Cancer curiosities

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 behaviour11, 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.

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. 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. The future of cancer research certainly looks promising.

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, Şenbabaoğlu 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.

झूला

कह दो भला मुझसे क्यों इतने मौन हो तुम
सुकूं दे दो ये बताकर कि मेरे कौन हो तुम

लिखाते रहते हो मुझसे हमेशा बात अपनी ही
फिर क्यों माँग लेते हो कलम क्या द्रोण हो तुम?

दूर हो मगर ख़याल तो है मेरे डीएनए का
दहकता सूरज है ज़माना और ओज़ोन हो तुम

चक्रव्यूह सी दुनिया है, भँवर के बीच अभिजित
सरल रेखा सा मेरा जीवन जिसका कोण हो तुम

Sucking up to Lamarck

Do we really inherit acquired traits?

Parenting is full of paradoxical situations. There are times when you hate to see your kids doing things that you also do, or at least did, oftentimes. When it first dawned upon me that my child has developed a habit of sucking her lower lip, I couldn’t decide if I should be concerned or happy. I was aware that my dental structure was ruined because of that very habit during my childhood. I have always been casual about looks, but the habit also affected my jaw function in the long run. Now, like most parents, I do not want my child to repeat my mistakes.

Lamarckian inheritance of acquired characteristics
Photo by Isaac Quesada on?Unsplash

The sort of “happy” side to it was that I saw in this a potential living proof of Lamarck’s theory of evolution. The theory roughly goes like this: an individual acquires some traits during its lifetime and thus adapts to changes in environment; the traits then get passed on to the next generation and become evolutionary changes. Giraffes evolving longer necks and front legs is often cited in books as a likely example of Lamarckism. In my case the lip-sucking habit was acquired purely by my actions in my lifetime. I didn’t inherit it from my parents. No big deal, one might say, many babies suck lower lip. True, some babies do this as a natural reflex of sucking nipple for feeding. However, seldom do babies continue with this habit for months. I was doing that even after I started earning. My daughter at least stopped the habit when she had braces.

Proposed at the beginning of the nineteenth century, Lamarck’s theory has been out of favour for over a century now. Another theory, one by Weismann which caught the fancy of scientific world, killed it. Almost. Let me explain.

Let’s start with the development of an embryo inside mother’s body. Very early during the process, a specialised group of cells of the foetus is kept aside safely to be used later exclusively for sexual fusion after puberty. These forbidden cells are known as germ cells. All other bodily cells (jargon: somatic cells) eventually develop into organs which perform day-to-day activities. As far as exchange of genetic material is concerned, these two types of cells don’t talk to each other. Weismann argues that ongoing life characteristics can at best affect the somatic cells which are involved in the activities. Such changes cannot be transferred to the germ cells. And unless the changes affect the germ cells they cannot be passed on through heredity. This is called Weismann barrier which, most scientists agree, forbids inheritance of acquired characteristics. Lamarck therefore failed to become a legendary figure of evolutionary biology.

The new millennium however saw reemergence of Lamarck’s ideas. Certain acquired characteristics of brain were found to be inherited in rodents (Singer, 2009). The mechanism of transfer of such traits does not involve genome. Rather it’s attributed to things that affect how genes of the DNA are expressed for protein making (jargon: epigenetics). The “things” are chemical molecules acting like tags that tell a gene to be active or inactive. Even though the recipe for a particular protein is written in a gene, whether it will be made or not is determined by such tags. The tags are modified throughout the lifetime as the environment we live in changes. Note that the genome doesn’t change. In that sense it does not break the Weismann barrier. Yet the net effect is one of transfer of acquired traits.

When male and female germ cells fuse after mating to create the new fused cell (jargon: zygote), it was believed that the new formed DNA does not inherit the epigenetic tags. They are meant to be erased to provide the new cell with an “epigenetic blank slate”. It has been discovered recently that the erasure of tags is not complete. Some tags indeed pass through from parent cells to the next generation. Thus two generations are exposed to an environmental change such as smoking, and three generations in case of direct exposure of a pregnant mother. This is because a developing foetus has germ cells ready for contributing to the next generation. So before your baby comes out of your body, the seeds of your grandchild are already there.

Weismann barrier is thus no longer a valid objection to Lamarckian inheritance. There is another problem with Weismann’s theory which stems from lack of clear distinction between germ cells and somatic cells during embryo development. In fact the zygote initially divides into many cells which at that phase are like somatic cells, some of which go on to become germ cells for the next generation. Thus germ cells have a brief period of “somatic” life before they are assigned their role.

With the Weismann barrier gone and evidences of transgenerational epigenetic inheritance emerging, acceptance of Lamarckism is definitely on the rise. That may not necessarily mean however that I have passed on my lip sucking habit to my daughter. Though tempting to the scientist in me, until someone clearly explains the mechanism from end to end as a case study, I am not pleading guilty.

References:

Koonin, EV. (2014) Calorie restriction ? Lamarck. Cell 158, 237-238.

Singer, Emily (2009) A comeback for Lamarckian evolution. MIT Technology Review. https://www.technologyreview.com/2009/02/04/216134/a-comeback-for-lamarckian-evolution/amp/

Believing is seeing

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.

Just another plant

It was just a weed. For this to lead to a serious ethical dilemma was the last thing I expected. But it did. Our thought process indeed knows no bounds.
It was a sunny Sunday after a rainy Saturday. I was pulling out weeds from my garden. The moist soil made the job easier. While pulling one tiny plant thinly spread over the pebbles I paused and thought of the effort and energy the plant had spent growing that far. And here I was nullifying all that expense in a snap by uprooting it. It’s a “weed” for me. For nature, it’s just another plant. It started its life like any other living creature. Its cells must have multiplied everyday and worked hard on the environment gathering nutrients and fixing carbon. So why did I single out that plant? Because it’s ruining the appearance of my garden. I wouldn’t be bothered about thinking beyond that. Until that time.
“We should have goats. I would rather this weed become part of food chain than throw it away.” I told my daughter who was weeding another section of the garden.
“Goats are good,” she said. “They feed on pretty much anything and grow. A self-sustaining organic mower.”
“And then they give milk which you could drink.”
“Umm… I don’t like goat milk. It tastes weird.”
“It’s an acquired taste. Nutrient-wise the milk is very good.”
“But it has to give birth to be able to produce milk. Have you thought about that? Which means you need to also keep male goats.”
“Not necessarily,” it was my wife who until then was quietly listening to us while sowing seeds in a fresh veggie patch. “You could take it to a goat farm.”
I added, “Also, there must be facilities these days for artificial insemination I am sure. But of course we need to think from end to end before taking any step.”
I noticed that my daughter was unusually quiet. I asked, “What happened?”
“I don’t like this idea of producing babies that will be ultimately killed for the sake of us having milk.”
“But we do drink milk…”
“Yeah I know…”
“Then isn’t it like turning a blind eye to a problem and pretending it doesn’t exist? It’s like the milk comes from fridge or at best from supermarket and I don’t want to know anything beyond that. Or even if I know I don’t care.”
“Yes I know. Perhaps it’s best to be as sustainable as we could.”
“And what about this weed?” I was hell bent on dragging the discussion back to weeds. “Just because this poor creature does not have a central nervous system to feel the pain, we can do anything with it?”
“Well we can put this in compost. That way there is reuse of resources.”
The argument ended there. But not the one brewing inside my mind. It’s not just the patch of land I own. We have changed the entire land habitat of the world in a big way.
We control lives of not only domesticated plants and animals but also wildlife. We decide which species should thrive alongside us. Artificial selection by us is rivalling natural selection at least in the ecosystems close to where we live. We have also made wholesale changes to ecosystems, for instance, by altering course and storage of surface water flow.
Our horizons are expanding by leaps and bounds. We are seriously looking beyond the planet we inhabit. We like to believe that we are the only creatures to have a pan-global outlook. With this self-confidence however comes greater responsibility. We cannot afford to be selfish anymore. Not even in the name of doing things beneficial to humankind. We must look beyond our species. Pandemic period has opened our perspective to alternative ways of leading our lives. As a living animal, we have to consume for survival. Yet what we consume and how we do it can be better managed. We must question what we have been doing as a matter of habit. Even a small act like weeding. We humans have been bestowed with exceptionally large neocortex for a reason.

