Do Not Seek Your Goal

You do not seek your goal, you encounter it.

In today’s post I want to get back to connecting principals from the martial arts to everyday life and research. The above quote is from a Brazilian Jiu Jitsu (BJJ) seminar by Ryron Gracie which I attended a while ago. Ryron attributed it to someone attending his seminar in Spain.

The point Ryron was trying to make is that at high levels of BJJ you should not look for a submission, trying to “get it”. Instead, you just observe and seize the opportunity when it arises. I thought it was a great point, something to strive for in my training. I also thought it was a manifestation of a much older and general principal in Martial Arts by which “technique will occur in the absence of conscious thought”. This quote (Te wa ku ni to sunawachi hairu) is from the  Kempo Hakku, a passage in the Bubishi [1]. I relate this principal to ultimately achieving the mental state of Mushin. Mushin, or mushin no shin, is a Zen term translated to English as “no mind”, or “the mind without mind “. The term refers to a state of “no-mindness” where in combat, but in everyday life as well, your mind is free from thoughts. You do not think what should be the next move – it naturally occurs, without hesitation and without disturbance from any thoughts/anger/fear/ego. In modern studies of combat you can find descriptions of high level of performance on “autopilot”, where different parts of the brain “take control”, with high levels of awareness and heart rates of 175 pbm [2]. But what does all that have to do with our work as researchers? Ah, I’m glad you asked.

In research, and life in general, we also need to keep our mind, eyes, and ears open in all directions. Then serendipity will come knocking. Instead of being married to an idea, trying to “get it”, You “listen to what the data tells you” (see a previous post on that here). Moreover, you are likely to start working towards idea A encounter B and end up doing C [3]. But that’s OK – because you were never married to the A idea, and you knew to let it go noticing C when you “encounter it”. You will not “encounter it” though if you are too busy seeking your goal, being married to A or bummed down by B.  A good example from our work is how we ended up developing MAJIQ, described here.

Seemingly, this “mindless” approach is almost contradictory to the rational way we are brought up to approach problems, especially in the Life Sciences – format a hypothesis, test it, etc. There is no real contradiction though: I would say that the “classical” formulation of the scientific methodology is the local tool that moves you forward in your research, allowing you to test/verify things, while the “no mind” approach is the more general rule by which you strive to live, fight, or direct your Science.

Possibly related to that, Francis Crick said [4]:

“…It is amateurs who have one big bright beautiful idea that they can never abandon. Professionals know that they have to produce theory after theory before they are likely to hit the jackpot. The very process of abandoning one theory for another gives them a degree of critical detachment that is almost essential if they are to succeed”

To be fair though, I don’t think Crick was thinking about Mushin, and the above quote has to do more with a specific confounding factor in Scientific research – our egos. But that’s maybe something for another post.

[1] https://en.wikipedia.org/wiki/Wubei_Zhi
[2] On Combat: The Psychology and Physiology of Deadly Conflict in War and in Peace, lieutenant colonel David Grossman, 2004
[3] Related to that: see Uri Alon’s excellent talk about getting lost in the research “cloud” https://www.youtube.com/watch?v=RVoz_pEeV8I
[4] Crick F., What mad pursuit: A personal view of scientific discovery 1988, P. 142, Basic Books, NY

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MAJIQ and The Naming of Things

In an earlier post I discussed how we might benefit by learning from other cultures/fields a term or concept that we never had, then implement it in our everyday life. I also suggested a way we can actually hope to achieve that: importing the (native) term into our own vocabulary, then actively look for opportunities to observe/implement it. The examples I gave came from Hindi, living in Canada, and my army service. In this blog I want to expand on the idea of “the naming of things”, connecting it to ideas in linguistics and our recent research work.

In linguistics the Sapir Whorf hypothesis [1] states that language determines or at least influences our thought. This idea was followed in many works, from the study of cultures to programming languages. Franz Boas for example popularized the idea that the Eskimo languages has a reach vocabulary to describe the many possible forms of snow. Kenneth Iverson, the turing awardee and developer of APL (the historical ancestor of Matlab and math operation based coding languages), argued for this idea in the context of coding languages.

I know this all sounds theoretical and ancient but I was thinking about Sapir Whorf when we ran into some surprising findings during our research. Our lab is interested in RNA processing and post-transcriptional regulation. Historically, the study of RNA splicing variations has focused on two main approaches: studying whole transcripts or quantifying alternative splicing “events”. The latter have been identified in model systems and categorized to basic subtypes such as a cassette exon (including/skipping an exon), intron retention, and alternative 3’/5′ splice sites. The common wisdom, supported by high-throughput studies since 2008, was that these are the most common forms of splicing variations. And so, the fields “vocabulary” was set for the decades that followed and subsequent works either studied whole transcripts or these AS “events”.

When we started working on MAJIQ (Modeling Alternative Junction Inclusion Quantification) 2.5 years ago we just wanted to better quantitate alternative splicing “events” from RNA-Seq. But working on MAJIQ led us to define LSVs, or local splicing variations. LSVs can be thought of as splits in a gene splice graph coming from or going into a single exon (hence “local”). Here is a simple illustration of such LSVs on a splice graph:

LSVIllustration

Besides the intuitive definition, one nice thing about LSVs is that while they are graph based, they actually correspond directly to biology (i.e. which RNA segments should the spliceosome splice together at any given point) as well as direct experimental evidence (the junction spanning reads). The second nice thing about LSVs is that unlike full transcripts they can be directly inferred from short RNA-Seq reads, yet still offer a much more expressive language than previously defined AS “events”. Specifically, previously defined AS “types”, appear as special cases of binary LSVs, but much more complex variations can be captured. Here is a simple illustration of this:

BinaryComplexLSVIllustration

Now that we suddenly had this reacher language at hand we could actually study the full spectrum of LSVs – identify, quantify, and visualize those. We realized that complex, non binary, variations made up over a third of the variations in mouse and human and were highly enriched in regulated variations. In our recent paper published in eLife we started characterizing the spectrum of LSVs and how they are relevant to gene regulation, development, and disease. But this is really the tip of the iceberg. And we hope that with the tools we created (MAJIQ and the matching visualization package VOILA), the full effect of LSVs will be discovered by the greater scientific community. Or, to put it in linguistics terms, now that we have the ability to name those variations, we can bring those to the focus of our attention.

[1] https://en.wikipedia.org/wiki/Linguistic_relativity