What time is it - Part 2

Please read Part 1 of this blog here: What time is it? Part 1

Time Dilation and Time Travel:

Einstein showed time is "relative" to the speed of the observer, and time can be “dilated” or "slowed" when something or some one is moving very fast – at relativistic velocities approaching speed of light "C" – through the spatial dimension. Another of Einstein's revolutionary idea was the force we call gravity is nothing but "distortions" in the fabric of space time created by massive objects and energy. Gravity in turn changes how time moves, just like how velocity along spatial dimension changes how time moves. A clock at lower gravity will tick faster than will a clock at higher gravity. In other words, if you live in a multi story apartment, time passes more quickly in the top floor penthouse apartment than it does in your basement apartment! The slowing is of such a minute quantity it would go un noticed and billions of years will have to pass before your clock will gain one extra second before your penthouse neighbour. However at conditions of extreme gravity, time indeed slows down significantly. The poster boys for extreme gravity are the Black Holes. What happens to time at the center of black holes? Well it actually comes to a standstill – just as a photon don’t perceive the passage of time, time also comes to an absolute standstill at the center of a black hole. 

Strange as it may be, but what is remarkable is that the so-called time dilation effects have been verified in a number of experiments, which used to depend on large scales of distance or velocity. However with exquisitely sensitive modern clocks, scientists are now able to document the extremely small time dilation that happens in ordinary situation. In a series of experiments described in the September 24, 2010, Science, researchers at the National Institute of Standards and Technology (NIST) registered differences in the passage of time between two high-precision optical atomic clocks when one was elevated by just a third of a meter or when one was set in motion at speeds of less than 10 meters per second!

Time travel is a favorite of ploy of fiction writers. But what does Einstein’s theory of general relativity says about time travel? As noted, the faster one moves in the space dimension, the slower the same person’s movement in the time dimension. So time travel to the future is quite feasible, theoretically at least – and the two ways to do this is either to travel very, very fast, or get inside an intense gravitational field. However to have a meaningful time travel to the future, the “fast” means travelling very close to the speed of light, or to be in a gravitational field so intense that can only be provided by a structure like a black hole. 

As an example, one could imagine an astronaut taking off from earth in an imaginary rocket that can travel at 99.995 % the speed of light in year 2015. Let us assume he travels at this speed to a star around 500 light years and then travel back to earth. Due to relativistic time dilation (see my blog How fast does Brahma moves? for details), as far as the astronaut is concerned, the whole trip would have lasted only 10 years! While for earth and earthlings, moving leisurely around the sun (at speeds far less than the speed of light), time would have moved on by 1000 years, and when the astronaut is back, 10 years older, earth year would be AD 3015! Again, though it may appear confusing – both the astronaut and earth has moved the same distance in “space time”. The difference is that while most of the astronaut’s movement was in the “space” dimension of space time, for earthlings, most of the movement occurred in the “time” dimension of space time. 

How about going backward in time? This is much harder, even theoretically. In fact Einstein’s special theory of relativity forbade both backward travel as well as travelling faster than speed of light. However Einstein’s general theory of relativity lifted this restriction. The first person to use general relativity to describe a universe that permits time travel into the past was Kurt Godel, one of the towering mathematicians of the 20th century. The story is that Godel presented this model universe (where time can move backwards) as a gift to Einstein on his 70th birthday. 

The universe Godel described is mathematically complex but accurate, and remains within the bounds of general relativity. These mathematical models or trajectories where time can "flow" backwards is called “closed time like curves.”

A closed time like curve is any path through space time that loops back on itself. In Godel’s model of a rotating cosmos, such a curve would circle around the entire universe, like a latitude line on Earth’s surface. Though it was mathematically accurate, Einstein did not like a universe where time could flow backwards – since if such a curve exists, it would question some our fundamental notions of causality as could be shown by the classic "Grandfather's paradox"“ (What happens to a time traveler who kills his or her grandfather before the grandfather meets the grandmother? Would the time traveler ever be born?)

Fortunately, there is no evidence universe actually has any “closed time like curves”. Godel might not have devised a realistic model of the universe, but he did prove that closed time like curves are completely consistent with the equations of general relativity. The laws of physics do not rule out traveling to the past.

A Universe that birth itself: 

Godel conjured an entire universe that allowed CTCs, but more recent interest is in warped space time within parts of our universe. As noted previously, according to general relativity, planets, stars, galaxies and other massive bodies warp space time. Warped space time, in turn,guides the motions of those massive bodies. Physicist John Wheeler put it succinctly, “Space time tells matter  how to move; matter tells space time how to curve.” In extreme cases, space time might bend enough to create a path from the present back to the past. Kip S. Thorne, a physicist at the California Institute of Technology, was the first to explore the possibility that a type of closed time like curve called a "wormhole" —a kind of tunnel joining two different locations in space time— might allow for time travel into the past. If we can connect two different regions of space, we are also connecting two different regions of time! (of note: Kip Thorne was deeply involved in the recent blockbuster movie “Interstellar” which explores these possibilities in a fictionalized way)

As correctly portrayed in the movie, the entrance into a wormhole would be spherical—a three dimensional entrance into a four dimensional tunnel in space time. However the theory predicts that, even for a traveler going through a wormhole, time flows forward at one second per second. It’s just that the traveller’s version of ‘forward’ might be globally out of sync with the rest of the universe.  Although physicists can write equations that describe wormholes and other closed time like curves, all the models have serious problems. For one thing, to get a wormhole in the first place, one need negative energy. Negative energy is when the energy in a volume of space spontaneously fluctuates to less than zero.  Without negative energy, a wormhole’s spherical entrance and four-dimensional tunnel would instantaneously implode. But a wormhole held open by negative energy “seems to be hard, probably impossible,” As per Sean Carroll. Moreover as the particles moving through a wormhole would loop back an infinite number of times, leading to an infinite amount of energy. And as energy deforms space time, the entire thing would collapse into a black hole—an infinitely dense point in space time.   Unlike black holes, which are a natural consequence of general relativity, wormholes and closed time like curves in general are completely artificial constructs— a way of testing the bounds of the theory. 

A recent publication (Can the Universe Create Itself? by Gott and Li) on the origin of universe argue that closed time like curves were not merely possible but essential to explain the origin of the universe.  They investigated the possibility of whether the universe could be its own mother— whether a time loop at the beginning of the universe would allow the universe to create itself! Gott and Li’s universe “starts” with a bout of inflation—just as in standard big bang cosmology, where an all-pervasive energy field drove the universe’s initial expansion. Many cosmologists now believe that inflation gave rise to countless other universes besides our own. “Inflation is very hard to stop once it gets started,” Gott says. “It makes an infinitely branching tree. We’re one of the branches. But you have to ask yourself, where did the trunk come from? Our theory suggest that one of the branches just loops around and grows up to be the trunk.” A simple two-dimensional sketch of Gott and Li’s self-starting universe looks like the number “6,” with the space time loop at the bottom and our present-era universe as the top stem. A burst of inflation, Gott and Li theorized, allowed the universe to escape from the time loop and expand into the cosmos we inhabit today. 

