Replenishing the Brain

An intrinsic mechanism of corticogenesis from embryonic stem cells
http://www.ncbi.nlm.nih.gov/pubmed/18716623

Rating: Thought-Provoking

Article Summary:
The Hypothesis
The brain is an extraordinarily complex organ, and the portion of it we refer to as the cortex - the most recent portion, evolutionarily speaking - is the most complex. When you think of a stereotypical image of 'the brain', that's predominantly the cortex that you're picturing. It is generally thought that the highest level brain functions and calculations occur there. Like the rest of the nervous system, the primary type of cell used to send, receive, and process information of all sorts is the neuron, and the cortex contains many different varieties. We are only beginning to scratch the surface when it comes to understanding the differences, from the perspective of the calculations they perform, to the partners (other neurons) that they interact with, to how they are born and develop. Many terrible neuro-degenerative diseases lead to irreversible death of neurons; most neurons in the brain cannot regrow (note: the list of exceptions is growing). Parkinson's and Alzheimer's are two examples of such diseases. As such there is an abiding interest in the neuroscience community to discover ways that we might be able to replace lost neurons. One way might be through the use of stem cells - those amazing little cells that have the capacity to become any cell in the body if given the correct instructions. The researchers behind today's study successfully program mouse stem cells to become neurons, and can also successfully integrate them into the brain with almost no further manipulation. Although this field is still very young, it yields promise that we might one day be able to replenish damaged brains. That certainly leads us to some interesting questions concerning possible changes to perception, memory, and identity - but read on, we'll come to those issues later.

The Setup
As mentioned, the cortex is a vast and complicated region of the brain. Different neurons residing in the cortex 'project' (connect) to many different regions of the nervous system; all of them, in fact. The cortex exerts control over most concious thought and action, and even some involuntary functions as well. Within the cortex, neurons reside in different layers - there are six layers altogether - and their functions and connections to other neurons are mainly determined by their layer. The cortex itself is lossely divided into different regions representing different functions, such as movement control and visual processing. Information such as sights, sounds, and smells comes into the first three layers of the cortex (1 - 3), and any resulting changes or interpretations - 'processing' - of those inputs are sent out from the last three layers (4 - 6) although layer 3 also sends significant output. The better understood neurons in the cortex are the 'projection' neurons, which send and receive information via long arms called axons and dendrites, respectively for their functions. These are the wires of the nervous system. In the visual cortex, one of the better understood regions, calculations are performed in vertical columns as information flows up from layer 1 to 6. Raw information comes up from 'lower' brain regions, is processed in columns, and passed on for further processing in other columns - and finally is 'perceived'. The current study is not so concerned with the functions of the cortical areas, although eventually the researchers will have to show functional integration of their stem cell derived neurons. For now however, it is concerned with the typical placement of neurons in layers and regions, and with the connections of the those neurons to 'lower' brain regions, and other cortical areas. I hope I've provided enough information to show you that the cortex has a complex but in many ways predictable architecture, and this can be exploited for the purposes of studying integration of new neurons.

The experiment presented in this article is quite simple, yet elegant. The researchers exploited the fact that when grown in the absence of any other cues, stem cells form primitive neurons, often called precursors or progenitors. So they obtained mouse stem cells, and raised them in petri dishes under very minimal conditions. The researchers also took this one step further, and provided a chemical that inhibits the action of a protein called Sonic Hedgehog (no, I'm not joking). Sonic Hedgehog is a protein released by neurons that causes them to develop away from the type of cortical projection neurons I was discussing above, and instead become interneurons (another variety of neuron). Inhibiting its activity allowed the researchers to produce very nice projection neurons of different types. The type produced was dependent upon the amount of time that the stem cells were allowed to grow in their petri dishes. The longer the cells grew, the higher layer neurons they came to resemble; so after 10 days, the new neurons resembled layer 1 neurons. After 17 days, they resembled layer 3 neurons or above. These results are based on different proteins found in the neurons from different layers.

Then came the real test. The researchers surgically grafted their stem cell-derived neurons into normal adult mouse brains, in the frontal area of the cortex. They had engineered a protein that glows green into the new neurons to identify them as distinct from the original neurons. After a month, the researchers examined the results of the graft. Impressively, the new neurons appeared to have integrated fully into the mouse brains. They were arrayed as expected in layers, and also exhibited the expected pattern of axons and dendrites. There was one very unexpected aspect of their integration, however. Almost to a cell, the new neurons had all formed connections with brain regions involved in vision and image processing. This was in spite of the fact that they had been originally grafted into the frontal cortex, an area that is not associated with vision. They did not form connections with other brain regions. This demonstrates that specific types of projection neurons can be created from stem cells and properly integrated back into the brain at first glance.

What does the pithy scientist think?
Disclaimer: what follows is merely opinion, possibly speculation, and occasionally hearsay. But it's the best part, darn it!

I find this paper to be quite provocative, and it certainly sets the ball rolling for further investigation. Let's hit our pros and cons:

Let's review the points that support the hypothesis that stem cells can be instructed to produce neurons that can successfully integrate back into the adult brain:

1. Stem cells can easily be instructed to form cortical projection neurons.
2. These neurons contain the expected proteins that define different type of cortical projection neurons.
3. When Introduced into adult brains, these new neurons are appropriately located and oriented, assessed visually.
   

What are some shortcomings of the paper?

1. There is no evidence that the new neurons, observed visually, actually function as expected in the appropriate brain circuits.
2. There is no evidence that the new neurons could help an injured mouse recover lost brain function.
3. It is not clear we can create anything other than projectiong neurons geared toward the visual system, although if I had to guess I'd say it probably would be possible.
   

What further experiments should be done?

1. The researchers need to find mice with damage to their visual cortex, and see if grafting in these neurons can recover lost visual function.
2. We need to discover if other growth conditions can lead to the development of other types of cortical neurons (auditory, motion control, and so on).
3. I would be interested to know if the researchers can develop sub-cortical neurons, from the so-called 'lower' brain regions, in a bid to address damage to the spinal cord.

Replenishing neurons in the brain that have been lost to damage or disease is a fantastic idea, but is not without its share of ethical implications. Obviously it will take a lot of study to show that stem cell grafts do not cause any adverse pathological effects, such as cancer or epilepsy. But beyond the obvious health concerns, come the interesting issues of how much the different neurons in our brains define who we are. A heart, a kidney, a ligament - these are, as we understand them, just machines that allow our bodies to survive. Our brains are a different matter altogether. Even the seemingly unobtrusive idea of replacing lost neurons within the motion and motor function circuitry might alter not only our ability but our preference for different motions. Replenshing dopamine neurons lost to Parkinson's might dramatically affect our sense of reward, success, and satisfaction. This is to say nothing of restoring neurons to areas of the brain associated with memory or personality. I do not possess any great insight into the approach to these ethical dilemnas, other than to repeat the age old mantra that only fools rush in. We must take our time and fully understand the consequences of how these potential treatments might affect our humanity before jumping blithely in.