by Thomas Hopp
I studied the two ladders on the screen. Against a white background, the DNA indeed looked like two tall ladders with dark gray rungs, standing side by side - except that these ladders were missing many of their rungs and had no side rails at all - just ascending sets of rungs, each rung shaped like a hyphen with rounded ends. Each ladder had more than a dozen rungs, and these were unevenly spaced, as if someone had knocked out half of the rungs in random fashion.
“Do the two ladders look identical to you, Fin?” McKean asked after I had taken a moment to study them.
“Yes, they do,” I responded. “The pattern of rungs missing or present in each ladder is the same.” The two un-climbable ladders were a matched pair.
“Nineteen rungs in each ladder,” Janet added. “Just what we expect for normal Bangladesh strain smallpox.”
McKean took a schoolmasterly, lecturing tone. “These nineteen rungs, or bands as we normally call them, are the expected result of reacting Hind-III enzyme with smallpox DNA.”
“So,” I said, “Let me make sure I understand what you’re showing me. Each of the rungs - or bands - is a DNA sub-fragment molecule?”
“Exactly,” McKean responded. “Or to be more precise, each band formed when millions of copies of the same DNA fragment moved together down from a starting point at the top, pulled through a gelatinous material by an electric field which draws them downward at a rate determined by their size. All the DNA molecules in those bands started their journey at the same place, but the smaller molecules moved faster while the larger ones were impeded by their greater size and moved at slower rates.”
He pointed at the topmost band.
“The DNA molecules in this band, called Fragment A, are more than ten-thousand code letters long, while the smallest DNA in the band at the bottom of the ladder, Fragment S, has only a few hundred A’s, T’s, G’s and C’s in it.” He looked at me cagily down his long nose. “Are you sure you don’t see any differences between the two ladders, Fin?”
I looked at the screen again. “No. They look identical.”
“That’s what I thought at first,” Janet said, smiling a little smugly.
“But look carefully, right here.” McKean pointed a long index finger at the bands that were the second from the top of each ladder. “Do these B Fragments really match?”
I looked more carefully. “The left-hand one is slightly higher. I see it, now that you point it out, Peyton.”
“Careful observation is the key to success in DNA analysis,” McKean asserted. “Without meticulous thought and observation, many researchers miss much of what’s right before their eyes. Here, we see Fragment B from Mr. Fenton’s virus has moved just slightly slower than that of the normal virus. That means it’s heavier than the normal Fragment B. Perhaps twenty or thirty code letters longer.”
“Twenty, out of thousands,” I remarked. “Can you really measure such a slight difference?”
“That’s one thing we’re concerned about right now,” Janet replied.
McKean explained. “Such a small variation might not be real - just an experimental error, a wrinkle in the gel presented here. But I suspect it’s not. I think we should sequence Mr. Fenton’s B fragment, don’t you, Janet?”
“Sure,” she said. “If it will help explain things.”
“Is that an easy thing?” I asked. “To sequence the fragment?”
McKean shook his head. “It will take some doing, although I’m sure Janet is up to the task.”
He tugged at his angular chin, doing some mental calculations. “Fragment B is the second largest in the entire viral genome. It’s too big to fully sequence without sub-fragmentation. You see, Fin, when we determine the sequence of DNA code letters - called bases, or nucleotides - we start from one end of the DNA chain and read as many letters as we can, moving along the chain. However, the reading process is a chemical reaction, which begins to fade out after a few hundred code-letters. We have to start reading again, farther along the DNA, overlapping the first sequence and continuing past the stretch where the first analysis faded out. It can take quite a few overlapping sub-fragments, which we make by cutting the fragment with more restriction enzymes other than Hind-III. It can take a while to read the entire sequence.”
“Weeks, or months” said Janet.
McKean raised an eyebrow at her. “Maybe a little quicker, if we prioritize the project high enough.”
Janet sighed. “I foresee more late nights in the lab.”
“All for a worthy cause,” McKean replied with a fond smile. There was warmth between them that rang of good fellowship, at least.
