Age Twelve: A Hidden Dance of Pairs
In the “double slit” experiment conducted by Thomas Young in 1801, a light wave beamed toward two closely spaced adjacent slits created an interference pattern on the back surface (see the entry for Quantum Probability Fields). Experiments two centuries later showed that the photons making up the light beam actually pass through one slit or the other. The most common interpretation of this experiment is that each photon (light particle) is actually a probability wave, and the probability that the particle will go through one slit or the other is determined by the value of this probability wave as the photon approaches the two slits.
Danielle proposes a different interpretation that involves a “hidden variable.” In this interpretation, there is some physical mechanism in the photon, a hidden variable, which is continually changing its phase (for example, its rotational position). The state of this hidden variable determines whether the particle takes one path or the other, so there is no indeterminacy. Therefore, if you simply examine the state of this hidden variable, you can precisely determine the particle’s future path. However, this mechanism is “hidden” so that we are not able to actually access it. It may be the case, however, that the mechanism is only hidden based on a particular level of sophistication of technology so that a more refined monitoring tool could in fact access it. On the other hand, if there exists no method to access the hidden mechanism, we can still say that the outcome is determined but that there is no practical way to actually determine it. Whether the outcome is determined or not in such a situation then becomes a philosophical issue.
Einstein was a famous early proponent of a hidden variable explanation of quantum mechanics when he said, “God does not play dice with the universe,” expressing his disdain for a theory (quantum mechanics) that ascribed basic movements of subatomic particles to an innate randomness. No one has been able, however, to actually describe such a hidden mechanism or variable.
The most common interpretation of quantum mechanics is that the movement of subatomic particles, such as photons, is not determined but follows probabilities based on a probability wave.
In the alternative reality of Danielle: Chronicles of a Superheroine, Danielle proposes a theory of quantum mechanics that is not probabilistic, rather it is based on a hidden variable that is determined but possibly not detectable.
If I state an hypothesis that there exists a white polar bear, I can prove this theory by demonstrating the existence of a single white polar bear. If I keep seeing lots of polar bears and all the ones I encounter are white I might devise a broader hypothesis that All polar bears are white. This assertion is falsifiable because the observation of a single nonwhite polar bear would invalidate it. Even if we never see a nonwhite polar bear, the hypothesis remains falsifiable because there is always the possibility that a counterexample to the hypothesis will be discovered.
In the 1930s Karl Popper (1902–1994) wrote The Logic of Scientific Discovery which established falsifiable theories as the foundation of science. He successfully changed the basis of science from what he called the “observationalist-inductivist” view in which scientific truths are “proven” by arguments from basic principles to what he called “critical rationalism,” in which scientific conjectures inherently remain theories until disproven by the discovery of a falsifiable example.
For example, the theory of general relativity (proposed by Albert Einstein in 1915) is a legitimate scientific theory because it is possible to envision experimental outcomes that would be inconsistent with it. The existence of the possibility of inconsistent experimental outcomes is precisely what makes it a scientific theory. Over the past century there have been many experiments conducted to determine whether any of these inconsistent outcomes can be demonstrated and all have failed. These experiments have greatly bolstered the credibility of Einstein’s theory but it nonetheless remains a theory. A theory that has been repeatedly confirmed by the failure of attempts to find counterexamples is the best we can hope for according to Popper’s thesis, and this view has been largely accepted by scientific philosophers.
Thus no matter how many times scientists run experiments that confirm a scientific theory it still remains a theory. A single counterexample, on the other hand, would show the theory to be false. On yet another hand, once we find a counterexample, we can seek to find narrower conditions for which the original theory remains true. For example, Newton’s theory of gravity was disproven by experimental findings that supported Einstein’s alternative view that large masses actually distort the geometry of space-time. However we can nonetheless define circumstances in which Newtonian mechanics still provides an adequate model of how planets and objects interact. Predictions of the future orbits of satellites based on Newton’s theory remain reasonably accurate even though they do not take into account Einstein’s more precise theory.
Popper asserted that the possibility of falsifiability, that is the existence of experiments that can disprove a theory, is precisely the demarcation between what is scientific and what is not. He attacked Marxism’s claim to be scientific because its theories were not falsifiable. Philosopher Wolfgang Pauli described purportedly scientific ideas that are not falsifiable as not only “not right, but not even wrong.”
Some modern theories such as string theory are falsifiable in theory but may not be falsifiable in practice because experiments that could falsify string theory would require energies far greater than could be provided by any particle collider we can imagine building. On the other hand, just because we cannot carry out such an experiment with today’s technology does not rule out the possibility that a future technology will be able to do it, thus string theory remains a legitimate theory.
Some recent philosophers of science are questioning falsifiability as the demarcation line of science and argue that other attributes such as explanatory power and elegance should “lighten falsifiability’s load,” to quote MIT computer scientist Scott Aaronson. What if the falsifiable experiments are shown to be inherently impossible? Does that make the theory not scientific? A good example of this is the multiverse theory, that the universe we live in is just one universe among many. Since there appears to be no way to communicate with another of these universes, we may be unable to design any experiments that would confirm or falsify this theory. However, there nonetheless remains the possibility that such a communication method could be discovered in the future and thus the theory is at least theoretically falsifiable, and thus can still be considered a scientific theory.
In the alternative reality of Danielle: Chronicles of a Superheroine, twelve-year-old Danielle explains to Dad an idea she has for a falsifiable experiment that would demonstrate her idea for measuring the hidden variable, which Danielle asserts determines the apparently unpredictable “decision” of subatomic particles to take one state or another. At a later time, Claire points out to Danielle that if she measures the hidden variable that it would no longer be hidden.
The collapse of the wave function refers to what is perhaps the most philosophically intractable issue in modern physics. Consider Thomas Young’s famous “double slit” experiment in 1801 (see the entry for Quantum probability fields). Each photon is essentially going through both slits at the same time. It has a certain probability of going through the first slit and 1 minus that probability of going through the second slit. That ambiguity is resolved when the position of the photon is measured, for example by an observer looking at the interference pattern of photons on the back screen of the experiment.
The wave function refers to the probability field that specifies the probability that the photon is in a particular position. This field of probabilities is said to “collapse” when the location (or other state) of the particle is measured. However, what does “measurement” mean in this context? There are different schools of thought on this question. One interpretation is that any measurement will do. However, any interaction with any other particle or field can be considered a measurement so this approach does not remove the ambiguity.
Another school of thought says that observation by a conscious observer is required. This approach is also perplexing. What if the observation takes place long after the original event?
Austrian physicist Erwin Schrödinger described a paradox in 1935 which has become known as the Schrödinger’s Cat Paradox, which illustrates the problem. One or more decaying atoms is in a sealed box with a cat and a mechanism that detects whether or not an atom has decayed. If the mechanism detects radioactivity (in other words, that an atom has decayed), the mechanism shatters a flask releasing poison which instantly kills the cat. At a certain point the atom will be in both simultaneous states: decayed and not decayed. And thus the cat will be both alive and dead. However, when an observer looks inside the box, she will find the cat alive or dead but not both.
Suppose instead of a cat the mechanism releases a bomb that destroys the building that the box is in. Thus the building will be both intact and destroyed at the same time. It is hard to imagine someone looking inside the box as the explosion would have destroyed the box along with the building it resides in.
Another perspective is called the “many worlds” interpretation first proposed by Hugh Everett in 1957 and popularized by Bryce Seligman in the 1960s and 1970s. In this formulation, there is no collapse of the ambiguity (that is, of the wave function); the universe simply splits into two universes. So Schrödinger’s cat is alive in one universe and not in the other. This may seem an extreme length to go to in order to resolve this ambiguity, especially when you consider that there are innumerable subatomic particles entering quantum ambiguous states at a very fast rate, so the number of possible universes would become unimaginably great.