अपनी राखी

जिस दिन मिलेंगे हम उस दिन होगी अपनी राखी
सब पर्व एक हो जाएँगे विशु, नववर्ष औ बैसाखी
बस यही नहीं पता कि दिन और हैं कितने बाक़ी

सच का हिस्सा

बाहर का झूठ निभाना अगर मजबूरी है
अंतर के सच को ज़िंदा रखना भी ज़रूरी है
ना मिले या मिलते रहें यूँ ही हम यदा-कदा
तुम मेरे सच का हिस्सा हो और रहोगे सदा

कंकरीट में ढले और शीशे से सजे सब रिश्ते
मोल जिनका करे मांग-आपूर्ति की किश्तें
इनसे हटके है बहुत अपने सम्बंध की अदा
तुम मेरे सच का हिस्सा हो और रहोगे सदा

Oxygen: the necessary evil of life

The pandemic’s catastrophic effects have made a generation aware of the power of microbes. Our anthropocentric perspective usually ignores other powerful forces of nature. We might feel vulnerable against some natural calamities and acknowledge the might of inanimate forces such as earthquakes and cyclones. But we fail to admit that there are more dominating biological forces than us humans. Until of course the time a pandemic strikes. Like now.

Yet the fact remains that bacterial cells outnumber cells of our type (eukaryotes) by some orders of magnitude and viruses are even more widespread. Forget biosphere, our own bodies contain more bacteria than our own cells. If nature at all has concerns about survival of life, it makes more sense to think that she will worry more about bacteria than us.

As we have seen during the second wave in India, oxygen shortage affects us. What about bacteria?

The earliest bacteria lived deep in the ocean floor. The Earth’s oceans and atmosphere were practically free from oxygen molecules back then. It was all peaceful some three billion years ago. The earth had settled from the turbulent times of its formation.

Then some adventurous bacteria invented a machinery to harness sunlight for making energy that can be stockpiled. We know the process by the name of photosynthesis. Cyanobacteria were the pioneers of the technique long before plants came about. In fact, plants acquired photosynthesis from the cyanobacteria via a sort of technology transfer.

Photosynthesis was quite an invention. It splits water with the help of sunlight and uses hydrogen for energy generation and storage. With the help of this technological revolution cyanobacteria flourished and began to dominate the near-surface ocean. And the world had to deal with a new element – oxygen – the byproduct of the process of photosynthesis. Oxygen rose substantially in the atmosphere as a result of waste removal by cyanobacteria. That was some 2.5 billion years ago. It may sound contradictory or even weird to our perspective, but the arrival of oxygen wasn’t good news for life. Oxygen easily gives rise to some chemical entities collectively known as reactive oxygen species that are toxic to life. They damage DNA – the very core of life.

Life had this dilemma. Either face the wrath of the deleterious oxygen or shut down the photosynthesis factories. Gaining extra energy from the free Sun was too attractive a proposition to forego. And it did not make sense to not use a technology for which life had invested millions of years in R&D. Executive decision was made – photosynthesis will continue. Let’s find a solution to the problem created by oxygen. A group of bacteria took up the challenge.

While that group was working on the solution, photosynthesis was gaining popularity among microorganisms and some bigger organisms that arose 650 million years ago. This pumped more waste oxygen into the atmosphere and even oxygenated near surface ocean waters. Now there was no escape. The oxygen problem had become too big to ignore.

Fortunately just about that time the solution was ready. Life has this knack for turning threats into opportunities. It made use of one special virtue of oxygen, its hunger for electrons.

The earlier energy generation processes that life had at its disposal were all dependent on maintaining a pool of hydrogen ions (protons) on the other side of a membrane dam. Like a hydroelectric dam, release of protons is regulated via a channel which rotates a mechanical ATP generator to produce the life’s currency of energy. This pretty much is the fundamental process of energy generation in organisms.

Now all that a cell needs to do is maintain the proton concentration in the reservoir behind the membrane. This is where a series of electron acceptors come into play. They serially accept high-energy electrons to a lower energy regime and the energy thus made available is used to pump protons across the membrane.

Oxygen, because of its strong affinity for electrons, does this job more efficiently than other electron acceptors. Therefore when added to the series of electron acceptors, it makes a big difference to the cell’s ability to pump protons. Presence of oxygen enables organisms to make 15 times more ATP than primitive cells. One such energy generating entity is mitochondrion which lives inside our cells.

Relegated to the status of an organelle inside cell, mitochondria are now universally regarded as progeny of once free living bacteria. We know them as the power house of the cell. That is precisely because of their role in respiration via consumption of oxygen as per the method described above. Our body then can be considered as a colony of bacteria. The same applies to an ocean dwelling animal or any animal for that matter.

Oceans have a much less amount of dissolved oxygen compared to atmosphere. Remember, fundamentally life does not require oxygen. And it is toxic too as we have seen above. Yet once life had tasted the blood of oxygen via respiration, it didn’t look back. When animals came out of water onto the land, they were faced with extraordinary quantity of oxygen in the atmosphere.

Too much oxygen is like a flammable gas. You cannot have a flammable gas in a quantity that would set your house on fire. Yet you need gas regularly at a lower pressure to be able to sustain the flame for cooking food. Think of the supply of natural gas from producing region to your home. As it flows down the chain from processing plant through distribution mains and finally to your home, there is a cascading drop in pressure of the gas. Life does a similar balancing act to handle atmospheric oxygen. From atmosphere-body interface through lungs, blood and cell membrane, there is a cascading drop of oxygen pressure at every interface. When the oxygen finally enters the mitochondria, its pressure has dropped significantly to the level that a free living aerobic bacterium can handle.

Our entire body then seems like an infrastructure that helps make oxygen available at the right pressure to each of the mitochondria inside trillions of cells. The cumulative surface area of skins of all land animals thus becomes a defence wall against the toxicity of oxygen with nasal and mouth openings being the permissible channels for controlled entry of oxygen inside for further distribution.

So effectively by breathing in air we are allowing oxygen inside in a calculated manner for mitochondria to generate energy required for life activities. But more importantly, we are protecting mitochondria from “burning” by presenting several barriers in the path of oxygen – first by humidifying air after intake, then by mixing with carbon dioxide inside lung sacs, then mixing with blood and finally by diffusion into tissue cells and diffusion into mitochondria. See, we are letting our cells avoid oxygen rush. As does a fish which presents the first barrier in the form of gills.

At the heart of the architecture of such multicellular organisms lies a special material called sterol which imparts special properties to the cell membrane. In yet another example of how life turns threat into opportunity, sterols are made using oxygen and they in turn protect cells from oxygen toxicity.