       Gott-Li Model of a Universe Giving birth to itself with Closed Time Like Curves                           (Note that each funnel like structure represent separate universes) 

It is difficult to contemplate the model, but its main appeal, Gott says, is that it eliminates the need for creating a universe out of nothing. (Note here that Stephen Hawking and Lawrence Krauss have proposed models in which the universe does indeed arise out of nothing. According to the laws of quantum mechanics, empty space is not really empty but is filled with “virtual” particles that spontaneously pop into and out of existence. Hawking and his colleagues theorized that the universe burst into being from the same quantum-vacuum stew). But in Gott’s view, the universe is not made out of nothing; it is made out of something—itself.

These wildly speculative ideas may be closer to philosophy than to physics. But for now, quantum mechanics and general relativity—powerful, counter intuitive theories—are all we have to figure out the universe.

Singularities and the End of time: 

Just like origins, we are equally fascinated by endings. In our experience, nothing really ends – when we die, our bodies decay and the material in them returns to the earth and the air, allowing for the creation of new life. But will that always be the case? Might there come a point sometime in the future when there is no “after”? Modern physics suggests the answer is yes. Time itself could end. All activity would cease, and there would be no renewal or recovery. The end of time would be the end of endings.

This scary prospect was also an unanticipated prediction of Einstein's general theory of relativity. Albert Einstein showed that time can slow down, or stretch out, or let it rip. Time not only affects what matter does but also responds to what matter is doing. But when time begins or ends we call them singularities. The term actually refers to any boundary of time, be it beginning or end. The best known is the big bang, the instant 13.7 billion years ago when our universe—and, with it, time—burst into existence and began expanding. If the universe ever stops expanding and starts contracting again, it will go into something like the big bang in reverse—the big crunch—and bring time crashing to a halt.

Time needn't perish everywhere. Relativity says it expires inside black holes while carrying on in the universe at large. It took physicists decades to accept that relativity theory would predict something so unsettling as end of time itself. To this day, they aren't quite sure what to make of it. Singularities are arguably the leading reason that physicists seek to create a unified theory of physics, which would merge Einstein's brainchild with quantum mechanics to create a quantum theory of gravity. They do so partly in the hope they might explain singularities away. Still, one need to be careful what you wish for. Time's end is hard to imagine, but time's not ending may be equally paradoxical.

To figure out what goes on will take a more encompassing theory, a quantum theory of gravity. Physicists are still working on such a theory, and they figure that it will incorporate the central insight of quantum mechanics: that matter, like light, has wavelike properties. These properties should smear the putative singularity into a small wad, rather than a point, and thereby banish the divide-by-zero error. If so, time may not, in fact, end.

Physicists argue it both ways. Some think time does end. The trouble with this option is that the known laws of physics operate within time and describe how things move and evolve. Time's end points are would have to be governed not just by a new law of physics but by a new type of law of physics, one that does not have temporal concepts such as motion and change in favor of timeless ones such as geometric elegance. One such notion comes from Brett McInnes of the National University of Singapore who used string theory to explain away the singularities. He suggested that the primordial wad of a universe had the shape of a torus; because of mathematical theorems concerning tori, it had to be perfectly uniform and smooth. Such a geometric law of physics differs from the usual dynamical laws in a crucial sense: it is not symmetrical in time. The end wouldn't just be the beginning played backward.

Other quantum gravity researchers think that time stretches on forever, with neither beginning nor end. In their view, the big bang was simply a dramatic transition in the eternal life of the universe. Perhaps the "pre bangian" universe started to undergo a big crunch and turned around when the density got too high—a big bounce. Artifacts of this prehistory may even have made it through to the present day.

By supposing that time marches on, proponents of this approach avoid the need to speculate about a new type of law of physics. Yet they, too, run into trouble. For instance, the universe gets steadily more disordered with time. If it has been around forever, why is it not in total disarray by now?

The bottom line is that physicists struggle with these questions no less than philosophers have. Faced with this dilemma, some people throw up their hands and conclude that science can never resolve whether time ends. It would seem that the boundaries of time are also the boundaries of reason and empirical observation. 

Is time continuous or granular (quantized)?

About 100 years ago, most people thought of matter as continuous. Although since ancient times some philosophers and scientists had speculated that if matter were broken up into small enough bits, it might turn out to be made up of very tiny atoms, few thought the existence of atoms could ever be proved. Today we have imaged individual atoms and have studied the particles that compose them. The granularity of matter is old news.

In recent decades physicists and mathematicians have asked if space is also made of discrete pieces. Is it continuous, as we learn in school, or is it more like a piece of cloth, woven out of individual fibers? If we could probe to size scales that were small enough, would we see “atoms” of space, irreducible pieces of volume that cannot be broken into anything smaller? And what about time: Does nature change continuously, or does the world evolve in a series of very tiny steps, acting more like a digital computer?

The past 25 years have seen great progress on these questions. A theory with the strange name of “loop quantum gravity” predicts that space and time are indeed made of discrete pieces. The picture revealed by calculations carried out within the framework of this theory is both simple and beautiful. The theory has deepened our understanding of puzzling phenomena having to do with black holes and the big bang. Best of all, it is possible that current experiments might be able to detect signals of the atomic structure of space-time—if this structure actually exists—in the near future.

Quanta of time

The theory of quantum mechanics was formulated in the first quarter of the 20th century, a development that was closely connected with the confirmation that matter is made of atoms. The equations of quantum mechanics require that certain quantities, such as the energy of an atom, can come only in specific, discrete units. Quantum theory successfully predicts the properties and behavior of atoms and the elementary particles and forces that compose them. No theory in the history of science has been more successful than quantum theory. It underlies our understanding of chemistry, atomic and subatomic physics, electronics and even biology.

Quantum theory and Einstein's general theory of relativity have each separately been fantastically well confirmed by experiment—but no experiment has explored the regime where both theories predict significant effects. The problem is that quantum effects are most prominent at small size scales, whereas general relativistic effects require large masses, so it takes extraordinary circumstances to combine both conditions.

Allied with this hole in the experimental data is a huge conceptual problem: Einstein's general theory of relativity is thoroughly classical, or nonquantum. For physics as a whole to be logically consistent, there has to be a theory that somehow unites quantum mechanics and general relativity. One of the candidates for this long-sought-after theory is called quantum gravity. Because general relativity deals in the geometry of space-time, a quantum theory of gravity will in addition be a quantum theory of space-time.

The theory of loop quantum gravity predicts that space is like atoms: there is a discrete set of numbers that the volume-measuring experiment can return. In other words, space is not continuous. It comes only in specific quantum units of area and volume. The possible values of volume and area are measured in units of a quantity called the Planck length. This length is related to the strength of gravity, the size of quanta and the speed of light. It measures the scale at which the geometry of space is no longer continuous. The Planck length is very small: 10⁻³³ centimeter. The smallest possible nonzero area is about a square Planck length, or 10⁻⁶⁶ cm2. The smallest nonzero volume is approximately a cubic Planck length, 10⁻⁹⁹ cm3. Thus, the theory predicts that there are about 10⁹⁹ "atoms of volume" in every cubic centimeter of space. The quantum of volume is so tiny that there are 10 million trillion more such quanta in a single cubic centimeter of space than there are atoms in the known universe (estimated to be 10⁸⁰!