The idea that conscious observation resolves the actual position of particles is similar to what actually happens in simulated worlds such as we find in computer games. The user has the impression that portions of the simulated world exist even if we don’t observe these portions on the screen. However, the computer program running the simulation does not actually bother to render the parts of the simulated world that the observer is not looking at (that is, that are not on the screen). Similarly, the celestial computer rendering our universe does not bother to decide where particles are until we look at them.
In the alternative reality of Danielle: Chronicles of a Superheroine, Danielle rejects these interpretations by hypothesizing that there is actually no quantum probability field. Rather, she imagines a hidden mechanism (called a hidden variable) that determines the state and position of the particle (such as where a photon ends up in the double slit experiment). She conducts an experiment that does end up demonstrating her hypothesized hidden variable but it reveals another ambiguity.
One interpretation of quantum mechanics is that it is the presence of an observer, that is observation by a conscious observer, that resolves the ambiguous state of a particle.
Life Bits is a system in which a person records every detail of their life including video of what they are seeing and hearing and potentially videos showing the person herself.
In the alternative reality of Danielle: Chronicles of a Superheroine, Danielle and Claire adopt a Life Bits system when Danielle is ten and Claire is eighteen.
Life Bits Share is a feature of Life Bits in which the user can open the video streams to another observer so that that person can watch their experiences in real time. Danielle and Claire implement this capability and open up their Life Bits streams to each other when Danielle is twelve and Claire is twenty.
See entry for Life Bits.
Standard PGP (pretty good privacy) encryption relies on the difficulty of factoring very large numbers because of the very large amount of computation required. If the encryption key is a large enough number, the amount of computation required to break the code is impractically large. It is not impossible, however.
Quantum encryption is theoretically unbreakable. If two subatomic particles (photons, for example) are created from the same interaction and are thereby quantum entangled, they can move in different directions and maintain their entanglement. If Bob receives one of the entangled photons and observes it, he will determine a random bit 0 or 1. The photon traveling to Jane will be disambiguated at the same time and with the same value even if Jane is far away. By disambiguating a sequence of particles in this way, Bob and Jane will receive the same random sequence. The sender can then use this code (that they both have and that no one else has) to encrypt a message, send it to the other, and the recipient can decode it with the same code. No one else would have access to this code. Interception of the entangled particles by a third party would be detected by the intended recipient.
There are a few assumptions being made with quantum encryption. One is that there is no hidden variable. If there is a hidden variable, then a future technology that allowed observation of the hidden variable (without disturbing the particle) would allow a third party to intercept the code.
Even barring the scenario above of reading a hidden variable, if a third party were to impersonate Bob (the intended recipient) then that third party could receive and decode the coded messages sent by Jane (the sender).
In the alternative reality of Danielle: Chronicles of a Superheroine, twelve-year-old Danielle presents her theory that there is indeed a hidden variable underlying quantum uncertainty. If true, this would mean that a quantum encryption could in theory be broken as described above.
If two subatomic particles (photons, for example) are created from the same interaction and are thereby quantum entangled, they can move in different directions and maintain their entanglement. If one observer receives one of the entangled photons and observes it, she will determine a random bit 0 or 1. The photon traveling to another observer will be disambiguated at the same time and with the same value even if the second observer is far away. By disambiguating a sequence of particles in this way, two parties will receive the same random sequence. This can be used to create and transmit a random coding key to these two parties who wish to send messages to each other. (See entry for Quantum encryption code.)
In the alternative reality of Danielle: Chronicles of a Superheroine, one interpretation of this phenomenon is that there is a “quantum” connection between the two particles, in other words there is a communication from the particle that is first disambiguated to the second one. However, this communication appears to happen instantly and has been measured to be at least thousands of times faster than the speed of light. The interpretation that Danielle articulates is that there is no communication between the two particles. Instead there is a hidden variable in both particles and they are set to the same phase because the two particles were created at the same time. The hidden variable controls the disambiguation of the state of each particle and will read out the same if measured at the same time.
In string theory, basic subatomic particles are actually strings (curved lines with zero width in a space of more than two dimensions). Danielle presents a thesis that subatomic particles are actually folded membranes of more than two dimensions in a space of more than three dimensions. Thus if two particles can be entangled, then the two membranes representing these two particles can also be entangled.
However, Danielle is presenting this ideas as a metaphor for a relationship between two people.
The world we are familiar with appears to have three dimensions plus another one for time. However, versions of String Theory contemplate more than these 3+1 dimensions, up to 25+1 in certain forms. Superstring theory, a popular version, has 9+1 dimensions, and M theory, another popular version, has 10+1.
However, in many of these theories, most or all of the dimensions beyond the 3+1 we are familiar with are “curled” on themselves.
To imagine this (even though it is nearly impossible to imagine more than 3+1 dimensions), consider a virtual world displayed on a screen and you are controlling a spaceship portrayed on the screen. When you fly off the right edge of the screen, the ship immediately appears coming in from the left of the screen. Thus the left-right dimension is effectively curled on itself.
Another way to envision this is to consider a garden hose. If you are a small creature on the hose, the long dimension of the hose appears to go on indefinitely. However, you can also walk perpendicular to this long dimension (around the curved part of the hose) and you will soon come back to where you started. This second dimension is curled. If you look at the hose from a distance, it appears to be just a curved line as the width is so narrow that you don’t see it. That is essentially how these additional dimensions (in the string theories that have more than 3+1 dimensions) appear to us.
In the alternative reality of Danielle: Chronicles of a Superheroine, and her Chinese physicist friend, Cheng Liu, discuss their mutual theory of reality having more dimensions than the 3+1 we are familiar with, and the existence of curved membranes (also potentially of many dimensions) representing particles in the world.
In physics, subatomic particles such as electrons and protons have corresponding antiparticles which are identical in mass but have opposite electrical charges and opposing properties of other characteristics. An important aspect of antimatter is that a collision between a particle and its antiparticle, for example between a proton and an antiproton, results in the destruction of both particles and gives rise to intense gamma rays (that is, to high energy photons), neutrinos and the creation of other particle-antiparticle pairs that have significantly less mass. In such an interaction, much of the mass is converted to energy in accordance with Einstein’s formula E=mc2 (energy equals mass times the speed of light squared), thereby resulting in a great production of energy.
Antiparticles can form more complex structures just as particles do. For example, a positron (the antiparticle for an electron) can join with an antiproton to form an antihydrogen atom. In theory, more complex antiatoms and antimolecules are feasible. Thus, complex objects such as an anticheeseburger are conceivable, but only simple antiatoms such as antihydrogen and (with difficulty) antihelium have actually been detected. The problem is that the universe is so permeated with matter that any antimatter that is created is quickly destroyed by encountering its matter equivalent.
The reason for this asymmetry is one of the great open questions in physics. One explanation is that the random processes that produce matter and antimatter particles are almost certain to produce at least a slight inequality between the two forms, so whichever form had a slight edge would ultimately predominate as it would destroy the opposite form by encountering it. Had antimatter won, we would have just called it matter (and the opposite form antimatter).
In the alternative reality of Danielle: Chronicles of a Superheroine, Danielle uses the relationship of matter and antimatter as a metaphor for the bond between two soul mates. It is true that two human soul mates encountering each other may very well give off a shower of energy and light (photons) as do opposing forms of particles but it is to be hoped that they do not destroy each other.
“A hidden dance of pairs that is invisible, undetectable except for their intrinsic, inseparable oneness. Always apart. Always together. Two sides of the same whole,” is a poetic metaphor by Danielle in which she uses two entangled particles to refer to two people entangled by a cosmic connection.