Deep inside some big organisms including humans, the infrastructure is so designed that there are few chambers where oxygen is completely shut off. These protected chambers allow some bacteria to thrive using the “old technology” of fermentation in the absence of oxygen. Which is what some deep ocean bacteria do too. So what such animals like cow are effectively doing is creating the deep ocean like environment on land for bacteria to do their cooking the primitive way. That we oxygen breathing creatures do not like the waste methane – generated in the process and ejected from their mouth and anus – is another matter.

In our journey since we left the resourceful oceans and began conquering land areas, we animals have made progress working hand in glove with plants. Interdependence of plants and animals goes beyond the obvious oxygen-carbon dioxide exchange. We rely on plants to provide us with the essential amino acids. The stationary plants on the other hand rely on us for a number of functions such as reproduction. Together our march continues – away from the oceans and deep inside the continents. While cyanobacteria produce most of the oxygen in the atmosphere, plants chip in with their contribution. We in turn help with proliferation of plant life. By aiding in pollination, providing water, dispersing seeds and, more recently, by creating suitable environments for plants in unfavourable conditions. Have we been doing enough lately? Or merely consuming what the plants offer? Something to ponder over once the harshness of the pandemic wanes off.

चंद्र माँ

तुम चाँद सी सरकती जाती हो
हौले हौले कि मुझे दूरी महसूस ना हो
मैं पृथ्वी सा अपनी धुन में
बल खाता, घूमता रहता हूँ

तुम चाँद सी सिकुड़ती जाती हो
आगामी पर सब न्योछावर कर
मैं पृथ्वी सा अपनी धुन में
ऊर्जा पाकर फूला नहीं समाता

तुम चाँद सी तकती रहती हो
हर पल मुझे आँखों में रखती हो
मैं पृथ्वी सा अपनी धुन में
सारा ब्रम्हाण्ड देखा करता हूँ

बल खाता, घूमता, फूलता, देखता
तारों में उलझा था इतने दिन
अब तुम पर नज़र आ टिकी है
अब समझ पा रहा हूँ तुम्हें
पर तुम इतनी दूर हो अब
चाँद जितना दूर है!
मैं भी चाँद बनकर एक पृथ्वी रचूँगा
और तुम्हारी तरह
उसे फलते देख
विलीन हो जाऊँगा शून्य में
इस तरह तुम्हारा ऋण मैं चुकाऊँगा
माँ

Competition is overrated

The world actually runs on cooperation. The scientific and technological advancement we humans have achieved is impossible without cooperation. We shared knowledge. We worked together on projects. Our organ cells work in sync with each other to achieve outcomes. An organ going selfish invites cancer. Why do we then celebrate competition which motivates selfish behaviour? I ask and explore in this article: The devil is in the headline

Death isn’t end of everything

“Thou’art slave to fate, chance, kings, and desperate men,
And dost with poison, war, and sickness dwell”
– John Donne (1572?1631) on Death

I live in a 35 years old house. It is showing signs of ageing. Some doors do not operate as smoothly as before. Ceiling walls have layers peeling at places. Insulation is not effective anymore. The worst thing is that the house is no longer energy efficient. Something needs to be done. We discuss options. I bring up demolishing the house and building a new one. Though not the preferred option, we do not mind it either. The thought of demolition triggers a slight feeling of sadness because of memories of time spent in the house. It is our home after all. The house is inanimate. It never reciprocated our feelings. That’s probably why this parting does not affect us much. However, when a living being dies, even a pet dying of old age, it is a different matter altogether.

Talking about death and bereavement is never easy. Death scares the hell out of us. “Death is not only inevitable; it is controlled by the fates, programmed into the very fabric of life,” says the British biochemist and writer Nick Lane. True, the realisation that death is the only certainty in life occurs to us many times. Yet there are curiosities surrounding this certainty, some explained by science and some still being worked out.

What happens to a body after death?

Exactly when does life actually move out of a living body?

What is the root cause of death?

Let?s work on these curiosities one at a time.

What happens to a body after death? With due warning that words in the rest of this paragraph might create imageries of disgust for some, here I go. Simply stated, life processes stop when a living body dies. For instance, the machineries for waste removal, breathing and blood circulation cease to operate. When an animal is alive, the circulating blood helps maintain a high body temperature. The heart does all the hard work of pumping thick blood to every nook and corner of the body. With no circulation after death, body temperature continues to drop till it attains room temperature. Without breathing, oxygen cannot get inside. Even if the lungs had oxygen, without blood circulation there is no oxygen supply to the cells anyway. Consequently, the cells fail to produce ATP – the energy currency needed for pretty much everything our bodies do. No energy means the muscles cannot relax by breaking the bridges which under normal conditions cause them to stay rigid. So the body appendages become rigid. When the muscles eventually relax, the last bits of excreta are ejected. Blood drains out leaving the skin pale which then shrinks.

An animal body is a storehouse of bacteria. We humans too possess more bacterial cells than our own cells, most of them residing in the digestive tract. These bacteria spring into action when cells are no longer capable of offering a resistance. They begin consuming the organic resources of the body while ejecting sulphur and other gases. The odour produced attracts scavengers to the party. Tiny organisms and bacteria finish their job of decomposition leaving behind only the hard parts such as bones and teeth that undergo a slow decay.

Alright, we are done with the disgusting part. Now the second question.?Exactly when does life actually move out of a living body??This at once feels like heading towards spiritualism. We will stick to science however. The decomposition process described above happens at body and organ level and the effects can be observed using our senses – visual and olfactory. But if cell is the fundamental unit of life, shouldn’t we consider cell death as the time when life ultimately leaves an organism? This profound question does not have a straightforward answer. Billions of cells are born and billions die every day while we are alive. Cells die even when we are in the process of development before birth. Our fingers and toes, for instance, are joined by tissues in between when they first arise. The cells making up these tissues are programmed to die thus freeing up the digits while the foetus grows. Thus cell death has been occurring even before we were born. Yet the body that is composed of living cells cannot be considered fully dead until all the cells have died off.

A possible answer could be: when the very last cell dies. That surely happens during the process of decomposition. It is worthwhile then to understand how cells die in general. Cells possess an enzyme family broadly called caspases which, when activated, carry out controlled demolition of the cell?s structural elements without causing stress to adjacent cells. How do caspases get activated? When a cell is under stress, mitochondria release a protein called cytochrome c through its outer membrane. Out of the mitochondria and inside the cytoplasmic pool of the cell, cytochrome c, which is otherwise integral to the basic function of energy currency generation inside mitochondria, activates the death director caspases that then do their job to perfection. This, in a nutshell, is how a cell undergoes programmed death. A very simplified depiction of a highly complex process.

The root cause of what makes the mitochondria release cytochrome c is still not fully understood. Many think that the stress is caused by production of reactive oxygen species (aka free radicals) generated because of excess electrons in the ATP manufacturing unit. We are talking of massive increase in free radical production. Because free radicals are regularly leaked by mitochondria and they act as signals to a number of normal cellular processes. It might start to look complicated now. The bottomline is that mitochondrion appears to be the key entity that decides not only how energetically the cell lives its life, but also the time when the cell must bid adieu to the world. Nick Lane reckons that it was ancient mitochondria that gave the caspase enzymes to our cells in the first place. Of course he means the genes that make the caspases.

