Death Benefit (7 page)

“Okay, guys, find a seat.”

The condition of Yamamoto’s office in comparison with Rothman’s was as different as the men’s personalities. Yamamoto’s looked like a typhoon had passed through it. Books, journals, files, documents, papers lay everywhere, including on each of the two seats in front of the desk. Visitors took it on faith that Yamamoto actually had a desk as every square inch was under paper, including a mountain of academic journals positioned so that a curious passerby couldn’t see whether the doctor was sitting behind his desk or not.

“Just move those papers,” Yamamoto said, as Pia and Lesley Wong gathered them up from the chairs but searched in vain for a free surface on which to put them down. Yamamoto gestured to the floor, a suggestion the women took. He leaned his posterior against the front of the desk and folded his arms. “You could get a chair from the lab,” he suggested to Will.

“No problem,” Will said. “I’ll stand.”

“I thought it appropriate for us to do a small review and go over some introductory material so you people can better appreciate what you’re about to see,” Yamamoto said. “You are in for a treat today. I’ve gotten special dispensation from Dr. Rothman to show you our organ bath program, which has been kept a secret of sorts up until now. It couldn’t have been kept a complete secret as there are too many people working here, and we’re here in a very public medical center. Since the professor and I are close to publication, secrecy is no longer the issue it was since the university has already seen to it that the appropriate patents have been applied for. At the same time, we would prefer that you keep what you see today to yourselves. Deal?”

All three students nodded.

“All right, let’s start at the beginning. But I don’t want to make this a boring monologue so help me out! Somebody tell me what a stem cell is.”

The three students eyed one another. Will spoke up. “In simple terms it’s an undifferentiated immature cell that has the potential of becoming a differentiated mature cell.”

“Right on,” Yamamoto said. “An example is a bone marrow stem that can become an adult blood cell. These cells are often called adult stem cells. What’s a pluripotent stem cell?”

Lesley spoke up: “A stem cell that can turn into any of the three hundred or so types of cells that make up the body of a multicellular organism like a human.”

“Right on again. You guys are making this easy for me.”

Pia felt a wave of impatience wash over her. She was eager to see the organ bath unit. Had it been up to her, she would have preferred to forgo any review session.

“Up until four or five years ago, how were pluripotent stem cells obtained?”

“From blastocysts.” Pia spoke up by reflex. She wanted this little talk over with.

“Right,” Yamamoto said. “Blastocysts from fertilized eggs, meaning very early-stage embryos. Why was that a problem that led to serious delays in stem cell research?”

“Because it offended conservatively minded people,” Pia said. “Particularly here in the United States, limitations were placed on what could and could not be done in stem cell research with government funds.”

“Well said,” Yamamoto commented. “Here’s a harder question. Let’s say that the research on embryonic stem cells had been allowed to proceed unimpeded. Can anyone say what the major problem would have been if the research had advanced to a point of using the stem cells to treat patients?”

None of the students moved.

“Let me give you a hint,” Yamamoto said. “I’m referring to an immunological problem.”

“Rejection!” Lesley called out, her eyes lighting up.

“Exactly. Rejection, meaning that any use of such embryological stem cells would have elicited some degree of rejection reaction. Some techniques would have reduced this problem but not completely eliminated it.”

All three students nodded. Everything that Yamamoto was saying they had heard before. “Now, can anyone define ‘induced pluripotent stem cells’ in contrast to embryological stem cells? These are the cells that Dr. Rothman and I have been working with exclusively.”

“They are pluripotent stem cells made from mature cells, usually a fibroblast and not egg cells,” Pia explained. “They are ‘induced’ by particular proteins to revert back from being a mature fibroblast to being a stem cell.”

“Exactly,” Yamamoto said. “And isn’t it a marvel that it works? For a long time one of the tenets of biological science was that cellular differentiation was a one-way street, meaning the process could never revert. But people should have known that this particular tenet was false. After all, it was known that certain animals could regrow body parts, like starfish and salamanders. Also cancer should have been a hint that the process of differentiation could go in the opposite direction, as many cancers are composed of immature cells that arise in organs populated by mature cells.”