If two subatomic particles are created in the same interaction and travel in opposite directions at the speed of light, they can remain quantum entangled with each other even as they fly far apart from each other. Experiments have shown that if the position, velocity and other quantum ambiguous properties are resolved for one of the two particles as a result of measurement, the same properties will be also be instantly resolved (and to the same values) in the other particle.
See also entries for Entangled membranes, Quantum probability fields, Hidden variable, Probabilistic nature of quantum mechanics, Collapse of the wave function, Presence of an observer, and Hidden dance of pairs.
The speed of light (c) is perhaps the most important constant value in physics and underlies several of the counterintuitive findings of twentieth century physics. According to Einstein’s Theory of Special Relativity, c is the maximum speed at which energy can travel and is therefore the maximum speed at which information can travel. Light slows down in transparent materials such as glass (in which it is two thirds of the speed), and air (in which it slows down just slightly by a factor of 1.0003).
Prior to 1676 it was thought that light traveled instantaneously from one place to another, in other words its speed was infinite. By studying Jupiter’s moon Io, Ole Rømer demonstrated in 1676 that the speed of light was finite. In 1873, James Clerk Maxwell described light as an electromagnetic wave which therefore traveled at the speed c which appeared in his theory of electromagnetism. In 1975, c was measured to be 299,792,458 meters per second.
The remarkable implications of the speed of light came early in the twentieth century with a series of simple thought experiments by Albert Einstein in which he overthrew the orderly world of nineteenth century physics. At the age of sixteen, he daydreamed about riding on a beam of light. He was aware of English mathematician Thomas Young’s (1773–1829) experiment in 1803 that established that light is composed of waves. The conclusion at that time was that light waves must be traveling through some sort of medium; after all, ocean waves traveled through water and sound waves traveled through air and other materials. Scientists called the medium through which light waves travel the “aether.” Einstein was also aware of the 1887 experiment by American scientists Albert Michelson (1852–1931) and Edward Morley (1838–1923) that attempted to confirm the existence of the aether. That experiment was based on the analogy of traveling in a rowboat up- and downstream in a river. If you are paddling at a fixed speed, then your speed as measured from the shore will be faster if you are paddling with the stream as opposed to going against it. Michelson and Morley assumed that light would travel through the aether at a constant speed (that is, at the speed of light). They reasoned that the speed of sunlight when Earth is traveling toward the sun in its orbit (as measured from our vantage point on Earth) versus its apparent speed when Earth is traveling away from the sun must be different (by twice the speed of Earth). Proving that would confirm the existence of the aether. However, what they discovered was that there was no difference in the speed of the sunlight passing Earth regardless of where Earth was in its orbit. Their findings disproved the idea of the “aether,” but what was really going on? This remained a mystery for almost two decades. In hindsight, the answer was obvious, but all other scientists who thought about it rejected the apparently absurd conclusions.
As the teenage Einstein imagined riding alongside a light wave, he reasoned that he should be seeing the light waves frozen, in the same way that a train would appear not to be moving if you rode alongside it at the same speed as the train. Yet he realized that this was impossible, because the speed of light is supposed to be constant regardless of your own movement. So he imagined instead riding alongside the light beam, but at a somewhat slower speed. What if he traveled at 90 percent of the speed of light? If light beams are like trains, he reasoned, then he should see the light beam traveling ahead of him at 10 percent of the speed of light. Indeed, that would have to be what observers on Earth would see. But we know that the speed of light is a constant, as the Michelson-Morley experiment had shown. Thus, he would necessarily see the light beam traveling ahead of him at the full speed of light. This seemed like a contradiction—how could it be possible?
In 1905, when Einstein was 26, he came to the shocking conclusion: time itself must have slowed down for him (while traveling next to the light beam at 90 percent of the speed of light). If observers on Earth were to look at the watch they would see it ticking ten times slower. Indeed, when he got back to Earth, his watch would show that only 10 percent as much time had passed (ignoring, for the moment, acceleration and deceleration). From his perspective, however, his watch was ticking normally and the light beam next to him was traveling at the speed of light. The ten-times slowdown in the speed of time itself (relative to clocks on Earth) fully explains the apparent discrepancies in perspective. In the extreme, the slowdown in the passage of time would reach zero once the speed of travel reached the speed of light, hence it was impossible to ride along with the light beam. Although it was impossible to travel at the speed of light, it turned out not to be theoretically impossible to move faster than the light beam. Time would then move backward.
This resolution seemed absurd; indeed, no other thinker was able to come to this explanation. The thinking behind Einstein’s key insights is not complicated and does not require any math beyond junior high school algebra. Einstein’s genius was the courage to believe in his own thought experiments regardless of the conclusions.
Another startling but simple thought experiment by Einstein concerns himself and his brother flying through space. They are 186,000 miles apart. Einstein wants to move faster but he also desires to keep the distance between them the same. So he signals his brother with a flashlight each time he wants to accelerate. Since he knows that it will take one second for the signal to reach his brother, he waits a second (after sending the signal) to initiate his own acceleration. Each time the brother receives the signal he immediately accelerates. In this way the two brothers accelerate at exactly the same time and therefore remain a constant distance apart.
But consider what we would see if we were standing on Earth. If the brothers were moving away from us (with Albert in the lead), it would appear to take less than a second for the light to reach the brother, because he is traveling toward the light. Also we would see Albert’s brother’s clock as slowing down (as his speed increases as he is closer to us). For both of these reasons we would see the two brothers getting closer and closer and eventually colliding. Yet from the perspective of the two brothers, they remain a constant 186,000 miles apart.
How can this be? The answer—obviously—is that distances contract parallel to the motion (but not perpendicular to it). So the two Einstein brothers are getting shorter (assuming they are flying headfirst) as they get faster.
Perhaps the most important (and the most explosive!) formula in physics E=mc2 also results from a simple thought experiment by Einstein. Also in 1905, Einstein contemplated the relationship of matter and energy. James Clerk Maxwell had shown in the 1850s that particles of light, called photons, had no mass but nonetheless carried momentum. The issue that Einstein struggled with is that momentum is a function of mass: Momentum is equal to mass times velocity. Thus, a truck traveling at 30 miles per hour has a lot more momentum than, say, a bird traveling at the same speed. How, then, could there be positive momentum for a particle with zero mass?
Einstein contemplated a box floating in space. A photon is emitted inside the box from the left toward the right side. The total momentum of the system needs to be conserved, so the box would have to recoil to the left when the photon was emitted. After a certain amount of time, the photon collides with the right side of the box, transferring its momentum back to the box. The total momentum of the system is again conserved, so the box now stops moving. But consider the perspective from the vantage point of Mr. Einstein, who is watching the box from the outside. He does not see any outside influence on the box: No particles—with or without mass—hit it, and nothing leaves it. Yet Mr. Einstein, according to the scenario above, sees the box move temporarily to the left and then stop. According to our analysis, each photon should permanently move the box to the left. Since there have been no external effects on the box or from the box, its center of mass must remain in the same place. Yet the photon inside the box, which moves from left to right, cannot change the center of mass, because it has no mass.
Einstein’s conclusion was that since the photon clearly has energy, and has momentum, it must also have a mass equivalent. The energy of the moving photon is entirely equivalent to a moving mass. We can compute what that equivalence is by recognizing that the center of mass of the system must remain stationary during the movement of the photon. Working out the math (okay, this math was high school level), Einstein showed that mass and energy are equivalent and are related by a simple constant. However, there was a catch: The constant might be simple, but it turned out to be enormous; it was the speed of light squared (about 1.7 × 1017 meters2 per second2—that is, 17 followed by 16 zeroes). Hence, we get Einstein’s famous E=mc2. Thus, one ounce (28 grams) of mass is equivalent to 600,000 tons of TNT. Einstein’s letter (written by physicist Leó Szilárd and signed by Einstein) of August 2, 1939, to President Roosevelt informing him of the potential for an atomic bomb based on this formula ushered in the atomic age.