If death is inevitable, what good could this be doing to nature or to life? Is death a means of gathering and reusing the building materials of life for a fresh build? Deciduous trees shed their leaves every autumn which enrich the soil for new growth to occur in spring. Animal carcasses become breeding grounds for maggots and provide nutrients to bacteria and soil. Yet this cannot be the main purpose of death. Why would nature bring down bigger houses to build/maintain smaller houses? It maybe that death in some cases helps bring resources to places where they normally don’t exist. I am thinking of Pacific salmon which start their lives at the source of a river, spend their youthful days in the ocean and, having matured there, begin an ultimate journey upstream to their birthplace to release eggs and sperms and die. That way they do bring nutrients available in ocean waters onto the land. They are genetically programmed to do this.

One idea is: death is all about discarding a life institution when it has served its main purpose – reproduction. Gerontologists use a term ‘essential lifespan’ to indicate the age when a species is supposed to have fulfilled the purpose of reproduction and beyond which it undergoes progressive loss of function and fitness. For?Homo sapiens, the essential lifespan is 45 years. Reproduction indeed is a precursor of death. Most animals die soon after losing their capability to reproduce. We humans, along with short-finned pilot whale and killer whale, are exceptions in that females live for decades after they stop producing eggs. Advances in medical sciences too have helped increase our longevity. This makes us live with the problems of old age that we see as diseases. Nick Lane considers old age diseases as mere symptoms and ageing as the real ‘disease’. Ageing has been attributed by various theorists to genetic programming and to wear and tear. Either or both of these could cause mitochondrial dysfunction leading to production of reactive oxygen species. This in turn results in damage to the DNA and eventually death. This is a convoluted and imperfect answer to the third question:?What is the root cause of death??There is a lot more to know and understand in this domain.

Yet again, we have come back to mitochondria while discussing death. Mitochondria do appear to take centre stage in most cellular processes including death. It would be interesting to find out what happens to mitochondria after cell death. What we know is that during cell death mitochondrial shape is transformed via fragmentation and cristae remodelling. These shape changes are being investigated for finding possible avenues for killing cancer cells. At cellular level, cancer is quite opposite to death although it is one of the common diseases that leads to death of an organism. Cancer happens when certain type of cells defy the death machinery and refuse to die. Mutations of mitochondrial genes have a lot to do with onset and spread of cancer.

The body, its processes and all the cells are destroyed as a result of death. The metaphorical old house demolishes itself after building a new house via reproduction. Across a generation, half of nuclear genes of each parent are inherited by an offspring. But what truly survives over generations is the mitochondrial DNA that a mother passes on to her children – like that friend who lives on beyond the bounds of life and death… “jibon moroner simana chharaye”?as Tagore puts it. Who knows, mitochondria could be the ones that make death die and that wake eternally as envisaged by John Donne centuries ago.

References:

Lane, Nick (2005)?Power, Sex, Suicide: Mitochondria and the Meaning of Life.?Oxford University Press, Oxford.

Lane, Nick (2010)?Life Ascending: The Ten Great Inventions of Evolution?(Kindle Location 4363). Kindle Edition.

Wallace, D.C. (2012) Mitochondria and cancer.?Nature Reviews Cancer?12, 685-698.

কুয়াশা

না বললে দোষ আমার হবে
বললে যে অত্যাচার হবে
এই দ্বিধায় সময় ফুরোলো
আসছে বছর আবার হবে

Building Myself from Scratch

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 …

दस्तक

कहीं से उठकर फिर एक दिन चला आता है
रिवाज़ों को गोद लिए पलछिन चला आता है

इस उम्र में अच्छा नहीं लगता है जो दस्तूर
न जाने क्योंकर भला तुम बिन चला आता है

बड़ा हो गया हूँ अब तारीख दस्तक नहीं देते
दुआ बूँद में भर आँसू लेकिन चला आता है

छुप जाती हो तुम फिर कभी न आने के लिए
औ’ बचपन मेरा दस तक गिन चला आता है

Post-COVID-19 World: Is De-urbanisation on the Cards?

Cities emerged most likely as a consequence of the mankind’s shift to agriculture as the dominant occupation. Unprecedented urbanisation happened as an aftermath of the industrial revolution. So it’s basically the economic need that drove us here. Social needs hardly require us to live amidst hundreds of thousands of other people around. Now with internet connecting us without the need to be physically connected, it’s time we questioned the old, and still very much in vogue, model of city based services. Do we continue to allow the megacity dinosaur grow or let the small town/village birds fly? Here in this article I compare evolution of civilisation with evolution of life. Read on…

The Loan of Water

We animals are, in a way, freeloaders. Plants do primary production and we consume. However we owe plants some favour in return. Here in my interdisciplinary take on animal-plant interactions and the water scenario I try to explain the give-and-take relationship. A bit of philosophy too is thrown in the mix. I find the overlapping boundaries of different scientific disciplines most interesting. 5 minutes read…

The Bright Side of Viruses

It’s natural to think of viruses as enemies of mankind. More so when we are in the middle of a pandemic. But things aren’t quite that bad when we extrapolate the impact to all living beings throughout the history of life. I wrote this short article where I tried to explain one benefit of viruses which has had a huge impact on who we are. There is also a high level overview of how viruses operate. Please read if you are interested. If the topic fires your curiosity, Carl Zimmer’s ‘A Planet of Viruses’ is a good beginners level book and the book referenced in the article is a pretty detailed take on the science of viruses.

Lovelock Writes at 100

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…

मारके टिंग

मैं परेशान हूँ। रेस्तराँ चेन का धंधा है। अच्छा चल रहा है।ऊँहु… ‘है’ नहीं ‘था’। जब से ये कल्पित आया है…

वैसे कल्पित से मुझे कोई व्यक्तिगत शिकायत नहीं है। दिल का हीरा है वह। उसका पिता – आदर्श – एक ज़माने में मेरा सहपाठी हुआ करता था। बड़ी इज़्ज़त करता था मैं आदर्श की। बड़ा ही नेक बंदा था। बरसों बाद जब व्हाट्सऐप ग्रूप के माध्यम से आदर्श से फिर बातचीत होती थी तो पुराने दिन लौट आते थे। फिर एक दिन पता चला कि आदर्श अचानक इस दुनिया से चल बसा। बहुत सूनापन महसूस किया था तब। धीरे धीरे तमाम व्यस्तताओं में उलझ व्हाट्सऐप ग्रूप भी कब छोड़ दिया था, पता ही ना चला।

आदर्श के देहांत के क़रीब दो साल बाद कल्पित का एक ईमेल आया था। उसे काम की तलाश थी। जो बात मुझे भली लगी थी वो यह कि उस ईमेल में किसी तरह का कोई दबाव नहीं था। ना उसमें अपने बुरे दिन का बढ़ा-चढ़ाकर बखान था और ना ही जज़्बाती ब्लैक्मेल। उलटे उसने मेरे सहायता न कर पाने की स्थिति में भी बुरा ना मानने की बात कही थी। मुझे अच्छा लगा था। आदर्श की छवि एक बार फिर उभरकर सामने आ गयी थी। मैंने बातचीत आगे बढ़ाई।

ग़नीमत से वह उसी शहर में रहता था जहाँ मुझे अपने चेन की रेस्तराँ खोलनी थी। सो मैंने काफ़ी समझा-बुझाकर उसे ये ज़िम्मेदारी सौंपी। रेस्तराँ बिज़्नेस के कुछ नुस्ख़े बताएँ और एक विश्वसनीय शेफ़ उसे दिया।

