Blood transfusions may some day become obsolete - superseded by mass-produced human adult stem cells (ASCs).

"The industry of the future is growing ASCs," foresees biological engineer James Sherley, at the Massachusetts Institute of Technology. "We'd like to have industries that can grow these cells and warehouse them," he added. "Our vision is that we'll no longer need to have blood banks, because we'll have identified and isolated hematopoietic stem cells from a collection of donor people. So when a patient needs a blood transfusion, what they'll get is appropriately typed adult stem cells."

This far-sighted glimpse over the horizon informs Sherley's paper in the twice-monthly journal Cancer Research, dated Dec. 1, 2002. Its title: "Cosegregation of chromosomes containing immortal DNA strands in cells that cycle with asymmetric stem cell kinetics." Sherley is its senior author.

"The overall finding of this paper," he told BioWorld Today, "provides direct experimental evidence that cells that divide like adult stem cells have a mechanism that prevents them from re-using DNA copies. As an adult stem cell divides," he explained, "it makes new copies of DNA. If it were to keep all those copies, it would run the risk of getting gene mutations."

No Second-Hand DNA Need Apply

"So we defined a mechanism," Sherley continued, "by which cells dividing like adult stem cells discard all new copies, and keep only one original copy of the DNA template. That mechanism greatly limits mutations that occur because new copies of DNA produce errors. If the stem cells were to keep copies, they would accumulate those errors, which are the kinds of mistakes that ultimately lead to carcinogenesis.

"A well-known person in these parts, John Cairns, came along in 1975," Sherley recalled, "and predicted many more tumors than people actually incur. He came up with an explanation of how adult stem cells - the main cells that give rise to cancerous tumors - could avoid mutations. Cairns proposed what he called the immortal DNA strand mechanism,' and promulgated the idea that this happened in mammals.

"Then a British scientist, Christopher Potten, gave evidence that this mechanism happened in mammalian tissues. He inferred from in vivo experiments that it happened in mouse small intestines. To this we added," Sherley went on, "that mammalian cells growing outside of the tissue, can do this. But the most important thing that we've done is show this mechanism directly. We visualized and isolated those immortal DNA strands in mammalian cells in culture. We had engineered fetal mouse cells to divide like stem cells. That division of ASCs is called asymmetric cell kinetics. Most cultured mammalian cells divide exponentially. Every cycle produces two daughter cells. Both of them divide; then their progeny divide, and so forth.

"When our cells divided, they made another dividing cell, which made nondividing cells in vivo every cycle. That one cell is like a stem cell. And what our paper shows is that that stem-like cell discards all new copies of DNA, and keeps one original copy for many divisions in culture. It's direct proof that a mammalian cell can do this.

"It's an interesting balance in how mammals evolved," Sherley observed. "If we humans didn't have this mechanism, we would get tumors before we were able to reproduce. We would all get mutations when we were children - prereproductive-age cancers. By having this mechanism, we manage to reproduce, but the cost of having it is that we age. We can think of DNA as an aging chemical molecule that over time interacts with water, with oxygen, and eventually wears out. Aging may reflect the damage that happens in those DNA strands."

P53 - Tumor Suppressor, Tumor Abettor

"We took those mouse cells, labeled their DNA molecules, and shifted them to a condition where they started to divide like stem cells. These cells had an inducible gene in them, which encoded p53, the well-known tumor suppressor protein. We took mouse fetal fibroblasts that had no p53 gene in them - p53 nulls - and stably replaced a normal p53 gene with an inducible DNA promoter. When these calls were cultured under their normal growth conditions, they didn't make any p53, but proliferated exponentially.

"When we restored wild-type p53 levels to the cells," Sherley recounted, "we had a culture system where we engineered p53 gene expression from null to normal. So when the cells were growing with no p53, like cancer cells, we could label all the DNA molecules that we wanted, that we could track at a later time. So the way the experiment worked was we took those cells and then turned on p53. Now they grew asymmetrically, which meant that the cells divided and made nondividing cells - just like stem cells.

"We haven't yet done this experiment with natural adult stem cells," Sherley recounted, "and our link to ASCs is the fact that we have cells dividing like them. And we found that cells dividing exponentially like cancer cells do not have this mechanism - only those that are dividing asymmetrically like stem cells. What we'd like to do is apply our in vitro methods to some natural tissue model - cancerous or normal. The fact that p53 is driving everything also raises the question whether this is another role for p53 in tissue. The idea being that when you have a stem cell that carries a p53 mutation, it may happen when p53 function is lost that mutations occur at a higher rate, because the immortal strain mechanism is gone.

"We have several patent applications in the works already," Sherley allowed. "One that's pending right now covers the immortal DNA strand work, with the idea that this demonstration is an invention for identifying adult stem cells. I'm principal inventor. There is no licensee in the offing right at this moment," he said, "but it's something we'd like to do.

"One thing we're trying to accomplish right now," he added, "is to apply some of these neat assays that work for model culture systems to human donor bone marrow, and see if we can show evidence that there are cells present which divide with the immortal DNA strand mechanism. There's definitely a potential for that."