Mini brain grown from body cells can now play Pong

To grow, the embryonic brain does not need a building plan; it organizes itself. In 2013, scientists managed to mimic the first few weeks of that process in the lab. Their research shows how body cells in a dish can grow into a brain-like organ.

To grow a mini-brain, proceed as follows. Take a few body cells, for example from the skin, a bioreactor, nutrients and a special support gel. First you make the cells think they are embryonic stem cells, which are cells that can still specialize into a certain type of cell, including nerve cells for example. You do this by activating a specific piece of DNA from these cells. Then you administer growth factors (for example, certain proteins) that promote the development of brain tissue. And voilá: the cells specialize into neuroectoderm tissue that, in an embryo, eventually grows and develops into the central nervous system.

Magnifying glass

The next step is to use the support gel to help the ectoderm develop into a spatial structure. Run the whole thing in the bioreactor for a while and after about a month, a tiny brain will have formed. You do need a magnifying glass to see the result clearly, because it doesn't get any bigger than 2 to 3 millimeters.

The research team from Austria and the United Kingdom used proteins with fluorescent properties to make visible which cell types had formed where. However minuscule; the mini-brain had already begun to form individual brain regions such as the cortex, something akin to a hippocampus and, in some cases, retinal tissue. In addition, the cortex also already showed initial differentiation into layers, and the beginnings of the formation of the various lobes could be seen.

The brain organization also showed some typical human traits such as the relatively strong development of cortex tissue, and these brains made in glass even appeared to function. At least, the researchers saw that the neurons sent electrical currents through their axons that allowed them to communicate with their neighbors.

Pong

That was the state of affairs in 2013. In late 2022, a major step forward was made in the world of neurons on petri dishes. Scientists in Australia managed to get a mini-brain consisting of cortical mouse embryo cells to play Pong. For those unfamiliar with the game, it's similar to Pingpong; you control a "paddle" (a rectangle) to rebound a virtual ball against a wall. When you miss the bouncing ball, you are finished.

The mini-brain in this experiment consisted of 800,000 cells whose activity could be regulated and measured via electrodes. One part of the neurons was the sensory region, which received the location of the ball and bat. The other part represented the motor region, which could provide output to control the bat. It was a closed-loop system, giving the system instant feedback on whether it was doing it right or wrong. Every time the mini-brain missed the ball, it received random electrical signals. This was interpreted as a kind of punishment by this artificial brain. After all, it doesn't like getting unpredictable input. When it managed to hit the little ball, it received predictable input (all sensory electrodes were activated at the same time), which was interpreted as a reward. Within 5 minutes, the mini-brain had figured out the purpose of the game.

Just for nuance, The group of neurons did not play pong at top level, but rather above chance level. However, this does mark the first time cells in a petri dish have accomplished goal-directed tasks. Because this was thought impossible until recently, it has led to much debate in science. Does this group of neurons now have a form of consciousness? What ethical implications would that have? And could this way of learning have implications for artificial intelligence? Scientists and ethicists haven't decided yet. We're curious what you think!

Authors: Daan Schetselaar, Pauline Gils & Joyce Burger

Image and Text Reference:

Kagan, Brett J. et al. 2022. In vitro neurons learn and exhibit sentience when embodied in a simulated game-world. Neuron, Volume 110, Issue 23, 3952 - 3969.e8

To fast or not to fast

What is intermittent fasting?
Fasting has been part of human history for millennia. During our hunter-gatherer ages, we would run into times where food was scarce, we then had to fast till the next successful hunt. Later, fasting became a religious activity, to cleanse the body or increase sobriety. Since the 1800s fasting has been rediscovered to treat a variety of ailments. Nowadays fasting is often used to lose weight quickly. Intermittent fasting is an umbrella term for a group of fasting methods, to give some examples: Time-restricted feeding (TRF) is a fasting method where we go without caloric intake for 12 to 20 hours per day. Other methods are related to reducing caloric intake to a level between 0-25% for consecutive days, for example 5 days of fasting and 2 days of non-fasting (periodic fasting), or to fasting on alternating days (alternating day fasting).

Studying the effects of fasting
That intermittent fasting (IF) is such a broad concept also makes it difficult to study. Benefits of the different methods may depend on very specific parameters such as duration of the fasting period, amount of restriction etc. Most of our knowledge about intermittent fasting is translated from animal studies. Early studies indicated that the life span of rats could be prolonged by up to 80% when the right caloric restriction (CR) was applied. However, more recent analyses that looked at many CR studies showed that lifespan prolongation might be between 14-45% in rats. However, to what extent this can be translated to humans remains unclear, as even within mice the lifespan prolongation is significantly smaller at 4-27%. Furthermore, animal models indicate that intermittent fasting upregulates a protein called brain-derived neurotrophic factor (BDNF), which is important for neuronal survival and growth.

While data in humans is lacking, there are some findings that showcase benefits of intermittent fasting. Intermittent fasting might be beneficial over caloric restriction, as it yields more benefits for insulin sensitivity. Furthermore, while effects are small to mixed in healthy participants, there might be a bigger benefit in people who are developing neurological disorders. Mild cognitive impairment (MCI) is the stage in between the impairment of a neurological disorder such as dementia and the expected decline from healthy aging. A study in people with MCI revealed that intermittent fasting can lead to broad improvements in metabolism which might modulate cognitive improvements, as the group which underwent IF showed.

While it’s hard to reveal the mechanisms of each different form of intermittent fasting, there is one overlapping mechanism. The mechanism that triggers while practicing intermittent fasting is a switch in metabolism. Where the body normally extracts its energy from glycogen into glucose, it will now gain energy from stored fat.

Author's note
I was quite skeptical about intermittent fasting before diving into the topic again. I think that people making strong claims without scientific evidence made me more pessimistic about it than I should be, because it seemed too good to be true. Overall, I think it’s a field where further research needs to be done to get a better understanding, at the moment there is too much still unknown. However, the effects in animal studies and the promising findings of human studies are exciting. Who knows, I might even try fasting sometime.

Author: Kobus Lampe

References

Duregon, E., Pomatto-Watson, L. C., Bernier, M., Price, N. L., & de Cabo, R. (2021). Intermittent fasting: from calories to time restriction. Geroscience, 43(3), 1083-1092.
The article by Gudden et al. (2021) is interesting as it reveals benefits of intermittent fasting in different target groups (such as neurological disorders).
Gudden, J., Arias Vasquez, A., & Bloemendaal, M. (2021). The effects of intermittent fasting on brain and cognitive function. Nutrients, 13(9), 3166.
Harding, S. (2021). Intermittent Fasting: Clinical Considerations. The Journal for Nurse Practitioners, 17(5), 545-548.
Ooi, T. C., Meramat, A., Rajab, N. F., Shahar, S., Ismail, I. S., Azam, A. A., & Sharif, R. (2020). Intermittent fasting enhanced the cognitive function in older adults with mild cognitive impairment by inducing biochemical and metabolic changes: a 3-year progressive study. Nutrients, 12(9), 2644.
Seidler, K., & Barrow, M. (2022). Intermittent fasting and cognitive performance–Targeting BDNF as potential strategy to optimise brain health. Frontiers in Neuroendocrinology, 65, 100971.
Xu, S., Jiang, Y., Zhang, Y., Xu, W., Zhang, H., Yan, Q., ... & Shang, L. (2022). Dietary recommendations for fasting days in an alternate-day intermittent fasting pattern: a randomized controlled trial. Nutrition, 111735.