A key strategic issue for the human-machine civilization in the decades ahead is whether or not there is any way to exceed the speed of light. If we can, then universewide engineering will be feasible. If not, then it will take a very long time for information to spread across the universe given the enormous distances. Even if a way to surpass the speed of light is subtle, engineering past the Singularity (a point in human history when we will multiply our intelligence a billionfold by merging with the intelligent technology that we are creating, which I estimate will take place in 2045) will be so great that we will be able to leverage that insight. That, after all, is what engineering does. One subtle observation is that because of the Heisenberg Uncertainty Principle, the exact position and velocity of particles varies around an expected value. Thus measurements of some particles will show that they have exceeded the speed of light.
Another possibility is that if the universe actually has more than the three spatial and one time dimension (3+1 dimensions) that we are familiar with, then we can find (or engineer) shortcuts to other apparently faraway locations through spatial dimensions other than the three we can readily measure. Contemporary versions of String Theory contemplate such additional spatial dimensions.
In the alternative reality of Danielle: Chronicles of a Superheroine, Danielle talks to Liu about how the speed of light puts a limitation on their relationship.
At the age of 24, Werner Heisenberg (1901–1976), a German physicist, published a foundational paper on quantum mechanics. Over the next two years he articulated his uncertainty principle which has become one of the core principles of the field.
Heisenberg’s Uncertainty Principle states that there are limits to the precision with which certain paired physical properties of a particle, called complementary variables, can be known. To limit the precision of a measurement of one variable inherently limits the precision of the other complementary variable.
The best known complementary pair is position and momentum. Momentum is essentially equivalent to velocity (speed) since momentum is mass times velocity and the mass of a particle is known and fixed. This conclusion has nothing to do with the precision of a particular measurement technology. It has to do with the inherent limit of measuring properties of quantum particles with classical measurement tools.
One implication is that there is an inherent uncertainty to measuring the velocity of particles traveling at the speed of light. Because of this uncertainty, the measured velocity will be a distribution of values around the speed of light, thus some particles will appear to be going slower than the speed of light, and some faster. It remains a philosophical question as to whether or not such particles (the ones measured going faster than the speed of light) are actually going faster than the speed of light, or just appear to be doing so.
In the alternative reality of Danielle: Chronicles of a Superheroine, Danielle postulates this phenomenon as a possible way of exceeding the speed of light, and draws a conclusion about her relationship with Liu.
The Gaussian (or normal) distribution is a well-known curve in statistics that peaks at an expected value and falls off gradually to the left and right in what looks like a bell (hence it is sometimes called the bell curve). The theorem underlying the Gaussian distribution is that if you sum multiple independent distributions, they will converge to the Gaussian distribution as you add more and more independent variables. Thus, distributions of values that are affected by many random variations will take on this shape. For example, there are a great many variables that affect people’s height including genetic variations and health and dietary variables. Thus, an adult person’s height is the result of many independent variables and indeed the distribution of the height of adults is governed by a Gaussian, or normal, distribution.
There are three parameters that characterize any Gaussian distribution: the position on the x axis at which the peak of the curve lies (in the case of a distribution of people’s height, this would be the most common height), the position on the y axis of the peak of the curve (which in the example of height would be the number of people with this height), and the standard deviation of the curve, which reflects how spread out the distribution is. Here are three normal curves in which these three parameters vary:
Because of Heisenberg’s Uncertainty Principle (see entry on Heisenberg’s Uncertainty Principle), measurements of certain properties of a subatomic particle such as velocity will reflect a Gaussian distribution around an expected value, which is often the speed of light. Thus, some particles will be measured as traveling faster than the speed of light.
In the alternative reality of Danielle: Chronicles of a Superheroine, Danielle hypothesizes that this could provide an effect that could be leveraged to travel faster than light.
John Galsworthy was an English novelist and playwright whose celebrated works include The Forsyte Saga, A Modern Comedy, and End of the Chapter. He promoted causes which Danielle also espouses, including the rights of women, animals, and prisoners. He turned down a British knighthood, saying that a writer’s reward comes simply from being read; but he did accept the Nobel Prize for literature six weeks before his death.
Quotations from Galsworthy include “The beginnings and endings of all human undertakings are untidy” and “If you do not think about your future, you cannot have one.”
In the alternative reality of Danielle: Chronicles of a Superheroine, Danielle cites Galsworthy’s quotation “Love has no age, no limit, and no death,” from The Forsyte Saga, to comment on the issue of age differences in relationships.
According to the Biblical story, around the fifteen century BC, an insecure and cruel Egyptian Pharaoh became worried that the increasing population of Jewish slaves might forge an alliance with Egypt’s enemies and represent a threat to his power. He ordered that all male Hebrew newborns be drowned in the Nile river, an order that was largely carried out. A Hebrew woman Jochebed wove a basket out of papyrus, coated it with tar so that it would float, and placed her baby in the small ark and set it into the water. Jochebed asked her daughter Miriam to follow the basket as it floated down the river.
Miriam watched as the daughter of the Pharaoh discovered the baby and had her slave girl fetch him from the water. “This is one of the Hebrew babies,” the Princess said about the crying child. Miriam approached the Pharaoh’s daughter and offered to find one of the Hebrew women to nurse the baby for her. “Yes, go, take this baby and find a Hebrew woman to nurse him for me, and I will pay you,” the Princess replied. Miriam took the baby to her (and the baby’s) mother who then nursed her own baby at the Princess’ request.
The Princess was herself a child when she discovered the baby. When she and the baby grew older, the Princess adopted him as her own and she named him Moses meaning “drawn from the water.”
The names of these primary characters in the Moses story are not identified in the Bible and have been the subject of considerable academic research. In an influential 1989 article in the journal Archaeology and Biblical Research by J. LoMusio, he argues convincingly that the Pharaoh was Amenhotep II, whose proud and arrogant personality as described in Egyptian texts matches his description in the Bible. The young daughter of the Pharaoh who adopted and named Moses is identified as Hatshepsut, who herself became the powerful Pharaoh of Egypt. She is one of the most influential figures in Egyptian history, was a great builder, and had a relatively enlightened rule. Her early empathy was demonstrated with her rescue of the baby Moses in the basket. She ruled Egypt as regent with her stepson Thutmoses III who is believed to have been the Pharaoh when the exodus of the Jews took place.
The next phase of Moses’ story is that he received an education that was excellent even by Egyptian nobility standards. He remained an Egyptian prince for about forty years. One day he witnessed an Egyptian soldier beating a Hebrew slave. Enraged, Moses killed the Egyptian. Whether Moses’ rage resulted from his humanity or his realization of his Jewish roots or both has been a question of considerable debate. The Pharaoh decreed Moses should be killed for his transgression so he fled to Midian, a desert country south of Egypt.
In the desert, Moses had his first encounter with God. On Mount Horeb, God revealed himself in a burning bush, revealed his name as Yahweh and commanded Moses to rescue his “chosen people” (the Hebrews) out of slavery and bring then to the Promised Land (Canaan). Moses began this mission by demanding that the Pharaoh “let my people go,” but the Egyptian ruler resisted.
To assist Moses in his mission, God brought ten plagues to the Egyptian people, the last of which was to kill all the Egyptian firstborn babies. This last plague convinced the Pharaoh to set the Jewish slaves free. Moses hurriedly led the nascent Israelite nation out of Egypt. The “Exodus” was so hurried that they did not have time to allow the bread they were making to rise, hence the invention of “matzoh,” which has become a symbol of the Exodus.
