Stem Cell Update: Important Research Breakthrough

Another important step has just been taken toward achieving the medical promise of stem cell research. For the first time, researchers at the Max Planck Institute for Molecular Biomedicine in Münster, Germany, have reprogrammed skin cells directly into multipotent stem cells.

Over the past five years, stem cell researchers have learned how to induce or reprogram skin cells to become pluripotent stem cells—cells capable of becoming any type of cell in the body. The result: induced pluripotent stem cells or iPSCs. Scientists have also discovered how to reprogram cells to become precursor or progenitor cells. Precursor cells have a much narrower range of potential for development. They are able to become one very specific type of cell in the body.

Expanding on previous work, the latest breakthrough achieves a kind of “goldilocks” or just-right level. Working with mice, the team led by Hans Schöler discovered how to reprogram fully differentiated skin cells into neuronal stem cells (NSC)s. Unlike pluripotent cells, NSCs are far more suitable for clinical use. And now, with this breakthrough, the Max Plank Institute team has learned how to reprogram or induce NSCs or iNSCs.

And unlike precursor or progenitor cells, iNSCs are capable of multiplying and diffentiating once they are implanted. When researchers implanted their iNSCs into mouse brains, iNSCs generated new cells that began to take on some of the characteristics of ordinary developing brain cells.

Caption: This is an immunofluorescence microscopy image of the induced neural stem cells (iNSCs) using antibodies against two neural stem cell markers SSEA1 (red color) and Olig2 (green color). Credit: MPI for Molecular Biomedicine

The field of stem cell research has faced many obstacles, some moral and some medical. The main moral objection is that the prime source of human pluripotent cells is the human embryo, and many object to the destruction of the embryo for medical purposes. One of the medical challenges is that implanted cells are likely to be rejected by the immune system, much as transplanted organs are rejected unless immunosuppressant drugs are given.

Unless, of course, the source of the cells is from the patient’s own body. That’s why this achievement is important. If this technique can be applied to human cells—and there’s no reason to think it can’t—then someday it may be possible to take a small sample of cells from a patient’s skin, convert them to iNSCs, and then implant them in the patient’s brain to repair damage from disease or injury.

Not only does the iNSC discovery use the patient’s own cells as the source. It also by-passes the pluripotent stage. That fact should help researchers avoid creating cancer or other problems.

According to Schöler, "pluripotent stem cells exhibit such a high degree of plasticity that under the wrong circumstances they may form tumours instead of regenerating a tissue or an organ."

"Our research shows that reprogramming somatic cells does not require passing through a pluripotent stage," Schöler said in a press release issued by the Max Plank Institute. "Thanks to this new approach, tissue regeneration is becoming a more streamlined—and safer—process."

The article, "Direct Reprogramming of Fibroblasts into Neural Stem Cells by Defined Factors," appears in the March 22 issue of Cell Stem Cell.

Humans Beings, DNA Nano-Robots, and Implantable Chips

Technological devices inside the human body are fast becoming more fact than fiction, and two reports released on February 16 are significant milestones along that path.

In one study, appearing in Science Translational Medicine, microchips were implanted in women suffering from osteoporosis. Researchers at Harvard Medical and Case Western worked with MicroCHIPS, the manufacturer of the device.

Patients with advanced osteoporosis, whose bones have weakened and lost density, are currently able to give themselves with a daily injection of a drug that requires refrigeration. By implanting a device, researchers want to make the process easier compliance more consistent.

The microchips implanted in the study contain tiny reservoirs of the drug. The device releases a daily dose when it receives a wireless signal. It also monitors the release of the drug and reports back to the physician, who is able to modify the prescription by sending new instructions to the device from another wireless device, such as a smart phone. This is believed to be the first wirelessly controlled implanted drug-delivery device.

"This trial demonstrates how drug can be delivered through an implantable device that can be monitored and controlled remotely, providing new opportunities to improve treatment for patients and to realize the potential of telemedicine," according to Robert Langer of MIT and the cofounder of MicroCHIPS, Inc. "The convergence of drug delivery and electronic technologies gives physicians a real-time connection to their patient's health, and patients are freed from the daily reminder, or burden, of disease by eliminating the need for regular injections," Langer said in a release issued by the MicroCHIPS.

