I should have loved biology

I should have loved biology but I found it to be a lifeless recitation of names: the Golgi apparatus and the Krebs cycle; mitosis, meiosis; DNA, RNA, mRNA, tRNA.

In the textbooks, astonishing facts were presented without astonishment. Someone probably told me that every cell in my body has the same DNA. But no one shook me by the shoulders, saying how crazy that was. I needed Lewis Thomas, who wrote in The Medusa and the Snail :

For the real amazement, if you wish to be amazed, is this process. You start out as a single cell derived from the coupling of a sperm and an egg; this divides in two, then four, then eight, and so on, and at a certain stage there emerges a single cell which has as all its progeny the human brain. The mere existence of such a cell should be one of the great astonishments of the earth. People ought to be walking around all day, all through their waking hours calling to each other in endless wonderment, talking of nothing except that cell.

I wish my high school biology teacher had asked the class how an embryo could possibly differentiate—and then paused to let us really think about it. The whole subject is in the answer to that question. A chemical gradient in the embryonic fluid is enough of a signal to slightly alter the gene expression program of some cells, not others; now the embryo knows “up” from “down”; cells at one end begin producing different proteins than cells at the other, and these, in turn, release more refined chemical signals; ...; soon, you have brain cells and foot cells.

How come we memorized chemical formulas but didn’t talk about that? It was only in college, when I read Douglas Hofstadter’s Gödel, Escher, Bach , that I came to understand cells as recursively self-modifying programs. The language alone was evocative. It suggested that the embryo—DNA making RNA, RNA making protein, protein regulating the transcription of DNA into RNA—was like a small Lisp program, with macros begetting macros begetting macros, the source code containing within it all of the instructions required for life on Earth. Could anything more interesting be imagined?

Imagine a flashy spaceship lands in your backyard. The door opens and you are invited to investigate everything to see what you can learn. The technology is clearly millions of years beyond what we can make.

–Bert Hubert, “Our Amazing Immune System”

In biology class, biology wasn’t presented as a quest for the secrets of life. The textbooks wrung out the questing. We were nowhere acquainted with real biologists, the real questions they had, the real experiments they did to answer them. We were just given their conclusions.

For instance I never learned that a man named Oswald Avery, in the 1940s, puzzled over two cultures of Streptococcus bacteria. One had a rough texture when grown in a dish; the other was smooth, and glistened. Avery noticed that when he mixed the smooth strain with the rough strain, every generation after was smooth, too. Heredity in a dish. What made it work? This was one of the most exciting mysteries of the time—in fact of all time.

Most experts thought that protein was somehow responsible, that traits were encoded soupily, via differing concentrations of chemicals. Avery suspected a role for nucleic acid. So, he did an experiment, one we could have replicated on our benches in school. Using just a centrifuge, water, detergent, and acid, he purified nucleic acid from his smooth strep culture. Precipitated with alcohol, it became fibrous. He added a tiny bit of it to the rough culture, and lo, that culture became smooth in the following generations. This fibrous stuff, then, was “the transforming principle”—the long-sought agent of heredity. Avery’s experiment set off a frenzy of work that, a decade later, ended in the discovery of the double helix.

In his “Mathematician’s Lament,” Paul Lockhart describes how school cheapens mathematics by robbing us of the questions. We’re not just asked, hey, how much of the triangle takes up the box?

That’s a puzzle we might delight in. (If you drop a vertical from the top of the triangle, you end up with two rectangles cut in half; you discover that the area inside the triangle is equal to the area outside.) Instead, we’re told that if you ever find yourself wanting the area of a triangle, here’s the procedure:

Biology is like that, but worse because it’s a messier subject. The facts seem extra arbitrary. We’re told to distinguish “lipid bilayers” from “endoplasmic reticula” without understanding why we care about either in the first place.

Enormous subjects are best approached in thin, deep slices. I discovered this when first learning how to program. The textbooks never worked; it all only started to click when I started to do little projects for myself. The project wasn’t just motivation but an organizing principle, a magnet to arrange the random iron filings I picked up along the way. I’d care to learn about some abstract concept, like “memoization,” because I needed it to solve my problem; and these concepts would lose their abstractness in the light of my example.

Biology is no different. Learning begins with questions. How do embryos differentiate? Why are my eyes blue? How does a hamster turn cheese into muscle? Why does the coronavirus make some people much sicker than others?

