Growing human retinas in vitro, patching damaged brains, and imaging an entire brain's activity.

26 June 2014

In the journal Nature earlier this month a paper was published by one Dr. Valeria Canto-Soler who works in the field of regenerative medicine at the Wilmer Eye Institute of Johns-Hopkins University. Medical science has gotten pretty good at creating induced pluripotent stem cells, or stem cells which started out as other kinds of human body cells that were hacked to devolve back into pluripotent stem cells which can then be caused to differentiate into other, more specialized kinds of cells. Dr. Canto-Soler and her research team have taken this process to the next logical step: Causing those cultured stem cells to organize themselves into a functional organ, in this case a retina. The stem cells were redifferentiated into retinal progenitor cells which then further transformed into the various sorts of cells that make up a retina, spontaneously arranging themselves in the process. The cultured structure matches the structure of 'natural' retinas, including the seven major types of cells (one of which is actually a family of six different kinds of neurons) which are arranged into multiple interconnected layers. The cultured proto-retina not only has the same general structure and organization as a human retina but even evidences the appropriate behaviors. When the cultured retina reached a developmental stage roughly matching that of a 28 week old embryo it was instrumented with electrodes and deliberately illuminated; the cultured retina showed the bioelectrical activity which one would expect in a human eye. While implanting cultured retinas are still a ways off (we can't yet reliably splice neurons) we now have a working model which can be used to study different diseases of the eye as well as test treatments for them.

For many years it was believed that if the brain was damaged, that was it. Scar tissue might form but neurons were thought not to regenerate. More recently we've learned that this isn't actually the case. Damaged neural networks in the brain and spinal cord are capable of healing, albeit very slowly. Rachel Okolicsanyi of the Institute of Health and Biomedical Innovation at the Queensland Institute of Technology (whew!) is working on manipulating stem cells extracted from bone marrow so that they turn into neural progenitor cells, plug into the damaged neural networks, and differentiate into the appropriate neurons to restore normal functioning. As it turns out, the outer membranes of human cells are coated with patterns of variants of proteins called heparan sulfate proteoglycans which seem to act as chemical receptors that control the inner mechanisms of the cells. Her research involves figuring out what patterns of chemical stimuli are appropriate to get those stem cells to eventually transform into neurons. It's probably going to take a while but I think a lot of useful data is going to come from her experiments; if she accidentally creates cartilage cells, for example, medical science will have a better idea of how to grow cartilage from stem cells on demand. There's a high potential for fringe benefits here. I don't know where her work is at right now, but I'm going to be keeping a sensor net peeled for her work.

In nature there is a species of nematode with the scientific moniker of caenorhabditis elegans which has some interesting qualities that make it ideal for scientific study. It's a relatively complex organism with a fairly simple genetic structure comprised of about 97k 100 million base pairs that has been completely sequenced. They're easy to breed in the lab and have a fairly short life cycle, so there's no shortage of test subjects. They are also surprisingly consistent from specimen to specimen on a cellular level. Every male c.elegans has exactly 1031 cells and every hermaphroditic c.elegans (there don't seem to be purely female versions) has exactly 959 cells. Both have exactly 302 neurons arranged in a simple nervous system consisting of approximately 8000 synaptic connections. All of these things sound like trivia but they also made c.elegans one of the best studied organisms in history. When you combine these things with recent advances in biotech, some very interesting things come about... there is a biomedical technique called optogenetics which involves using genetic modification methods to make certain kinds of cells (usually neurons) sensitive to different frequencies of light; shine a light on them and they fire. Recently a scientific team at Research Institute of Molecular Pathology in Vienna, Austria published a paper which describes how they monitored all of the chemoelectrical activity of c.elegans in one shot, a heretofore unaccomplished feat in medical science. First, a group of c.elegans were bioengineered so that only the nuclei of their neurons would emit light when stimulated with laser light instead of the whole cell (which would make it difficult to see exactly what's going on inside them). A new optical technique called light sculpting had to be created to illuminate the nematode's entire neural network simultaneously to capture a nearly complete picture of the activity 80 times per second. They were able to image about 70% of the total activity of the nematodes' brains with each sample taken, something that has not been done before. The team's imaging equipment can go up to 200 frames per second, which will give a much more finely grained image of what's going on inside the diminutive critter.

Where to go from here? C.elegans is the testbed for this particular imaging technique. Once it's worked out, it seems reasonable to say that it could be applied to successively more complex organisms, gathering data each step of the way, until it can be applied to the most complex organism that we know of at this time - the human race.