शुरुआत बड़ी अच्छी रही। एक बार उसके शहर दौरे पर गया था। रेस्तराँ की तरक़्क़ी देखकर मुझे बड़ी ख़ुशी हुई। बाहर निकलते समय मेरी आँख काँच के दरवाज़े पर टिक गयी। अंदर की ओर से दरवाज़े पर PUSH लिखा हुआ था। कल्पित ने दरवाज़े को हल्के से धकेला और अपने बायें हाथ से मेरी ओर कृतज्ञता भरे भाव से इशारा किया। बाहर निकल मैंने नज़र घुमाई और देखा बाहर से उसी दरवाज़े पर PULL लिखा हुआ था। मैंने कल्पित के काँधे पर हाथ रखा। उसे दरवाज़े पर लिखे शब्द दिखाए। वह समझा नहीं।

मैंने कहा, “देखो बुरा मत मानना। ये वैसे कोई बड़ी बात नहीं। पर बात एटिट्यूड की होती है। अगर आप कस्टमर चाहते हो तो आप उनका अंदर आना आसान करोगे और बाहर निकलना मुश्किल। आई बात समझ में? अगली बार मुझे यह सही नज़र आना चाहिए।”

उसे गम्भीर होते देख मैं मुस्कुरा दिया।

आठ महीने बाद मैं दूसरी बार वहाँ पहुँचा। गरमी का मौसम था। हर दुकान की तरह उस रेस्तराँ में भी कम लोग मौजूद थे। रेस्तराँ में क़दम रखते ही बाहरी दरवाज़े पर PUSH लिखा देखकर मुझे ख़ुशी हुई। मैंने उससे हालचाल पूछा। उसने बताया कि उसके पुराने ग्राहक अब भी आते हैं, पर नए ग्राहक कुछ ख़ास नहीं आ रहे हैं। मैंने उसे कुछ स्ट्रटीजिक क़दम उठाने को कहा।

मैंने कहा, “तुम्हें क्या करना है, तुम ख़ुद सोच कर निकालो। पढ़े लिखे हो, जवान हो। इस एज की डिमांड तुम्हीं को बेहतर पता है। मैं प्रोग्रेस मॉनिटर करूँगा।”

सुनते ही उसने बड़े जोश से बोलना शुरू किया, “सर मैं भी सोच रहा था कि कुछ पहल करना ज़रूरी है। दरअसल मैंने कुछ सोच भी रखा है। अगर बुरा न माने तो अपना आइडिया बताऊँ? कोई ज़रूरी नहीं कि आपको अच्छा लगे। आप सुन लीजिए। फिर आप कुछ और चाहे तो ठीक है।”

“अच्छा बोलो।”

“सर पाँच इन्द्रिय जो है हमारे? फ़ाइव सेन्सेज़, इनमें स्वाद, गंध और दृष्टि को तो हम तृप्त करते ही हैं…”

मैं मन ही मन उसकी शुद्ध हिंदी पर हँस रहा था। शायद उसने मेरे कौतुक का कारण भाँप लिया था। वह बोले जा रहा था, “हमारे डिशेज़ की क्वालिटी और प्रेज़ेंटेशन हमेशा टॉप क्लास होते हैं। मैं सोच रहा था कि जो दो और सेन्सेज़ हैं – टच और हियरिंग – इनको लेकर कुछ किया जाय। शायद एक डिस्टिंक्ट इमेज बन जाए अपने रेस्टोरेंट की।”

उसका ‘रेस्टोरेंट’ कहना मुझे ज़रा चुभ गया। मैंने कहा, “बहुत बहकी बहकी बातें करते हो यार। कुछ स्पेसिफ़िक प्लान बताओ। आजकल मार्केटिंग के नए नए टेक्नीक निकले हैं। चाहो तो किसी आइ टी एक्स्पर्ट को साथ ले लो।”

“सर एक बार ट्राई करते है। मुझे भरोसा है कुछ अच्छा होगा।”

“ठीक है, अगले हफ़्ते तक मुझे बताओ कि इग्ज़ैक्ट्ली क्या सोचा है।”

ठीक सातवें दिन उसका फ़ोन आया। हमेशा की तरह पंक्चुअल था बंदा।

“सर वो जो सेन्सेज़ की बात कर रहा था मैं। श्रवण और स्पर्श… आइ मीन हियरिंग और टच। हियरिंग तो सर मेलोडीयस गाने सुनाकर सैटिस्फ़ाई कर सकते है। म्यूज़िक तो बहुत सारे रेस्टोरेंट में चलता है। पर अपने यहाँ एकदम चुने हुए मोस्ट मेलोडीयस गाने ही बजेंगे। मैं ख़ुद चुनूँगा। धीरे धीरे लोग समझेंगे सॉफ़्ट मेलोडी के साथ ज़ायक़ेदार खाने का आनंद। ख़ैर ये तो एक प्लान है। पर इससे ज़बरदस्त प्लान है टच वाला। हमारे वाशरूम में सेन्सरी टैप्स लगाएँगे ताकि कस्टमर को नल छूना ना पड़े। और हर नाइफ़ और फ़ोर्क में सॉफ़्ट ग्रिप लगाएँगे। मतलब टोटल एक्स्पिरीयन्स सर। रेस्टोरेंट में क़दम रखते ही पकवान की सुगंध और मधुर गीतों से उनका स्वागत होगा। फिर जब विसुअली अपीलिंग डिशेज़ को सॉफ़्ट टच के सहारे मुँह में ले जाएँगे तो उसका स्वाद बाक़ी सेन्सेज़ के साथ मिलकर ज़बरदस्त सेन्सेशन पैदा करेगा दिमाग़ में। सारे बाहर आकर इसकी चर्चा करेंगे। तब मार्केट बढ़ेगा।”

“ख़र्चा कितना लगेगा?” मैंने निर्विकार भाव से पूछा।

“सर कुछ पाँच लाख वन टाइम पड़ेगा। और ऑपरेटिंग में समझिए १० पर्सेंट ज़्यादा। पर सर लॉंग टर्म में बहुत फ़ायदेमंद रहेगा।”

“यार पाँच लाख में तो कितने टारगेटेड ऐड बन जाते। फ़ेसबुक, व्हाट्सऐप, इंस्टाग्राम, यूट्यूब, वग़ैरा। इतना सब करने की क्या ज़रूरत है?”

“सर लॉंग टर्म में सब्सटांस ही मैटर करता है।वो सब कुछ दिन के लिए ठीक हैं।”

थोड़ी झिकझिक के बाद मैंने कुछ कम ख़र्च की मंज़ूरी दे दी थी।

*****

आज फ़ायनैन्शल अड्वाइज़र के साथ अपने बिज़्नेस का क्वॉर्टर्ली रिपोर्ट देखकर मन भारी हो गया। कहीं से कोई अच्छी ख़बर नहीं है। कल्पित का रेस्तराँ तो डूबने के कगार पर था। और उसी में सबसे ज़्यादा इन्वेस्टमेंट हुआ था। दूसरे दिन ही मैं वहाँ पहुँचा।

“अगर कुछ बेचना है तो इंसानों से उम्मीद मत रखो। आदमी लोग कुछ ख़रीदते नहीं। ख़रीदते वो हैं जिनके सेन्सेज़ नहीं होते। सीधे दिमाग़ पर जिनके असर होता है। अगर तुम्हारे पास बस इंसान आते हैं तो पहले उन सब को मारके टिंग बनाओ। उनके सारे सेन्सेज़? वो तुम क्या कहते हो, इन्द्रिय… हाँ उनके इन्द्रिय निष्क्रिय कर दो। ख़त्म कर दो उनके महसूस करने की ताक़त। फिर बेचो जो बेचना है। बिक जाएगा। मेरी गैरंटी है। वो क्या कहते है ना ‘कस्टमर इस किंग’? सब बकवास है। टिंग इस किंग। हाँ, सबको मारके टिंग बनाओ। और बंद करो तुम्हारी बकवास। कोई सेन्सरी सैटिस्फ़ैक्शन नहीं। उन्हें डोपामिन दो इंटर्नेट के ज़रिए, मोबाइल के ज़रिए। तुम सेन्सेज़ की बात करते हो? पहले अपने आँख-कान खोलो और देखो आसपास क्या हो रहा है। देखो इंफ़्लुएंसर लोगों को, नेताओं को, बड़े बड़े बिज़्नेस को। सब सपने बेच रहे हैं सपने। और सपने दिखाने के लिए पहले लोगों को सुलाना ज़रूरी है।”

