“Jo sovat hai so paavat hai”

Those were the days when the brain would imagine a lot. All we had for input was the voices of the likes of Sushil Doshi and Narottam Puri to help us visualise how the events during a cricket match were unfolding at Wankhede Stadium or Feroz Shah Kotla. The gap in input and reality was not just due to limited engagement of sensory devices. We would also have to imagine what was happening during the time we were inside classrooms. Recesses were the only times when we would rush to the houses near our school to catch up on running commentary. To watch a match live was a luxury we could not even afford to imagine. And here I was watching a cricket match between India and West Indies sitting on a stand at a “khachakhach bhara” stadium. B.S. Chandrasekhar had just hit Andy Roberts for a boundary. A text book straight drive. Yes, Chandrasekhar! As I raised my hands to applaud, I felt the seat has become unstable and I was about to fall. Coming to my senses, I saw that I was sitting on the sewing machine cover in the middle of night. How I sleepwalked from bed to that point, I had no idea.

Such incidents of acting out dreams, while in the middle of REM sleep, arise because of partial failure of the brain to paralyse the body. But why do we dream in the first place?

Although the realms of sleep and dreams are active research areas, we know that during sleep time, the brain flushes off toxic substances. It also consolidates our learnings that happen via processing of sensory inputs during the day. More importantly, it clears the synaptic connections to make room for the next day’s learning.

Dreams are much harder to account for. There are a few initial hypotheses of which one appeals to me. The one by Erik Hoel.

A common thing about dreams is that they are weird. Some are more weird, even horrifying, than the cricket match dream I had. Hoel finds value in this weirdness. Let me see if I can explain in simple terms.

Stereotyping sucks. We hate it when people overemphasise our one trait/behaviour ignoring many others. Technology in the form of social media takes it to another level. The algorithmic intelligence as it stands now presents you with more of what you are consuming. It takes you down the specialisation route and, if you don’t control it, could potentially turn you into an extremist. There is a hidden assumption there that you want to only consume things similar to what you are consuming now. Imagine if nature behaved in a similar way. Let’s suppose that you encountered a dead bird on your morning walk and stood there for a while trying to figure out what might have happened. The next day you see three dead birds. Ten the following day. And so on. Do you see the problem? The world of Artificial Intelligence has this problem of overfitting to a specific dataset which hinders new learnings. We won’t be learning anything new if our brain worked the same way as the current state of AI. This does not happen thanks to the weird dreams that we see, according to Hoel.

The dreams purposefully provide random weird inputs to the brain to prevent it from overgeneralising based on the immediate past inputs it has been fed with. And by doing so it allows us to keep learning from each new experience in life. True or not, I find this hypothesis intriguing.

Hoel, E. (2021). The overfitted brain: Dreams evolved to assist generalization. Patterns, 2(5), 100244.

Cancer has baffled mankind for a variety of reasons. It is a malady that arises from within – from inside our very own cells – and not from outside of the body, although onset of some cancer types, such as cervical cancer, is linked to viral infections. Unlike other diseases, which tend to stress cells and cause them to not function properly or even die, cancer causes cells to proliferate. Therapeutic strategies therefore target killing cells rather than saving them or repairing their functions. In the strictest sense, cancer has no cure. No one can guarantee that a cancer, once remitted via treatment, will not come back or will not have side effects. In spite of unprecedented money spent on cancer research, medical community is yet to come close to finding a cure. Continuing reliance on the age-old approach of “slash-poison-burn” for cancer treatment has frustrated the likes of Azra Raza who seek a shift in cancer research focus to detection of the first signs of cancer rather than finding a cure¹. Finding the root cause is the key to solving a problem. As far as cancer is concerned, we are definitely not there yet. But are we on the right track in the first place?

Veteran scientist Paul Davies and his team tried to look at the problem from a different perspective – as having an evolutionary root at “the dawn of multicellularity”. Stated simply, they posit a model wherein cancer is caused by reactivation of ancient ‘vestigial’ genes that promoted proliferation of cells more than 600 million years ago when early multicellular organisms existed as tumour-like colonies of cells². Multicellularity of the present kind where cell groups (tissues) are differentiated to perform specialized tasks had not evolved then. Their outside-the-box atavistic model points to an extremely deep trait of living beings of rising from the dead. I have witnessed such risings in the sprouts of eucalypts growing on trees decimated by the 2020 bushfires here in Australia. The strategy for cancer treatment, therefore, should target the conditions that trigger reactivation of these ancient genes, suggest Davies and colleagues³.