Moses led the Israelites, estimated at about 600,000 people, directly toward the Red Sea. The Pharaoh changed his mind and ordered his best 600 chariots to pursue the fleeing former slaves. The Israelites found themselves trapped between the Red Sea and the mountains to either side and the approaching Egyptian army behind. Frustrated, the Israelites cried out to Moses, “Was it because there were no graves in Egypt that you brought us to the desert to die?”
In a miracle and another demonstration of God’s power, the Red Sea parted allowing Moses to lead the Israelite people across a land bridge to the other side. The Egyptian army pursued them but were all drowned as the Red Sea again covered the land bridge. There has been considered research analyzing the possibility that the precise timing of the Red Sea tides might provide a plausible explanation for the story.
Moses then led his followers on a winding course through the desert. Frustrated that the people were worshiping what he regarded as false gods, he made a personal retreat up the biblical Mount Sinai. There, once again, he encountered God who gave him two tablets containing the Ten Commandments. Here is the full text of the Ten Commandments as recorded in Exodus 20:2–17:
- I am the LORD your God, who brought you out of the land of Egypt, out of the house of bondage. You shall have no other gods before Me.
- You shall not make for yourself a graven image—any likeness of anything that is in heaven above, or that is in the earth beneath, or that is in the water under the earth; you shall not bow down to them nor serve them. For I, the LORD your God, am a jealous God, visiting the iniquity of the fathers upon the children to the third and fourth generations of those who hate Me, but showing mercy to thousands, to those who love Me and keep My commandments.
- You shall not take the name of the LORD your God in vain, for the LORD will not hold him guiltless who takes His name in vain.
- Remember the Sabbath day, to keep it holy. Six days you shall labor and do all your work, but the seventh day is the Sabbath of the LORD your God. In it you shall do no work: you, nor your son, nor your daughter, nor your male servant, nor your female servant, nor your cattle, nor your stranger who is within your gates. For in six days the LORD made the heavens and the earth, the sea, and all that is in them, and rested the seventh day. Therefore the LORD blessed the Sabbath day and hallowed it.
- Honor your father and your mother, that your days may be long upon the land which the LORD your God is giving you.
- You shall not murder.
- You shall not commit adultery.
- You shall not steal.
- You shall not bear false witness against your neighbor.
- You shall not covet your neighbor’s house; you shall not covet your neighbor’s wife, nor his male servant, nor his female servant, nor his ox, nor his donkey, nor anything that is your neighbor’s.
Moses had been gone so long, that many Israelites thought he would not return. They melted down their gold jewelry and sculpted a golden calf which they worshipped as a symbol of God. When Moses came down from the mountain, he was shocked to witness this false idolatry as it violated the first three of the Ten Commandments. In a fury, he broke the tablets, as depicted in the painting by Rembrandt at the beginning of this entry. He ordered that the golden calf be destroyed and its creators and worshippers destroyed.
In accordance with the Ten Commandments, Moses objected to depictions of God as an animal but also as a human person as he regarded God as encompassing all of creation.
After leading the Israelite people for forty years through the desert, they reached the banks of the Jordan River. There he died just before the Israelite people reached the Holy Land.
The historical accuracy of the Biblical accounts of Moses have been debated for centuries. Kenneth Kitchen (born in 1932), a British Egyptologist, claims that there is an historic core to the Biblical story. Others, such as Biblical scholars Philip R. Davies and Niels Peter Lemche, argued that the stories were essentially fiction.
Moses is regarded by Jews, as well as Christians and Muslims, as the “lawgiver of Israel.” In addition to the Covenant Code which contains the Ten Commandments, Moses wrote several other codes of moral and ethical law including the Book of Leviticus, the Book of Numbers, and the Book of Deuteronomy.
The moral laws which Moses laid down provided the foundation for these three major religions. In addition to his Biblical role as the liberator of the Jewish people, the creator of Jewish moral law, and the founder of ancient Israel, Moses is also highly celebrated by Christians and Muslims. Moses is mentioned in the Bible’s New Testament, the principal holy book of Christianity, more than any other person from the Old Testament. Moses is also mentioned 502 times in the Qur’ān, Islam’s holy book, more than any other person. Muhammad himself is not mentioned directly in the Qur’ān because he wrote it.
Moses’ ethical teachings were also influential in the ideas that formed and inspired the United States. The official seal of the United States designed by John Adams, Thomas Jefferson, and Benjamin Franklin in 1776 after writing the Declaration of Independence shows Moses leading the Israelites through the Red Sea, and also depicts the Burning Bush representing God that Moses encountered on Mount Horeb. It contains the word “Rebellion to Tyrants is Obedience to God” thereby drawing a comparison of the American Revolution to Moses fighting the Pharaoh.
When George Washington died in 1799, the majority of his eulogies referred to him as “America’s Moses,” with one referring to Washington as having “been the same to us as Moses was to the Children of Israel.”
In the alternative reality of Danielle: Chronicles of a Superheroine, Danielle compares the forty years of waiting for the Holy Land that Moses endured to her pact with Liu. Liu points out that Moses never reached the Promised Land.
God promises the Promised Land to Abraham and his descendants if they remain true to him as the one and only God. He describes this land as running from the River of Egypt to the Euphrates River, an area which roughly comprises the modern state of Israel.
Moses led the Hebrew people out of slavery to the Pharaoh and out of Egypt after God inflicted the ten plagues on Egypt. He led the nascent Israeli nation through the desert for forty years and they finally came to the Promised Land, but Moses died before he reached it.
The “Promised Land” has become a metaphor for salvation and liberation, generally. It is referred to in Negro spirituals as an escape from slavery and oppression. In some spirituals, this release is only achieved through death.
Martin Luther King alludes to Moses never reaching the Promised Land with his people in his seminal 1968 speech “I’ve Been to the Mountaintop,” “I just want to do God’s will. And He’s allowed me to go up to the mountain. And I’ve looked over. And I’ve seen the Promised Land. I may not get there with you. But I want you to know tonight, that we, as a people, will get to the Promised Land.”
And so I’m happy, tonight.
I’m not worried about anything.
I’m not fearing any man.
Mine eyes have seen the glory of
the coming of the Lord.
In the alternative reality of Danielle: Chronicles of a Superheroine, Liu points out the poignancy and irony of Moses successfully leading his people to this goal but never realizing it himself.
See entry for Moses.
The classic problem with antipathogen medications, such as antibiotics for bacterial infections, antiviral drugs for viral infections, and anticancer drugs such as chemotherapy for cancer cells, is that due to genetic variation in the pathogen (bacteria, viruses, cancer cells), a very small fraction (maybe 1 in 10 million) will not be susceptible to the medication. It is rare that a medication will destroy every single pathogen. The infection then grows back.
A typical example is illustrated in the graph above. Note that the y (vertical) axis is logarithmic meaning that it is showing orders of (decimal) magnitude rather than absolute values. Every labeled level is 10 times greater than the level below it, thus a very wide range of values can be displayed.
In this example, we start out at day 0 with a billion pathogens (bacteria, viruses, or cancer cells, etc.). On day 0 we administer a medication (such as an antibiotic for bacteria). The typical action of such a drug, assuming it is effective against the pathogen, is that it will kill a certain percentage of the pathogens with each time period. In this case, it kills 90 percent of the pathogens each day. So after one day, the number of pathogens is reduced to 100 million. After two days, the number of pathogens is down to 10 million, and so on. By day 7, the number is reduced to 100. At this level, the infection (or tumor, as the case may be) will appear to be gone.
In this (typical) example, however, 1 in 10 million of the pathogens is resistant to the medication due to natural genetic variability of the pathogens. Thus once the number is reduced to 100 pathogens (which is 1 in 10 million of the original 1 billion pathogens), these surviving 100 are not affected by the medication. They then start to multiply and grow back exponentially. Note that (virtually) all of the descendants will also be resistant to the medication since they are descended from the resistant strain. As shown in this example, they grow back stronger than the original infection, to 10 billion pathogens by day 15, all resistant to the medication.
