bookmark_borderA 7 Minute Timer Has Been Discovered in Neurons

How does the brain keep track of time? This question has been intriguing neuroscientists for decades. Circadian clocks, which oscillate every 24 hours, are known to be implemented at the level of molecules and genes. But it is widely believed that keeping track of time for shorter durations (e.g. seconds and minutes) arise from electrical/synaptic activity patterns, not from molecular activity. The idea is that cells can be connected in ways that result in oscillations or sequential activity (e.g. one neuron fires at the 1s mark, the next fires at the 2s mark, etc.). As with most of our theories of short-term memory, if all the cells in a network go silent for a moment the timer falls apart. The spiking activity is what keeps the clock going. This theory has had its opponents, but I think it is fair to say that it has been a commonly held view in neuroscience.

A recent study, however, has made a serious crack in this paradigm. In a series of two papers from the Crickmore lab at Harvard University (one published last year and another last month), Thornquist and colleagues show that a single neuron can keep track of time in a completely silent manner. The time interval they studied was a 7 minute period in mating fruit flies. I believe this is a landmark study that every neuroscientist should know about. So here is my attempt at explaining it in simple terms.

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bookmark_borderBreaking Free from Neural Networks and Dynamical Systems

This blog post is written as a dialogue between two imaginary characters, one of them being myself (H) and the other a stubborn straw man (S). It is broken into four parts: the dogma, the insight, the decoy, and the clues. If you do not feel like reading the whole thing, you can skip to part 4; it contains a summary of the other parts.

[image adapted from Song et al. 2016]
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bookmark_borderQuantifying Evidence (2): Evidence Is Limited By How Much a Study Can Be Trusted

In part 1, we defined evidence and showed that evidence across independent studies can be aggregated by addition; if Alice’s results provide 2 units of evidence and Bob’s results provide 3 units of evidence then we have a total of 5 units of evidence. The problem with this is that it doesn’t account for our intuition that single experiments cannot be trusted too much until they are replicated. 10 congruent studies each reporting 2 units of evidence should prevail over one conflicting study showing -20 units of evidence.

Let’s try to model this by assuming that every experiment has a chance of being flawed due to some mistake or systematic error. Each study can have its own probability of failure, in which case the results of that experiment should not be used at all. This is our first assumption: that any result is either completely valid or completely invalid. It is a simplification but a useful one.

We define trust (T) in a particular study as the logarithm of the odds ratio for the being valid versus being invalid. In formal terms:

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bookmark_borderQuantifying Evidence (1): What Are Units of Evidence?

I am going to introduce a statistical framework for quantifying evidence as a series of blog posts. My hope is that by doing it through this format, people will understand it, build on these ideas, and actually use it as a practical replacement for p-value testing. If you haven’t already seen my post on why standard statistical methods that use p-values are flawed, you can check it out through this link.

My proposal builds on Bayesian hypothesis testing. Bayesian hypothesis testing makes use of the Bayes factor, which is the likelihood ratio of observing some data D for two competing hypotheses H1 and H2. A Bayes factor larger than 1 counts as evidence in favor of hypothesis H1; a smaller than one Bayes factor counts as evidence in favor of H2.

In classical hypothesis testing, we typically set a threshold for the p-value (say, p<0.01) below which a hypothesis can be rejected. But in the Bayesian framework, no such threshold can be defined as hypothesis rejection/confirmation will depend on the prior probabilities. Prior probabilities (i.e., the probabilities assigned prior to seeing data) are subjective. One person may assign equal probabilities for H1 and H2. Another may think H1 is ten times more likely than H2. And neither can be said to be objectively correct. But the Bayesian method leaves this subjective part out of the equation, allowing anyone to multiply the Bayes factor into their own prior probability ratio to obtain a posterior probability ratio. Depending on how likely you think the hypotheses are, you may require more or less evidence in order to reject one in favor of the other.

    \[ \dfrac{Pr(H_1 | \text{data})}{Pr(H_2 | \text{data})} = \dfrac{Pr(\text{data} | H_1)}{Pr(\text{data} | H_2)} \times \dfrac{Pr(H_1)}{Pr(H_2)} \]

    \[ \text{posterior odds ratio} = \text{Bayes factor} \times \text{prior odds ratio} \]

Let us define ‘evidence‘ as the logarithm of the Bayes factor. The logarithmic scale is much more convenient to work with, as we will quickly see.

    \[ E = \text{(evidence for $H_1$ against $H_2$ given $D$)} = \log_{10}(\text{Bayes factor}) =  \log_{10}(\dfrac{Pr(D | H_1)}{Pr(D | H_2)}) \]

Evidence is a quantity that depends on a particular observation or outcome and relates two hypothesis to one another. It can be positive or negative. For example, one can say Alice’s experimental results provide 3 units of evidence in favor of hypothesis H1 against hypothesis H2, or equivalently, -3 units of evidence in favor of hypothesis H2 against hypothesis H1.