In the space-time way of looking at things, a snapshot at a specific time is like a slice cutting across the space-time. But it would be wrong to think of such a slice as moving continuously, like a smooth flow of time. Instead, just as space is defined by discrete geometry, time is defined by the sequence of distinct moves that rearrange the spin network. Time flows not like a river but like the ticking of a clock, with “ticks” that are about as long as the Planck time: 5.4x10⁻⁴⁴ seconds. Or, more precisely, time in our universe flows by the ticking of innumerable clocks—in a sense, at every location in the spin foam where a quantum “move” takes place, a clock at that location has ticked once.

The arrow of time: 

How do we explain the arrow of time—the asymmetry of past and future. This appear one of the most common sense things to most people, that time should always move forward. However our fundamental laws of physic concerning space time are time invariant, meaning they could work equally well in both time moving forward as well as time moving back ward directions. One fundamental law that could explain the arrow of time – always moving to the future - is the second law of thermodynamics, which states that entropy, loosely defined as the amount of disorder within a system, increases with time. Yet no one can really account for the second law.

The leading explanation, put forward by 19th-century Austrian physicist Ludwig Boltzmann, is probabilistic. The basic idea is that there are more ways for a system to be disordered than to be ordered - this is our every day experience too, look at our children's room! If the system is fairly ordered now, it will probably be more disordered a moment from now. As Boltzmann recognized, the only way to ensure that entropy will increase into the future is if it starts off with a low value in the past. Thus, the second law is not so much a fundamental truth but related to events early in the big bang. The entropy or disorder of the very early universe at Big Bang had to be extremely small, so it could create an arrow of time. A common example to describe entropy is that we can break an egg easily, but “all the king’s men and all the king’s horses” can’t put the egg back as unbroken again. Big Bang was the cosmic egg that broke, and entropy has been increasing ever since, and this is what we perceive as the arrow of time.

Let me end my blog by quoting what Einstein himself thought of time, best summarized in a letter he wrote on the death of his beloved lifelong friend Michele Besso. (Especially poignant in that this was written only few weeks prior to Einstein’s own death)  

"...for us physicists belief in the separation between past, present, and future is only an illusion, although a persistent one." 
Dedication: I dedicate this blog to Moossa Koya sir, my Physics teacher from Pre Degree days, for instilling the love of physics in me with gratitude.
Suggested further reading:

1) My previous blog: How fast does Brahma moves?
2) A Brief History of Time: Stephen Hawking

3) From Eternity to Here: Sean Carroll

4) Origins: Cosmos, Earth and Mankind: Reeves, Rosnay, Simonnet and Coppense

5) The First Three Minutes: Steven Weinberg

6) A Universe from Nothing: Lawrence M. Krauss

7) The Meaning Of It All: Richard P. Feynman

8) The Accidental Universe: Alan Lighhtman

9) Time Reborn: Lee Smolin

10) Our Mathematical Universe: Max Tegmark

11) Cosmic Jackpot: Paul Davies

What time is it?

"Sometimes I think

When I see trees from a moving train, 
It seems
They go in the opposite way. 
But in reality
The trees are standing still. 
So can it be
That all our centuries, 
Row upon row, are standing still? 
Can it be that time is fixed, 
And we alone are in motion?" 

Javed Akhthar, "Waqt" 

Below is the above beautiful poem on time (Waqt) recited by the poet Javed Akhthar with his wife Shabana Azmi translating it to English:

Who among us have not agonized over the passing of time? But what is this unyielding force we call time anyway? Everyone has an idea what time is but defining time is much more complicated. Time and the flow of time have fascinated poets, philosophers and scientists from the dawn of humanity. In fact one could even make an argument that human ability to perceive the passing of time, our ability to remember and recall the past and our propensity to worry and plan about the future probably defines our species and human consciousness more than anything else. Even though other species may have a rudimentary understanding of the passing of time, human consciousness is so exquisitely attuned to the passing of time. While the primitive men divided their days approximately based on the position of the sun and other natural phenomenon, once we found out how to make accurate clocks that can measure time at ever smaller intervals, our perception on the passing of time have become ever more acute.  

Till Einstein came along and completely changed our understanding of what time is, every one - whether it was a Newton or an average Joe- thought of time (and space) as this fixed, immutable back ground up on which the cosmic drama played out. However the modern understanding of time has not really been understood by many, including myself, till I started reading many excellent books on the topic, listed at the end of this blog. Here is my attempt at summarizing what I have been reading on time. The books at the end of this blog is recommended for those interested to understand this most elusive and fascinating of concept in more depth. The blog is organized in to several sub headings, each addressing a salient question on the nature of time.

What is meant by space-time and how is it different from just time?

We don't think time and space has anything to do with each other - and until about 100 years ago these entities - space and time - were indeed considered separate domains. Space as this nearly infinite expansion through which things move; and time as this almost mythical and all pervasive entity in which everything including our own life plays out - from the irretrievable past, to the fleeting present, to the as yet unknown future, time reigns supreme over our very being. Then came Einstein. Of all his major and path breaking contributions to science, it would be his truly revolutionary re branding of what time is that will be most likely to be remembered for posterity. He was the first person to truly grasp that time is truly a 4th dimension of what would be called "space time".  Time and space were created together and will remain bound to each other for eternity - there is no space without time and even more strangely, there is no time without space.

A Relativistic version of Javed Akhtahr's poetry:

So are we, like the poet Javed Akhthar beautifully wrote, passing through space time which stands still while we move? What Einstein showed with his remarkable theory of Special Relativity is that nothing moves through time and space independently – instead we move through "space time" – which is an inseparable 4 dimensional entity. The great cosmic drama as well as our own individual life is played out in "space time". It took some time and several books for me to finally "get" it but it is a pretty amazing and in fact quite a simple idea and only needs some basic geometry to grasp. Below is an ultra simplified version of what moving through space time means:

Think of a simple graph paper, with an X and a Y axis. To simplify let us change the three spatial dimensions to just one - X. Now let us make the Y axis as the "time" axis. Or think of a cross road with one road going straight in the North - South axis (time or Y axis ), one going straight in the East - West (space or X axis) direction. If you travel exactly East West, your movement along the North South axis would be 0 and vice versa. But you can also travel in a slanted direction some time (like North-East direction) where you will be displaced along both the X and Y axis - but for a shorter distance along the both North and East axis than if you were traveling straight North or straight East - right? Just imagine yourself driving a car.

