Food and Drug Chapter 7
The word "prion" was a portmanteau of the words "protein infection".
A prion was an infectious protein. It caused disease.
Most proteins were not infectious. Most proteins were good citizens of the cell. They were large molecules, produced by the cell to perform all its functions. They were encoded by DNA, also large molecules, in units called genes. Genes were genotype - instructions. Proteins were phenotype - constructions.
The central dogma of molecular biology stated that information flowed from DNA to protein. DNA sequence determined protein sequence. Protein sequence determined protein structure. Protein structure determined protein function. Genotype to phenotype, instructions to constructions.
As with all dogmas, there were exceptions.
In the case of prions, information flowed from protein to protein. Protein structure determined protein structure.
In a batch of protein molecules, all of the same type, a single molecule folded incorrectly into a misshapen structure. All the other molecules folded correctly into the normal structure, the one that allowed the protein to perform its function. The misshapen structure conferred a new function to the rogue molecule. The rogue molecule gained the ability to bind and re-shape normal molecules into copies of itself. Over time, the rogue molecule replicated, propagating the misshapen structure to all the normal molecules. Each time a normal molecule was converted into a rogue molecule, it went on to convert other normal molecules. Eventually, all the molecules lost their original structure and their original function. The protein, originally a good citizen of the cell, joined the pantheon of pathogens - bacteria, viruses, prions.
In the brain, prions aggregated into strands and sheets. Every now and then, the fibrils that formed the strands and sheets broke down the middle. Two ends became four ends, the better to recruit normal molecules, binding and re-shaping them into rogue molecules. The strands and sheets grew at an exponential rate, gathering into indestructable deposits, called amyloid plaques, that accumulated in the brain. Cells died. Tissues withered. Gray matter became gray goo. The brain became a sloppy spongy mass of holes.
The disease was called spongiform encephalopathy. In humans, spongiform encephalopathy was tastefully designated as a family of related diseases - Creutzfeldt-Jakob Disease, Fatal Familial Insomnia, Gerstmann-Straeussler-Scheinker Syndrome. In bovines, spongiform encephalopathy was unceremoniously designated as mad cow disease.
Reid stared at the MALDI-TOF results on the computer screen. He stared at the other computer screen, displaying the matches between the unknown protein in the CSF sample and all the proteins in the UniProt database. There was only one match, to a protein called prion protein, PrP for short.
In mammals, PrP came in two forms. PrPC was the normal form that performed an unknown function in the cell. PrPSc was the rogue form that caused the fatal neurodegenerative disease that one acquired from eating tainted beef. One did not actually have to eat tainted beef to acquire the disease. A protein molecule might fold incorrectly in a completely spontaneous manner. The misshapen structure might propagate from one molecule to many molecules. Whether one acquired the disease depended on the luck of the draw. The disturbing part was that cards were constantly being drawn, in every single cell of the body, at every single second of the day.
"Whatcha doin'?" Emily snuck up behind Reid.
"God, Emily! You scared me half to death again!" Reid tumbled off his chair.
"You lied to me," Emily wagged her finger at Reid.
"What? When?" Reid felt his face flush, his ruddiness signaling contraction of the brain, which immediately raced to synthesize all his lies into a self-consistent alternate version of reality that he prepared to unfurl as needed.
"You said that you'd be seeding cells all night and that you wouldn't have time to run the MALDI-TOF," Emily replied. "But I guessed that you'd finish the cells early, so I came to see if you were running the experiment. And indeed you are."
"Oh," Reid felt his face un-flush, his paleness signaling relaxation of the brain, which immediately generated new lies. "I'm just running the control sample to make sure that the experiment works. Mass spec can be finicky sometimes."
"Ah," Emily nodded in understanding, "Well, I'll leave you to it as soon as you give me your professional opinion on some new data that Garcia has just sent me."
"What data?" Reid closed all the windows on both computer screens to give Emily his full attention.
"Garcia's been digging up information on the patients in the clinical trial," Emily said. "Remember how we determined that patients under age 45 were primary targets for the rogue agent? What am I saying? Of course you remember! Anyway, here's a list of younger patients," she handed over a piece of paper, "And here's a list of older patients," she handed over several stapled pages. "Notice anything unusual?"
"The IQ scores of the younger patients form a very strange distribution," Reid noticed the anomaly right away.
"Exactly!" Emily ran her finger down the list. "As we'd expect, the IQ scores of the older patients form a bell curve, with the majority of patients in the 90-110 range and fewer patients on the low end and the high end. The IQ scores of the younger patients don't form a bell curve. They're totally flat! Everyone has pretty much the same IQ...Around 100, which is pretty much the average IQ for the human species. Are you thinking what I'm thinking?"
"The younger patients were recruited to the study based on their IQ scores," Reid concluded. "They were chosen to fall into a narrow range of average intelligence."
"My thoughts exactly! But why?" Emily blinked expectantly.
"The pr..." Reid cut himself off before he could say the word "prion", "The rogue agent modulates intelligence."
