“It’ll be fun,” Kim said.
With some awkwardness they separated, and Kim climbed into her car. She opened the passenger-side window and Edward leaned in.
“I’m sorry I’m so preoccupied about this alkaloid,” he said.
“I understand,” Kim said. “I can see how excited you are. I’m impressed with your dedication.”
After they said their goodbyes, Kim drove toward Beacon Hill feeling a lot happier than she had just a half hour earlier.
7
Friday, July 29, 1994
Edward’s excitement escalated as the week progressed. The database on the new alkaloid grew at an exponential rate. Neither he nor Eleanor slept more than four or five hours each night. Both were living in the lab for all practical purposes and working harder than they had in their lives.
Edward insisted on doing everything himself, which meant he even reproduced Eleanor’s work in order to be one hundred percent certain of no mistakes. In like manner he had Eleanor check his results.
As busy as Edward was with the alkaloid, he had no time for anything else. Despite Eleanor’s advice to the contrary and despite mounting rumblings from the undergraduate students, he’d given no lectures. Nor had he devoted any time to his bevy of graduate students, many of whose research projects were now stalled without his continual leadership and advice.
Edward was unconcerned. Like an artist in a fit of creation, he was mesmerized by the new drug and oblivious to his surroundings. To his continued delight the structure of the drug was emerging atom by atom from the mists of time in which it had been secreted.
By early Wednesday morning, in a superb feat of qualitative organic chemistry, Edward completely characterized the four-ringed structural core of the compound. By Wednesday afternoon all of the side chains were defined both in terms of their makeup and point of attachment to the core. Edward jokingly described the molecule as an apple with protruding worms.
It was the side chains that particularly fascinated Edward. There were five of them. One was tetracyclic like the core and resembled LSD. Another had two rings and resembled a drug called scopolamine. The last three resembled the brain's major neurotransmitters: norepinephrine, dopamine, and serotonin.
By the wee hours of Thursday morning, Edward and Eleanor were rewarded by the image of the entire molecular structure appearing on a computer screen in virtual three-dimensional space. The achievement had been the product of new structural software, supercomputer capability, and hours of heated argument between Edward and Eleanor as each played devil’s advocate with the other.
Hypnotized by the image, Edward and Eleanor silently watched as the supercomputer slowly rotated the molecule. It was in dazzling color, with the electron clouds represented by varying shades of cobalt blue. The carbon atoms were red, the oxygen green, and the nitrogen yellow.
After flexing his fingers as if he were a virtuoso about to play a Beethoven sonata on a Steinway grand piano, Edward sat down at his terminal, which was on-line with the supercomputer. Calling upon all his knowledge, experience, and intuitive chemical sense, he began to work the keyboard. On the screen the image trembled and jerked while maintaining its slow rotation. Edward was operating on the molecule, chipping away at the two side chains he instinctively knew were responsible for the hallucinogenic effect: the LSD side chain and the scopolamine side chain.
To his delight, he was able to remove all but a tiny two-carbon stump of the LSD side chain without significantly affecting either the three-dimensional structure of the compound or its distribution of electrical charges. He knew altering either of these properties would dramatically affect the drug’s bioactivity.
With the scopolamine side chain it was a different story. Edward was able to amputate the side chain partially, leaving a sizable portion intact. When he tried to remove more, the molecule folded on itself and drastically changed its three-dimensional shape.
After Edward had removed as much of the scopolamine side chain as he dared, he downloaded the molecular data to his own lab computer. The image now wasn’t as spectacular, but was in some respects more interesting. What Edward and Eleanor were looking at now was a hypothetical new designer drug that had been formed by computer manipulation of a natural compound.
Edward’s goal with the computer manipulations was to eliminate the drug’s hallucinogenic and antiparasympathetic side effects. The latter referred to the dry mouth, the pupillary dilation, and partial amnesia both he and Stanton had experienced.
At that point Edward’s true forte, synthetic organic chemistry, came to bear. In a marathon effort from early Thursday to late Thursday night, Edward ingeniously figured out a process to formulate the hypothetical drug from standard, available reagents. By early Friday morning he produced a vialful of the new drug.
“What do you think?” Edward asked Eleanor as the two of them gazed at the vial. They were both exhausted, but neither had any intention of sleeping.
“I think you’ve accomplished an amazing feat of chemical virtuosity,” Eleanor said sincerely.
“I wasn’t looking for a compliment,” Edward said. He yawned. “I’m interested to know what you think we should do first.”
“I’m the conservative member of this team,” Eleanor said. “I’d say let’s get an idea of toxicity.”
“Let’s do it,” Edward said. He heaved himself to his feet and lent Eleanor a hand. Together they went back to work.
Empowered by their accomplishments and impatient for immediate results, they forgot scientific protocol. As they had done with the natural alkaloid, they dispensed with controlled, careful studies to get a rapid, general data to give them an idea of the drug’s potential.
The first thing they did was add varying concentrations of the drug to various types of tissue cultures, including kidney and nerve cells. With even relatively large doses they were happy to see no effect. They put the cultures in an incubator so that they could periodically access them.
Next they prepared a ganglion preparation from Aplasia fasciata by inserting tiny electrodes into spontaneously firing nerve cells. Connecting the electrodes to an amplifier, they created an image of the cells’ activity on a cathode ray tube. Slowly they added their drug to the perfusing fluid. By watching the neuronal responses, they determined that the drug was indeed bioactive although it didn’t depress or increase the spontaneous activity. Instead the drug appeared to stabilize the rhythm.
With mounting excitement, since everything they did yielded positive results, Eleanor began feeding the new drug to a new batch of stressed rats while Edward added the new drug to a fresh synaptosome preparation. Eleanor was the first to get results. She was quickly convinced the modified drug had even more calming effect on the rats than the unaltered alkaloid.
It took Edward a little longer to get his results. He found that the new drug affected the levels of all three neurotransmitters, but not equally. Serotonin was affected more than norepinephrine, which was affected more than dopamine. What he didn't expect was that the drug seemed to form a loose covalent bond with both glutamate and gamma-aminobutyric acid, two of the major inhibitory agents in the brain.
“This is all fantastic!” Edward exclaimed. He picked up the papers from his desk that recorded all their findings and allowed them to rain down like massive sheets of confetti. “This data suggests that the potential of the drug is monumental. I’m willing to bet it’s both an antidepressant and an anxiolytic, and as such it could revolutionize the field of psychopharmacology. It might even eventually be compared with the discovery of penicillin.”
“We still have the worry about it being hallucinogenic,” Eleanor said.
“I sincerely doubt it,” Edward said. “Not after removing that LSD-like side chain. But I agree we have to be sure.”