Conformational Disease

Every miracle born on this planet began with folding.

If not for that gold-prospecting trip five months ago, I would never have discovered this cruel and simple fact.

Somare Island, in northeastern Papua New Guinea, was a barren island rarely visited by people, until a fisherman repairing his boat picked up a palm-sized, scale-like piece of gold ore beneath a coconut tree. Under a cooperation agreement between my mining company and Papua New Guinea’s mining ministry, I led a four-person team on a flight from Beijing to Port Moresby, then made my way by a roundabout route to Somare.

Preliminary exploration indicated gold reserves of 40 to 60 tons, a mining grade of over 4 g/ton, and a projected investment of 400 million US dollars. The results thrilled everyone. I stayed on Somare to help Papua New Guinea’s geological exploration bureau write the exploration report, and during that time I learned that the island was not uninhabited. There had been signs of Fore tribespeople in the high mountains.

On one sampling trip, I found that small Fore tribe among the mountains: a few collapsed thatched huts and dozens of scattered skeletons. I was no anthropologist, but even I understood that a closed community of this size could hardly keep up its genetic diversity. They had been forgotten by the world. So I buried those remains with my own hands and heaped up crude graves—an act the Papua New Guineans found bizarre in the extreme.

I was wrong.

Not long after returning to China, I fell into a periodic rhythm disorder: trembling hands and feet, insomnia, endless dreams. After infectious diseases and parasites had been ruled out, the company forced me to take paid leave on the grounds of a mental disorder. My health drained away with time, and the psychiatrists were helpless. My memories began to blur. Little by little, I could no longer remember what dishes I had eaten for lunch half an hour earlier.

When my illness was at its worst, a good friend who worked at a biotech company came to visit, and I babbled incoherently about the changes happening to me. Pain always fades eventually, but what I was going through was a different kind of torment: I was degenerating into some unknown creature, a beast hiding in a dark corner with its teeth chattering. My appetite and sex drive were both gone. The only accurate thing left in my narrow world was the change from day to night.

My friend took away a sample of my blood and buried himself in the lab. I wasn’t sure he could make sense of my delirious mumbling, but he soon found some clues.

Kuru: a fatal degenerative disease discovered in the early 20th century among the Fore tribes of Papua New Guinea’s northeastern highlands. Tremors, paralysis, death. No effective drugs. A mortality rate of 100%. The pathogen was a prion born from the Fore custom of eating the bodies of dead relatives as a sacrificial rite. It acted on the nervous system and caused spongiform degeneration of the brain. From infection to death generally took 6 to 9 months.

Since the Papua New Guinean government banned the eating of corpses in 1962, kuru had all but vanished.

This wasn’t scientific.

During one of my lucid intervals, my friend pronounced my death sentence. Then he said that what he couldn’t understand was this: prions could only spread through diseased organisms or through blood. As infectious proteins, there was no way they could survive on their own in old bones.

I didn’t care.

I locked my door from the inside and waited for death amid the alternation of day and night.

Ironically, my condition began to improve.

After three days on the brink of death, I dragged my burning body out of the bedroom, opened the fridge, and drank a whole jug of ice-cold orange juice. I could feel the sourness and sweetness working on my taste buds, my stomach lining twitching from the stimulation, my heart leaping, my body aching. I walked upright again, used fire, learned language, and slowly evolved into the beast called “Homo sapiens.”

Once I had control of my fingers again, I opened a search engine and tried to find out why fate had played such an enormous joke on me. As a mining engineer, I knew nothing about biology, so I was soon astounded by how exquisite and fragile the creation called humanity was:

Kuru, Creutzfeldt–Jakob disease, and similar conditions are called conformational diseases, because prions act on how proteins are folded. A protein folds from a loosely structured polypeptide chain into a protein molecule with its native spatial structure. This process is called protein folding.

From my point of view as an engineering student, it was the conversion of one-dimensional information into three-dimensional information. All biological activity comes from the three-dimensional conformations of proteins. From genes to amino acid chains, from chains to three-dimensional structures, protein folding is life’s second genetic code.

If a protein’s three-dimensional structure changes, it cannot perform its corresponding activity, even if its amino acid sequence is exactly the same. That is conformational disease. The possible conformations of a protein are endless, but folding is a contest between energy and entropy. Proteins always seek the direction of lowest energy and fold, in the most ingenious way, into correct and stable structures. And over the long history of evolution, those correct structures decided what the world looks like.

Wrong folding means total catastrophe. Prions act on the folding process and make proteins take on a different conformation.

A useless conformation.

A mortality rate of 100%, because the smallest units of life have turned into something else.

But why was I alive?

