Rainbow (3): The Search Function
Alice stood in a luxury condo in Palo Alto, holding fish food. She tapped lightly on the side of her aquarium. Her sturgeon rose to the surface of the small tank. It was only about the size of a palm. She had originally wanted to keep a real shark, but even a lemon shark would have required facilities far too large for her to manage alone. A sturgeon, on the other hand, needed no saltwater and demanded little maintenance.
She watched the armored fish with a satisfied expression. Its dorsal fin stood upright like a shark's. The sturgeon took the food and sank back below the surface. Alice let out a sigh of relief and sank onto the sofa. Today had been a peaceful day. She wondered what her colleague was up to. He had mentioned heading to some quiet academic conference this weekend. Knowing him, he was probably busy with something even there.
The microbiology conference was smaller than expected. Only a few dozen people had come. I sat in the banquet hall, waiting for the presentations to begin. They were serving cookies. I ate one of the chocolate cookies provided by the conference. It tasted better than I had anticipated. Maybe the hotel kitchen had made them. Anyway.
Next to me, Dr. Mullis was still lost in deep thought, his expression grave. Thanks to the eureka moment he had experienced at the hot spring earlier, he seemed to have lost all interest in the actual content of the microbiology conference. The invention of the PCR machine was right in front of him. The mind of the future Nobel laureate was working furiously. Or perhaps he had taken LSD before coming here today. He looked at me.
“Do you really think we can isolate a gene-synthesizing enzyme from bacteria that live in high-temperature environments?”
“Yes,” I answered simply.
“In a laboratory?”
“If you look, you’ll find it. Yellowstone microbial research has been going on for decades.”
It was something that existed in the original history. If one searched the papers, there would be researchers who had already isolated the gene-synthesizing enzyme from that archaeon. The paper might even have been published already. As I recalled, the isolation of the replication enzyme had come a few years earlier. It had simply taken Cetus’s researchers time to find the paper. Isolating a gene-replicating enzyme was a technique perfectly feasible even in this era.
Dr. Mullis nodded slowly. I kept eating my cookie.
“Will raising the temperature really cause the double helix to unwind on its own, and lowering it make the strands reattach? It can’t be that simple.”
It was that simple. Chemistry worked that way. When the strands of a gene came together, they found their complementary sequences and aligned themselves automatically. This held true for both long genes and short fragments. It was similar to a search function. There were hundreds of millions of books in the world, and countless texts on the internet. Yet a book containing an exact sentence was rare, and finding that same sentence in an internet article was not difficult. This was no coincidence. Genes were information-storage devices, and they operated on the same principle.
I looked at Dr. Mullis.
“Think of it as a search function.”
“What do you mean by search?”
Come to think of it, internet search engines did not exist yet. I scratched my head. I tried a simpler explanation.
“Genes function as information-storage devices. The fact that information can be retrieved through simple physical stimuli originates from the structure and function of the gene molecule rather than from chance.”
“Is that so……”
“Cells must be able to retrieve the information they need from genes, just as you intend to do in the laboratory.”
“Ah, I see.”
Dr. Mullis, still wearing a serious expression, was writing down my words in his notebook. He looked up.
“So, raising the temperature separates the double strands, and lowering it makes them reattach—in the correct positions.”
“That’s right.”
“And every time we raise and lower the temperature, the amount of synthesized gene doubles?”
I nodded. Dr. Mullis was now considering the most critical practical problem of gene replication, based on what he had just learned.
The content was becoming quite complex. What Dr. Mullis sought was a method to manipulate and synthesize genes. In the 1970s, only slow and expensive processes existed, but the goal was, of course, medicine—understanding the human body, developing drugs, conducting research. Reduction. Let us simplify the problem to its most basic form and follow the logic once more.
First reduction: Humans were too complex to handle directly in the laboratory, so we studied bacteria instead. We had found bacteria capable of surviving high temperatures at the hot spring, in order to locate a gene-synthesizing enzyme that could function at high temperatures.
Second reduction: We discussed the structure of the gene itself. Moving beyond bacteria, we spoke not of biology but of chemistry. We designed the experiment based on the chemical properties of the gene molecule. That was the work completed so far.
Third reduction: The final step was mathematics. Each time the temperature in the test tube was raised and then lowered, the amount of synthesized gene doubled. What did that mean? Exponential growth. The function in nature that reached infinity the fastest.
I sipped the coffee that had come with the cookies. Dr. Mullis seemed to have realized it.
“The amount of replicated gene will increase exponentially? After several dozen cycles, it would consume all the nutrients inside the test tube.”
Two to the twentieth power was 1,048,576. Exponential functions diverged toward infinity at tremendous speed.
“Exactly.”
“It’s a shame…… It would be nice if we could replicate only a specific target segment.”
I looked at Dr. Mullis. Why wouldn’t that be possible?
“The gene-synthesizing enzyme works by attaching to the end of a short strand and extending it while reading the complementary bases on the opposite strand.”
“That’s right.”
“Think simply. If you want to replicate the insulin gene, you just add the starting and ending sequences of the insulin gene.”
“Ah!”
The information between those two sequences—the insulin information—would have a higher probability of being replicated. That was the nature of exponential functions that diverged rapidly toward infinity. After repeating the process several times, the test tube would become filled with the insulin gene due to exponential growth. To use a restaurant analogy……
“Even if you don’t fully understand how a car works, disassembling it to build a bicycle or a fan isn’t difficult.”
He nodded gravely.
“Truly…… If we can implement this, the Nobel Prize is practically guaranteed.”
“Would implementation really be that difficult? Compared to spending two years with an entire research institute just to sequence a single virus……”
It would actually be simpler. Dr. Mullis grabbed my hand.
“Come to Cetus.”
I simply smiled. Was he joking?
“If you merely explain to Cetus’s board what you just told me…… the company would give you anything you asked for.”
Dr. Mullis’s gaze was serious. Indeed, if someone could point to the location of molecular biology’s Holy Grail, it would not be strange for a research institute to offer a blank check. Still, I shook my head.
“I’m fine. I intend to stay at the hospital.”
After all, the patients were at the university hospital, and both clinical work and clinical research happened there. Corporate research belonged at a corporation. He frowned.
“Wouldn’t someone like you contribute more to the world through research than through hospital work?”
I had no intention of going to Cetus.
“My field is medicine. It begins with patients and ends with patients. That’s why I discussed this with you, Doctor.”
“Understood……”
He let out a small sigh, looking genuinely disappointed.
“Well, that aside, I would like us to collaborate and publish a paper. Let’s see if those three stages of reduction work as planned.”
Dr. Mullis nodded.
The conference concluded without further incident. I waited with Professor Berg for the flight back to Palo Alto. The professor glanced at his wristwatch.
“Did you learn anything new?”
“I looked at papers on bacteria that live in high temperatures.”
“How does that relate to medicine?”
It did, Professor. The story was simply too long and complicated to explain right now.
“Would it be all right if I used the molecular biology lab next month? I heard about an interesting research topic related to gene synthesis.”
“Go ahead. Just submit the paperwork to the university administration. I’m sure you’ve brought back something extraordinary again.”
Professor Berg answered as if it were nothing out of the ordinary. Such things happened often enough.
“Thank you.”
Now that I had met the person who would originally make the discovery, the next step was to send a letter outlining the theoretical background of PCR to a major journal. I could simply write down what I had told Dr. Mullis. There would be no difficulty.