C-CAMP have been set up. Simultaneously, new grants (Wellcome-DBT Indian Alliance, BIRAC-Wellcome joint-call for translational medicine and other grand challenges initiatives funded by overseas foundations) are being made available. Most, if not all international organizations, committed to curing a certain disease, do not limit their support to specific countries.

However, most of these initiatives are at the end of getting basic research transformed into a potentially usable treatment modality. There are sizable roadblocks at the end of getting the said modality delivered in usable form to practicing physicians. A good discussion of the India-specific problems can be found at this freely accessible speech by Dr. Kiran Mazumdar, Biocon. Problems also exist in the business model of Indian pharma companies that focus largely on producing generic drugs. The upcoming biotech sector, is attempting to foray into more high-risk-high-gain arena, but they also face problems in securing funding, getting multi-tiered governmental approvals, and finally, the lack of proper framework to conduct early stage clinical trials. While many clinicians were previously content to conduct trials for foreign companies, recent IP issues and withdrawal of many funded trials is slowly forcing them to look inwards for innovation-driven research and therapy. We are in a state of flux, and the coming years will be critical in deciding how we overcome existing problems and utilize the opportunities. For now, translative work is well funded and supported on the bench-to-candidate therapy side; but for it to complete the journey to the patients’ bedside, we need additional infrastructure to kick in. But if you, like me, are doing the trapeze act from the bench side end of things, the scenario is bright and exciting.