I opened web page after web page at lightning speed and skimmed paper after paper. I remembered that when I was four and wet my pants in kindergarten for the first time, the handkerchief a girl in my class took out had a little cat embroidered on it in red. With one glance, I could count the 673 characters on the page in front of me. In Rain Man, Dustin Hoffman counts a pile of spilled toothpicks in seconds, and the most he takes in at once is 82. Before this, the most items I could take in at a glance had been 5.

Are we really the one correct answer, tempered out of countless thousands of failed evolutions?

The central dogma of molecular biology “deals with the detailed residue-by-residue transfer of sequential information. It states that such information cannot be transferred from protein to either protein or nucleic acid.”

DNA → DNA (replication), DNA → RNA (transcription), RNA → protein (translation): these are the most important basic laws and the theoretical cornerstone of modern biology. Once genetic information has passed to a protein, it can neither pass from protein to protein nor flow back from protein to a nucleic acid molecule. Information travels from nucleic acids to proteins through an extremely complicated translation apparatus, and this translation cannot run in reverse. Nucleic acids carry the genetic code, proteins make up living bodies, and the two kinds of molecules are as distinct as the clear Jing and the muddy Wei.

Translator’s note: The Jing and Wei are two rivers that meet but stay visibly separate, one clear, one muddy. It’s the standard image for things that never mix.

My mind didn’t stop for a moment.

The discovery of prions was once seen as a subversive blow to the central dogma: they were proteins, yet they could copy themselves and spread disease.

In 1991, Prusiner laid out how prions cause disease. He showed that a prion is a special protein encoded by a normal human gene, which copies itself and spreads by changing the conformation of normal PrP protein. It isn’t a living thing carrying genetic material, so it shouldn’t be called a “prion virus.” The accurate name is “prion particle” or “prion protein.” Seen this way, the central dogma was never challenged.

Translator’s note: The everyday Chinese word for prion is ruan bingdu, literally “prion virus,” which is why the narrator bothers with this point.

I closed the web page.

I remembered sitting in the computer lab in college, the Win95 startup screen on the CRT monitor. A drop of sweat ran down the broad side of Teacher Li’s nose. He taught our computer principles class. The fan turned, blowing the blue plastic bags on my feet so they rustled. Teacher Li rubbed the sweat off the tip of his nose with his shoulder and said there was a kind of program that could use floppy disks as a carrier to copy itself from one computer to another and wreck operating systems and software. This kind of program was called a computer virus.

Translator’s note: Chinese computer labs back then made students wear plastic bags over their shoes to keep the dust out.

Is a computer virus a form of existence that carries consciousness?

What makes living things wondrous is their ordered complexity, their purposefulness, their dynamic character, and their state far from equilibrium. Over the long course of evolution, life self-organized into order, and proteins likewise complete their folding through self-organization. The countless self-organized critical points of life’s evolution are the turnover of generations and the rise and fall of species. The misfolding of proteins in three-dimensional space is this process made concrete at the microscopic level.

As I tapped the keys, my fingertips began to go numb and tremble slightly.

Existence needs no will.

Perhaps there is a protein polypeptide chain that, after one fold that broke the second law of thermodynamics, came to exist in the world under the name of prion. It withstands heat and radiation, resists digestion by proteases, can enter the human body through skin contact and the air, and quietly changes how homologous proteins fold, mutating nerve cells and bringing tremors, paralysis, and death. But in the tides of evolution, it is the one drop of water at the critical point. A tiny change in protein conformation gave nerve cells a new color. After passing the test of death, the nerve cells’ sodium-potassium pumps grew more efficient, and the neurons glowed with a vitality never seen before, letting a human observe, think, remember, and judge more efficiently.

It brought evolution.

Maybe because of individual tolerance, or lack of oxygen, these highly efficient nerve cells gradually began to die. But they once flashed with dazzling sparks never seen before in Homo sapiens’ 200,000 years of evolution.

The conformational disease this prion brings is a phase-transition critical point in human evolution.

How many deaths will it bring, or how many geniuses will it make? It won’t answer, and I can’t answer.

I am losing my body. I am greedily enjoying the afterglow of my intellect. Just like in Flowers for Algernon, everything will return to nothing.

After I finish writing this, I will send the email to you, fold my laptop shut, go back to my bedroom, and wait for the darkness to come. The tide rises and falls. All life, humanity, my own lifetime: all of it is those pumpjacks from my childhood, working silently on the Gobi, under the setting sun, in the wind and sand. Head down, then up again, on and on like this, never stopping, never resting.

You don’t need to grieve for me, for yourself, or for humanity.

Every miracle on this planet began with folding. What you and everyone else have to do next is simply wait.