Los Angeles, 2017. Not that far away, really. LAPD Blade Runner Rick Deckard (Harrison Ford) in Ridley Scott’s classic film tracks down escaped replicants – artificial persons – to “retire” them. Replicant Roy Batty and his friend Leon approach Hannibal Chew, creator of “Nexus 6” model replicant eyes in a frozen tissue manufacturing facility. They rip off his jacket, exposing him to the cold, and interrogate him about extending their four-year lifespans while he freezes.
Poor Hannibal Chew. The creator of artificial eyes in this science fiction epic must face the consequences of his engineering agility. But is the acumen to produce artificial eyes, livers, or kidneys really that far off? A new technique developed at UC Berkeley and the Lawrence Berkeley National Laboratory uses a bottom-up approach to create multicellular tissues with defined structures. Unlike top-down synthesis in which scientists build cell structures on scaffolds (cells that are implanted or “seeded” into an artificial structure), the new technique “allows tissue engineers to dictate the precise geometric interactions of individual cells.”
The results, published by Zev Gartner and Carolyn Bertozzi, appeared recently in an early online edition of Proceedings of the National Academy of Sciences. Cells coated with short nucleic acid polymers – “sticky bits” of DNA to impart specific adhesive properties – self-assemble into functional three-dimensional microstructures. Hybridization (that is, joining two strands) of complementary DNA sequences, “enables the assembly of multicellular structures with defined cell-cell contacts.” This is done using a paracrine signaling network – a form of cell signaling in which the target cell is near the signal-releasing cell.
How does this work? Gartner and Bertozzi started with two cell types: one that secretes a growth-factor protein that the other type requires in order to grow. When the different cells were combined, their complementary DNA fragments joined into double strands, linking the cells together. Joined to their protein producing partners, the protein-dependent cells do well. But without the sticky-bit DNA coating, the two cell types can’t signal, and the dependent cells die.
The researchers varied the relative concentrations of the two cell types. When the cells were combined in a one-to-one ratio they merely formed pairs. . But when the growth-factor-dependent cells vastly outnumbered their counterparts, they formed three-dimensional microtissue structures with a single growth-factor-secreting cell in the center.
Ali Khademhosseini, assistant professor at Harvard-MIT’s Division of Health Sciences and Technology and Harvard Medical School, says this technique "provides a new way of recreating tissue complexity." He cautions that it’s too early to tell whether this sticky bit DNA approach will eventually produce tissues “suitable for use in regenerative medicine.”
What would it take to actually manufacture a new kidney using microtissues? Dialysis is a method for removing waste products such as potassium and urea, as well as free water from the blood when the kidneys are in renal failure. When it comes to currently available kidney replacement therapies, you’ve got either dialysis or kidney transplant using donor organs. In order for tissue to be manufactured commercially for use as a kidney, cells to grow the tissue would have to be readily available, the human body would need to generate new blood vessels to feed the transplanted tissue, and the tissue itself would have to remove the waste products in the blood.
So far the sticky-bit DNA microtissues are only in the beginning stages and don’t have the structural refinement of a whole organ. Researchers Gartner and Bertozzi, however, hope to build larger and more involved structures “by tweaking the ratio of cell types, the density of DNA on the cells’ surfaces, and the complexity of the DNA sequences.”
Dutch-born physician Willem J. Kolff invented the first artificial kidney during World War II using sausage casings and orange juice cans (he also built the first artificial heart). Refinements to his artificial kidney dialysis machine have resulted in an estimated 55,000 people kept alive in the US with end-stage renal (kidney) disease.
Clearly it’s not only fictional Nexus 6 replicants who would benefit from the perfection of cheaply manufactured Kidney microtissues.