“Please forgive the fact that I’m still worried about terrorist plots,” I said. “But doesn’t this DNA alteration confirm that the virus’s genetic structure has been tampered with?”
McKean looked thoughtful. “Altered by a human hand?”
“That’s what I mean.”
He thought for a long moment. “It’s certainly not beyond nature’s ability to change the virus this way. But a human-generated change might look the same.”
“So how will you decide if it’s man-made or a natural change?”
“I’m not sure if we will be able to tell that or not. We’ll simply have to take a detailed look at the altered genetic sequence and see if there are any telltale signs of genetic engineering. If so, then foul play would indeed be indicated.”
“How soon will you know?”
“Tomorrow at the soonest, when the first of the sequencing data are in hand. Maybe not for some time, though, if the mutation is in a hard-to-reach portion of the DNA sequence.” He looked at his watch. “There is one thing I would like to do, and now might be the best time. Janet, I think I’ll go and have a look at Kay Erwin’s data for this virus. She carried out this same sort of restriction-mapping experiment to confirm the diagnosis of smallpox, but she didn’t mention any altered fragments. Given how slight the change is, her people may have missed it. After all, they were looking for similarities in the ladders, not differences. I have a hunch their data may record the same subtle alteration. Just a glance at her results would confirm our finding.”
“While you go to see her,” Janet replied, “I’ll make the sub-fragments and set up the sequencing apparatus for the first run.”
McKean turned to me. “Fin, would you like to join me in a dash to Seattle Public Health? You might find the isolation ward interesting. Mr. Fenton is still there, still hanging on to life by a thread.”
“I’d love to see the place, and Mr. Fenton. That’s a rare opportunity for a medical reporter.”
While McKean phoned Kay Erwin and arranged a visit, I considered my good fortune. My instincts told me the more time spent with Peyton McKean the better, although I was surprised he wanted me to tag along on such a crucial mission. I suspected the inventor of the Congo River vaccine, who chafed under the dominion of Stuart Holloman, liked the idea that I might provide some press coverage as an embedded journalist.
“Do you have a car?” McKean asked. “I would like you to drive if you don’t mind.”
“Glad to. My car’s just a few blocks from here.”
“That will be fine. I’m a poor driver. Too easily distracted by abstract thoughts, I’m afraid.”
* * * * *
We walked to my Mustang, and several minutes later I drove us into the delivery area of Seattle Public Health Hospital. Using Kay’s name, McKean cajoled a security guard to let us park beside the loading dock and board a stainless steel elevator, in which the guard used his passkey and pressed a floor button marked “Restricted Access” and sent us up. When we stepped off, we were greeted by an intern in a white hospital staff uniform. He led us to the end of a corridor where a wall-sized window of wire-reinforced safety glass bared the way. A sign above the window wall read, “Infectious Disease Isolation Facility.”
“Wait here,” the intern said before taking leave of us. “Dr. Erwin will be right with you.”
Beyond the window was
an entire hospital corridor perpendicular to one in which we stood, running to the left and right down the length of two opposing wings of the hospital. Spaced at regular intervals along both halls were doorways leading to patient rooms and other facilities. Directly in front of us, in the center between the two wings was an open area with a square nursing-station counter replete with television monitors, phones, and file cabinets. In essence, an entire hospital ward had been sealed off behind the glass wall.
McKean said, “The entire area behind this glass is as securely isolated as the BSL-4 cabinet you saw in my lab. Nothing gets out without being thoroughly sterilized. That includes equipment, supplies, clothing, and, er, other things. Ah, there’s Kay.”
Erwin stood just inside the open door of a room immediately to our right within the facility. She was dressed in a yellow spacesuit-like isolation suit made of inflatable plastic with a small air compressor on her back. Inside the room were two beds, in the nearest of which I could just glimpse the sheet-covered feet of a patient. McKean rapped a knuckle on the window. Erwin turned and smiled at us through her clear plastic faceplate. She came out of the room, stopped on the opposite side of the window wall, and pushed a button on a desktop console that abutted the window. A small speaker set into the glass at about head height clicked on. Kay’s voice came across, distantly, and ringing with the sound of her plastic suit. “Hi, Peyton. Hi, Fin. Sorry, this moon suit makes it hard to talk. Can you hear me okay?”