Now for moving in the spatial dimension, there is a cosmic speed limit that just can’t be broken – and this speed limit is the speed of light (denoted as C). Note here that this is a universal constant and the speed of light (C) is one of the few things that are not "relative" in relativity - everyone irrespective of their frame of reference and speed would always agree that the speed of light C as the same; surprisingly however for this to work people will have to disagree on the measurements of space as well as the passing of time, and this forms the core principle of Special Relativity. 

Assume something is moving at speed (C) in the X axis (meaning through space), it has no movement along the Time (Y) axis. That is another way of saying photons, that is moving at
speed "C" don't "feel" the passing of time as all its movements are along the "space" dimension of space time and none in the time dimension.

If something is stationary in the "space dimension" (our tiny movements barely count when compared to C) then all the movement occurs in the Y or time axis. This is what we perceive as the flow of time. It is not like new time is being created for us to move through - all of space time - past, present and future - is all there already, just that our "light cone" has not yet reached a "future" part of this light cone. But as we are "standing still" in the space dimension our only movement through space time is along the time axis - and we are constantly being moved along our light cone, at a rate of one second per second. (To be more specific, we are moving at one Plank second increments - a time so small, there are more Planck seconds in once second than there are seconds since the beginning of Big Bang. As we will discuss later, time, like space, matter and energy, is also "quantized" and granular and not continuous.) 

So unlike what our intuition suggest, it is not like the past is lost forever and future not happened yet - it is more like we can't go back to our past light cone and we have not yet interacted with the already existing future light cone. Assume moving through time is like travelling north on highway I-95, and assume "north" represent your future along the time axis. Say you are travelling from Washington towards Boston and currently you are in New York. Your past is Washington; your present is New York, your future is Boston. Surprising as it may sound, just because you can't go back to Washington (your past), it does not mean "Washington" does not exist anymore, also just because you have not reached Boston yet (your future) that "Boston" does not exist. Similarly the past, present and future are all spread out in the 4 dimensional tapestry of space time. An imaginary being (call it God if that makes you feel better) that is outside of space time could potentially see the whole of space time - past, present and future - spread out, and everything moving through this 4 dimensional vista. See the picture below that shows the past, present and future parts of what is technically called a "light cone" of space time. 

Let us come back to Javed Alhthar's poetry - is past, present and future just illusions of our mind, are we just consciousness moving through a fixed and immutable space time? Another very simple "thought experiment" could help to clarify this further: Assume you are at the beach today sunbathing. Let us also assume there is another conscious being who lives in a planet around a star 5 light years away, who has a super sensitive telescope that could see a person lying on a beach on earth. It is possible for him to see you, lying on the beach, if he looks towards earth 5 years from now! Which means your "Present day" is in his "future". Let us reverse roles now - assume you have a super sensitive telescope with which you could see an alien sun bathing (or "proxima centauri" bathing!) - and assume you are seeing this alien today, what you are actually seeing is the past, say some thing the alien did some thing like 5 years ago (if the alien is 5 light years away). Now the alien could be a billion light years away - and then what you are seeing is what the alien did 1 billion years ago. We do agree that when we look at the night sky with a powerful telescope and see a star billions of light years away we are actually seeing the past. 

In fact one can extrapolate that thought experiment even further - assume a super civilization who lives 1 billion light years away would develop a technology to capture extremely detailed space time data 1 billion years from now - aiming at earth, it should be theoretically possible for that alien to recapture every moment of some one who is living on earth right now, but it would be happening "right now" according to their clocks - every single detail of a person long dead will appear to be preserved in their present! In other words the changes we create on our light cone never really goes away. In other words, what happens in Vegas does not stay in Vegas - it stays as permanent imprints on our light cones. On a more positive note, nothing of the past is ever totally lost.

So the past is not lost; and present is not fleeting; and future is already there - it is just that we have not yet crossed our own future light cone. Our "past" light cone is not actually gone from the universe but is going to be in some one else's future. In other words, while our past and present are permanently imprinted on our light cone, and while our future light cone is already there, it is just that we are yet to interact with it. We can thus show that, even without resorting to any kind of space travel or moving at relativistic velocities, the concept of "past, present and future" is much more fluid than what our intuitions suggest.

To recap again on the concept of moving through "space time" - see the graph below. The green line shows movements along space time. The left most graph represent how we - and most everything else - move through space time. As stationary objects (for all practical purposes the minimal movements we make when compared to the speed of light can be considered to be 0), all our movement are along the Y (time) axis, at 1 second per second.  The right most graph represent how photons move through space time - all it's movement are along "space" axis, none through time, so time is standing still for a photon. The middle graph represent movement of particles moving along at near relativistic velocities - say at 90 percent of C - it moves along a diagonal in the graph, in both space and time. The faster in spatial movement, the slower in the time axis.

Also note here the equivalence of moving through space and time can also lead to equivalence between mass and energy. Mass–energy equivalence arose originally from special relativity as a paradox first described by French mathematician and philosopher Henri Poincare. It can be shown with few simple steps, once we assume things move through space time and not space, that energy "E" and mass "m" is reliant on the speed of light "c" and described by the famous equation, E=mc^2

What is meant by "Time is relative?"

The above graph also explains what we mean by saying that time is relative. In our every day experiences time is absolute. Whatever else may change, time moves forward at the same constant rate for at the same rate for every one - we automatically assumes there is a "universal clock" and time moves the same all throughout the universe. 

But as the graph shows time (how much one move along the Y axis in the above graph) depends on one's speed of movement along the spatial dimension.  Every thing has to move through "space-time" - it's actually not possible to move through space and time separately. One has to move through time and through space simultaneously. Also note that there is no state of absolute rest. If you are not moving through space, then you are moving through time. One could also say that when we move through space-time by 1 second to the future, it is equivalent to a spatial movement of 300,000,000 meters by a photon.

If you could extend the ideas of Special Relativity to a photon, you might conclude that its (theoretical) clock never beats. But if the photon did have a brain, it would be thinking the problem lies with your clock and that its clock is just fine. Instead, it would seem to the photon that all of space had shrunk down so small that it (the photon) occupied all of it. It would arrive "everywhere at once", not because of its non-beating clock, but because of its peculiar view that it occupies the entire universe at once.

Thus for even the earliest photons ever created - the photons that make up the cosmic microwave background, no time would have passed in the photon's reference frame since it was emitted almost 13.7 billion years ago. Similarly for something moving close to the speed of light but not the speed of light itself, the time that has passed would be correspondingly low. We could calculate that an imaginary traveler moving at about 99.99999999999999999999999999999999973% the speed of light would have completed a 13.7 billion light year (in our time and space scale) journey in a mere second according to his own watch.

Does Time have a beginning?

In one form or another, the issue of the ultimate beginning has engaged philosophers and theologians in nearly every culture. It is entwined with a grand set of concerns, one famously encapsulated in an 1897 painting by Paul Gauguin: D'ou venons-nous? Que sommes-nous? Ou allons-nous? “Where do we come from? What are we? Where are we going?” The piece depicts the cycle of birth, life and death—origin, identity and destiny for each individual—and these personal concerns connect directly to cosmic ones. We can trace our lineage back through generations, back through our animal ancestors, to early forms of life and proto life, to the elements synthesized in the primordial universe, to the amorphous energy deposited in space before that. Does our family tree extend forever backward? Or do its roots terminate? Is the cosmos as impermanent as we are with its own cycles of birth, life and death as the Hindu philosophy suggests?


