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.
5.
COLUMBIA UNIVERSITY MEDICAL CENTER NEW YORK CITY MARCH 1, 2011, 2:00 P.M.
Using 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