Note that the slope of the regrowth will not necessarily be the same as the original destruction although that is what is shown in this example. It might grow back faster or slower, and thus the downward and upward lines will have different slopes.
Sometimes people will refer to this situation as the pathogen having evolved a resistance to the assault by the medication. That is possible, but the more typical situation is that a small number (1 in 10 million in this example) of the pathogens is simply resistant to the medication in the first place due to genetic variability.
This is why there is concern with the overuse of antibiotics, such as using them in livestock. Such overuse provides the opportunity for bacteria that are resistant to the antibiotic to survive and then flourish. We are now seeing emergence of such resistant diseases. For example, most strains of Staphylococcus aureus (MRSA) are now resistant to benzylpenicillin.
A typical strategy to combat such resistance and reemergence of infections of pathogens is to use a cocktail of drugs. If a cocktail of several (typically four or five) drugs is used, and if the drugs have orthogonal mechanisms (meaning they work differently) then it is likely that not a single pathogen will survive, which is what is required to prevent the reemergence of the infection.
In the alternative reality of Danielle: Chronicles of a Superheroine, Danielle is giving a lecture to Claire on her idea for a cocktail of drugs that would kill cancer stem cells, the true cause of cancer. She describes the phenomenon of resistance to a single drug and how to overcome it.
A logarithmic scale is a scale or continuum in which the values are logarithms of the value being measured. A logarithmic graph is a graph in which one or both axes uses a logarithmic scale.
On a logarithmic scale, each value shown is a multiple of the adjacent value. In this way, a logarithmic scale allows a very wide range of values to be shown. For example, consider the graph at the beginning of the entry for Asymptoting logarithmic response curve. It shows values from 1 to 10 billion, and each value on the Y axis is 10 times greater than the value directly below it.
The formula for logarithms is as follows:
log (base n)x=y
which means that:
log (base 10) 1,000,000=6 (because 106=1,000,000)
10 is a common base for logs (log (base 10) is called the decimal log), but other values can be used. For example:
log (base 2) 256=8
because 28=256. Log (base 2) is called the binary log.
Another common base for logs is the number e which is approximately 2.71828. e is considered an “irrational” number in that it requires an infinite sequence of digits to define precisely. Log (base e) is called the natural logarithm.
There are a number of ways to define the number e. It is the limit of (1+1/n)n as n approaches infinity. In other words, if you compute the formula in the preceding sentence, the resulting value gets closer to e as n gets higher.
Another formula to compute e is as follows. It is the sum of the infinite series:
A unique property of the natural logarithm is found at log (base e) of 1. All logs of 1 are 0. The slope (angle) of the curve log (base e) at 1 is also 1. Logs with a base higher than e have a slope of less than 1 and logs with a base lower than e have a slope greater than 1. Only the natural log (log (base e)) has the property that its slope is 1 at log(e) of 1.
In the alternative reality of Danielle: Chronicles of a Superheroine, Danielle explains to Claire that the size of the population of a pathogen (such as a bacteria or a cancer stem cell) will decrease on a logarithmic scale when exposed to a medication (such as an antibiotic for a bacteria), thereby decreasing by orders of magnitude as time goes by, but that it will then grow back by increasing on a logarithmic scale, thereby increasing by orders of magnitude as time goes by, as a result of resistance to the medication. Danielle points out that this is the key challenge in fighting pathogens, whether they be bacteria, viruses, cancer cells, or cancer stem cells.
See entry for Asymptoting logarithmic response curve.
Charles Darwin established the hereditary basis of the characteristics of organisms with his theory of natural selection in the mid-nineteenth century. Almost a century later, American biologist James D. Watson (born in 1928) and English biologist Francis Crick (1916–2004) provided the first accurate characterization of the structure of DNA, describing it as a double helix of two long twisting molecules. It should be noted that their finding was based on what is now known as “photo 51” taken by their colleague Rosalind Franklin using X-ray crystallography, which was the first representation that showed the double helix.
The primary purpose of the DNA molecule is to encode information. Thus biological evolution devised a digital storage system which itself guided evolution and stored its designs. Each strand of DNA is comprised of a chain of nucleotides of which there are four types: adenine, cytosine, guanine, and thymine, abbreviated as A, C, G, and T. The nucleotides are matched with an complementary type (adenine with thymine and guanine with cytosine) in the opposing strand.
All living organisms on Earth use a similar process of DNA replication which produces two identical DNA molecules from one original and is the basis for the inheritance of biological traits. During replication, the two strands are separated and the now disconnected nucleotides are matched up with their opposing types thus recreating the double helix.
In addition to providing the basic mechanism for reproduction, the double helix design of DNA provides for a means of error correction because each nucleotide is matched with a corresponding one. The reproduction of the DNA strand codes as well as the proofreading and error correction are all performed by biological molecular machines. The ability of molecular machines to perform these intricate tasks can be considered an existence proof of “nanotechnology,” that is creating machines, including computational capabilities, out of atoms.
A molecule called DNA polymerase creates the new strand. It also performs the first stage of proofreading and error correction. Other molecular enzymes are responsible for a second pass of error correction after the strand has been created. The error rate by the DNA polymerase in creating the strand is 1 error out of 108 (1 in 100 million) nucleotides. The second phase corrects 99 out of 100 of these errors so the overall error rate is 1 error out of 1010 (1 in 10 billion) nucleotides. These errors are called point mutations and are generally of little consequence.
There is also DNA in the mitochondria, which are organelles responsible for energy production. The mitochondria are actually descendants of ancient bacteria that were engulfed by ancient predecessors to the (eukaryotic) cells that comprise our bodies. The mitochondria have only 37 genes organized in a circle. We inherit our mitochondrial DNA only from the mother. The mitochondria use only single-stranded DNA and use a completely different molecular machinery to reproduce. Thus they do not have the error checking and correction capability. Error rates in mitochondrial DNA reproduction are much higher as a result, about 1 in 105 (1 in 100,000), higher than nuclear DNA by a factor of about 100,000. This constitutes a significant aging process, as the mitochondria become less effective as we grow older due to accumulating genetic errors. Evolution actually “noticed” this and began copying the mitochondrial genes into the nucleus which has a much lower rate of DNA transcription errors. Thus if a mitochondrial gene is defective due to DNA replication errors, its equivalent gene in the nucleus can take over. Evolution did not finish the job, however, and 13 of the 37 mitochondrial genes do not (yet) have a counterpart in the nucleus. This provides a strategy for overcoming this particular aging process: we can “simply” copy those remaining mitochondrial genes into the nucleus using gene therapy.
Cancer stem cells (the progenitors of cancer) have yet another DNA reproduction method and machinery. They use a DNA-RNA duplex and its reproduction does not have error correction so its error rate is similar to mitochondrial DNA. This is a factor in the genesis of cancer. See the entry for Cancer stem cell for a full explanation.
In the alternative reality of Danielle: Chronicles of a Superheroine, Danielle explains to Claire the significance of DNA replication errors in the formation of cancer.
The typical response of a pathogen infestation (such as a bacterial or viral infection or cancer tumor) to an antipathogen medication (such as an antibiotic for a bacterial infection) is that the medication wipes out almost all of the pathogens but a small fraction survive (for example, one in ten-million). As explained in the entry for Asymptoting logarithmic response curve, the surviving pathogens are resistant to the medication and grow back. This new infection can be worse than the original because the pathogens are now all descendants of a resistant (and often heartier) form.