The ancient Greeks debated the origin of time fiercely. Aristotle, taking the no-beginning side, invoked the principle that out of nothing, nothing comes. If the universe could never have gone from nothingness to "somethingness", it must always have existed. For this and other reasons, time must stretch eternally into the past and future. Christian theologians tended to take the opposite point of view. Saint Augustine contended that God exists outside of space and time, able to bring these constructs into existence as surely as he could forge other aspects of our world. When asked, “What was God doing before he created the world?” Augustine answered, “Time itself being part of God's creation, there was simply no before!”

When applied to the whole cosmos, Einstein's famous theory of General Relativity (celebrating 100th year this year) would have predicted the universe would have to be either contracting or expanding. But when Einstein formulated his theory, even Einstein, like everyone else at the time, thought of the universe as eternal and never changing, so he added a "cosmological constant" to his equations so the universe would be static – something Einstein later called his “biggest mistake”. A few short years later American Astronomer Edwin Hubble proved that the universe was actually expanding, as General Relativity would have predicted years before if Einstein did not introduce the “cosmological constant” to fit with people’s perception of a static universe. So naturally if the universe is expanding, then one could also easily play this cosmic drama backwards, where all of space and time will shrink to a singularity – which we now call the Big Bang. Now almost universally accepted, Big Bang (more specifically Inflationary Big Bang) is our best explanation on the origin of the universe - all of space, matter, energy and most importantly time itself started at this point. Big Bang singularity was not only a singularity of all of space, matter and energy of the universe to a point, some thing which we can barely imagine, it was also the singularity of all of time (which I personally have a hard time even imagining). Time as we know it was created at Big Bang. The almost universal question that would follow this statement is then "what happened before Big Bang"?

Was the "Big Bang" really this beginning of time? Such a question seems almost blasphemous as cosmologists insisted that it simply made no sense—that to contemplate a time before the big bang was like asking for directions to a place north of the North Pole. But developments in theoretical physics, especially the rise of string theory and ideas of parallel universes have changed our perspective. The pre-bang universe has become the latest frontier of cosmology. As far as we currently know our our Universe contains about 10¹¹ galaxies, 10²³ stars, 10⁸⁰ protons and 10⁸⁹ photons (particles of light). That is a lot of stuff, but looks like even that is a tiny microcosm, a microscopic bubble in an even more unfathomable multi verse.  

As we play cosmic history backward in time, the galaxies all come together to a single infinitesimal point, known as a singularity. Each galaxy or its precursor is squeezed down to zero size. Quantities such as density, temperature and space time curvature become infinite. But this is a polite way of saying our most powerful equations - of relativity and quantum mechanics - breaks down at this point of the very beginning of space time. Conditions at time Zero of the big bang were so extreme that no one yet knows how to solve the equations. Nevertheless, string theorists have hazarded guesses about the pre-bang universe. Two popular models are floating around.

One of the pre–big bang scenario combines something called T-duality with the better-known symmetry of time reversal, whereby the equations of physics work equally well when applied backward and forward in time. The combination gives rise to new possible cosmologies in which the universe, say, five seconds before the big bang expanded at the same pace as it did five seconds after the bang. Yet the rate of change of the expansion was opposite at the two instants: if it was decelerating after the bang, it was accelerating before. In short, the big bang may not have been the origin of the universe but simply a violent transition from acceleration to deceleration. 

The beauty of this picture is that it automatically incorporates the insight of standard inflationary cosmology - namely, that the universe had to undergo a period of acceleration to become so homogeneous and isotropic. In the standard theory, acceleration occurs after the big bang because of an ad hoc inflation field. In the pre–big bang scenario, it occurs before the bang as a natural outcome of the symmetries of string theory.

According to the scenario, the pre-bang universe was almost a perfect mirror image of the post-bang one. If the universe is eternal into the future, its contents thinning to a meager gruel, it is also eternal into the past. Infinitely long ago it was nearly empty, filled only with a tenuous, widely dispersed, chaotic gas of radiation and matter. The forces of nature, controlled by the dilation field, were so feeble that particles in this gas barely interacted.

As time went on, the forces gained in strength and pulled matter together. Randomly, some regions accumulated matter at the expense of their surroundings. Eventually the density in these regions became so high that black holes started to form. Matter inside those regions was then cut off from the outside, breaking up the universe into disconnected pieces.

Inside a black hole, space and time swap roles. As noted above, the center of the black hole is not just a point in space but an instant in time. As the infalling matter approached the center, it reached higher and higher densities. But when the density, temperature and curvature reached the maximum values allowed by string theory, these quantities bounced and started decreasing. The moment of that reversal, called a big bang, was later renamed a “big bounce.” The interior of one of those black holes became our universe.

The other leading model for the universe before the bang is the ekpyrotic (“conflagration”) scenario. Developed five years ago by a team of cosmologists and string theorists —the ekpyrotic scenario relies on the idea that our universe sits at one end of a higher-dimensional space and a “hidden brane” sits at the opposite end. The two branes exert an attractive force on each other and occasionally collide, making the extra dimension shrink to zero before growing again. The big bang would correspond to the time of collision. In a variant of this scenario, the collisions occur cyclically. Two branes might hit, bounce off each other, move apart, pull each other together, hit again, and so on. 

Continued on What time is it? Part 2

References and suggested for further reading:

1) My previous blog: How fast does Brahma moves?
2) A Brief History of Time: Stephen Hawking

3) From Eternity to Here: Sean Carroll

4) Origins: Cosmos, Earth and Mankind: Reeves, Rosnay, Simonnet and Coppense

5) The First Three Minutes: Steven Weinberg

6) A Universe from Nothing: Lawrence M. Krauss

7) The Meaning Of It All: Richard P. Feynman

8) The Accidental Universe: Alan Lighhtman

9) Time Reborn: Lee Smolin

10) Our Mathematical Universe: Max Tegmark

11) Cosmic Jackpot: Paul Davies

A brief reflection on death and resurrection

If there is one universal truth about all life, from the gigantic dinosaurs to the microscopic DNA strands making up a virus, is that it will all eventually die. Death lurks over life as a constant shadow. In fact, the “dying process”, a process of increasing entropy, starts the moment life itself begins. However, no living creature other than humans has to endure their life with this deep-rooted and primal anxiety that life is evanescent, a brief candle of individual conscious awareness with dark voids of nothingness extending to the remote past and infinite future.

Of course, most of us, in the service of sanity, don’t fixate on our inevitable death. We go about the world focused on worldly concerns. We accept the inevitable and direct our energies to the mundane chores of living. Yet the recognition that our time is finite is always lurking deep within each of us, helping to shape the choices we make, the stories we tell ourselves and the physical and the spiritual monuments we create as a species.

