The advent of biologics

Small molecules have always formed the basis of drug development. They still do but biologics have begun taking a definitive role. Biologics are defined to be derived from natural sources and can take the form of whole blood and organs, proteins, stem cells, antibodies, antigens, interfering RNA and viruses for gene therapy. In contrast to small molecules which have known structures, and are manufactured by chemical processes, biologics are heterogenous, complex and more challenging to synthesize. A simple picture demonstrates their complexity:

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Despite their complexity, biologics have proven extremely essential for treatments of various debilitating diseases. Perhaps the most well-known example would be insulin, the hormone secreted by the pancreatic islet cells which lowers blood glucose levels. This hormone was initially isolated from cattle and pigs and injected into patients suffering from diabetes to lower their blood sugar levels. This created a fair share of problems due to human allergic responses but was overcome in 1978 by scientists at Genentech that were able to produce human insulin using our good old trusty bacteria, E. coli.

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Since then, there have been many more biologics approved for treatment. Perhaps the greatest proportion are represented by monoclonal antibodies, with over 300 in development and 32 approved for treatment. Most of them target cancer, autoimmune disease and infectious diseases (see pie chart). The exponential increase of monoclonal antibody therapeutics may be attributed to the rapid technological advancements involved in their engineering, production, and screening against various targets. One of the key movers and shakers in developing monoclonal antibody therapies is Munich-based Morphosys AG (http://www.morphosys.com/). They have the industry’s largest fragment antibody library and utilize phage display techniques for screening selective binders and humanized mice to generate high-affinity specific monoclonal antibodies. Perhaps the numbers speak for themselves:  90 antibodies in development and 22 already in clinical trials. It is interesting to see a company that consistently innovates (and are not afraid of shedding staff from 420 in 2012 to a trim 299 in 2013) and acquires new technologies to advance a focused goal, in this case, producing quality antibodies against specific targets.

These are exciting times with promising novel technologies ahead, one being the use of bispecific antibodies, offering some hope to the bleak and barren landscape that small molecule therapy is currently facing.

*Images taken from Medicines in Development -Biologics 2013 report  http://www.phrma.org/sites/default/files/pdf/biologicsoverview2013.pdf

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Life in big pharma

My dream job used to be to work in a big pharmaceutical company, to be part of the process where drugs are created and produced, to have a role in making life better for patients worldwide. I was lucky to get into a big pharma company as an assistant scientist right out of university. I had not even done my PhD then, I was a freshly minted graduate with hardly any prior work experience aside from internships.

It was very impressive to be part of such a big multinational company. Everything had a process. We even used Lotus Notes at the time. There were E-Learning courses, orientations, safety briefings, lab tours. Equipment was state of the art and built for high-throughput. There was ample support and funding in the early years. I was a junior scientist yet was given the responsibility of setting up a pharmacokinetics lab with my young team leader boss. We were a small site with few people, and functioned very much like a biotech to begin with. Slowly we built up the processes needed for running pharmacokinetic screens, then we were screening compounds shipped to us like pros on speed. It was a good environment, great people, reasonable pay and working hours.

After two years it started getting routine. I was just repeating processes over and over. We grew bigger though and now we had our own chemists making compounds. People came and people left. Projects got started, cut, transferred, whole sites were sometimes shut down. There was never any clear explanation, just people following orders. My boss still looked out for me though, I got sent on training courses, I pursued a part-time Masters when I got too bored of the routine. And soon, I left.

It was not the dream job I had in my mind. In all four years I spent there, I do not think I aided in the making of any drug that went into the clinic. Yet it was time spent, and work done, screening and screening. I suppose if I was a senior scientist, which I was almost becoming, just one promotion away, I may have played a bigger role. But looking at my senior scientist colleagues, and even team leaders, they never seemed to have a clear vision or goal, they appeared lost at times.