A key strategy to combat this issue of residual resistance is to use a cocktail of drugs. If the drugs in the cocktail all work using the same mechanism then pathogens resistant to one of the drugs will likely be resistant to all of them, which is not what we want. For this strategy to work, the drugs in the cocktail need to use different (sometimes called orthogonal) approaches. A cocktail of typically four to five drugs with orthogonal mechanisms is often enough to destroy every single pathogen and thus prevent the infection (or tumor) from returning.
However, there is a problem with this approach concerning the approval process by the US Food and Drug Administration (FDA). Although the rules do not explicitly rule out cocktail drug approaches, it is almost impossible to gain approval for a cocktail therapy in a single cycle. Since each cycle can take five to ten years, this makes approval for cocktail approaches impractical in a reasonable timeframe. The FDA will allow testing and approval of one drug at a time, but this means that each drug has to show efficacy on its own which may not be feasible.
In the alternative reality of Danielle: Chronicles of a Superheroine, in the case of AIDS, the key breakthrough in turning an AIDS diagnosis from an almost certain death sentence to a difficult but usually manageable condition was the advent of the AIDS cocktail. Claire asks Danielle about the AIDS cocktail as contradicting her assertion that the FDA is not sympathetic to drug cocktails. Danielle replies, “Since the AIDS activists were already orphaned from society and were allied with like-minded doctors and lawyers and knew exactly what they wanted, they rammed it through with very forceful political, legal, and extralegal tactics. If only the cancer patients were as alienated and aggressive.”
Danielle invents a treatment for cancer that involves two drug cocktails, one to combat cancer cells and the other to combat cancer stem cells, which are the progenitors of the cancer cells. She is concerned that millions of people will die of cancer unnecessarily given the amount of time it would take to get not one but two drug cocktails through the approval process. She decides instead to do an end run around the FDA and nearly brings down the US Government in the process.
Cancer stem cells are special stem cells that are hypothesized to be the progenitors of cancer cells. Chemotherapy drugs are effective at killing cancer cells, but according to the cancer stem cell thesis, the cancer tumor returns because chemotherapy drugs are not effective at killing the cancer stem cells which created the cancer cells in the first place. Cancer stem cell research has been an active focus of cancer research since the early 2000s.
A stem cell is characterized by being able to undergo both symmetric reproduction (to create a copy of itself and therefore another stem cell) and asymmetric reproduction (to create a differentiated cell, such as a colon cell or a lung cell). In the case of cancer stem cells, asymmetric reproduction creates cancer cells which then form the bulk of a cancer tumor. They are the originators of cancer.
In 2003, biologist Elena Gostjeva discovered an unusual type of cell that appeared to be a stem cell giving rise both to fetal organs (starting around the 13th week of gestation) and to cancer tumors. It had the classical properties of a stem cell reproducing both symmetrically (to produce more stem cells) and asymmetrically (to produce differentiated cells). These stem cells give rise to the fetal organs, but they also remain and continue to reproduce in humans after birth. If certain genetic transcription errors occur, one of these stem cells will “decide”—inappropriately—to start a new fetal organ. Since the regulatory (hormonal) environment in a mature person is different from a fetus, this “fetal organ” grows in an uncontrolled manner and becomes a cancer tumor.
They called these newly discovered cells “metakaryotes” because they had a reproductive mechanism and other characteristics in-between prokaryotic (primitive) cells and the eukaryotic cells that constitute mature human cells.
Gostjeva and her research colleague (and husband) MIT professor and scientist Bill Thilly wrote in a 2006 paper, “For more than a century, cancer researchers have seriously considered tumors to reflect characteristics of embryos … “Adenocarcinoma [such as colon cancer] looks as if it were embryonic tissue simply growing at the fetal rate to form embryonic colon. In addition, metakaryotic nuclei can divide both symmetrically and asymmetrically, a capacity generally reserved for stem cells.”
Gostjeva, Thilly and their colleagues have discovered these unusual stem cells in fetal organs, in precancerous tissues, and in large numbers in solid tumors. They are almost never seen in normal adult tissues.
The following microphotographs show these metakaryotic stem cells undergoing symmetric reproduction to create additional metakaryotic stem cells and asymmetric reproduction to create a differentiated cancer cell.
The thesis of Gostjeva and Thilly is consistent with a theory first articulated around 1876 by Julius Friedrich Cohnheim and Rudolf Virchow that cancer tumors were essentially fetal organs growing inappropriately in a mature individual. This theory is based on the observation that the cellular organization and growth rates of solid tumors and fetal tissues are essentially the same.
The DNA in these cancer (metakaryotic) stem cells use a different reproductive machinery (that is, different enzymes) to reproduce than either normal nuclear DNA or mitochondrial DNA. This machinery does not have the effective error checking and correction capability of nuclear DNA replication so the error rate is high, comparable to mitochondrial DNA. This results in greater variability in its DNA which facilitates the ability of these cancer stem cells to evolve around particular attacks. This means that using a cocktail of drugs would be especially important in combating these cancer stem cells.
I worked with Gostjeva and Thilly on this project at MIT for seven years from around 2005 to 2012. Funding was provided by the biotechnology company United Therapeutics (UT). I serve as a director of UT and was its liaison to this MIT project during this time period.
As of 2012, Gostjeva and Thilly had identified several drugs that appear to be “metakaryocidal,” that is, are effective in either killing metakaryotic cancer stem cells or interfering with their reproduction. They have been working on a cocktail of such drugs, possibly to be administered sequentially.
In the alternative reality of Danielle: Chronicles of a Superheroine, Danielle bases her cancer cure on a similar observation about cancer stem cells and develops two cocktails of drugs, one for cancer cells and another for the cancer stem cells. Because it is very difficult to get approval from the US Food and Drug Administration for even a single cocktail of drugs, she comes up with a novel approach to dealing with this regulatory challenge.
Founded in 1978 by Robert Redford, the Sundance Film Festival is the largest independent film festival in the United States. It is held every year in Utah and had more than 71,000 attendees in 2017. It is regarded as a prestigious showcase for new films by American and international independent filmmakers.
In the alternative reality of Danielle: Chronicles of a Superheroine, Claire is nominated for a Sundance Film Festival Award for Best Screenplay for a movie she wrote called Liberté, a story about a secret society of teenage girls in Paris during the French Revolution.
The French Revolution was a decade-long period of upheaval in France that started in 1789. It was influenced by liberal ideas of democracy and personal freedom. It went through contrasting phases of democracy and dictatorship, included mob violence, and was deeply influential throughout the world.
Although the French Revolution included periods of instability, violence, and a dictatorship by Napoleon, it transformed France into a democratic and secular society with liberal values that characterize France today including freedom of religion, legalization of divorce and same-sex relationships, and civil rights for minorities including Jews and blacks.
A ten-month period starting in September of 1793, known as the Reign of Terror, resulted in the death of about 16,000 people by guillotine (including King Louis XVI and his wife, Queen Marie Antoinette) and up to another 25,000 by other means. These excesses of the French Revolution were widely criticized, especially by the American press.
The causes of the French Revolution are varied and complicated and continue to be debated. There was a financial crisis in France in the 1780s caused by the debts accumulated during the Seven Years War (a major European war involving all of its powers organized into coalitions led by France and Great Britain) and France’s support for the American Revolutionary War. King Louis XVI was accused of mishandling this crisis through unpopular and oppressive taxation plans.
Although lasting ideas of the French Revolution included democracy and the power of the individual, the ten year period of the revolution included periods of dictatorship. In 1793, there was an effective dictatorship by the “Committee of Public Safety” with the rise of Maximilien Robespierre. The Reign of Terror occurred under the Committee of Public Safety. This period also saw the abolishment of slavery in the French colonies and the separation of the Christian Church from influence in the government. This led, in 1795, to an executive council known as the Directoire (Directory) which pursued persecution of the Catholic clergy and military conquests which were popular with the French public.