From artistic exploration to scientific discovery to religion, pursuits that truly separate us, humans, from all other species are our attempts to turn our ephemeral life into personal and collective immortality. Jean-Paul Sartre once noted, “life itself is drained of meaning when you have lost the illusion of being eternal.”  So, it is no surprise that across cultures and through the ages, we have placed such a significant value on permanence.

Our dichotomy of an incredibly nimble mind in a fragile body has been beautifully captured by Ernest Becker who suggested “we humans live under constant existential tension, pulled toward the sky by a consciousness that can soar to the heights of Shakespeare, Beethoven, and Einstein but tethered to earth by a physical form that will decay to dust; Man is literally split in two: he has an awareness of his own splendid uniqueness in that he sticks out of nature with a towering majesty, and yet he lives with an awareness that one day he will go back into the ground to rot to nothingness.” 

According to Becker, we are compelled by such awareness to deny death the capacity to permanently erase us. We soothe the existential yearning through a commitment to family, a team, a movement, a religion, a nation—constructs that will outlast the individual’s allotted time on earth. Others leave behind creative expressions, artifacts that extend the duration of their presence symbolically. “We fly to Beauty,” said Emerson, “as an asylum from the terrors of finite nature.” Once the domain of the Pharaohs who could afford to build pyramids or the supremely gifted who could conjure timeless art or everlasting equations, now even ordinary mortals like us could attempt at this "virtual immortality" thanks to modern technology. 

Across the millennia, one consequence of our mortality awareness has been a widespread fascination with all things, real or imagined, that touch on the timeless. From prophecies of an afterlife to teachings of reincarnation, we have developed strategies to contend with knowledge of our impermanence and, offer hope for permanence.

What’s unique now in our age is the remarkable power of science to tell a lucid story not only of the past, back to the Big Bang but also of the far future. What is also unique is that unlike our pre-scientific ancestors who thought of the universe – the sun, the planets, and the distant stars - as eternal, modern physics have taught us that even such heavenly bodies – from planets to stars, solar systems to galaxies, black holes to swirling nebulae share with us in their impermanence. While for us humans the time allotted is measured in decades, for stars and planets they are in the billions of years, yet they also perish as surely as we humans do. In fact, the basic stuff that makes up matter itself would disintegrate once the decay of the proton starts, which is calculated to happen in 10³⁵ years, a duration so long, it is meaningless for us humans, but this puts an upper bound on how long intelligent life could exist in the universe, even theoretically.  Moreover, even space-time could disintegrate in the very far future. The fact that even those majestic and heavenly bodies, even matter and space-time itself share our impermanence is at once comforting, and terrifying. 

One of the more uplifting stories from the Hebrew Bible is that of the resurrection of Jesus, being celebrated today throughout the world as Easter. The power of the story of life triumphing over death is immense and timeless and often repeated throughout human history and across various cultures. And this year, we are also going through a global pandemic that is sowing death and destruction around the world. So the resurrection story is an especially powerful reminder this year and takes on an added significance on how the human mind, when faced with existential threats, still could come up with such a hopeful and uplifting narrative to give meaning to existence.

References

1) Being and Nothingness: Jean-Paul Sartre
2) The Denial of Death: Ernest Becker
3) Ode to Beauty: Ralph Waldo Emerson
4) The Greatest Story Ever Told: Lawrence M. Krauss

Update on Cancer Immunotherapy and Immuno Oncology

The past several years have been a particularly optimistic period for immuno-oncology. The first approval of modern cancer immunotherapy was interferon-alpha in 1986 for hairy cell leukemia, and later for chronic myelogenous leukemia, follicular non-Hodgkin lymphoma, melanoma, and AIDS-related Kaposi’s sarcoma (1) Several other agents have been approved since then, but a transformation in the landscape of Immuno Oncology (IO) started with the approval of ipilimumab—a checkpoint inhibitor targeting cytotoxic T-lymphocyte antigen 4 (CTLA- 4) for advanced melanoma in 2011(2) 

Since then there has been an explosion of agents that work by enhancing body’s immune response to cancer. As of this writing there has been 26 immunotherapies approved in various cancers, and 17 types of cancer have at least one approved immunotherapy as a treatment option. 

Image 1: Approved Immuno Oncology agents against cancer. (Courtesy: Annals of Oncology)

In the past 3 years alone, five new checkpoint inhibitors (targeting PD-1 or PD-L1), two new cell therapies (targeting CD19), and one new CD3-targeted bispecific antibody (also targeting CD19) have been approved (3-6). Below is a brief summary of the clinical and scientific update on these exciting new class of molecules which has shown remarkable activity across a wide array of cancer types. 

Checkpoint inhibitors 

Immune cells navigate the body looking for anything that does not belong—bacteria, viruses, and even cancer cells. They do so by using their molecular receptors to scan for foreign molecules that intruder cells display on their surface. Once an intruder is detected, a class of immune cells, known as cytotoxic T cells, move in to eliminate it. Unfortunately, cancers have a number of ways to hide from immune cells and avoid their attack. One of the most successful classes of Immuno Oncology uses drugs that are known as immune checkpoint inhibitors.

“Check points” are certain proteins that down regulate the immune system, acting as a “break” and examples include the protein PD-1 (programmed cell death protein 1), PD-L1 (programmed death-ligand 1), PD-L2 (programmed death-ligand 2), and CTLA-4 (cytotoxic T-lymphocyte antigen 4 (CTLA-4). Why do our body need these “check points” that down regulate our immune system? Because body has to work hard to suppress its own immune reactions most of the time. The immune system has enough arsenal that it can kill us faster than whatever ails us, and in healthy individuals, these immune checkpoints prevent autoimmunity. 

Many Cancers have unfortunately learned to exploit this check point pathways so it will be spared from destruction by the immune cells. The immune check point inhibitors are monoclonal antibodies against these “check points”, which work by taking “the brakes off” the immune system. Checkpoint-blockade immunotherapy has hence been the most exciting advance made in cancer treatment in recent years and has now become a new arsenal in the fight against several cancers, often showing dramatic response even in advanced stages.

The science behind Immune Oncology:

It has been known for decades that immune surveillance is critical against the development of various malignancies and patients with impaired immune system are at high risk for the development of cancer. It has also been known for more than 50 years that the human immune system has the potential to be a very powerful anticancer therapy. Part of the rationale for doing bone marrow transplantations was to give the patient a new immune system, which could help fight the patient’s cancer, with the so called graft versus leukemia / lymphoma effect, and that’s where so much interest in cellular immunotherapy originated.

In many cancers, oncogenesis is accompanied by the accumulation of mutations, which can provide a selective advantage to populations of cancer cells by increasing their degree of genetic diversity and accelerating their evolutionary fitness. Yet this diversity comes at a cost to the cancer cell: the further a cancer cell diverges from a normal cell, the more likely it is to be recognized as foreign by the immune system. Although long considered a possibility, it has been demonstrated only in the past five years that the mutational burden of tumors contributes to immune recognition of cancer and that it may, at least partly, determine a person’s response to cancer immunotherapy (7)

The role of the immune system in cancer remained unappreciated for many decades because tumors effectively suppress immune responses by activating negative regulatory pathways (above described checkpoints) that are associated with immune homeostasis or by adopting features that enable them to actively escape detection (8) Two such checkpoints, cytotoxic T-lymphocyte protein 4 (CTLA4) and programmed cell death protein 1 (PD-1), are the most studied so far. 