Figure 1: In this example, two hypotheses are being tested against one another. H1 is the hypothesis that the opossum is genetically closer to humpback whales than salmon is. H2 is the hypothesis that salmon is closer to humpback whales than the opossum. The data D that is being used to compare these hypotheses can be some DNA sequencing data, for instance. (The data here isn’t real).
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bookmark_borderWhen Biology Isn’t Messy

There is a belief in biology that goes like this: Biology is messy. Nature has no interest in making things easy to understand. So for many scientific questions, there will not be a straight-forward answer.

  • Q: Where and how is a particular memory stored in the brain? A: Biology is messy; memories are distributed all over the brain and stored in many different forms: as molecules and as structure, inside neurons and in the connections between them.
  • Q: How do genes determine the number of fingers per hand? A: Biology is messy; there isn’t a single factor for it. It emerges from the interactions of numerous different genes.

Now it is not always the case that our answers are so unsatisfying. Ask a biologist how the eye works and, well, there are quite a lot of similarities to how cameras work. And living organisms aren’t messy globs of formless flesh. They have an organized body plan, with separate organs, each responsible for specific functions that we can talk about; the heart pumps blood and the lungs pump air.

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bookmark_borderThere Is a Fundamental Flaw in How We Do Statistics in Science

Suppose I tell you that only 1% of people with COVID have a body temperature less than 97°. If you take someone’s temperature and measure less than 97°, what is the probability that they have COVID? If your answer is 1% you have committed the conditional probability fallacy and you have essentially done what researchers do whenever they use p-values. In reality, these inverse probabilities (i.e., probability of having COVID if you have low temperature and probability of low temperature if you have COVID) are not the same.

To put it plain and simple: in practically every situation that people use statistical significance, they commit the conditional probability fallacy.

When I first realized this it hit me like a ton of bricks. P-value testing is everywhere in research; it’s hard to find a paper without it. I knew of many criticisms of using p-values, but this problem was far more serious than anything I had heard of. The issue is not that people misuse or misinterpret p-values. It’s something deeper that strikes at the core of p-value hypothesis testing.

This flaw has been raised in the literature over and over again. But most researchers just don’t seem to know about it. I find it astonishing that a rationally flawed method continues to dominate science, medicine, and other disciplines that pride themselves in championing reason and rationality.

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bookmark_borderCan a finite physical device be Turing-equivalent?

If you believe in the following, I am going to try to change your mind:

“Turing machines aren’t realistic. They need infinite memory so they can’t be implemented. Any real computing device is limited in its memory capacity and, therefore, equivalent to a finite state machine.”

Cartoon of a Turing Machine by Tom Dunne 2002
Cartoon of a Turing Machine by Tom Dunne, 2002

This is a fairly commonly held view. I used to believe in it myself, but had always found it deeply unsatisfying. After all, modern-day computers have limited memory capacity but closely resemble Turing machines. And Turing’s abstract formulation arguably led to the digital revolution of the 20th century. How, then, can the Turing machine be a physically irrelevant mathematical abstraction? If all of our computers and devices are of the weaker class of computers, namely, finite state machines, why do they have to look so much like Turing machines?

It is important to clarify this, especially for neuroscience and computational biology. If we think of Turing-equivalence as this abstract level of computation that is impossible to physically achieve, then we block out classical insights from the theory of computation and cannot even begin to ask the right questions. (I recently wrote a manuscript asking the question “where is life’s Turing-equivalent computer?” and showed that a set of plausible molecular operations on RNA molecules is sufficient to achieve Turing-equivalent computation in biology).

It took a good amount of reading and thinking to finally understand the meaning of Turing-equivalence. I will explain what I believe to be the only consistent way of looking at this issue. Here is the short version:

When we say Turing machines require “unbounded memory”, what we mean is that memory cannot be bounded by the systems descriptor, not that it cannot be bounded by other things such as the laws of physics or resource constraints. Turing-equivalence only requires a system in which memory usage grows, not one in which memory is infinite.

Below I explain precisely what all that means. I will try to convince you that this is the only consistent way of looking at this and that Turing, himself, shared this perspective.

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