How are complex biological systems (like the Krebs cycle) figured out?

It’s always amazing hearing about how the human body functions. All the complicated systems that have to correctly interact is staggering. But it’s also amazing to me that those systems can be figured out in the first place. Take Krebs cycle as an example. With all those steps and all those molecules interacting, how do scientists figure this all out? I would guess these components are too small to observe in action under a microscope, and even if they could, it seems like it would just be a big jumble of activity anyway. So how do they figure out how all these molecules work together in our bodies?

It’s really, really complicated. At the cellular level, biology is such a tightly integrated complex system of tens or perhaps hundreds of thousands of different individual processes that all have to occur in well-regulated clockwork in order for an organism to perform nominally that it seems impossible that they could have come together by natural evolution alone until you start looking at the commonality between creatures at different levels and scales and realize that all of life on Earth shares a pretty narrow (if quantiatively large) set of principles and processes.

As for how scientists find how these processes work: a small team of biologistis, biochemists, physicists, et cetera work on one very small process like enzyme reactions, gene replication, or paracrine signalling for years or even decades. They finally uncover some novel phenomenon or can characterize a reaction, publish their work in a peer-reviewed journal, and then someone else reads a few articles and puts individual processes together to create a complete cycle. It is painfully tedious, uncertain, and failure-prone work even by the standards of research science, and even a brilliant bio-researcher may fail to uncover the kind of work that is necessary to get universal acclaim. Only a very few people actually work at the high level of biological systems integration because the field requires both a grasp of a large number of disciplines from signals theory to electrochemistry to molecular biology, as well as a knack for writing grant proposals convincing review boards that you aren’t just trying to create a giant green rage monster in your lab for fun.

It is painful how little we actually know about biology, and expecially the function of really complex organs like the brain or intestine, but it is also amazing that we actually know as much as we do, and have learned the vast majority of it only within the last century.

Stranger

One of the more useful techniques is isotope tagging. Different isotopes of an element will behave almost identically in chemical reactions, but they’re still distinguishable. So if you take one biological chemical and replace, say, all of the oxygen atoms in it with O-18 instead of the usual O-16, and then let biology take its course, and find O-18 atoms showing in some other compound, then you know that there’s some reaction which takes oxygen atoms from the first compound and uses them to create the second. This also lets you tell, for instance, whether some enzyme or other catalyst is being consumed and re-created during a reaction, or if it’s just a bystander molecule (there are some catalysts that work each way).

While the above is a commonly-mentioned argument ostensibly proving “intelligent design”, it’s an even better argument against “intelligent design”. Hardly modular, and with extensive tight coupling. Horribly difficult to maintain without messing things up.

Oh, I agree; I wasn’t trying to argue for any validity of the notion of Intelligent Design, just that it is easy to understand from a novice viewpoint how that degree of complexity may seem “irreducible” to naturally occuring variation, even though many of the basic elements of cellular function are repeated across classes of life, often performing widely differing functions. You are correct that while these elements are commonly used, the overall system of an organism is not at all modular, requiring deep integration that seems to defy practical variation that an intentional designer would use. It would be as if every car manufacturer used common gears, clutches, differentials, CV joints, et cetera but came up with totally unique and often goldbergesque ways of connecting the engine to the wheels.

Stranger

Nice bio of Krebs which also goes into some detail about the discovery of what is now called the “Citric Acid Cycle”.

You can also figure out the sequence of reactions by doing this procedure for short time intervals, i.e. radiolabelling a substrate and then seeing in what molecules it ends up after various intervals of time. This was how C4 photosynthesis was discovered in the 1960s.

Nowadays you can also identify what specific proteins might be involved in a physiological response by looking at what genes are being highly expressed- genes code for proteins, so by looking at the gene expression profile that will tell you something about what enzymes might be particularly active.

‘Systems biology’ has been a big deal in recent years - the idea that the reductionist approach of studying individual protein structures, enzyme mechanisms, receptor signalling etc in isolation is never going to be enough to understand a complex biological cycle, even if you have all of the pieces of the ‘jigsaw’ to hand. You need to take a step back and take a mathematical look at the whole network.

This has probably always been appreciated at some level, but (ISTM) had to take a back seat to the structural revolution of biology. Once this subsided (ie things like getting a protein structure and some mechanistic insight became more routine), allied with the rise of computation capability, then the systems approach became ascendent.

Speaking as a software engineer, I don’t find this particular argument against ID to be all that compelling. :wink: