Monday, March 10, 2014

Stem cells

Adult body is a specialized machine with each part perfected for its intended function. Most cells in the adult body are irreversibly differentiated to form parts of this machine. Such as the heart, where the myocardial cells form an interconnected bundle that can contract in unison upon receiving instructions from the cardiac pacemaker. Or the brain, which contains millions of neurons connected through synapses designed for this command centre to integrate and control all the activities of the organism from digestion to perspiration to locomotion to reproduction to introspection.

The life of every animal starts off from a single cell known as the zygote. This single cell divides prolifically to give rise to the embryo, where progressively cells exit cell cycle, specialize for a particular function and differentiate. However, there are organs in the body that undergo regular wear and tear and require continuous repair and replacement of lost cells. Examples include the skin, gut lining, blood etc. These organs retain a small population of reserve cells that do not differentiate. These cells proliferate, repair, renew and regenerate the organs as and when required. These are the ‘stem cells’. 

In 1877, the famous German biologist Ernst Haeckel used the term ‘‘Stammzelle’’ (German for stem cell) in his book Anthropogenie to mean the zygote as the originator of all cells in the organism. Towards the end of the century, scientists studying hematopoiesis arrived upon a cell that they called the ‘stem cell’, which was capable of giving rise to all the diverse lineages of blood cells viz. the erythrocytes (red blood cells) and leukocytes (T-cells, B-cells, macrophages, neutrophils, eosinophils etc.). This modern concept of stem cell, as a cell that can divide and self-renew indefinitely and that could differentiate into a number of different cell types was introduced and demonstrated by James Till and Ernest Mcculloch in 1960s. Mice irradiated with high dose of X-ray die rapidly because the radiation kills blood cells essential for oxygen transport and immunity.  Till and Mcculloch found that these mice could be rescued by injection of bone marrow from a normal mouse. The bone marrow contained ‘hematopoietic stem cells’ (HSC) that could recolonize the marrow of the irradiated mice and thus provide a steady supply of all blood lineages for life.

Adult stem cells thus reside in niches, usually within the tissue that they repair and regenerate. In the stem cell jargon they will be defined as ‘multipotent’, i.e. having the potential to differentiate into a number of different cell types. Usually one stem cell population can replenish losses in a few different cell types e.g. the intestinal stem cells that reside in the crypts of the intestinal villi are multipotent. These stem cells continuously undergo cell division and supply the gut with enterocytes (absorptive cells that absorb nutrients from the food), goblet cells (that secrete mucin to form mucus), enteroendocrine cells (that secrete intestinal hormones) and the Paneth cells (that provide defense against microbes). They also replenish the stem cells themselves. However, an adult stem cell does not have ‘pluri’potency; an intestinal stem cell cannot form heart or brain cells.

The zygote is a ‘totipotent’ cell; it has the potential to form any tissue or cell type in the animal body, rather the zygote gives rise to the whole animal. Embryonic stem (ES) cells are created by growing young embryos in artificial culture conditions. These cells are ‘pluripotent’ i.e. they have the potential to differentiate into almost all cell types in the animal. By controlling their growth conditions they can be made to differentiate into brain, heart, muscle, pancreas and many other cell types. In 1998 James Thomson of the University of Wisconsin created the first embryonic stem cells from human embryos donated by individuals after informed consent. These embryos had been created by in vitro fertilization (IVF) for fertility treatments. The scientists were able to keep these cells dividing in culture conditions for months and they became established cell lines, being used by scientists around the world even today.

James Thomson’s discovery came in a climate of controversy and regulations. Since 1970s successive American governments headed by Ronald Reagan, George H W Bush, Bill Clinton and George W Bush have instituted a series of bans on embryonic research. In 1993, the United States President Bill Clinton had lifted an existing moratorium on government funding for embryonic research, only to rapidly reverse the order under public pressure. In 1995, the U.S. congress banned federal funding for any research involving the destruction of human embryos under the Dickey-Wicker Amendment. It was during this time that Thomson created the first ES cells using private funding.

The funding and legal problems in working with human embryos and embryonic stem cells had prompted scientists to think about alternatives. In 1960s John Gurdon in Oxford University, U.K., had demonstrated that you could replace the nucleus of a frog oocyte (an immature female reproductive cell) with the genetic material (contained in the nucleus) of an adult frog cell and create a live tadpole. The tadpole was thus a clone of the adult frog, which donated the nucleus.  Gurdon hypothesized that all the genetic information needed to create a whole organism is contained in the differentiated adult cells of the organism. However, you need the ‘reprogramming’ environment of an egg cell to activate this potential. This was the origin of the cloning of ‘Dolly’, the sheep cloned from the udder cells of a Finn-Dorset ewe in 1996.

Thus, the hunt was on to define the reprogramming molecules that were needed to make an adult cell regain its pluripotency. In 2007 using a combination of just four proteins, the Shinya Yamanaka and James Thomson labs simultaneously published the successful generation of pluripotent stem cells from adult human  somatic cells that they called the ‘inducible pluripotent stem cells’ or iPS cells. This has opened the door to patient-specific stem cell therapies for diseases ranging from neurodegenerative diseases, cardiovascular diseases, and accidental damage to tissues such as the spinal-cord and many others.

The creation of iPS cells frees stem cell research from the dependency on human embryos and thus religious and political controversies. However, stem cell therapies will continue to be controversial and will have to be administered with great caution. Stem cells are cells with immense potential for growth, a hallmark of cancer.


Stem Cell Resources

as published in the Manorama Year Book ® 2014

Tuesday, February 4, 2014

Real or Imagined?

Real or Imagined?

Right now I have a time-lapse experiment in progress at home. An infant beginning to appreciate that a person disappearing behind the curtain is not gone, just hidden; now a toddler who enlists me in pretend-play.  The neuronal circuits necessary for imagination are busy being built.

The history of western art charts an analogous course for human civilization. Early examples of art relied heavily on ‘true-to-type’ representation of reality. From ancient Greece to Rome to Renaissance, art was all about how well you could recreate in stone or canvas what you see, as you see it. Parisians graduated to Impressionism when one day in 1874, Claude Monet’s ‘Impression, Sunrise’ (Impression, soleil levant) was unveiled. A few seemingly random strokes of paint on canvas, enough for us to visualize the luminescent descent of the sun into the sea, was equated to an unfinished wallpaper by the art connoisseurs of 19th century.

How is it that a few daubs of paint can evoke a whole scene in our mind? How is it that a stray strain of music or a whiff of a smell can bring alive a long forgotten experience? These are complex problems of imagination that we are nowhere near answering. But starting from the most basic examples of imagination, we are getting closer to understanding what our brain is capable of.

When I look at the park through the bars of my bedroom window, I don’t see ten different square-shaped pieces of the tree outside; I see a whole tree and the squirrel scurrying up to its hole in the trunk. As I stare at the computer screen through my thick-rimmed glasses, my brain fills in the letters that are hidden behind the frame. More extremely, as VS Ramachandran describes in Phantoms in the Brain, patients who have injured their visual cortex and develop what is known as a scotoma, a hole in their visual field, live on apparently quite normally, filling-in appropriate information into the missing regions of their visual field; as a patient describes it, just occasionally walking into the wrong toilet by mistake when his scotoma hides the WO in the ‘WOMEN’.

Our brain, or more specifically the left hemisphere, is a master at glossing over the anomalies in our otherwise mundane world. It learns at an early age, with perhaps some contribution from evolution, the lay of the land. Confronted with confusing and apparently counter-intuitive information it confabulates to reassure our ‘mind’ that all is well. The right hemisphere on the other hand, specializes in dealing with new information. Thus, patients with a damaged right hemisphere and consequent left-side paralysis often become anosognosic, unaware of their disability, even to the extent of claiming to hear their two hands clapping!

Another version of anosognosia is described by Oliver Sacks in his ‘The Man Who Mistook His Wife for a Hat’. The patient is an accomplished musician who is living an apparently normal life although he is progressively unable to recognize objects, faces, his wife (whom he mistakes for a hat!) and even his own foot. He describes a glove as “a continuous surface, infolded on itself. It appears to have five outpouchings ...”, but does not recognize it as a glove, until by trial and error he manages to put his hand into it. Sacks happens to see a series of paintings done by the patient in the years leading up to and during the progression of his disease. They begin as realistic scenes with an attention to detail and progressively move towards geometric representation, then to a complete abstract lines and splotches.

This brings me neatly back to art and its move towards increasingly abstract forms. Today, we flock to see the cubist representations of Picasso, the surrealism of Dali and the experimental installations of Olafur Eliasson. Each in its own way challenges our senses, questions our perceptions of the world around us and makes us rethink our experience of what we call reality. The modern forms of art speak differently to each one of us. Richard Dawkins in his book, Unweaving the Rainbow, describes how when we all stand together and admire the rainbow in the rain-washed sky, each of us is, in reality, appreciating a slightly different rainbow, reaching our eyes through a slightly different set of prisms blowing in the wind.

Schizophrenia is defined as a mental disorder that makes it difficult for the patient to tell the difference between the real and unreal (according to Pubmed Health). The deeper we dig into the workings of this wondrous mass of lipids we call ‘brain’, reality, as we know it, becomes all the more unreal. Perhaps it is just a question of where we are when viewing the rainbow.

Sources:
The story of Art by EM Gombrich
Phantoms in the Brain: Probing the Mysteries of the Human Mind by VS Ramachandran  and Sandra Blakeslee
The Man Who Mistook His Wife for a Hat and Other Clinical Tales by Oliver Sacks
Unweaving the Rainbow by Richard Dawkins
Pubmed Health
Lots and lots of Google!!

Only as far as we imagine…

Only as far as we imagine…

On a clear night 20,000 years ago a man lay next to the warming fire and gazed upward; he saw a glittering dome that contained the world he lived in. Today when I lounge on my balcony and stare up at a smog-obscured-night-sky, I see an infinite universe, perhaps one of many; a vast nothingness punctuated by millions of insignificant balls of fire with finite life spans, around one of which we spend our precariously short existence. Over the last many thousands of years, we have shattered that domed-roof over our heads and thrown back its limits into the reaches of infinity. And all because we dared to imagine, imagine an infinity, imagine a time even before time.

However, our world is only as big as we can imagine. Our discoveries will remain contained within the boundaries of our imagination. If we cannot imagine it, we shall not discover it. The 17th century philosopher Benedictus Spinoza once saidif a triangle could speak, it would say, in like manner, that God is eminently triangular’. So do we, a carbon-hydrogen-based life-form think that life is where water is. We go hunting for obscure marks of water-that-once-flowed on the surface of far away planets. But is that the limit of possibilities or is that just as far as our imagination can take us?

We are a species capable of unparalleled imagination. In these last 20,000 years our brain has taken us on journeys beyond experience; shading our eyes to gaze outward as far as the edges of universe or peering inward to dissect the minutiae of that brain itself. But these boundaries were not reached in one leap but in steps, some small, some giant.

In his book A short history of nearly everything Bill Bryson says, ‘Once in a great while, a few times in history, a human mind produces an observation so acute and unexpected that people can’t quite decide which is the more amazing ­– the fact or the thinking go it.’ He is talking about Newton, but the same could be said of the other few times that mankind has taken that giant step forward. ‘The thinking of it’ is so amazing, so freeing, that like that first thin stream of water breaching the crack in the dam, it lets the rest of the river of human knowledge burst through, washing away the remnants of the dam. Our imagination leaps ahead into the space opened up, suddenly free and unrestrained, until that is, a new wall is reached. 

The history of science is littered with such ‘feats of thinking’. Like when John Snow was faced with a cholera epidemic decimating 19th century Londoners. London was a vile place full of disease. Under the ramshackle houses lining the busy streets were cesspits with years of accumulation of refuse and excrement. Snow focused his attention on one street where nearly 500 people had died in a matter of two weeks. In an inspired epidemiological study he identified the commonalities between the patients and proposed that the source of the disease was contaminated water coming from a single pump down the street. In a world that believed diseases were either punishment from the gods or a result of bad air, this required quite a leap of imagination. The authorities were reluctantly persuaded to disable the pump, saving hundreds of lives.

James Hutton lived in 18th century Britain. He trained to be a medical doctor, became a farmer but is now known to us as the man who founded modern geology. Just as we all do, he too liked a beautiful landscape of mountains and valley and rivers and lakes. But he went further to note that although wind and water constantly erodes mountains and carries the sediments down to the sea and the plains, the world has no dearth of mountains. That sometimes you can find remains of sea-creatures high up on the mountains. The Christian faith maintained that earth was created 6000 years ago and that all change happens by cataclysmic events such as the Great Flood. Hutton’s imagination came up with another explanation. After years of painstaking observation and collection of data from various parts of the Europe, he proposed that the reshaping of earth’s landscape is the result of continuous but slow incremental change wrought over millions of years. These geological changes are constantly restructuring the earths crust, moving not just mountains even continents, thus today’s oceans may become tomorrow’s mountains and vice versa.  In one fell swoop Hutton pushed the age of earth back from a mere 6,000 years to millions of years. 

Most scientific discoveries are made by a handful of people. Another handful of people are intellectually able to understand and critique the discovery. The rest of us merely struggle to interpret the results and how it changes the world as we know it. Nowhere is this more true than the science of the origins of our universe. In early 20th century, astronomers began to suspect that we live in an expanding universe. In the 1920s Edwin Hubble, after whom the Hubble telescope is named, realized that everywhere you look, galaxies are moving away from us. This led to the idea that, at the beginning of this expansion all the contents of our universe must have been concentrated in one place, from where it shot out in all directions, in other words, in the beginning there was an explosion, the Big Bang. Since we know how far the galaxies are from us today and also the rate at which they are receding from us, we can calculate the time at which it all began, around 13-14 billion years ago. In 1940s George Gamow and colleagues imagined that if the universe did indeed begin with a big bang, there must be residues of the ‘bang’ still reverberating through space. A prediction that was proved correct when in the 1960s Arno Penzias, Robert Wilson and Robert Dicke in their experiments encountered an annoying all-pervasive background radiation that wouldn’t go away. So after 14 billion years our world still resonates with the violence that began our universe.

Our imagination has carried us far. We have discovered much. But each discovery births new questions, new wonders, new boundaries to be breached, new walls to be scaled. As Ralph Sockman said, ‘the larger the island of knowledge, longer the shorelines of wonder’. 

But how much can we discover? Is there a limit to our knowledge? Do we still live inside a dome in the sky, no matter how big? Perhaps that dome is not in the sky, rather we carry it around with us, in our heads. The day we stop imagining, we would have found that dome. Nature is not an easily read book. It allows us only tiny glimpses of its secrets, opening only those windows we knock on. As long as we have the zeal to find a new window to knock, there will be secrets waiting to be discovered.  

Readings:
 A Short History of Nearly Everything by Bill Bryson (an excellent light reading!)
A History of Western Philosophy by Bertrand Russell
Lots and lots of Google!!