"Is that even possible?" Emily frowned.
"In theory, yes," Reid replied. "Human intelligence is not well-understood, but like all bodily functions, it arises from the cells and tissues of the brain. Anything that modulates the brain at the cellular level has the potential to modulate intelligence. We just don't understand any of the mechanisms."
"So the rogue agent is a smart pill?" Emily asked. "That's crazier that I could have ever imagined."
"We don't know that," Reid said. "The rogue agent could be a stupid pill instead. We don't have any evidence either way. All we know is we have a group of patients recruited to the study based on IQ, which may or may not be a good quantifier of intelligence. But it makes sense that the UnSubs would do the study this way - recruit a bunch of people at the same IQ level and see if the agent causes IQ scores to increase or decrease from there. I really wonder if the agent has any effect."
"Could it actually work?" Emily shook her head in disbelief. "Could someone have actually figured out a way to make people smarter or...stupider?"
"Actually, that might explain the acetylcholine..." Reid mumbled softly.
"The neurotransmitter that controls muscle contractions?" Emily asked.
"Yes," Reid gazed at the wall beyond the computer screens. "Acetylcholine has a variety of functions in both the central and peripheral nervous systems. In the CNS, acetylcholine plays a role in synaptic plasticity, the neurological foundation for learning and memory and cognition, all the functions that we wrap up in a box and label as intelligence. A change, especially an enhancement, in the strength of the connection between two neurons in a synapse is thought to underlie most cognitive functions. Neurotransmitters like acetylcholine are the messengers between the neurons in the synapse. The pre-synaptic cell sends neurotransmitters across the synaptic cleft to the post-synaptic cell, which binds the neurotransmitters through receptors on the cell surface. Somehow, this process allows us to think."
"And your point is?" Emily frowned at the mass of terminology.
"The increased level of acetylcholine in the CSF sample may be the mechanism by which the rogue agent modulates intelligence," Reid replied robotically. "If it modulates intelligence at all," he added as a sanity check.
"Let's say that the agent is supposed to make people smarter," Emily said. "We'll give our UnSubs the very best of intentions. Is the agent supposed to make people smarter by giving them seizures and putting them into medically induced comas?"
"The seizures indicate that something has gone wrong in a small subset of people exposed to the agent," Reid transferred his gaze to the papers. "Of the 72 people presumably exposed to the pr...agent, only two have displayed adverse reactions. The rest appear to be perfectly healthy."
"So my mother has gotten the shitty luck of the draw?" Emily asked angrily. "First, she gets the pills that were meant for the younger group. Then, she gets the seizures that only show up in a small subset of people who take the pills. Meanwhile, everyone else is turning into you!"
"Pretty much," Reid replied impassively, "Except for the part about everyone else turning into me. We don't know enough to draw any conclusions about that. But regarding the seizures, personal biology is an important factor in determining the effects of drugs upon the body. Some people experience side effects when they take certain medications. Other people get off scot-free on the same meds. Many cancer drugs are only effective in 20% of patients, because those patients possess the requisite phenotype, essentially the correct protein profile, to respond to the drugs. Gleevec inhibits the bcr-abl fusion protein in patients with chronic myelogenous leukemia, but it doesn't work quite as well on related proteins, so it's not quite as effective for other types of cancers not caused by the bcr-abl fusion protein."
"Reid, can you please cease and desist with the medical terminology?" Emily sighed. "It's officially giving me a headache."
"In your mother's case, the rogue agent probably went haywire in her system, because she possesses an unknown feature of personal biology, such as a mutant protein that is normally asymptomatic but interacts with the agent to produce adverse reactions," Reid ignored Emily's complaints. "Isabella Torres has the same feature. My guess is we'll never know what it is."
"Thanks, Reid," Emily said sarcastically, "That's exactly what I needed to hear."
"The pr...agent may be modifying the structure of the synapse, causing the pre-synaptic cell to release excessive amounts of neurotransmitters into the synaptic cleft. PrPC, the normal version of PrP, is a membrane protein implicated in cell-cell communication in the brain. It may be present at the synapse."
"PrP? PrPC? What are you talking about?" Emily stared.
"PrP?" Reid snapped out of his trance at the mention of the problem that must not be named. "Oh sorry, I'm getting way off track. What I meant to say was that the rogue agent might be modulating synaptic transmission through an unknown mechanism."
"Thank you, Dr. Reid. That clears everything up tremendously. Please forgive my ignorance," Emily grabbed The Book and sucked up all its lukewarm contents. "Please summarize for me, in plain English, what you've been talking about for the past fifteen minutes."
"Sorry, Emily," Reid apologized, "I guess I was just thinking out loud. Uh...To summarize, your mother has gotten the shitty luck of the draw."
"Ugh!" Emily looked up at the ceiling in frustration. "You know what? I have an idea. We're both too sleep-deprived to have this conversation right now. How about we go home, get some sleep, and try this again later?"
"Yeah, OK," Reid agreed, "I'll see you back here tonight. I'm really tired, so I probably won't be going into the office this afternoon."
