Systems Thinking in Systems Biology: Part 1

Let’s say we inhibit an enzyme in a metabolic pathway by perhaps reducing the expression of the gene that makes the enzyme or more easily by adding a drug that inhibits the enzyme.What do you think will happen?

When I ask my students in class a similar question I will get all sorts of answers ranging from utterly wrong to almost right. I suspect I’d get a similar range of answers from my colleagues. Here are some of the answers I’ve had in the past:

  1. The reaction rate of the inhibited enzyme slows down, but nothing else happens.
  2. The reaction being inhibited must be the rate-limiting step otherwise nothing will happen.
  3. Nothing happens unless the drug acts on the first enzyme in the pathway.
  4. The enzyme rate changes and this affects the substrate concentration, the product concentration stays the same because it is being continually used up by the next enzyme.
  5. All the steps before the inhibited enzyme slow down, the other enzymes are unaffected.
  6. The inhibited enzyme gets ‘knocked out’ so that its rate goes to zero, this kills the cell (somehow).

All the above answers are of course wrong, the question is why are so many students (and even colleagues) unable to think through the effects of a drug? Considering that the NIH and NSF spend literally billions on drug research one would think we’d have a firm grasp (at theoretically) of what happens at the systems level.

If I asked a similar question to an electrical engineer I would get a different response. Ask an electrical engineer the following question. I have a complicated circuit, I double the resistance of a particular resistor in the circuit, what will happen? An electrical engineer will immediately think in terms of the entire circuit. For one, the current will start to decrease through the resistor, this in turn will change the immediate voltages which will affect further currents and so on until the change we made has rippled through the entire circuit. This way of thinking is natural to an electrical engineer and from my own experience strangely alien to a biologist. For some reason, and I don’t have an explanation, we don’t teach our students to think of cells as systems where a change in one place will ripple through the rest of the cell. The advent of high throughput technologies in the last 10 years or so has helped enormously to change this way of thinking because it is easily shown that one change can often lead to many changes in gene expression. And yet, ask the question I posted above to a class and you might be surprised at the range of answers you’ll get. For some reason we still find it difficult to think systems.

I will give the answer to the original question in the next post.

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