एक साँस में मैं सब कह गया। और ग़ुस्से से उफ़नते हुए बाहर निकल गया। बाहर के दरवाज़े पर भीतर से PULL लिखा देखकर इस बार मैं खीज उठा। दरवाज़े को इतनी ज़ोर से खींचा कि कुछ देर तक वह पेंडुलम की तरह हिलता रहा।

*****

एक साल पहले की बात थी यह। आज वह रेस्तराँ शान है मेरे चेन की। सारे शहर में बड़ी चर्चा है। बस अफ़सोस इस बात का है कि कल्पित अब वहाँ नहीं है। मेरे उस लेक्चर के दूसरे दिन ही उसने इस्तीफ़ा दे दिया था। उसके बताए रास्ते पर चलकर शेफ़ ने बिज़्नेस जारी रखा। कितने घटिए तरीक़े से पेश आया था मैं उस दिन! और वो सलाह – इंसान को मारके टिंग बनाओ! भला ऐसी शिक्षा भी कोई अपने बच्चों को देता है? क्या सोचेंगे आजकल के नौजवान हम बड़ों के बारे में? वह मुझमें अपने पिता आदर्श को ढूँढता था। और मैं?

सपने के झरोखे से

बुलाया था कहाँ मैंने
मगर हो गया सामना
हज़ारों दस और जुड़े
बस इतनी सी कामना

Minding the Body

Right now I am aware that my mobile is just about 30% charged. The battery icon at the top right corner is staring at me. The phone will prompt me as soon as the charge goes down below 20%. If I don’t plug it in, it will shut itself down when it is fully discharged. Thankfully, the risk is limited to me not being able to use the phone. It cannot cause much harm to me or to the device. I can afford to be lazy for now. It’s an altogether different story however when something similar happens inside my body.

When I am running out of energy, my body tells me to go and get some food. Or drink. Its alerting mechanism comprises of, among other things, the feelings of hunger and thirst. I cannot ignore these prompts for long. These are bodily sensations that belong to a particular type of feelings. Some other feelings are purely mental. Being happy or feeling disgust for example. There is a whole heap of feelings that are generated by our central nervous system which prompt us to do something. Researchers in Finland have mapped our 100 core feelings by analysing how pleasant and how prominent these feelings are. A much simplified view loosely based on their work is presented here.

Right in the middle of this chart sit the feelings which help us maintain a normal body state (jargon: homeostasis). Move diagonally down left and the feelings there tell you that your body is not well. Do something about it or at the very least don’t put pressure on it. Get some rest. On the top right are feelings of being on a high. Positive Emotions. A place where you’re motivated to keep doing the good work. Reproduction being one of the good works. On the two sides of this diagonal representing bodily sensations are feelings that are more “mental” in nature. More prominent of these feelings, which are unpleasant too, tend to indicate that we are not well mentally. Some feelings here dissuade us from doing things that land us in this place. Feelings like ‘fear’ are derived from primary emotions that originate in most animals in their “deeper” brains. Diagonally opposite to this area of ‘Negative Emotions’ lie “mental” feelings that make us humans special or so we like to think. Cognition. Consciousness. Reasoning. The realm of perception, research, analysis, dreaming, art, science, language, creativity, …

These cognitive feelings originate in neocortex which is the most evolved (and evolving) part of the brain. While earlier researchers delineate this superficial area functionally from the deeper limbic system, leading neuroscientist Antonio Damasio believes that the two systems are connected. He proposed an idea that the prefrontal cortex is responsible for a signal loop that aids the deeper primary emotions area in decision making based on mental images of hypothetical scenarios of body states representing different response options to a stimulus. I wish I could introduce this tortuous hypothesis in a more lucid manner. Hopefully the text below will make it clearer.

Fundamentally, animals need drive or motivation to do things. This necessity comes with the advantage of motility that distinguishes us animals from plants. For a plant, which is rooted, energy input mechanism is driven by physics and chemistry operating at its interface with soil and with air. Animals need to be driven so that they get close to food sources and then put the food inside their body. Similarly, they need to breathe to take oxygen in and discard carbon dioxide. Animals also need to be put to sleep to give active metabolism some rest so that some important cell level activities can operate smoothly. At the right age, a higher animal must also feel the need to perform sex. All these drives are regulated via hormones inside the body. Production of appropriate hormones at appropriate time is controlled by the brain’s primitive structures. So far so good. It’s like my mobile phone producing a hormone which pops up a message warning me about the remaining charge.

The chemical based system of hormones is not enough for complex animals. In higher animals, the need for motivation goes beyond provisioning of consumables. The evolutionary forces sought out to automate monitoring and maintenance of health of the system as much as possible. What if the phone falls and hits a hard surface? What if it encounters poor connectivity? What if the touch sensitive screen is damaged? That’s when the device depends entirely on its owner for survival/functioning. Nature wants higher organisms to be self-sufficient as much as possible. They must continue to explore which amounts to taking more risks by encountering new environments. That’s why organisms have been provided with systems to assist them in this mission. And nature keeps on updating the systems. That’s what we call evolution.

If the phone were a ‘life’ object, it would feel hurt and sadness when it’s screen is scratched, find a repair shop and drive itself there to get the scratch removed. Intelligence is all about decision making. It runs on a neural network as opposed to the chemical network of hormones. Damasio’s hypothesis says that our brain not only continuously creates images of current state of our body, but it also, when faced with a decision making scenario, creates images of “as if” scenarios. These images are basically how the body will look like when each of the available options are implemented. What if I don’t do anything? What if I consult a repairer? What if I rub the screen surface with a wet cloth? Damasio calls these images of “as if” body state somatic markers. The somatic marker images assist our conscious self to choose an option which is represented by the “outcome” image of our liking. It’s almost like visualising the immediate future states of our body and then choosing the best one. That’s how we make conscious decisions. That’s how we “mind” our body as it explores new environments.

References:

Nummenmaa, L. et al. (2018) Maps of subjective feelings. Proceedings of the National Academy of Sciences of the USA 115, 9198?9203.

Damasio, A. (1994)?Descartes’ Error: Emotion, Reason, and the Human Brain. Grosset/Putnam, New York.

 

Game, set, match Mother, by design

Almost like a ritual before preparing to serve, a tennis player picks up three balls, looks at them once and rejects one. How efficiently could one reject a bad ball out of three with just a casual glance? Yet statistically this process makes sense. If not for one’s inability to grab more than three, the player has a better chance of ending up with the best two balls if there are more balls to reject. Anyway, this act passes off as a trivial routine – too mundane to register in our minds focussed on what is going to happen when the ball is in play. But this is exactly the process that mitochondria follow at a crucial stage in our lives and this has a huge impact on who we are.