Eucalyptus sprouts on burnt tree

One such strategy is to expose the affected area with elevated oxygen levels. The idea stems from the fact that prior to extensive cell specialization, conditions on the earth were that of less oxygen. The cells used a different energy generation strategy then that relies on a mechanism called fermentation. The dominant energy generation mechanism in our cells uses oxygen to make more energy units via cellular respiration. Mind you, our cells also possess the provision of fermentation process. Cancer cells are known to downregulate cellular respiration in preference to this primitive mechanism of fermentation, a condition known to cancer specialists as Warburg effect. The idea of treatment with elevated oxygen levels is therefore an effort to eliminate the condition of less oxygen (hypoxia) in the vicinity of cancer cells which could have triggered reactivation of ancient gene and hence fermentation in these cells. The low oxygen environment of tumours is caused by high rate of proliferation of cancer cells which cannot have access to enough oxygen because of low rate of formation of new blood vessels for supply⁴.

Some researches ascribe the switch from cellular respiration to fermentation in cancer cells to malfunction in mitochondria, the organelle where respiration is carried out. The problem with such a conclusion is that Warburg effect is also detected in cancer cells with healthy mitochondria⁵. Mitochondrial functions, including energy generation, are now considered necessary for tumour formation and proliferation⁴. Not only that, some tumorigenic cells are found to depend on cellular respiration and, surprisingly, have defective fermentation line of energy generation⁶. Such cancer stem cells differ from other cancer cells in that they are also multidrug resistant.

Drug resistance is a major obstacle in cancer treatment and a cause of many cancer deaths. The most common cancer treatment of chemotherapy actually uses an inbuilt capacity of cells to self-destruct. The cell has a preprogrammed mechanism of demolishing itself without causing damage to adjacent cells. Programmed cell death occurs when mitochondria indicate to the cell that they are under environmental stress. Chemotherapy aims at signalling mitochondria to activate the death processes in cancer cells⁷. Such signalling works because cancer cells do not have their death machinery disabled. Cancer only causes cells to regulate some of their proteins that help with not initiating the death machinery and hence cancer cells continue to proliferate. In many cases, cancer cells gradually become resistant to chemotherapeutic agents during the course of treatment. Such resistance is allegedly caused by subdued response of mitochondria to the effects of agents⁸. What causes mitochondria to change their response is an intriguing unknown.

The pathways of fermentation and cellular respiration are connected in normal cells via an intermediate compound called pyruvate. Pyruvate forms outside of mitochondria from glucose and is carried inside mitochondria for further energy generation via respiration. Pyruvate is escorted into the mitochondria by a carrier complex. Intriguingly, in colorectal cancers, these carriers are found to be less in number. Thus the link between glucose metabolism outside of and inside mitochondria is broken in cancer. It has been further found that in such cases, fatty acid uptake from outside into mitochondria increases. Note that mitochondria can carry its functions via fatty acid metabolism in addition to pyruvate metabolism. With pyruvate pathway blocked because of loss of carriers, it relies for its functions on fatty acid pathway in cancers. This feature of break in pyruvate import into mitochondria is considered necessary and sufficient condition for cancer initiation⁹.

Normal (blue) and cancer (red) cell energy generation

Another feature of cancer that arouses curiosity is its uncanny resemblance to certain aspects of sex. One such aspect is that cancer cells frequently express genes that are normally exclusively expressed in testis¹⁰. Expression of such genes that are related to the sexual cell division (meiosis) and to germ cells in general has led to a notion that cancer development might represent transition from somatic to germline behaviour^{11, 12}.

During normal cell division (mitosis), there is an important stage called G1/S checkpoint where the key decision whether to proceed with cell division or not is made. The decision is made after taking stock of availability of nutrients and enzymes required for the process. This important checkpoint is inactivated in some special cases, such as in primordial germ cells in mice before sex determination¹³ and in induced pluripotent stem cell (iPSC)¹⁴. The checkpoint is also found to be inactive in a majority of cancer cases¹⁵. At this juncture, I remind myself of the role mitochondria play during G1/S checkpoint. A study has found that mitochondria form an unusually hyperpolarized giant tubular network at the G1-S transition¹⁶. This hints at mitochondria controlling G1/S checkpoint which has been found to be the case in the fly Drosophila¹⁷. What happens to mitochondria during this stage in cancer cells, I ask myself.

As with most cellular processes, mitochondria appear to be deeply involved in cancer too. Is the mitochondrial DNA (mtDNA) in cancer cells any different from normal cells? I searched and found that tumour cells usually have fewer mtDNA copies than normal cells¹⁸. Further, mtDNA fragments are found to be inserted into the nucleus in cancer cells during the lifetime of patients and this could have had causative influence in cancer development¹⁹. A rather interesting side note here is that in yeast such mitochondrial insertions have been found to promote replication of nuclear DNA²⁰. Also important in cancer development are mutations of mtDNA that exist in many cancers²¹, most notably in the control region of mtDNA but also of genes responsible for enzymes required for biosynthesis.

