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Some points also covered or better elaborated elsewhere*.

Assimilate the Scientific Method

  • What is it? To understand a natural phenomenon by using critical thinking skills to first formulate a hypothesis or two or three and then to conceive an experiment design to test these hypotheses rigorously.
  • The adage’ Practice makes perfect‘ is never truer than when applied to the scientific method.
  • In other words, in the beginning of one’s career not one experiment per month but ideally several per day.
  • This could be something as simple as learning how to properly titrate an antibody for use in an application, say flow cytometry or ELISA (Enzyme Linked ImmunoSorbent Assay).
    • What’s the goal of such an experiment?
    • To confirm that the optimal result is obtained from the same antibody dilution in every iteration, of course with all other variables being the same.
    • And learn the all-important lesson of appropriate controls necessary for each experiment.
  • However, boring repetitiousness isn’t the take-home here. Rather robustness of observations are.
    • When people with different strengths, weaknesses and quirks generate comparable data after using methods one has developed, each using them in their own unique ways, it’s a validation of one’s scientific approach.
    • After all, capacity of generalization or universality is a holy grail (pun intended) of the scientific method.

Unique Mindset of becoming Comfortable with Discomfort

  • Experiment didn’t work out the way it should have.
  • This is the one of the most common experiences in experimentation science, even one of its basic tenets.
  • Things not working out as they should. Stress-inducing in daily life perhaps but for a scientist, this is daily life, and not just daily life but normal daily life.
  • A good part of becoming a scientist is becoming habituated to this concept.
  • Inhabiting a zone that for others is nothing but discomfort, and not just inhabit it but consider doing so to be normal.
  • Another way of looking at it is to accept that empiricism, i.e., trial-and-error, is part and parcel of one’s work.
  • Only with such a mindset in place is it possible to pick up the pieces and repeat an experiment that went wrong, and not just repeat it once but multiple times.

Basic Mathematical Skills

  • One skill I couldn’t possibly stress enough? Mathematics, especially basic mathematical skills.
  • Isn’t this self-evident? Shockingly no, in my personal experience.
  • Maths in particular reveals vast cultural schisms.
  • Though far from a mathematical genius, I can handily perform the maths my work demands on a daily basis.
  • Imagine my shock after coming to the US to find Bachelor’s after Bachelor’s unable to solve even the most basic mathematical calculations necessary for the most mundane of cell cultures.
    • E.g., 50^6 cells need to be seeded at 0.5^6 per well in a volume of 50 microliters per well in a 96-well plate.
    • I’ve forgotten the number of times I’ve had to coach people with a US Bachelor’s degree how to calculate something so simple,
      • And in a job that requires dozens of such calculations every single day.
      • And that too coach slowly step-by-step, excruciatingly painfully slowly.
  • Serial dilutions?
    • Another everyday need, and again far beyond the capabilities of many Bachelor’s I’ve come across in the US.
    • So naturally a checkerboard with criss-cross serial dilutions across a plate isn’t even remotely within their scope.

Basic Lab Techniques

  • How to properly use and maintain incubators, water baths and centrifuges.
  • How to properly use a balance, a pipette, multichannel pipettes.
    • What’s the difference between the first and second stop in a pipette? When to use the latter?
  • How to work properly inside a biosafety hood.
  • Sterile cell culture techniques
    • The rarest of skills.
    • In my experience, the domain and expertise of the vanishingly scant in any lab I’ve been in.
    • For e.g., immortalized cell lines are much easier to maintain in culture compared to primary cell cultures.
    • Similarly, serum-free cultures are much easier compared to serum-laden cell cultures.

Learning to love Troubleshooting

  • Experiment didn’t work out the way it should have. Why? What to do next?
  • Part and parcel of a life in biomedical research.
  • Need to figure out how to explain the results to oneself first. Easier said than done.
  • Means needing to retrace each and every step of the experiment. Is that possible?
    • Likely not if each and every step of the experiment wasn’t accurately, comprehensively and legibly recorded.
    • Yes, especially all the fussy little details that seemed so cumbersome and irritating at the time.
    • After all, how to troubleshoot if a step where a mistake may have been made wasn’t even recorded?
  • Learning to troubleshoot in turn teaches the essential lesson of scope and scale.
    • Inexperienced novices invariably start big in both scope and scale. Predictable result? Failure.
    • Initially, I too fell prey to this tendency, both when I first started working with mycobacteria and with mice.
    • So essential lesson for a novice is to start small in both scope and size. Then scale up once the preliminary experiments start working out.
    • And scale up one must eventually if the goal is to report meaningful trustworthy data.
    • So need to get used to the idea of a series of experiments gradually expanding in scope and scale rather than one giant one-time experiment.
    • Small scope and scale experiments early in one’s career are akin to subjecting oneself to small doses of poison to build up the capacity to tolerate larger doses later. Think of it as a psychological ploy that helps train the mind to become comfortable with the discomfort of experiments that didn’t work out the way they should have, an inevitable part of the life of an experimentation scientist.

Learning to love looking under the Microscope

  • Look at experimental cells under the microscope every day. Sounds obvious, doesn’t it?
  • Yet I can’t honestly say that I’ve seen others look at their cells as much as I still do and would like them to do.
  • To my dismay, what I see happen more frequently is ‘set up the experiment, stick the cells in the incubator and then forget about them until the experiment is over‘.
  • Seen as a habitual pattern, it just turns on my skepticism antenna into high gear, as in be skeptical about the data that ensues.

Learning to love reading the Scientific literature

  • I’ve noticed that greatest enthusiasm prevails in the first 3 to 5 years, i.e., during the Ph.D. years, and then it tends to wane rapidly and rather precipitously.
  • In my opinion, love for reading the scientific literature could be used to separate vocational scientists from their more career-oriented counterparts.
  • The former will devour it, the latter more likely will dip their toes in as per the dictates of their career.
  • Today, it’s easier than ever to both become inundated as well as stay on top of the literature. Confused?
  • Just that the number of journals have proliferated like crazy.
  • Key is to look with some periodicity at major scientific journals, both broadly across science and within one’s speciality.
  • Easy to set reminders to look at early online publications. Each journal has its schedule for early online.
    • For e.g., Nature group of journals on Sundays.
    • Journal of Experimental Medicine on Mondays.
    • Immunity and Cell on Thursdays.
    • Science group on Fridays.

Final Words: Qualities uniquely required for exceptional experimentation

  • With experience, I learned to elaborate the qualities that are most important to me in life and in science. And it turns out they mostly overlap in a Venn diagram with only the following few unique to science.
  • Detail-oriented
    • Was the culture medium clear or cloudy?
    • Was there enough water in the incubator jacket?
    • Developing the habit to unconsciously and critically observe and analyze each and every movable (reagents and consumables) and immovable (equipment, devices, instruments) aspect of each and every experiment each and every day, day after day.
    • In other words, obsessive attention to detail.
    • Absolutely necessary to generate reproducible data which in turn is necessary to be a trusted and reliable, even exceptional experimentalist.
  • Imperviousness to criticism
    • In any and every circumstance in life is hardly realistic.
    • Rather to develop a thick skin towards criticism of one’s science in general.
    • Not all criticism is valid but valid criticism is crucial for great science because it is one of the foundational tenets of the scientific method.
    • Developing imperviousness to criticism is difficult but essential in helping develop an understanding (a feel or sense) of valid criticism, regardless of the person who delivers it.
    • Thus, learning to ignore the messenger but not the message is essential habituation for exceptional science.
    • Thicker the skin, better the communication, I say, and communication with one’s supervisor is key to a viable science life.
      • Let’s say a key experiment didn’t pan out as anticipated. Tell the boss or not?
      • Don’t tell and lose the boss’ trust. Tell and subject oneself to the risk of a humiliating dressing down (if boss is a jerk). See why it’s critical to develop a thick skin about one’s science?
  • Focus and thinking ahead
    • Think about the experiment ahead of time.
    • Set up the experiment with single-minded focus.
    • Not distracted about the party after work or plans for the week-end ahead.
    • Set up a perfectly executed experiment, did I? Wrong. Loads of room for improvement. For example, I could have labeled my tubes/plates ahead of time, even the previous day. That way, I wouldn’t have had the cells sitting those extra 10 minutes in buffer, would I?
    • Over time, an experienced experimenter learns to work out all the kinks in a particular type of repetitive experiment until the whole piece comes together like a perfectly rehearsed ballet.
    • Fred Astaire comes to mind at this point. There are several examples of Astaire doing the same dance at different times. When film historians carefully analyzed and overlaid the pieces side-by-side, they were astonished to find Astaire’s steps overlapped perfectly even when the different dance executions were days or even years apart. Same thing with experimentation science.
    • I still recall how I used to run over my experimental steps in my mind as I drove my moped across town from my home to my PhD institute. No detail was too small. Enter the building, put my bag down, enter the lab and switch on the UV light in my biosafety hood and then run downstairs to the autoclave room to pick up the freshly sterilized bijou bottles I’d need for my experiment.
    • Each experiment as close as possible to a perfectly executed dance. That’s the way I think about it.
    • And I’ve never regretted my habit of list-making.
    • Oh, and to think about what I’m doing as I’m doing it. That’s another critical aspect of the focus part.
      • Tedium is invariably part of experimentation science as it is in any aspect of life.
      • Trick is to learn to compartmentalize this tedium on a scale from avoidable to inevitable to diversion.
      • When is it ok to shoot the breeze with a colleague waiting for the centrifuge to stop and when is it more important to instead prepare the serial dilution of the drug into the plates and leave them inside the incubator?

*Tirumalai Kamala’s answer to What are your hearty suggestions to the students new to research?

Further Reading

  1. Almeida‐Souza, Leonardo, and Jonathan Baets. “PhD survival guide.” EMBO reports 13.3 (2012): 189-192. Page on embopress.org
  2. Williams, Richard Alun. “Spinning plates and juggling balls.” EMBO reports 14.4 (2013): 305-309. Page on wiley.com
  3. Yewdell, Jonathan W. “How to succeed in science: a concise guide for young biomedical scientists. Part I: taking the plunge.” Nature Reviews Molecular Cell Biology 9.5 (2008): 413-416. Page on www.ucm.es
  4. Yewdell, Jonathan W. “How to succeed in science: a concise guide for young biomedical scientists. Part II: making discoveries.” Nature Reviews Molecular Cell Biology 9.6 (2008): 491-494. Page on www.ucm.es