A mitochondrion is technically an organelle – a tiny organ inside a cell. One of the curious features of mitochondrion is that, like a cell, it has its own DNA. This sure sets it apart from other functional organelles inside the cell and raises its status as something that might have its own life. Indeed it is now widely recognized that mitochondria were once free living bacteria that an ancient cell had engulfed. It has been living inside and producing offspring ever since. Mitochondria multiply and so do mitochondrial DNA. Cells too multiply and divide the mitochondrial population among themselves.

So far so good. But then something happens to certain cells as a result of organisms performing sex which disturbs this usual peaceful settlement process. These ‘sex-related’ cells are called germ cells. When an organism performs the act of sex, a germ cell from outside (sperm) fuses with the resident germ cell (egg) along with its genetic content. The two DNAs recombine and become DNA of the fused cell. Now think of the mitochondria inside each of the fusing cells. There are two sets of populations – one from Mars (sperm) and the other from Venus (egg). Too many individuals to accommodate in a restricted space. Some primitive form of sex had the two parties settle the score among themselves by trying to kill each other. Things are much streamlined in higher organisms like us humans. Not sure if this was a peaceful solution but one set of mitochondria completely vanishes from the scene and the individuals belonging to the other set occupy the newly formed cell. No prize for guessing which group sacrifices itself. The intruders – the mitochondria that previously belonged to the sperm cell – of course.

The offspring of mitochondria that belong to the mother organism’s germ cell occupy the newborn fused cell which eventually develops into a new individual organism. And life goes on. In all animals and most plants and other eukaryotes, only mother’s mitochondria are passed on to the next generation. The male’s only contribution is in providing sperm for sex. Everything else is a dead end for male. So much for the patriarchal society we are proud of!

Besides nurturing the egg and, in mammals, the pre-birth baby, the female body carries out some amazing processes inside the egg cell before and after sexual fusion that are beneficial to the offspring and to the living world in general. To be precise, to the mitochondria. One such process of great significance is called mitochondrial bottleneck. Let me explain.

The single biggest threat to life is damage to its DNA. Back in the times of early Earth, ultraviolet radiation from the Sun would do most of DNA damage. These days, a slow process of damage happens in the form of mutation during the process of creating copies. A few random mutations here and there are non-life-threatening. However, in bacteria such mutations tend to accumulate in the cells and over a period of time could potentially cause extinction of the species. The phenomenon has a popular scientific name – Muller’s ratchet. Mitochondrial bottleneck during the process of fertilization is a mechanism to mitigate the risk posed by accumulating mutations. Just like that tennis player, the egg cell sorts its mitochondrial DNA in clusters and then selects only a few to be passed along while rejecting the rest. Statistically, this process leads to reduced mutations in the mitochondrial DNA that is eventually passed on to the offspring thus ensuring a safer mitochondrial genome for the next generation.

You may be thinking, but that ‘purifies’ the mitochondrial DNA and not the DNA of the cell that in reality is the blueprint of an individual. How important are mitochondria to the overall functioning of the cell and eventually to the organism is a topic in itself – too big to cover here. From the obvious respiration which provides energy, to control of almost every aspect of the cell including sex, ageing and death, mitochondria have a critical role in our well-being. And in a yet another clever design by nature, a mother will pass on more mutational load to her male offspring (that cannot pass on the deleterious mutations further) than to her female progeny. This phenomenon – often referred to as mother’s curse – has been studied in the fly Drosophila – the most common guinea pig for genetics studies (Innocenti et al., 2011) and is likely to be present in all animals. If you are a male reading this, bad luck, but it’s just nature’s design to ensure the protection of what matters most – mitochondrial DNA!

——————————————–

Innocenti et al. (2011) Experimental Evidence Supports a Sex-Specific Selective Sieve in Mitochondrial Genome Evolution. Science, 332, 6031.

कलाई

घड़ी उतार दी थी एक बार
फिर कभी पहनी भी नहीं
सूनी हो गई थी कलाई
बात समय की नहीं रिश्तों की थी
आज भी सूनी ही है कलाई
हाँ उम्मीद ज़रूर है
कि बात रिश्ते की नहीं बस समय की है

मोती

तू याद तो आता है तमाम उलझनों के बीच
मोती सा बसा है दिल की धड़कनों के बीच

Needless grapes

It took nature more than a billion years since the Earth was born to devise a mechanism for trapping Sun’s energy. This made life in the ocean self-sufficient. Then around half a billion years ago, it delegated the responsibility to plants and animals to carry life forward. To uncharted territories. Plants marched towards the land. Animals came along.

Passing the baton from generation to generation, life kept on conquering territories. There was a big deterrent on land though. In water based plants, male sperms swim to meet the female egg for fertilization. The fertilized egg then needs water to germinate. Water wasn’t as readily available on land as in the ocean. The very core of life’s survival – reproduction – was under threat.

After struggling for another 100 million years, nature invented pollens that carried the male sperms to the female egg using the wind. A neat strategy to overcome dependence on water. Sperms in the pollen and egg fertilize to produce seed which then germinates into a new plant on wet ground.

Now what if there’s not enough wind to carry pollens? Nature looked around and saw insects. They were feeding on pollen-bearing organs with no apparent benefit to the plant. Why not use these freeloaders to carry pollens? But they needed to be tricked into doing so. Thus came about one of the most effective innovations of nature – a rare combination of beauty and utility – flowers. Their colours and fragrance attracted the insects. They found nectar in there which they fed on unaware that the plants quietly loaded pollens onto them while they were busy feeding. This was a huge relief. Plants no longer needed to depend on natural agents – water or wind – to transport sperms to eggs. Reproduction was back on in full swing.

With plants going to far away places via this newfound reproductive strategy, a new challenge surfaced. The seeds that were produced as a result of fertilization still needed water to germinate. How do you carry the seed to wet grounds?

The plants went for the tried-and-tested strategy. They added an enticing structure called fruit around the seed. Again, it was not just a marketing ploy full of colours and fragrance. It did have value proposition too in the form of food. Many birds and mammals fell for it and inadvertently participated in dispersal of seeds.

And then came to this world a bipedal animal with specially modified thumb to easily pick fruits. This gave him advantage over other creatures. He did not however stop at helping the cause of plants by dispersing the seeds. He used the advantageous grip to pick and throw stones and other tools at fellow animals. He then began consuming the seeds on a large scale. Worse, he even invented seedless grapes!

Why this sexpensive business?

Sex is expensive. At a minimum, it requires persons of opposite gender to come together. It may superficially seem to be a non-issue because for every female, there is a male around (well almost). But it does take quite a lot for a person from Venus and another from Mars to come to a meeting place on Earth. Yet getting together is just the beginning. They must then like each other to begin a meaningful conversation that could lead them further. Thereafter they need to love each other. It demands a lot of effort to impress one another. Too much energy goes in singing, dancing, feeding, eating, gift buying, villain-bashing, showing off beauty and strength, chatting (love letters in the past), and so on. All done. Then each of the lovers need to shun the competition. Because signalling does not discriminate between individuals of the opposite gender. Ask a plant which spends so much energy producing flowers with all their visual beauty and fragrance and then gets a bunch of freeloader insects who would not assist with pollination. Is it all worth it?

The above para was intended for fun. But there is a huge scientific cost too to this whole business of sex. Finding mates is a huge biological/ecological problem. Then there are costs associated with the fundamental sexual process of cell division – meiosis. Unlike mitosis (cloning) which finishes in under 2 hours usually, the sexual cell division of meiosis takes much longer to finish. If a female were to self-reproduce, she could pass all of her genetic material to the offspring and not just half. And then, ecologically speaking, half of the progeny in the form of males would not need to be produced at all. Why even bring these un(re)productive beings to life just to eat up resources?