Meanwhile, support for the atavistic model of cancer is increasing by the day. Analysis of data from the Cancer Genome Atlas has shown that, in several cancer types, genes identified typically with unicellular organisms were upregulated and those belonging to multicellular organisms were inactivated²² indicating that cancer is driven by reactivation of ancient gene regulatory networks. Also supporting the atavistic model is a proposition that tumour growth represents an in-between mechanism of reproduction that utilises certain features of meiosis to reinstate tumour germline which manifests itself as altered chromosomes which is a hallmark of cancer²³.

What to make of all this? I cannot overlook the pointers which tell me that we need to continue to have a closer look at mitochondria and its DNA, more than that of the cell itself. Cancer defies cell’s preprogrammed limit of 40-60 replications (Hayflick limit) by manipulating the limit enforcing structure (telomere). The focus naturally is therefore on the cell’s DNA. One study²⁴ has even held random “bad luck” mutations of DNA mainly responsible for cancer over other factors such as environment and heredity. Such mutations, the study concludes, are caused by DNA replications and are responsible for variance of cancer risk among various organs. The root cause however must be a level deeper I believe. I think of my review article²⁵ which takes a holistic view of mutations of mtDNA at various levels of containment. Mitochondria maintains its health and keeps mtDNA mutations in check by a fusion-fission dynamism where it destroys mitochondrial fragments carrying more mutation via a process known as mitophagy. Does mitophagy have any bearing on cancer? There indeed is a connection. More on that later.

References:

1. Raza, A. (2019). The First Cell: And the Human Costs of Pursuing Cancer to the Last. Basic Books.
2. Davies PC, Lineweaver CH. Cancer tumors as Metazoa 1.0: tapping genes of ancient ancestors. Phys Biol. 2011 Feb;8(1):015001. doi: 10.1088/1478-3975/8/1/015001.
3. Lineweaver, C. H., Davies, P. C., & Vincent, M. D. (2014). Targeting cancer’s weaknesses (not its strengths): Therapeutic strategies suggested by the atavistic model.BioEssays, 36(9), 827-835.
4. DeBerardinis RJ, Chandel NS. Fundamentals of cancer metabolism. Sci Adv. 2016;2(5):e1600200.
5. Liberti MV, Locasale JW. The Warburg Effect: How Does it Benefit Cancer Cells? Trends Biochem Sci. 2016 Mar;41(3):211-218.
6. Viale, Corti and Draetta (2015) Tumors and mitochondrial respiration: a neglected connection. Cancer Research 75(18).
7. Sarosiek KA, Ni Chonghaile T, Letai A (2013) Mitochondria: gatekeepers of response to chemotherapy. Trends Cell Biol23:612-619
8. Coku, J., Booth, D. M., Skoda, J., Pedrotty, M. C., Vogel, J., Liu, K., … & Hogarty, M. D. (2022). Reduced ER-mitochondria connectivity promotes neuroblastoma multidrug resistance.The EMBO Journal, 41(8), e108272.
9. Bensard, C. L., Wisidagama, D. R., Olson, K. A., Berg, J. A., Krah, N. M., Schell, J. C., … & Rutter, J. (2020). Regulation of tumor initiation by the mitochondrial pyruvate carrier. Cell metabolism, 31(2), 284-300.
10. Bruggeman, J. W., Koster, J., Lodder, P., Repping, S., & Hamer, G. (2018). Massive expression of germ cell-specific genes is a hallmark of cancer and a potential target for novel treatment development. Oncogene, 37(42), 5694-5700.
11. Feichtinger, J., Larcombe, L., McFarlane, R.J. (2014) Meta-analysis of expression of l(3)mbt tumor-associated germline genes supports the model that a soma-to-germline transition is a hallmark of human cancers. International journal of cancer. 134(10):2359-65.
12. McFarlane, R. J., & Wakeman, J. A. (2017). Meiosis-like Functions in Oncogenesis: A New View of Cancer. Cancer research, 77(21), 5712-5716.
13. Bloom JC, Schimenti JC. Sexually dimorphic DNA damage responses and mutation avoidance in the mouse germline. Genes Dev. 2020 Dec 1;34(23-24):1637-1649. doi: 10.1101/gad.341602.120.
14. Araki, R., Hoki, Y., Suga, T. et al. Genetic aberrations in iPSCs are introduced by a transient G1/S cell cycle checkpoint deficiency. Nat Commun 11, 197 (2020).
15. Molinari M. Cell cycle checkpoints and their inactivation in human cancer. Cell Prolif. 2000 Oct;33(5):261-74.
16. Mitra K, Wunder C, Roysam B, Lin G, Lippincott-Schwartz J (2009) A hyperfused mitochondrial state achieved at G1-S regulates cyclin E buildup and entry into S phase. Proc Natl Acad Sci USA 106:11960-11965.
17. Mandal S, Guptan P, Owusu-Ansah E, Banerjee U (2005) Mitochondrial regulation of cell cycle progression during development as revealed by the tenured mutation in Drosophila. Dev Cell 9:843-854.
18. Reznik E, Miller ML, ?enbabao?lu Y, Riaz N, Sarungbam J, Tickoo SK, Al-Ahmadie HA, Lee W, Seshan VE, Hakimi AA, Sander C. Mitochondrial DNA copy number variation across human cancers. Elife. 2016 Feb 22;5:e10769.
19. Puertas, M. J., & Gonzalez-Sanchez, M. (2020). Insertions of mitochondrial DNA into the nucleus: effects and role in cell evolution. Genome, 63(8), 365-374.
20. Chatre, L., & Ricchetti, M. (2011). Nuclear mitochondrial DNA activates replication in Saccharomyces cerevisiae. PLoS One, 6(3), e17235.
21. Wallace, D. C. (2012). Mitochondria and cancer. Nature Reviews Cancer, 12(10), 685-698.
22. Trigos AS, Pearson RB, Papenfuss AT, Goode DL (2017) Altered interactions between unicellular and multicellular genes drive hallmarks of transformation in a diverse range of solid tumors. Proc Natl Acad Sci USA 114:6406-6411.
23. Salmina, K., Huna, A., Kalejs, M., Pjanova, D., Scherthan, H., Cragg, M. S., & Erenpreisa, J. (2019). The cancer aneuploidy paradox: In the light of evolution. Genes, 10(2), 83.
24. Tomasetti, C., & Vogelstein, B. (2015). Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science, 347(6217), 78-81.
25. Deonath, A. (2021). Evolution of eukaryotes as a story of survival and growth of mitochondrial DNA over two billion years. Biosystems, 206, 104426.

Our sense of sight mimics the mechanism of camera or maybe actually it’s the other way around. But that’s only half the story. Lights reflected by the dog’s face enter via lens and excite sensors at retina – the photographic film of the eye. That’s where the analogy ends I am afraid. The camera doesn’t interpret the image for us. We fall back on the eyes – rather the brain behind the eyes – for that, which is what you are doing right now if you are looking at the picture.

What is happening inside the brain is nothing short of miracle. Let alone the mechanisms we are yet to fathom, what we understand now is extremely complex processing. The retina map in the form of electrical signals are processed in many layers. The first layer deciphers the edges of the dog’s face and passes on that outcome to the next layer for a bit more detailed processing. And it goes on until we know it’s a dog’s face. But it needs to compare the outcome with something it knows. That aspect is taken care of thanks to our past experiences. We have seen many dogs before. This sums up how we experience seeing, most books say. The image analysis part of artificial intelligence is based on this processing. The ‘comparison with past experiences’ part is mimicked in deep learning. Recent success of AI then means that the above mechanism of ‘outside in’ processing really reflects how the conscious brain works. Right? Wrong – according to Anil Seth.

Seth in his book Being You says it all starts with our predictions based on our experiences. Sensory signals merely assist with error correction. In the end what we see is our best guess after all corrections. So it is ‘inside out’ processing and not ‘outside in’ that gives us our consciousness. The world our conscious mind sees is hallucination indeed, albeit a controlled one. That also explains why sometimes we only see what we want to see (the dog’s face in this picture for instance). The extra focus added by the camera kind of mimics the ‘precision weighting’ aspect of the brain’s mechanism.

I was watching a sixties movie last week. Halfway through the black-and-white classic I remembered having heard from my father’s mouth that this was an outstanding movie. I was surprised that I had that insignificant and meaningless (to me then) one sentence film review in my memory because I must have been under 10 then. The movie really was very well made. It wasn’t a popular movie then and isn’t remembered much now either. It suited my taste and style though. I asked myself if I had acquired that taste from my father. This could be my wishful thinking. Yet it always amazes me to think how that half set of genes of each of my parents eventually shaped me to this day. How this 60+ kilos of my body with all its fully functioning organs emerged from that single tiny cell formed about 38 weeks before my birth? Read on …

We are the “highest” species on the Earth, at least in our anthropocentric view. Would we continue to dominate in future? No, says the visionary James Lovelock. Who then is going to take over? When? Are we going to continue or become extinct? Read on… only 3 minutes long…