Tips for Methods Development and Optimization in Biology

I haven't posted anything in quite a while. Mostly that's because I haven't written anything that I thought would be of general interest. I once again have a young lab assistant to preach at, so I might as well preach at the world too. Here is what I've written for her about methods development in the biology laboratory.

 

Optimization and methods development:

In science, and particularly in biology, very rarely does an experiment work the first time a different scientist tries it. Ideally, when a paper is published, the methods will be explained in enough detail for anyone with access to the right materials to reproduce it. However, it is usually the case that experiments are described incompletely and people who try to use them need to spend a little bit of time optimizing and trying different parameters. Sometimes a citation is given to another publication where more details are available, but questions often remain even after following the entire paper trail. There are many cases of high-profile research where independent labs have failed to be able to reproduce the published results, this has been called the “Replication Crisis” and is a major issue in all branches of science today.

Here are some important points to keep in mind when developing or adapting a method:

1.       Define the victory conditions. This is the first, and most important step in methods development. How will you know that the method is good enough? Write it down. Be as specific as possible. Try to use quantitative parameters. Biology is still largely a qualitative discipline, so you will often find yourself defining success in terms of qualitative parameters. Defining the victory conditions is useful because it lets you know when you are done and can move on. Having a clear goal also helps you think more clearly about what you need to do to get there, for example, which parameters should be changed or observed. Many scientists have wasted years of their lives optimizing methods that were already good enough, or that could never be good enough because they were shooting at a moving or nonexistent target.

2.       Manipulate only one variable at a time. Try to keep as many aspects of the experiment as possible constant between trials, so that you can know for sure what causes the differences you’re observing. To cover a large parameter space, do a lot of individual trials. In some cases, for example if it is an expensive or time consuming experiment that you can’t do many trials of, you may have to change multiple variables at a time so you can cover a larger parameter space, but this is not preferred.

3.       Keep detailed and systematic records. Write down what you’ve tried and what you’ve observed. Tables are a good way to organize observations. Record exactly which variables you changed. Write a description of the results. If applicable, take pictures and save instrument data files. You can’t know which observations will be the most helpful later, so try to record as much as possible.

4.       Take time to stop and think. After you’ve done some experiments and recorded the results, look back at your observation notes. Look back also at the victory conditions you defined. What experimental conditions are getting you closest to your goal? What conditions are not working so well? Can you think of a mechanistic explanation for why some conditions work better than others?  Science may be one of the few disciplines where a day spent staring into space, occasionally jotting down notes, can be your most productive day of the year.

5.       Be persistent and have a long memory. If you have defined realistic victory conditions, and spent enough time researching the problem and trying different solutions, usually you will eventually either reach the victory conditions, or you will come to understand the system well enough to know why the victory conditions are unrealistic. In some cases, even after much thought and effort, your experiments still won’t behave as you expect them to, and you may not have any idea why. In these cases, it may be time to move on to a different question for a while. Brains work subconsciously on our unsolved problems, so perhaps in the coming weeks, months, or years something will click and you’ll suddenly understand the problem better and will be able to address it. We are fortunate to live in an age where there are countless interesting open questions in biology, and when our tools have become sophisticated enough to allow us to effectively attack many of them.