At first glance, our bodies seem impossibly complex, with dozens of organs built to precise specifications in exactly the right places. It seems almost miraculous that all this could develop automatically from a single fertilized egg.
But look a little closer and you'll see that evolution, the master architect, has been economical with that complexity, relying on the same components again and again in different contexts. Take tubes, for example. "We're basically a bag of tubes," says Celeste Nelson, a developmental bioengineer at Princeton University. "We have a tube that goes from our mouth to our rear end. Our heart is a tube. Our kidneys are tubes." So, too, are lungs, pancreas, blood vessels, and more — most of them intricate systems of tubes with many branches.
Branching tubes appear so often because they are the best solution to a key problem that organisms face as they get bigger: As an animal grows, its volume goes up faster than its surface area. That simple physical relationship means that the logistical challenges of supplying oxygen and nutrients, and removing waste products — all of which ultimately depend on diffusion through the surfaces of cells — get more daunting with size.
But a dense forest of branching tubes increases the available surface area enormously. "They allow us to be big," says Jamie Davies, a developmental biologist at the University of Edinburgh.
In recent years, Davies, Nelson, and a few other developmental biologists have made great progress in understanding how the body makes tubes and branches in a variety of organs. Though the details usually vary from one organ to the next, some basic principles are beginning to emerge, as outlined in an article coauthored by Nelson in the Annual Review of Biomedical Engineering. So far, it looks like there are only a few ways to make a tube, only a few ways to control how it branches, and only a few ways to regulate when branching should stop.
Finding success in simplicity
At the most general level, it's not surprising that development is based on a few simple processes. Every tissue is made of cells, and those cells have only limited options to choose among, such as moving (individually or en masse), changing shape, dividing, or undergoing self-destruction. "I normally tell my students that about 90 percent of what we make we can account for with only about a dozen actions," Davies says.
And once evolution forged a few ways to create tubes and branches (the two go together, more often than not), it makes parsimonious sense that bodies would fall back on that same handful of methods again and again.
Start with a dimple, then extend: Many tubes start from a flat sheet of tissue that develops dimples, or pits. It's likely that these pits originate when a ring of contractile protein molecules scrunches up on one face of the sheet, causing that face to cup as the opposite face bulges outward.
In organs like lungs, mammary glands, and kidneys, this initial pit can then get deeper, like dough as a finger pushes into it, until the pit deepens so much it becomes more like an extending tube. In one well-studied example, the ducts of the mammary glands, each growing duct has an unruly mob of cells at its tip. The cells in this mob respond to the hormones of puberty by dividing rapidly. As they pioneer the advance into new territory, some cells insert themselves into the lining of the tube, pushing the mob forward as the tube lengthens. Continued cell division keeps generating new cells that will in turn go on to line the tube.
"The cool thing about this mechanism is that puberty says 'Go,' and as long as hormones are still available, you're going to keep making cells, and they're going to keep inserting," says Andrew Ewald, a developmental cell biologist at Johns Hopkins University School of Medicine, who led the work. "In a mouse, this might be an inch of elongation. In a blue whale, you're talking about yards. You just leave the motor running longer."
Hollow out a rod: Cells in the interior of a solid rod die or release their contacts with one another to allow a space to form between them. The mammalian vagina forms by this sort of hollowing, as do the ducts of the pancreas, and probably the salivary glands.
Roll up, roll up: Still other tubes — especially the tiniest capillaries of the circulatory system — form when a single elongated cell rolls up to enclose a space. And the tube that will go on to form the nervous system arises from a much larger roll-up, in which two ridges of tissue atop the early embryo bend toward each other, like two breaking waves, until they meet in the middle and fuse, leaving a tube — the barrel of the waves, in essence — enclosed beneath a cover of cells.
From tubes to branches
Almost all the body's tubes form in one of these ways. And there's another level where developing organs rely repeatedly on a small set of tricks and techniques: the construction of elaborate networks of branches from all those tubes.
Branches generally form either when a single growing tip encounters two different zones of attraction and sends a tip in each direction, or when something physically restricts the tip's progression. In the lung, for example, branching occurs when a band of smooth muscle fibers forms across the tip of the growing tube, creating a barrier and forcing growth to both sides.
The developing embryo must also manage the spatial growth of branching tubes so that, for example, the lung fills with just the right amount of tiny, branched airways or the circulatory system delivers capillaries to every part of the body, all without overcrowding or gaps. Researchers are only beginning to understand this control process, although a few key points are emerging.
One simple management strategy is for tubes to branch if space is available and stop when they get crowded. That straightforward system seems to apply for the mammary glands, which are little more than masses of branching milk ducts embedded in a fatty matrix.
To better understand the process, Ben Simons, a developmental biologist at the University of Cambridge, and his colleagues examined preserved mouse mammaries in meticulous detail and mapped out where, and in what context, each individual branching event must have taken place to give rise to the final structure they saw.
They found that each tube continued to grow and branch only if it was not surrounded by other tubes. Actively growing tips formed a front at the edges of the mammary, advancing into new territory, but any new tips that turned inward, to territory already colonized, would shut down. These rules, played out over time, led the ducts to fill in the available space.
The molecular signals that govern this behavior have not been fully worked out, though presumably some sort of inhibition is involved. Simons suspects that the same signaling system may go awry in breast cancer, since the early stages of that disease are characterized by extra branching. "It's interesting to ask how tumors reactivate that branching program, and how come it doesn't terminate," he says — and he's actively working to understand this.
This system of branching to fill space has the virtue of simplicity, Simons adds. "Everything is local. The cells only have to sense what's happening in their neighborhood, and it doesn't require any memory. Cells don't have to remember what decision they made way back when."
But the downside is that the gland doesn't always fill the space perfectly. Occasionally, it leaves gaps in the interior — ones that can no longer be filled because the growing tips are now all out at the periphery.
Read the rest of the story at Knowable Magazine.