Pia found herself glancing at her watch and sitting up straighter in her seat. She wanted to speed up the review session but didn’t know how. She inwardly groaned when Lesley piped up with a question: “How exactly are the cells changed back from mature to immature?”

“The same way that everything else is accomplished in the cell,” Yamamoto said. “By switching on and off genes. Remember, every eukaryotic cell—that is, a cell with a nucleus—contains a copy of an organism’s entire genome. Meaning that every nucleated cell has all the information necessary not only to build itself but to build the entire body. How this works is a process called gene expression, meaning the turning on and off of genes in a kind of molecular ballet. I know you learned all this in your genetics courses in college and during your first two years here at Columbia. Anyway, cellular maturation proceeds by a sequential switching on and off of the appropriate genes. It used to be thought that genes functioned by producing specific proteins, sorta one gene for one protein. But now we know it’s far more complicated, as there are significantly fewer genes than originally thought. For the cell to go in the opposite direction of maturation, the sequence has to be reversed. Are you all with me so far?”

All three students nodded. Despite feeling impatient, even Pia was now finding Yamamoto’s review fascinating. Like all other researchers, Pia was aware that biological science was unfolding its mysteries at an ever-increasing, mind-boggling speed. The nineteenth century had been chemistry, the twentieth physics. The twenty-first was undoubtedly going to be biology.

Yamamoto checked his own watch. As if answering Pia’s hopes, he said, “We’ve got to move this along if we’re going to catch Dr. Rothman in the organ bath unit. Let’s go back to our discussion of stem cells. Now that we have the induced pluripotent type that are going to avoid immunological rejection problems and be more acceptable to religious conservatives, what is the first step toward making them useful to treat the patient who donated the fibroblast? Anybody?” Yamamoto glanced from face to face.

Will shrugged and offered, “Get them to mature again but into the kind of cell the patient needs.”

“Thank you,” Yamamoto said. “Indeed, that is exactly what most stem cell researchers have been busy doing for years: finding out how to regulate gene expression such that the stem cells mature into the kinds of cells that make up the body, like heart cells, kidney cells, liver cells, and so forth. Stem cell researchers have now gotten very good at this, including Dr. Rothman and myself. But here is where Dr. Rothman and I have separated ourselves from the pack and are about to usher in twenty-first-century regenerative medicine that’s going to extend and improve the quality of life. We have been able to make virtual leaps in the ability to have these mature cells organize themselves into whole organs. In other words, we’ve managed to stumble on a host of structural genes and other transcriptional processes that are responsible for creating the lattice-like scaffolding that forms the basis of a three-dimensional organ. Once we had the structure, it was relatively easy to get it populated by the appropriate cells. It’s a process called organogenesis. Take, for instance, a liver. Although we and others have been able to make hepatic cells for years, we have never been able to get them to organize themselves into a whole liver with collagen, nerves, and blood vessels, the whole deal. We can do it now. We’re doing it with rapidly increasing efficiency. It’s phenomenal.”

“I assume you’ve been doing this with animal models?” Pia said.

“Of course! Mostly mice. The whole stem cell field has extensive experience with the murine model.”

“And you believe what you’ve been learning will be applicable to human cells?”

“We do, and not only on a theoretical basis. Concurrently we’ve been carrying on this research with human cells as well.” Yamamoto held up his left arm and pulled his lab coat sleeve down with his right hand. Proudly he pointed to a number of inch-long scars of varying age along his forearm. “I’ve been the guinea pig for the source of human fibroblasts. Although most of our research is done with mice, we have some human organs functioning equally well, human organs that could be used to treat me if I needed one of them. You’ll see in a few minutes. Any questions before we head over to the unit?”