What on Earth then are the benefits of sexual reproduction that the nature has preferred this mode over cloning? Well, that is one of the trickiest questions which the scientific world is yet to find a satisfactory answer to.

Cloning would produce the same individual every generation with the exception of cases affected by mutation. Does sexual reproduction enable life to stay ahead in the arms race with the villain who wants to disrupt life? By disturbing the pattern of life form just a little every generation? Making every eukaryotic individual unique? So that the villain cannot come up with a strategy based on its understanding of the earlier generation? And under this ever changing guise, life quietly goes a step further? But who is this ‘villain’? Even harder question is: who or what is this ‘life’?

With science, every answer leads to further questions, no?

Two sigmas ruin the bell curve

Campus of a premier national institute in India in the nineties. It was dark. Sounds of some people stomping next to the hostel building followed by glass shattering broke the eerie silence. There was a sudden surge of activity in the ground floor wing and everyone came out of their rooms. It was first year Science post-graduate students’ wing. Soon their seniors emerged from the upper floors. An extraordinary general meeting followed. It was a war-like situation. An Engineering graduate student had attacked the room of a Science post-graduate student.

It was not a personal feud. A full-blown inter-caste war it was. The echoes of which were felt decades later when the Engineering almuni left out the Science post-graduates from the celebration of 25 years of graduation. Such deep rooted was the strife.

Chevron fold at Ulverstone, Tasmania in December 2016

Superficial cause: Engineering students who held the majority decreed that a second year Engineering student was equivalent in ‘campus social status’ to a first year Science student. The right of ragging (hazing) a Science post-graduate fresher came with it.

Deep cause: An Engineering candidate was superior to a Science graduate because, ha, no brilliant student in his right senses would do a Science graduation ahead of Engineering and Medicine. So yeah, notwithstanding an altogether different discipline, Science graduates represented an inferior ‘caste’ and needed to be treated as such.

A classic case of conflict due to combined effects of majority-minority dichotomy and social stratification it was. One hopes the current generation is more sensible and that things are much better now.

Call it race, caste, tribe, religion, institutional loyalty, nationalistic pride, geographic superiority or “phylumbaazi” (a colloquial term frequently in use in the region) – excessive invocation by these groups of collective entitlement of their members render them nothing more than refuges of mediocrity. For people who do that are not contributors to the value of the group, but are exploiters of the current value. This applies as much to the “superior” group as to the “inferior” group. Fundamentally they are doing the same. One wants to continue to get the benefits by victimising others for the current perceived superiority of its group, and the other wants to continue to get the benefits of being the victim. None is bothered about the declining perceived value of their respective groups because of their frequent stake at entitlements.

True value-adders of either group do not need benefits of perception. On the other extreme, the bottom-dwellers of either group are content with what they have. It’s the mediocre people in the group who stake a claim to the cake without actually contributing to its making. Unfortunately, the statistical bell curve ensures that such mediocre people will be in the majority. So in the end whether this majority follow the value-adders or dictate their terms onto them determines the merits of the group. It’s not hard to see then why true value-adders sometime leave a group they naturally belong to.

We see people seeking entitlements for various reasons, often at the expense of true merit. One common scenario is: we stuffed it up and are now entitled to prevent others from stuffing it up further. Yet another: we once studied head-down-bum-up to acquire this highly coveted qualification or get into this universally revered institution and now will reap benefits for the rest of our lives. Or: we were treated unfairly when we were new and now that we have reached this position of dictating terms, why should the freshers have it easy? Or simply, we are the sons of the soil and therefore entitled to chew up all the resources here without being accountable to anyone. Whatever the cause, such claims of entitlements have one thing in common – the rhetoric usually comes from the mediocre in the business. And when they seek to extend such entitlements for their offspring, the caste comes in handy.

How to create in zero easy steps

Ever thought of writing a story or composing a piece of music? And wondered what training courses might help? Training helps. Not in creativity though. It might help you master the tools and techniques. But that’s it. It won’t help at all with the creative process.

The very fundamental requirement of training is existence. Of processes. Of tools. Of things. That’s what one will train on. And the very fundamental requirement of creation is non-existence. That’s what one will bring about. Did you see the contradiction?

Music is an arrangement of sounds into patterns. Sounds need to be produced using tools and knowing techniques on how to use the tools. The tools are, to name a few, a flute where wind has to be blown into, a guitar where the string needs to be plucked, or a drum that needs to be struck. Voice is also generated using our own biological tools. One can train on efficiently using any of these tools by mastering the techniques. Does that mean however one can produce music? No.

Learning to ‘use’ a tool to produce sound is similar to being literate. Mere learning to use a language can never make a creative writer. One may just know how to convey a message using a language. Some other may be expert in using the language with correct usage of syntax every time. Still, he or she is just ‘using’ the tool and not creating anything. As long as, of course, he or she is not ‘composing’ a new tangible using a new idea. Unfortunately there is no training for that. There cannot be.

Idea-to-tangible realisation does require the help of people trained in skills, but that’s further down the line. The first step is ‘generating’ the idea which requires one’s intuition to work. The second step of ‘composing’ something from the idea also is intuition-heavy though it may be assisted by learned skills. It is when one wants to convert the composition into tangible outcome that skills become important. Because this is where we are talking of tangible things, people become aware of things from this stage on. Unfortunately, many wrongly presume this to be the first step in creation. Without the first two steps of ‘generating’ and ‘composing’ the idea, there really is nothing new. It can at best be a smart rehash or at worst outright plagiarism.

कैसे भूलूँ

वो तारीख कुछ और थी
चन्दन भी नहीं, रंग था
माथा मगर था मेरा
और हाथ तेरा संग था

उसी दिन की याद में
दिन आज बिताना है
यादों का ये रिश्ता है
यादों से निभाना है

Mother Keeps

Be. Do. Life seems to be constantly switching between these two modes. You would be hard-pressed to choose between the two. If activity is what makes life ‘life’, you can’t perform if you don’t survive. You can’t however rest easy just by surviving. What’s the point of living if you don’t do anything good? And to just survive also, you need to ‘do’ things – build shelter, find food, participate in the ritual of reproduction, etc. Survival and activity very much go hand in hand. And none is more important than the other. That’s life. An intelligent mix of survival and activity. Of be and do. Of maintenance and project. Of upkeep and progress. Of reproduction and metabolism.

There are different scales and perspectives at which we witness life’s survival and activity. One may go on to generalise the dominant role of plants in the ‘survival’ of life and of animals in the ‘activity’ of life. Animals after all have the attribute of motility which takes them around to perform. Plants on the other hand are literally rooted to protect life. Sure it does not mean that plants only ‘be’ and animals only ‘do’. It’s the dominant role we are talking about here. And remember neither of upkeep and progress is more important than the other.

In a similar vein, the nature appears to have conferred upon females the generic role of survival and upon males of making changes. Female body is equipped with ‘inward’ strength and male body with ‘outward’ strength. The nature has relied on the solidity of female’s inward strength and given her the principal role when it came to reproduction. The male’s contribution is restricted to providing sperm for fertilization. Even his mitochondria are not allowed to pass on to the offspring. In most plants too only the maternal mitochondria and chloroplasts are inherited by the offspring. Viewed this way, the heritage of life lies with the female. Mind you, life survives through reproduction only. Women are the true carriers of ‘vansh’ in that sense. Glad we have a festival that celebrates a female deity.