“Passably,” said McKean. I nodded.
She pointed a thumb toward the patient. “I just checked Mr. Fenton’s vital signs.”
“And?” McKean prompted.
She shrugged inside the bulging suit. “Not too vital. He’s comatose. High fever, lungs badly congested. May not last the night.”
“Poor fellow,” said McKean. “Nasty disease. But we’ve come to look at your DNA data.”
“Yeah. Okay. I’m finished here. I’ll meet you in my office once I’m clean.”
She moved down the corridor to our left and we tagged along on our side of the window. My reporter’s eyes were busy laying down mental notes about everything I saw inside the isolation facility. I felt awed and a little terrified to know the glass wall was all that held an epidemic in check. Kay moved past the on-duty station into the left-hand corridor. The first door on the far side was labeled, “Supply Commissary.” As she went down the hall, she passed another door labeled “X-ray,” and third labeled “Surgery.” I was unprepared for what came next. A closed green doorway with a small rectangular window in it had the ominous label, “Autopsy.” The efficiency of the ward, it seemed, ranged almost to ghoulish. Across the hall from the autopsy room Kay spun the wheel latch of a large stainless steel hatch doorway labeled “Sterility Control.” She sealed herself into an airlock and then went on to the Sterility Control room proper, which we could see into through a window that faced the outside of the facility. The room was a twelve-by-twenty-foot space with a tile floor and a hanging metal shower ring at the end where she entered. She pulled the ring and the shower sprayed her isolation suit from head to foot with sterilizing solution, which ran off her and into a drain in the floor. She then moved to a dressing area and removed the suit by opening a zipper that ran down its front from shoulder to crotch. She stepped out, wearing green surgical scrubs and paper booties, and hung the isolation suit on a wall next to several others. Then she passed through the hatch doors of the near-end airlock, exchanging her booties for street shoes on the way, and finally stepped out to join us in the outer corridor.
“That’s better,” she said, smiling. “Being on the ward is about as comfortable as being on the moon. But we follow procedures to the letter with something as deadly as smallpox onboard.” She ushered us across the hall and into her office, a typical medical doctor’s workspace. It was a neat, tidy place with a large metal desk, framed degree certificates on the wall, shelves of medical reference books, a window with a view of city office towers and sunlight streaming through half-drawn Venetian blinds. McKean and I settled into guest chairs as Kay pressed a button to wake her computer. A minute later she had her results on the screen, which she turned toward us. McKean leaned close and stared at the pair of DNA ladders.
“Have you noticed,” he asked Erwin, “how Fenton’s Fragment B looks a little heavy?”
“No,” said Erwin, turning the computer back to take another look. “But now that you mention it, it does seem a tad higher up the gel than the standard virus fragment, doesn’t it?”
“It does,” he said.
“I’m glad you noticed that,” said Erwin. “Too fine a shade of difference for my eye. I don’t do a lot of genetic analysis.”
McKean nodded. “Understandable. You’ve got your hands full with Mr. Fenton, and the DNA difference we’re looking at is quite subtle. But now I am certain it’s real. We’ll make a major time commitment to sequence Fragment B and find out how it has changed.”
“Good,” said Erwin. “Otherwise we’re still at a loss as to what makes this strain so virulent.”
“Fragment B contains some pretty interesting genes, you know.”
Erwin looked at him uncertainly. “The virus has so many genes. I’ve read about them, but my mind just boggles. It’s hard to keep track of them all.”
McKean nodded. “One hundred eighty-seven genes, at last count.”
“At last count?” I interjected. “The variola virus was sequenced in 1993. Its entire genome is known, isn’t it?”