Yamamoto looked at each of the students in turn and then paused. Finally he said, “Okay, let’s make our visit. Hope you guys are ready. You are about to visit the future.” He pushed himself up into a fully erect posture.

When the women started to replace the papers and journals they had removed from the chairs when they first arrived, Yamamoto motioned for them not to bother. With Yamamoto in the lead, the group exited his office. They walked the length of the sizable lab since the organ bath unit was located at the far end on the opposite side from the biosafety unit. As they passed through the lab, some of the technicians looked up from their work and eyed them questioningly. Visitors to the organ bath unit were not common.

First they entered an anteroom where there were caps, gowns, booties, masks, and gloves. There was a similar room on the other side of the lab that guarded entrance into the biosafety unit, just as this room guarded the organ bath unit. Interestingly enough, the rationale was just the opposite. For the biosafety unit the gear was for protection of the visitors. With the organ bath unit it was called reverse precautions and was for protection of the contained specimens. It wasn’t until everyone was suited up and had been checked by Yamamoto that they proceeded.

 

 

U
sing a keypad, Dr. Yamamoto punched in a combination, unlocking a simple door. Although she wasn’t trying, Pia noticed it was the same code used for the biosafety unit, an alphanumeric sequence that was the time and date of Rothman’s birth. Yamamoto stepped aside and ushered the three students into a starkly modern, brightly lit room filled with the gentle, hypnotic sound of running water. Pia felt a slight breeze against her as she advanced. She knew that was evidence of the room having positive pressure, meaning air came out of the room, not in. That was the opposite of the biosafety room, where the laminar flow was into the room.

Stepping beyond the door, Pia shaded her eyes against the sharp bluish light that came from banks of recessed fiber-optic fixtures. She assumed the light had something to do with sterility in the room. Stopping with the others, she took in the scene before her. They had entered a large space painted bright white. Pia was puzzled as to how this lab fit in with the rest of Rothman’s suite—it seemed larger than it feasibly could be. At the back of the room, a figure dressed in similar protective garb was hunched over a stainless-steel cart mounted on wheels, making some adjustments on a control panel. There were three rows of such carts and Pia counted thirty of them in all. Set atop each were clear rectangular Plexiglas aquarium-like containers of various sizes. Below were shelves holding various and sundry equipment. Each also had an attached pole supporting a control panel with an LED display. One of the carts was a few feet to Pia’s left and she moved over to take a closer look. Lesley and Will followed.

This was one of the organ-growing baths whose contained fluid was what Pia would be investigating for the month. She leaned over and peered into the container at a miniature translucent object suspended in the liquid by a kind of spiderweb that she was later to find out was made of the same material as real spiderwebs. As for the object itself, she could see it was connected by filament-thin lines to a central clamp where the lines were gathered. A thicker cable fed out of the bath and down into the body of the cart, where there was a boxy device with multiple readouts monitoring the conditions in the bath. An attached magnifying device on a movable arm was also connected to the cart. Pia maneuvered it into position so she could see the contained object better. Although it was not too much larger than a pine nut, its appearance was unmistakably that of a kidney, albeit a very tiny kidney. Most of the lines contained red fluid along one larger one that was clear. The red ones were presumably functioning as veins and arteries. The clear one was acting as the ureter to take away the urine the miniature organ was producing. To one side of the container was a jet, like one attached to a pool circulator, only in miniature. It was pulsating at a very rapid rate. Gentle eddies of liquid coursed around the container, causing the organ’s surface to pulsate slightly.

“We find that we must keep the fluid in the baths in constant motion despite the organs being perfused internally. But it has to be carefully modulated. Occasionally the rigid bath sets up a wash that can disturb the organ.” Yamamoto had stepped over to join the students. He noticed Pia straighten, looking down the length of the room.

“It’s quite something, isn’t it?” he said, speaking directly to her. “Of course, I see it every day, so I’ve come to take it all for granted.”