A few months ago, I started a magazine assignment to answer some questions about SARS-CoV-2 and the immune system. I encountered paragraphs like this:

In low-MOI infections (MOI, 0.2), exogenous expression of ACE2 enabled SARS-CoV-2 to replicate and comprise ~54% of the total reads mapping more than 300x coverage across the ~30-kb genome (Figures 1A and 1B). Western blot analyses corroborated these RNA-seq data… It is noteworthy that, despite this dramatic increase in viral load, we observed neither activation of TBK1, the kinase responsible for IFN-I and IFN-III expression, nor induction of STAT1 and MX1, IFN-I-stimulated genes (Figure S1A; Sharma et al., 2003)…

It was hard to get through a sentence without having to consult Wikipedia. In immunology in particular the nomenclature is expansive. One sentence might refer to “leukocytes,” the next to monocytes, the next to lymphocytes. There are a lot of squares-and-rectangles situations: all interleukins are cytokines, but not all cytokines are interleukins?

I’ve never come across a subject so fractal in its complexity. It reminds me of computing that way. A day of programming might involve constructing an elaborate regular expression, investigating a file descriptor leak, debugging a race condition in the application you just wrote, and thinking through the interface of a module. Everywhere you look—the compiler, the shell, the CPU, the DOM—is an abstraction hiding lifetimes of work. Biology is like this, just much, much worse, because living systems aren’t intentionally designed. It’s all a big slop of global mutable state. Control is achieved by upregulating this thing while turning down the promoter of that thing’s repressor. You think you know how something works—like when I thought I had a handle on the neutrophil, an important front-line player in the innate immune system—only to learn that it comes in several flavors, and more are still being discovered, and some of them seem to do the opposite of the ones you thought you knew. Everything in biology is like this. It’s all exceptions to the rule.

But biology, like computing, has a bottom, and the bottom is not abstract. It’s physical. It’s shapes bumping into each other. In fact the great revelation of twentieth-century molecular biology was the coupling of structure to function. An aperiodic crystal that forms paired helices is the natural store of heredity because of its ability to curl up and unwind and double itself with complements. Hemoglobin, the first protein studied in full crystallographic detail, was shown to be an efficient store of energy because of how oxygen atoms snap into its body like Legos, each snap widening the remaining slots, so that it loads itself up practically at a gulp. Most proteins are like this. The ones that drive locomotion twist like little motors; the ones that contract muscles climb and compress each other. Cells, too, are constantly in conversation, and the language they speak is shape. It’s keys entering locks: a protein might straddle the cell membrane, and when a cytokine (that’s a kind of signaling molecule) docks with it, it changes its shape, so that its grip loosens on some other molecule on the interior side of the membrane, as though fumbling a football—that football might be a signal itself, on its way to the nucleus.

I think my understanding of biology was too flow-charty in high school. I knew that DNA → RNA → protein and that this was called “gene expression,” but I was confused on the basics, like, how did genes actually “turn on”? And once they were on, were they on for good? It’s clearer when you think physically. Mammalian DNA isn’t laid out as one long double helix; it’s tightly coiled and coiled again, like this, around little circular proteins called histones:

The structure of the resulting fiber has an effect on which genes are expressed. This is because the little molecular machine that transcribes DNA into RNA has to actually ride along the helix , and it can only ride along some parts of it, namely the parts that aren’t curled up out of sight . “Expressing” a gene just means that at a given moment, the machine is accessing a specific portion of DNA, resulting in lots of RNA transcripts, resulting in lots of the protein that the gene codes for. Kink the fiber a bit and you change what the machine can see, thus changing the distribution of proteins it produces. You have “reprogrammed” the cell. (There are many ways to control gene expression, maybe the most common being “repressors” that park somewhere on the DNA, physically blocking the transcription machinery.)

One of the workhorse techniques in modern biology, called RNA sequencing , or RNA-seq for short, takes a frozen cell and counts the RNA transcripts inside it. In effect you get a snapshot of all the proteins being expressed at that moment. The result is literally a big table mapping genes to transcript counts. You see that being one kind of cell versus another—or being in one kind of cellular mood versus another, say in health versus disease—is just a matter of having a different distribution across this table. RNA-seq results are often represented as vectors in high-dimensional space, the counts in the table forming the coordinates; cells move through this expression space as they self-regulate and adapt to their environment.

How do you develop a physical understanding of biology? I like pictures. One of my favorite books is called The Machinery of Life , by David Goodsell. It’s full of gorgeous hand-drawn illustrations. Here a bacterium’s flagellar motor is shown in context, then zoomed in on in an inset, with a third picture highlighting its functional elements:

What makes the book work is that it’s basically a re-introduction to molecular biology with the following premise: the cell is a very fast and crowded place , full of little machines, most of them protein, which you understand by taking a close look. It does an especially terrific job through insets like the above relating things at different scales. “Imagine your room filled with grains of rice. That will give you an idea of the billion or so cells that make up your fingertip.”

The writing is very good. It somehow gets you imagining the motion of these machines. It’s tempting when thinking about the cellular world to simply miniaturize our own; but at the cellular scale things behave weirdly. Movement is essentially by random diffusion. “The motions and the interactions of biological molecules are completely dominated by the surrounding water molecules… Inside the cell, [a] protein is battered from all sides by water molecules. It bounces b