McKean chuckled condescendingly. “Remind me to explain multiple, overlapping reading frames, Fin. The ways in which variola DNA gets translated into proteins in the cell is still being worked out. There may be dozens of virus-encoded genes right before our eyes, of which we are still unaware. The number of genes might still grow.”
Erwin asked, “But you’ve got a favorite suspect gene on Fragment B?”
“Answer: yes,” said McKean. “The gene encoding the viral surface antigen, B7R. It’s the main target for anti-smallpox antibodies.”
Seeing my eyebrows knitting, he explained. “The bloodstream of immunized patients contains antibody proteins, which attach to the viral B7R surface protein in a lock-and-key fit, to aid in its destruction. If this strain of smallpox has an altered B7R protein, then - “
Erwin said, “Then we could explain the virus escaping Mr. Fenton’s pre-existing antibodies against smallpox.”
“Exactly,” said McKean. “A mutated viral surface protein might shake off Fenton’s old antibodies. I’ll keep Janet busy determining if and how this surface protein has been altered.”
“Good,” said Erwin. “The sooner we know how this virus has gone bad, the sooner we can take countermeasures.”
“By the way,” said McKean almost as an afterthought. “Are there any other cases of smallpox yet?”
Erwin’s expression clouded. “Yeah,” she sighed. “Two members of Fenton’s family have come down with fever and congestion. Two coworkers at the border station have come down with fevers. The CDC team’s got them all under watch at their homes. But there is worse news. A register clerk at Fenton’s local convenience store reported to a hospital with a fever last night. His home is outside the vaccination containment ring.”
“If he’s got smallpox,” said McKean, “we’re looking at a local break-out.”
“Uh huh,” Erwin murmured. “The CDC team is already setting up a larger temporary isolation facility, expecting more patients. The President just this morning authorized vaccination of the entire town of Sumas.”
“The President of the United States?” I asked. “Is that who you meant yesterday when you said you were under orders from high places?”
She shook her head. “Not directly. But I was informed that he wanted to downplay things. It seems he’s as worried about panic as about public safety. Says he doesn’t want businesses to be hurt if people needlessly lock themselves in their homes. But now I think even the President’s gotten the message. Vaccinating all
of Sumas tells me he’s on the same page with me.”
“But the outcome is still in doubt,” said McKean. “The old vaccine didn’t stop Fenton’s virus.”
“Let’s just hope it’s more effective in other vaccinees,” said Erwin. “And on the positive side, we’ve had no reports of smallpox in other cities yet.”
“But the incubation period for smallpox is long,” McKean countered. “An exposed person might take fourteen days to feel sick, and several more before breaking out in a rash that would give a definitive diagnosis. So a lot more cases could be brewing out there.”
“Given Fenton’s job as a customs inspector,” I said, “couldn’t he have exposed people crossing the border just before he got sick enough to go to his doctor? They could be anywhere by now.”
Kay nodded. “The CDC is watching carefully for that sort of thing. Nothing yet.”
“On the other hand,” I said, “if someone was transporting the virus on purpose, then Inspector Fenton might have snooped too deeply into someone’s luggage.”
McKean raised a finger. “Or he may have contacted someone in a car who had the virus but didn’t know it yet.”
“I don’t like the implication that someone was deliberately transporting the virus,” said Kay. “And I’m not willing to declare this a case of…”
“Bioterror?” I asked.
“It’s possible, of course,” she said. “But who would do such a thing?”
“I remember when one of our units in Afghanistan came across a safe house where Al Qaeda had a makeshift lab and notes on culturing biological warfare microbes.”
“Yes, Fin,” said Kay. “I remember too. But they didn’t have facilities sophisticated enough to genetically alter a smallpox virus.”
“You can’t do virology in a house, or a cave,” McKean remarked. “I’m certain we’ll never face a bioterror threat from unsophisticated religious radicals. It would require too much central organization and precision work in a completely modern laboratory.”
“Okay,” I allowed. “But it doesn’t mean such facilities couldn’t exist.”
