UCSF scientists Sonja Schrepfer and Tobias Deuse have used the CRISPR-Cas9 gene-editing system to create the first pluripotent stem cells that are functionally “invisible” to the immune system.
Two amazing fields of study in medicine and biology are gene editing and stem cell therapy. Now those two areas have converged in a way that promises to provide a miraculous tool chest for pain management physicians.
The recent growth of gene editing technology
The organizational plan for all multi-celled organisms is the iconic double helix of DNA (deoxyribonucleic acid). A DNA molecule looks like a pair of ladders twisted around each other. A human DNA molecule contains about 20,500 genes. Together, all those genes comprise an “assembly and instruction book” that controls the development and function of every human being.
What is gene editing?
Our understanding of the human genome has dramatically increased over the last few decades. Our ability to alter human genes is accelerating at an ever-increasing pace.
- In 1987, Japanese researchers discovered some quirky repeating sequences in the DNA of E. coli bacteria. These patterns were labeled Clustered Regularly Interspaced Short Palindromic Repeats, which led to the acronym CRISPR.
- In 2007 it was discovered that CRISPRs are part of a bacteria’s immune system. They enable the bacteria to fend off invading viruses by directing warrior enzymes (called Cas9) to track down an invading virus and identify it as an alien threat. The Cas9 enzymes then eliminate the threatening virus by literally chopping up its DNA.
- In 2013, scientists learned to use Cas9 enzymes to slice and resection the DNA of mice.
- Since 2013, researchers have learned to use the burgeoning CRISPR Cas9 gene editing technology to remove potentially harmful genes from human cells. The new technology enables a Cas9 enzyme to remove a gene that could eventually cause a fatal disease, and then insert a beneficial gene in the place of the harmful gene.
The only appropriate response to these apparent miracles is: WOW!!!
The parallel recent growth of stem cell therapy
Our burgeoning ability to design our own genes is amazing. But the continuing stream of breakthroughs in stem cell therapy is equally impressive.
What is a stem cell?
Stem cells are the original raw material from which all our bodily components are constructed. Pluripotent stem cells exist in a primitive and pure state. They have yet to differentiate into the specialized cells which make up our bodies’ various organs and structures. They are dazzlingly versatile.
The early research into stem cells was performed on material derived from human embryos. This meant that moral and ethical considerations were barriers to stem cell research.
However, in 2007, the now famous “Yamanaka experiment” provided a pathway to creation of pluripotent stem cells. Researchers learned to reprogram adult somatic cells back into their original pure and primitive pluripotent condition. These newly available pluripotent cells were named “induced pluripotent stem cells” (iPSC). Reliance on human embryos stopped and the tempestuous ethical and moral debates were immediately rendered obsolete.
The iPSC breakthrough came at a time when the awesome potential of pluripotent stem cells in regenerative and pain management medicine was just beginning to be glimpsed.
Stem cell therapy offers potentially effective resolutions of pain caused by a host of pain sources. This includes bone and cartilage injuries, rheumatoid arthritis, and osteoarthritis.
iPSC cells naturally home in on the site of damage or disease. They then effectively work to restore the affected structures. As one example, an iPSC clinical trial is underway in Japan for the treatment of age-related macular degeneration.
A feature of iPSC cells is the fact they can be produced autologously, i.e., from the patient’s own cells
Early on, this was thought to be a benefit. If autologous reprogrammed iPSCs were replanted back into the same patient who donated them, the thinking went, the body’s immune system would identify the new cells as friends, rather than foes. This should prevent the immune system from attacking and destroying the new cells.
However, the practical use of iPSC’s in the clinical setting has not gone as smoothly as was hoped. Many patients’ cells reject reprogramming. Further, it’s very expensive and time-consuming to produce iPSCs for every potential patient.
A new study converges gene editing with stem cell therapy
Tobias Deuse is the holder of an endowed chair in cardiac surgery at the University of California San Francisco. He’s the lead author of a new study published on February 18, 2019 in the journal Nature Biotechnology.
“There are many issues with iPSC technology, but the biggest hurdles are quality control and reproducibility. We don’t know what makes some cells amenable to reprogramming, but most scientists agree it can’t yet be reliably done. Most approaches to individualized iPSC therapies have been abandoned because of this,” Deuse said.
Deuse and his co-author, Sonja Schrepfer, MD, PhD, sought to circumvent these challenges by creating “universal” iPSCs that can work for any patient.
Two genes, called MHC genes, sit on the surface of most cells. These MHC genes display signals that help the immune system identify alien cells. Cells that don’t have MHC genes don’t emit those signals, so they don’t alert the immune system.
What are natural killer cells?
However, in a plot that’s beginning to resemble a Tarantino movie, cells that are missing MHC proteins become targets of a different class of immune cells, known as natural killer cells. (We’re really not making this up.)
Schrepfer and Deuse enlisted Lewis Lanier, Phd, chair of UCSF’s Department of Microbiology and Immunology. He’s an expert on how natural killer cells become activated. Together, the researchers discovered that a cell protein (CD47) that sends out a “leave me alone” signal to ward off attacking immune cells seems to also tame natural killer cells.
So the team loaded CD47 proteins into iPSC cells from which the MHC proteins had been removed. These newly designed “stealth stem cells” were then implanted into mice with fully functioning immune systems.
They observed no rejection. In fact, when iPSC stealth stem cells reprogrammed to function as cardiac cells were introduced into mice, they not only survived, they began to form heart and blood vessel tissue.
This convergence of gene editing technology with stem cell technology is astounding. All these near miraculous research results mean that, in the not too distant future, pain management physicians will have weapons in their armory that will rival the Avengers’.
Why Nuvo Spine and Sports is your best choice for pain management
We approach our work armed with tried and true medical techniques and state-of-the-art regenerative strategies bred from sports medicine and the neurological sciences.
The Nuvo team of medical professionals is solely dedicated to minimizing or eradicating pain by resolving the underlying conditions that cause the pain. We are proud that we consistently achieve that goal and successfully enhance our patients’ overall quality of life.
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Read the full article at: www.ucsf.edu
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