My observations just mirror what is going on in the pharma industry. The patent cliff has left the big players scrambling to push newer drugs into the market. The failure to produce enough new drugs to support the large scale of big pharma operations derive from a multitude of reasons. The first being just the obvious inefficiency of the current approach, which involves finding a single target that may alter a disease response, screening a large bunch of compounds, making chemical modifications to improve pharmacokinetics and pharmacodynamics while ensuring no toxicity ensues, and if there are still valid candidates left to put them through human trials (which may not be completely well-designed) and hope to see sufficient efficacy and safety. This whole process can cost more than a billion dollars and take 10 years or more. Added to this, the nitty gritty details of problems encountered in assay development, drug interaction effects, the cost and obstacles one can encounter chemically synthesizing the compound.. it all adds up to a big giant UGH. Added to this major reason, are other issues like increasing stringency of FDA approval regulations, variability in human patient responses, difficulties finding the right biomarkers (especially when it comes to neurodegenerative disease) to measure patient responses, problems encountered when transitioning from animal to human models, and so on and so forth.

Obviously, we need a better way of doing things. Life in big pharma used to be safe, but it is not any longer. And innovation and creativity is harder in big companies which is why we are seeing a rise in biotech investments. I work in a biotech now, and life is indeed different, but that is another story for another day.

To do a PhD or not?

workforce infographic ASCB COMPASS

Image taken from http://ascb.org/where-will-a-biology-phd-take-you/

There are numerous articles like the one above highlighting the disparaging fates of science PhD graduates. Indeed, many PhD students I know, myself included, have often been mocked for a decision to commit several prime life years in the noble pursuit of expanding scientific knowledge on a basic stipend with a definite promise of working weekends. Do not kid yourself, it is a large investment, so why the hell should anyone do it?

Here are some good reasons to do a PhD, with some bad reasons thrown in for good measure:

1. Good reason: To progress more rapidly in my scientific career. Unless you want to remain a lab technician for the rest of your life, you need a PhD (ok, MAYBE if you have a boss that recognizes your scientific prowess and fights for you, you may progress to senior scientist level without a PhD, but it will take a looong time and may not be easy). This applies to jobs in scientific research be it in academia or industry. It also applies if you want to make more money as a technical expert, for example by becoming a field application scientist. However, if you want to do sales and marketing, a PhD is definitely not a requirement, in fact, it may even be a hindrance.

2. Bad reason: It’s the only thing I can do for now. This is the reason I sometimes get sick of hearing. It just goes to show you have not TRIED anything else. I did not know I wanted to do a PhD. I only knew I wanted to work in science. So I tried a science job. I liked it, and I knew then that I needed a PhD to progress. If you are in a science job, and you like it and you want to grow better at it, do a PhD. If you are in a science job which you hate or feel apathetic to, but cannot think of what other jobs you can do, do NOT do a PhD. If you have just finished school and do not know what to do, do not do a PhD. It will only make matters worse. Try applying for jobs of some interest to you, it will be easier to get them if you do not have a PhD than if you did. And you would have saved a whole lot of time and heartache.

3. Good reason: I am really super duper interested in this field of study. Doing a PhD can sometimes actually be a privilege if you are in love with what you are studying. Imagine waking up everyday and doing something you are deeply interested in and getting paid for it, with flexible working hours. Not too bad a life huh? Be careful that your field of study has actual people working in it though, you do not want to be working in a vacuum where you have no one to learn from or share your findings with. And depending on your needs, give some thought to what you might do after the PhD. If you choose to study something really niche like the fecal-eating habits of the sub-saharan anteater, make sure you learn from the best so at the very least, you can be reliably considered one of the experts in your field.

4. Bad reason: I want to make more money. The honest truth is, scientists do not make a lot of money. If you want to make more money, be filthy rich etc., be an investment banker, an insurance agent, a real estate agent…. go into sales for goodness sake. Stop thinking a PhD will automatically leave you rolling in dough! There is more to it than that. If you are stuck at a postdoc level, you will be getting SGD$55-70K per year. A senior scientist may make slightly more than that, but you will definitely not be hitting the $100K mark unless you were in some managerial role, which takes more than just a PhD to obtain.

But that shall be another story for another day.