The concept that basic lab bench science produces discoveries that eventually lead to therapies is a touchstone of the research enterprise—and the principal was front and center in the opening “presidential” plenary session of the International Society for Stem Cell Research Wednesday afternoon.
Three of the four presenters relied in part on a subset of basic biology sometimes dubbed “reverse translation.” Just as translational research takes basic discoveries and gets them ready to be potential therapies, reverse translation kicks in when animal models or human patients don’t behave the way researchers hoped based on the basic biology. So, researchers must go back to the lab to try to figure out why.
In the past couple years many teams have gone back to the bench to figure out how to get pluripotent stem cells, whether embryonic or reprogrammed iPS cells, to become adult tissues that function like their normal counterparts. While this has become relatively routine for a few cell types (most notably heart muscle), others have been quite stubborn and resisted attempts to coax them into behaving like normal adults.
Researchers therefore have turned to a type of biology that was so new when I was an undergrad that when I decided to specialize in it, the only textbooks were compilations of scientific papers. That field, known as molecular developmental biology, seeks to understand all the genetic and molecular switches at work when a fertilized egg matures into an embryo and eventually develops into a newborn organism.
I have written about the field off and on for three decades. That may seem like a long time to answer some pretty fundamental questions, but there is nothing simple about how we are made. Now, with modern genetic tools and other, almost hocus pocus lab techniques, our mysteries our relenting at a much more rapid pace.
Olivier Pourquie of Harvard detailed his work trying to get pluripotent stem cells to become the type of cell needed to repair muscle in muscular dystrophy. When he started the project no one had shown an efficient way to get these cells. So, he tried to recapitulate what happens in the early stages of a developing embryo in a lab dish. He defined three specific steps in getting to the desired muscle precursor cells, found out what genes were turned on in those steps and then set about recreating those steps in the lab. He eventually got cells to become muscle fibers that seem to contract normally in the dish. He now has a pathway to creating cells for therapy.
Gordon Keller of the McEwen Centre for Regenerative Medicine at Canada’s University Health Network talked about one of the toughest nuts to crack in this field. There is a great need for a ready source of blood-forming stem cells to use in cancer therapy. Pluripotent stem cells seem like a natural source, but no one has been able to direct them to become fully mature blood-forming systems that engraft in the test animals. So, Keller resorted to what he called ‘developmental biology in a petri dish.’ He watched for the earliest stages of creating the blood-forming cells and clearly defined how to sort out two different early stage cells. He thinks he has isolated true blood-forming stem cells. They have been transplanted into mice that had their blood systems destroyed. As he said, those mice will let us know in a few months if he succeeded.
We certainly hope Keller did it. This has been such an intractable problem, CIRM held an international workshop on the topic and produced the paper Breaking the Bottleneck: Deriving Definitive Hematopoietic Stem Cells from Human Pluripotent Stem Cells.
The last speaker, Lorenz Studer of New York’s Memorial Sloan Kettering Cancer Center talked about going back to developmental biology to get sufficient numbers of dopamine producing nerves to work in a human-sized brain robbed of those cells by Parkinson’s disease. It had turned out to be much easer to get the number of nerves needed for a pea-brained mouse. He now has a protocol for efficiently generating dopamine-producing nerves and expects to begin a clinical trial in 2017.
I suspect reverse translation in the coming years will make good use of the developmental biology I studied so long ago resulting in many more therapies ready for testing in patients.