The Life of a Cell, or ‘What Do We Do Now?’

Look at you now, all grown up, living your best life, maybe even toward the end of your run. How did it go for you? You made some choices; you did your best. Most of the time. Argued some, agreed some, uncertain some.

I wonder how choices get made — yours, mine, our country’s.

I know a lot about how our cells make choices, but people have always been way too complicated for me. Earlier in my life I thought, “Maybe cells can teach me about decisions.” Every cell in your body is making decisions all the time. Some do skin, some do cancer, others everything else.

Last month, the Nobel Prize committee in Stockholm decided that two guys, one at Harvard, the other across the river at Mass General, saw something new and important in 1993. For about 10 years nobody cared. Then, slowly, the story grew into nothing less than a description of cellular decision-making. It’s still wildly complicated, a rich world of chemistry mostly inside the nucleus of each cell, sometimes shared among neighboring cells, the result of which is the formation of a community — an agreement that becomes you. They described microRNA.

I’ll tell you about it in a second, but first, let me describe what we knew before.

Mid-1800s, largely in Germany, biologists were studying the developing embryos of animals. They learned that some embryos were strictly determined, others adapt as they grow. A simple experiment: Separate the two cells that result from the first cell division of a fertilized egg. Some animals, worms and snails for example, just make two halves of the same animal, as if the cells knew nothing about what had happened to them. Others, including mammals like us, seem to recognize they’ve got a problem, and each daughter cell reacts and makes a complete animal, and you get twins. What’s the deal with that? How do they know, or not know?

A little more observation. If you cut off a frog’s leg (I know, gross, but stick with me), it just makes a wound stump. Do the same thing to a salamander, it regenerates the leg. Somehow, even between very closely related animals, the ability to adapt is very different. While we can regenerate the tip of a finger, especially if we’re young, we have to envy the salamander. Our livers have a surprising capability to regenerate, convenient to those of us who routinely abuse them. Again, what goes on to allow or not allow responses to these issues?

One more. In insect larvae, like maggots or caterpillars, tucked just under the “skin” there are little pockets of cells that grow as the larva grows, but otherwise wait until they get washed with hormones during metamorphosis, when they quickly differentiate into all the external structures of the adult animal, the eyes and wings and legs and antennae, etc. Each structure is formed from its own little pouch of larval cells. The cells clearly know what they are supposed to make when the time comes. If you cut one of these little pouches in half, and let it grow some more, one of the halves will regenerate the missing half, the other will make a duplicate of itself. Doesn’t matter if you cut them north to south, east to west, even center from periphery. That’s the observation I learned as a college student, blowing my young mind, and I tried to learn more about it in graduate school.

A related question is about where the growth happens. If all the growth is at the wound, then most of the cells wait a little longer and the new cells just repeat a decision. I worked hard but found only weak evidence of dispersed growth, which fit my own bias, and I published that. About a year later, some colleagues did some really elegant work clearly showing growth localized to the wound.

Two lessons from this: First, don’t bet on weak evidence. More importantly, thinking more clearly about localized growth drove us to consider not what was different about the two halves, but what they had in common — the wound. It made much more sense to realize that both halves in fact did the same thing. They both made the same kind of cells, it’s just that in one case it completed the structure, and in the other it made a copy of itself. What they made was determined by the cells at the cut itself, a response to a wound they shared.

Back to microRNA. One way to describe the decisions cells make is to describe the genes that the cells are expressing. All your cells have the same DNA, but some use the genes required to make skin, others brain, bones, etc. Many genes are used by all your cells, but lots are cell-type specific. And, surprisingly, most of your DNA doesn’t make anything at all. Most of it is used to control things, to keep things running, or to do something new. The way it controls things is by letting various genes work or not, and the way that happens is determined largely by what microRNAs are swimming around, binding or not binding to specific DNA pieces.

I am oversimplifying things; lots else goes into this story and the story is being rewritten by scientists all over the world every day, but what those guys saw in 1993 and all the rest of us ignored is now the hottest story in biology and will likely lead to a fundamentally new understanding of how our cells control themselves, or as in cancer, fail to control themselves.

There are other lessons in this, too. Faced with a sea of microRNA snippets, thousands of them, with conflicting or amplifying effects, each cell must forge its future. Competing for influence, these tiny operators create a maelstrom of ideas. It’s not that one is right or that the path is clear, ever. We have wounds too. We share them. Let’s focus on what we have in common and make a country that is complete.

Jack Dunne lives gratefully in Lakebay.