CTLA4 is a negative regulator of T cells, essentially acting as a break on T-cell activation.  The cell-surface receptor PD-1 is expressed by T cells on activation during priming or expansion and binds to one of two ligands, PD-L1 and PD-L2. Many types of cells can express PD-L1, including tumor cells and immune cells after exposure to cytokines such as interferon (IFN)-γ; however, PD-L2 is expressed mainly on dendritic cells in normal tissues. Binding of PD-L1 or PD-L2 to PD-1 generates an inhibitory signal that attenuates the activity of T cells. 

Both CTLA4 and the PD-1/PD-L system thus acts as “immune check points”, or “breaks” in the host immune response. Although it was found that blocking these check points can elicit antitumor response in mice as early as 1996 (9) it has been only in the last couple of years its role and significance found in humans. But once this flood gate has been opened, the development has been swift, and more marked than the development of any dug class against cancer. And response have been observed across a wide variety of cancer types, unlike traditional targeted therapies where the effect is often limited to a small subset of patients. (10) 

Even more importantly, the responses are often durable, lasting years or indefinitely, and occur without causing serious toxicity in most people. These results suggest that many people with cancer have pre-existing T-cell mediated immunity that is restrained by the PD-L1/PD-1-induced suppression of T cells. They also emphasize the role of immunosuppression as a main impediment to the series of steps that is required for effective anticancer responses — the cancer–immunity cycle (11) 

Figure 2: Cancer Immune Phenotype (Image Courtesy: Nature)

Anticancer immunity in humans can be segregated into three main phenotypes: the immune-desert phenotype (brown), the immune–excluded phenotype (blue) and the inflamed phenotype (red). Each is associated with specific underlying biological mechanisms that may prevent the host’s immune response from eradicating the cancer. A tumor that is characterized as an immune desert can be the result of immunological ignorance, the induction of tolerance or a lack of appropriate T-cell priming or activation. Immune-excluded tumors may reflect a specific chemokine state, the presence of particular vascular factors or barriers, or specific stromal-based inhibition. 

Inflamed tumors can demonstrate infiltration by a number of subtypes of immune cells, including immune-inhibitory regulatory T cells, myeloid-derived suppressor cells, suppressor B cells and cancer-associated fibroblasts. Tumor-infiltrating lymphocytes that express CD8 may also demonstrate a dysfunctional state such as hyper exhaustion. Tumor cells in inflamed tumors can also express inhibitory factors, down regulating MHC class I molecule expression or other pathways that de-sensitize them to anticancer immunity. 

The profile that responds best to immunotherapy are the so called immune-inflamed phenotype (Figure 2 above), which is characterized by the presence in the tumor parenchyma of both CD4- and CD8-expressing T cells, often accompanied by myeloid cells and monocytic cells; the immune cells are positioned in proximity to the tumor cells. (12) This profile suggests the presence of a pre-existing antitumor immune response that was arrested — probably by immunosuppression in the tumor bed. 

The second profile is the immune-excluded phenotype, which is also characterized by the presence of abundant immune cells. However, the immune cells do not penetrate the parenchyma of these tumors but instead are retained in the stroma that surrounds nests of tumor cells. The stroma may be limited to the tumor capsule or might penetrate the tumor itself, making it seem that the immune cells are actually inside the tumor. After treatment with anti-PD-L1/ PD-1 agents, stroma-associated T cells can show evidence of activation and proliferation but not infiltration, and clinical responses are uncommon. These features suggest that a pre-existing antitumor response might have been present but was rendered ineffective by a block in tumor penetration through the stroma or by the retention of immune cells in the stroma. T-cell migration through the tumor stroma is therefore the rate-limiting step in the cancer–immunity cycle for this phenotype. (13)

The third profile, the immune-desert phenotype, is characterized by a paucity of T cells in either the parenchyma or the stroma of the tumor. Although myeloid cells may be present, the general feature of this profile is the presence of a non-inflamed tumor microenvironment with few or no CD8-carrying T cells. Unsurprisingly, such tumors rarely respond to anti-PD-L1/PD-1 therapy. This phenotype probably reflects the absence of pre-existing antitumor immunity, which suggests that the generation of tumor-specific T cells is the rate limiting step. The immune-desert phenotype and the immune-excluded phenotype can both be considered as non-inflamed tumors.

Predicting response to immunotherapy:

The immune-inflamed phenotype correlates generally with higher response rates to anti-PD-L1/PD-1 therapy, which suggests that biomarkers could be used as predictive tools. Most attention has been paid to PD-L1, which is thought to reflect the activity of effector T cells because it can be adaptively expressed by most cell types following exposure to IFN-γ6, (14). In an increasingly large clinical data set, it is becoming clear that the expression of PD-L1 in pretreatment biopsies facilitates enrichment with people who are most likely to respond to antibodies against PD-L1 or PD-1. PD-L1 expression also correlates strongly with various markers of active cellular immunity, including IFN-γ, granzymes, CXCL9 and CXCL10. The presence of these biomarkers or others such as T cells that carry the CD3 antigen or tumor mutational burden may also enrich for responders. When used in combination with PD-L1 expression, these biomarkers may enhance predictive power (15)

As described previously, it is probable that the mutation burden of a given tumor will contribute to its immune profile with clearest association demonstrated between response and overall mutational burden. The greater the number of mutations in a given tumor, the more probable it is that some of the mutations will be immunogenic, providing targets for T-cell attack (16). Mutations that arise early in oncogenesis and are shared by almost all of the cancer cells in an individual (known as truncal mutations) may generate more effective anticancer T-cell responses than mutations that arise later on and are limited to only a subpopulation of cancer cells (known as branch mutations)

The importance of the cancer–immune set point

The cancer–immune set point is the threshold that must be overcome to generate effective cancer immunity. The set point can be understood as a balance between the stimulatory factors (Fstim) minus the inhibitory factors (Finhib), which together must be equal to or greater than 1, over the summation of all T-cell antigen receptor (TCR) signals for tumor antigens. The cancer–immune set point is shown as: 

∫ (Fstim) − ∫ (Finhib) ≥ 1 ∕ ∑ n=1, y (TCRaffinity × frequency)   (17)

It is probable that –immune set point of a particular person is already determined by the time of clinical presentation, driven by the inherent immunogenicity of the tumor and by the responsiveness of the individual’s immune system. Although it is reasonable to assume that various lines of cancer therapy or changes in environmental factors might alter Fstim and Finhib, such changes might only be transient. 

Often, the set point that is identified using pretreatment biopsies is similar to the set point determined by biomarker profiling from biopsies taken on progression after therapy. Likewise, despite the continued accumulation of mutations in a tumor as a function of time, primary and metastatic lesions can exhibit similar immune profiles. The features that determine the set point may therefore reflect genetic factors that are specific to a given tumor, the genetics of the person with cancer, or the extent to which antitumor immunity had developed initially. 

Although largely conceptual, the idea of a set point provides a framework to help organize the torrent of clinical and biomarker data that will emerge over the coming months and years. The number of targets that could prove effective for cancer immunotherapy is great; the number of potential combinations of therapeutic agents that are directed against these targets (or combinations of such agents with conventional standard-of-care agents) is even greater. The development of some cancer therapies may be largely empirical, but it can be guided by considering, even in general terms, the elements that comprise cancer immunity.

Adoptive cellular Immunotherapy:

Apart from immune check point inhibitors, another area of rapid development in immune oncology has been the use of CAR-T cells.  Adoptive cell immunotherapy boosts the body’s immune defenses against cancer in a completely different way—by genetically re-engineering a patient’s own immune T cells. It was Dr. Carl June and team from University of Pennsylvania who was the first to experiment with genetically reprogramming T cells, now known as CAR T cells. (18)

CAR T cells are custom made to work against the cancer in each individual patient. To create these cells, researchers collect immune T cells from the patient and insert an artificial gene into the cells. The gene is designed to endow T cells with chimeric antigen receptors that can detect unique molecules on cancer cells after CAR T cells are multiplied in the laboratory and injected back into the patient. In essence, CAR T-cell therapy is both a gene therapy and an immunotherapy.

When the CAR T-cell receptor attaches to a molecule on a cancer cell, it sends a signal to turn on the destruction machinery of the T cell. Unlike traditional cancer treatments, this living therapy needs to be given to the patient only once, because CAR T cells continue to multiply in the patient’s body. As a result, the anticancer effects of CAR T cells can persist and even increase over time.

Challenges

Immuno Oncology brings its own unique set of challenges. Selecting the appropriate patients for the highly expensive therapies are still not completely well defined. While markers like PD-L1 expression can act as a good predictor of response, the predictive value varies between various tumor types. While the response to these drugs could be dramatic some time even in terminally ill patients, the exorbitant cost prevents its use more widely in deserving patients. Not all patients respond to these medications, and in a sub group of patients the cancer cells could become resistant after a period of initial response. The mechanisms of resistance remains an active area of intense research but as of this writing clinical options for patients who progress on immunotherapy remains limited. (19)

Immunotherapy drugs also come with a unique set of side effects, and clinicians should familiarize with these often unusual side effects so that it could be recognized early, as some of the side effects could be serious, even fatal (20) 

Another challenge for future drug development is the identification of the appropriate targets on cancer cells.  The problem with many cancers is that they are too close to self and there aren’t easily identifiable target antigens that allow you to apply immune therapy without off-target toxicity. It is quite possible that over the next 5 to 10 years, some of the biggest advances will come from identifying new targets for various kinds of cancers and then applying vaccine therapy, antibody therapy, and cellular therapy against these specific targets. This will be done through extensive studies of cancer cell biology, DNA sequencing, and other techniques that will allow this type of immunotherapy to become increasingly personalized to a patient’s specific tumor and the tumor’s specific targets. 

It’s going to be a long time before chemotherapy is obsolete. Some chemotherapy may actually have a role concurrently with immunotherapy and may function to modulate the immune interactions. There will also be instances where we use multimodality therapy, including chemotherapy, radiation therapy, and immunotherapy.

Curing Cancer

Even the most successful targeted therapies like imatinib for chronic myeloid leukemia are rarely curative, and once the therapy is withdrawn the cancer could come back. Immunotherapy however could be curative even in some advanced malignancies. Going back to the example of bone marrow transplantation, there are circumstances when patients with leukemia or lymphoma relapse after allogeneic transplant and can be cured with infusions of normal T cells from their original transplant donor (donor lymphocyte infusion). There has been cases of patients with advanced malignancies who had received check point inhibitors or CAR-T cell therapy who have been cured and remains disease free despite not receiving any ongoing therapy. 

Immune therapies are the new frontier in cancer therapy, and the field is in its infancy. As of this writing, there were 940 IO agents in clinical development, with another 1064 in preclinical phase, with over 3000 interventional active clinical trials evaluating these clinical-stage immunotherapies with a target of enrolling over half a million patients across the world. So it can be anticipated that the application of immunotherapy in the treatment of cancer will grow dramatically over the next decade.

References:

1) Talpaz M, Kantarjian HM, McCredie K et al. Hematologic remission and cytogenetic improvement induced by recombinant human interferon alpha A in chronic myelogenous leukemia. N Engl J Med 1986; 314(17): 1065–1069.).

2) Hodi FS, O’Day SJ, McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363(8): 711–723.) . 

3) Topalian SL, Hodi FS, Brahmer JR et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366(26); 2443–2454.

4) Grupp SA, Kalos M, Barrett D et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 2013; 368(16): 1509–1518.

5) Locke FL, Neelapu SS, Bartlett NL et al. Phase 1 results of ZUMA-1: a multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol Ther 2017; 25(1): 285–295.

6) Topp MS, Kufer P, Gokbuget N et al. Targeted therapy with the T-cellengaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol 2011; 29: 2493–2498.

7) Rizvi, N. A. et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015). 

8) Mellman, I., Coukos, G. & Dranoff, G. Cancer immunotherapy comes of age. Nature 480, 480–489 (2011). 

9) Leach, D. R., Krummel, M. F. & Allison, J. P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 271, 1734–1736 (1996)

10) Zou, W., Wolchok, J. D. & Chen, L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci. Transl. Med. 8, 328rv4 (2016).

11) Chen, D. S. & Mellman, I. Oncology meets immunology: the cancer-immunity cycle. Immunity 39, 1–10 (2013).

12) Herbst, R. S. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014)

13) Salmon, H. et al. Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J. Clin. Invest. 122, 899–910 (2012)

14) Gajewski, T. F. The next hurdle in cancer immunotherapy: overcoming the nonT-cell-inflamed tumor microenvironment. Semin. Oncol. 42, 663–671 (2015)

15) Taube, J. M. et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin. Cancer Res. 20, 5064–5074 (2014)

16) McGranahan, N. et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351, 1463–1469 (2016)

17) Cho, J. H. & Feldman, M. Heterogeneity of autoimmune diseases: pathophysiologic insights from genetics and implications for new therapies. Nature Med. 21, 730–738 (2015)

18) Rosenbaum, L. Tragedy, Perseverance, and Chance — The Story of CAR-T Therapy. N Engl J Med 2017; 377:1313-1315 (2017)

19) Russell, W.J. Mechanisms of resistance to immune checkpoint inhibitors. British Journal of Cancer 118, 9–16 (2018)

20) Postow, M. et al. Immune-Related Adverse Events Associated with Immune Checkpoint Blockade N Engl J Med 2018; 378:158-168 (2018)