"That's fine," Emily said, "Hotch told us not to come in if we're not up to it. The rest of the team is working on a local case. Morgan assured me that they can survive this one case without us."
"Uh-huh," Reid nodded, tapping his heels against the metal legs of the chair, waiting for Emily to exit the lab so he could return to his cognitive trance. "I'll see you tomorrow. Hopefully, I'll have come up with some better ideas by then."
"Alright, see you later," Emily backed out of the lab, wheeling a large trash can behind her.
In the hallway, Emily applied the out-of-sight-out-of-mind principle to the conversation with Reid. Emily didn't know what was the matter with Reid. She had never seen him act this way before.
Normally, when Reid spewed out useless factoids, he did so with energy and focus, in a cadence of speech and a pitch of voice that conferred meaning to the obscure concepts. Today, he recited highly technical information in a trance-like state of distraction. He was only interested in his own train of thought. All other thoughts were pushed aside and shoved away, as if clearing a path to a goal. The path was a rainbow, and the goal was the pot of gold at the end of it.
Reid no longer cared about the case. He packed all the case-related information into boxes. He stacked the boxes into walls, like the walls of soda packs that adorned the entryways of grocery stores. He arranged the walls, pulling some of the boxes out and pushing some of the boxes in, until the walls spelled out the word "prion", over and over again.
Reid only cared about the prion. Now that he had found the problem, all he cared about was finding the solution.
The rogue agent was a prion. In Elizabeth Prentiss and Isabella Torres, it produced symptoms of a prion disease. Dr. Stanley Hawkins had read so many articles on the topic of myoclonic jerks and CJD, because myoclonic jerks were a late-stage symptom of CJD. Elizabeth Prentiss and Isabella Torres had only been participating in the clinical trial for a month. In a month, if the prion had already produced late-stage symptoms of a prion disease, then it was doing its work amazingly fast.
Prion diseases usually took years to develop. After the initial meal of tainted food, the symptoms took years to show up. It took years for the patient to experience cognitive impairments - memory loss, personality changes, hallucinations, dementia. In FFI, the symptoms began with episodes of insomnia and ended with total insomnia. The patient completely lost the ability to sleep. In CJD, the cognitive impairments were accompanied by physical impairments - myoclonic jerks, seizures, loss of motor control, loss of speech. After the symptoms appeared, the patient usually died within months. There was neither a treatment or a cure.
This prion was different. After the initial meal of tainted drug, the symptoms had taken one month to show up. Reid drew the only conclusion available.
If Thumper allowed the situation to go on for much longer, then by the time that Thumper came up with the magical elixir for Bambi's mother, there would be no use for it. The brain would have turned into a sponge, and the person within would have leaked out of the holes.
Reid jumped up from his chair, full of energy and focus, ready to go home and get some sleep. As long as he stayed awake, nothing would be accomplished. It was only in sleep that he could hope to solve a problem of this magnitude.
The three furry friends tapped their feet impatiently against the forest floor. They waited, eager for work, ready to tackle prions and synapses and neurotransmitters. They drew upon a vast store of irrationality that had no resting place within the brain of their host, because it permeated every crack and crevice. They - Thumper, Bambi, and Flower - and he - their host - believed that they could actually eliminate a prion that had already infiltrated the brain.
Emily no longer cared about the rules.
"Sorry, Hotch," she thought, "Blood is thicker than water."
Emily lay in bed, wishing that her bedroom were darker so that she could actually fall asleep. She used the downtime to formulate a plan.
Based on her research so far, Emily was convinced that Dr. Kenneth Lee and Dr. Sandra Maynard were guilty of wrongdoing. They were a husband-and-wife team working together to pursue a certain agenda. In the back of her mind, Emily had an inkling about the agenda. She didn't want to release the idea, not even to herself, until she had released the idea to someone else. The idea was bizarre, and Emily thought that Reid would be the only one who could appreciate it. She let it simmer, occasionally putting herself into its shoes, until it almost seemed like a good idea. She found herself almost agreeing with the rationale behind it.
Meanwhile, Emily focused on practical matters, ones that she could take into her own hands.
"Sorry, Hotch," she thought again.
Regardless of their specific roles in the case, Lee and Maynard were not innocent, because they had accepted a $50,000-check from PhenoPharm. They would not want the information, if it should leak out, to ruin their personal and professional reputations for life.
Emily held the information. It was the only power she had over the case. She was ready to abuse it. She thought that she could even abuse it within the confines of the rules. Nothing would ever leak into the media, because guilty parties, such as Lee and Maynard, would never publicize their interactions with other guilty parties, such as Reid and Prentiss.
Emily climbed out of bed. She plopped into an armchair and grabbed her laptop from the nightstand. She looked up the address of the Lee-Maynard home in College Park, Maryland.
"Sorry, Hotch," she thought a third time.
Emily dialed 7 for Reid as Google Maps displayed a satellite view of the neighborhood.
"Prion v. prion," Reid mumbled drowsily, "Hlllllllo?"
Master Post