The drug delivery device (on right) next to an everyday computer memory stick. Courtesy of MicroCHIPS, Inc., Massachusetts.

The company also reported that it is currently developing new designs of its microchip-based implant to include as many as 400 doses per device providing daily dosing for one year or multi-year therapy for less frequent dosing regimens.

In another study reported today, a team of researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University report on their work in assembling tiny robots out of DNA.

Building on previous advances in what is popularly known as “DNA origami,” the Wyss team used a computer to fabricate a barrel-like structure capable of containing specific molecules for delivery to targeted cells in the body. For example, cancer cells could be targeted with molecules that cause them to self-destruct, much the way the body’s own immune system carries out its functions.

“DNA origami” allows researchers to use DNA as a construction material. They are able to fold it and weave its strands together. What’s more, since DNA is a chemical code, specific patterns or sequences in the DNA can be used to “read” a signal and “act” accordingly. In this study, researchers built a DNA “latch” or locking mechanism. Their DNA barrel kept its molecular payload safely under wraps until it arrived on the surface of the target cell. On the surface of the target cell is a protein that unlocks the DNA latch, releasing the molecule at just the right location.

Cell-targeting DNA nano-robots bearing antibody-fragment payloads. [Image created by Campbell Strong, Shawn Douglas, & Gaël McGill using Molecular Maya & cadnano]

"We can finally integrate sensing and logical computing functions via complex, yet predictable, nanostructures—some of the first hybrids of structural DNA, antibodies, aptamers and metal atomic clusters—aimed at useful, very specific targeting of human cancers and T-cells," said George Church, Ph.D., a Wyss core faculty member and Professor of Genetics at Harvard Medical School, who is Principal Investigator on the project.

One way in which the researchers tested their DNA nano-robots was by programming them to target and destroy cancer cells growing in culture, including leukemia and lymphoma cells. The results were promising. According to the study, ” These findings demonstrate that the robots can induce a variety of tunable changes in cell behavior. Furthermore, biologically active payloads may be bound indirectly via interactions with antibody fragments, enabling applications in which the robot carries out a scavenging task before targeted payload delivery.”

The work reported here is built on advances around the world in nanotechnology and synthetic biology. What is new is the way the Wyss team combined several of these advances for the first time. For example, the release mechanism used here responds to the presence of a protein, not just to the presence of DNA or RNA. That feature alone makes this work more immediately applicable for medical purposes.

Put together, these two reports are part of a far wider panorama of basic advances in biomedical research. They stand out in part because of what they promise in terms of future treatment strategies. But more than that, they catch our attention because advances like these continue to blur the lines between ourselves and our technology.

In the first case—a wireless implanted drug-delivering chip—we are not simply injecting a medication or implanting a device. The patients in this study are hosts to a high-tech subsystem implanted within them that interacts in sophisticated ways with another human being (their physician). What’s more, that other human being—even if half a world a way attending a medical conference—can send instructions that immediately cause an effect within the body (but perhaps without the knowledge) of the patient. Surely there’s a spy story here just waiting to be written. More than that, this seems to be another significant milestone on the way to the (post?-) human future.

In the second case (the DNA nanoscale robot), nothing is yet implanted, but that’s clearly a next step. What are we to make of this elegant piece of tiny engineering? It is so small that it can only be made using computers. It is built from the same sort of DNA that we have in every cell, but it's engineered to hold a desired shape and to respond to a specific signal. Then, if inserted in great numbers into the human body, it can emulate the human immune system but take it in directions far beyond evolution.

The report on the implantable chip is entitled "First-in-Human Testing of a Wirelessly Controlled Drug Delivery Microchip" and appears in the February 16 issue of Science Translational Medicine. The report on DNA robots, "A Logic-Gated Nanorobot for Targeted Transport of Molecular Payloads," appears in the February 17 issue of the journal Science. Both journals are publications of the American Association for the Advancement of Science.