The Directoire period was also characterized by financial instability and charges of corruption. It collapsed as a result of a coup by Napoleon Bonaparte in 1799. He had become popular for leading a number of successful military campaigns. Napoleon was deeply influenced by the French Revolution and arguably advanced its ideals more than anyone, despite taking actions that were directly opposed to its democratic ideals. In 1804, he appointed himself Napoleon I, Emperor of France. During a ten-year period he led France in a series of battles known as the Napoleonic Wars, most of which were successful, creating an empire that ruled much of continental Europe. The French empire began to collapse with Napoleon’s disastrous invasion of Russia in 1812.
Napoleon brought the liberal ideas of the French Revolution to the rest of Europe including the rights of minorities, religious tolerance, universal education, and support of the arts and sciences. He established a legal code known as the Napoleonic Code which influences legal systems worldwide to this day.
Despite a chaotic history veering back and forth from democracy to dictatorship, the French Revolution ultimately led France to a system of democracy and a set of ideas that deeply influenced the world. One of its mottos, Liberté, Égalité, Fraternité (Liberty, Equality, Fraternity) became the official motto of France at the end of the nineteenth century and has influenced many democratic movements since. The thinkers of the French Revolution had in mind a revolution to benefit all of humanity which included ideas of the rights of the individual (ending the privileges of the noble class), and equality based on ability.
One of the key documents of the French Revolution is the Declaration of the Rights of Man and of the Citizen. It was introduced at the beginning of the French Revolution by French General Lafayette, who fought in the American Revolutionary War. The document was a collaboration between Lafayette and Thomas Jefferson. It declares the basic rights of all humans as a “natural right” deriving from human nature, and that these rights are held to be universal and valid at all times and places. It has become one of the fundamental documents in the history of civil rights and is included in the French Constitution.
The French Revolution was an inflection point for the worldwide spread of democracy. The women’s suffrage movements and the subsequent feminist movement drew many of their ideas from the French Revolution including the Declaration of the Rights of Man and of the Citizen. The French Revolution also led to the modern concept of total war as the establishment and expansion of the French Empire also took place at the same time.
In the alternative reality of Danielle: Chronicles of a Superheroine, Claire writes a screenplay for a movie called Liberté, a story about a secret society of teenage girls in Paris during the French Revolution who work behind the scenes to save a community of artists from the excesses of the revolution by hiding them in abandoned buildings. She is nominated for the prize for Best Screenplay at the Sundance Film Festival.
Juan Belmonte (1892–1962) was widely regarded as the world’s greatest bullfighter during his lifetime. He started his bullfighting career at the age of 16 and killed his first bull when he was 18. He was born with deformed legs so he was not able to follow the popular style of jumping out of the bull’s path. He turned this disability into a unique and signature style. He stood erect without moving, staying only inches from the bull, and forcing the bull to go around him.
This technique was considered courageous but also resulted in many injuries, including 24 serious injuries during his career. For example, in 1927 when performing for the King and Queen of Spain, he was gored through the chest and came close to being killed until other toreros saved him.
In 1919, he fought a record number of 109 bullfights in one year. The Mexican matador Carlos Arruza is said to have stopped at 108 bullfights in one season out of respect for Belmonte. Belmonte’s record was finally surpassed in 1965 by Manuel Benitez Pérez (“El Cordobés”).
The following story (which is widely believed but not possible to confirm) is told about his death. He was told by his doctor that because of his injuries and illnesses (he had been diagnosed with heart disease and lung cancer), he could no longer smoke cigars, ride his beloved horses, drink wine, or have sex with women. Upon hearing this advice, he took two of his favorite cigars, two bottles of his favorite wine, and rode his favorite horse to his estate where he was met by his two favorite “women of the night” of Sevilla. There he smoked his cigars, drank his wine, had sex with his female companions, and shot himself. He had told others prior to that evening that “If I cannot live like a man, I will at least die like one.”
Belmonte was a close friend of the American author Ernest Hemingway and he is a prominent character in two of Hemingway’s books, Death in the Afternoon, and The Sun Also Rises. Hemingway killed himself in 1961 and it has been suggested (for example by the writers Jeffrey Berman and Patricia Hatch Wallace) that Belmonte’s suicide by gunshot was a copycat act of Hemingway’s similar suicide less than a year earlier.
Woody Allen features Belmonte as a friend of Ernest Hemingway in his 2011 film Midnight in Paris.
In the alternative reality of Danielle: Chronicles of a Superheroine, Claire has been nominated for the Award for Best Screenplay at the Sundance Film Festival but is edged out by (a fictional) author Adolpho Cayetano for his screenplay titled Passing Passion, based on Cayetano’s popular erotic novel of the same name. Cayetano begins his acceptance remarks by calling his own book and screenplay “brilliant,” and goes on to defend his hubris by comparing himself to two other Spaniards: Juan Belmonte, who was also not shy about bragging about his bullfighting skills, and Salvador Dalí, who bragged about his artistic skills.
See entry for Salvador Dalí.
Salvador Domingo Felipe Jacinto Dalí i Domènech, Marqués de Dalí de Púbol (1904–1989), known as Salvador Dalí, is the best-known Surrealist painter. Surrealism was an artistic movement in art and literature that emphasized images and situations that were illogical and reflected a comparable movement in science and math in the early twentieth century. Physics had gone from the orderly mechanics of nineteenth century physics to the apparently illogic and mystery of Einstein’s theory of relativity and the perplexing uncertainties of quantum mechanics. Mathematics went from the formal and perfect axiomatic systems of the eighteenth century to the contradictions of twentieth century mathematics such as Gödel’s “incompleteness theorem” (which says there are as many unsolvable problems as solvable ones).
The understanding of the mind itself went from nineteenth century rationalism to Freud’s theory of the unconscious. Indeed, Surrealism sought to reveal the unconscious mind, and Freud was Dalí’s hero. Dalí also drew inspiration from the strange conclusions of contemporary science; his dripping clocks for example expressed Einstein’s clocks that mysteriously slowed down at high speeds. If Dalí’s paintings seemed bizarre, he was only reflecting the fantastic conclusions of contemporary thinkers in other fields.
As a person, Dalí engaged in apparently eccentric, grandiose, and self-aggrandizing behavior, which drew more attention than his artwork and attracted substantial criticism. In recent years, however, his behavior has been reinterpreted as performance art.
He believed in the sanctity of art and believed it should not be censored based on cultural, religious, and political considerations. When his father, Don Salvador, read that his son had exhibited a drawing showing and titled The Sacred Heart of Jesus accompanied by the inscription “Sometimes, I spit for fun on my mother’s portrait,” he was outraged and demanded that his son recant the artwork. When Dalí refused, he was physically thrown out of his father’s home on December 28, 1929.
Dalí was also resistant to exhortations from his fellow Surrealist artists, who were becoming increasingly associated with leftwing politics. They criticized him for refusing to condemn Hitler in the 1930s, but Dalí rejected this criticism saying “I am Hitlerian neither in fact nor in intention.” Dalí maintained that Surrealism and art in general should exist in an apolitical context. In 1934, there was a public (but not legal) trial in which he was expelled from an organized group of Surrealists. Dalí replied emphatically, “I myself am Surrealism.”
I conducted a small informal poll to test Dalí’s assertion by asking half a dozen colleagues to name a Surrealist artist. All immediately responded with “Salvador Dalí.” When I asked each to name a second Surrealist artist, all but one drew a blank. The one exception responded with “Max Ernst,” who is probably more closely associated with the Dada art movement, which constitutes one of the influences on Surrealism.
Dalí is also known for his self-promoting quotations, although in recent times these too have become associated with the grandiose style of his performance art. Some of his quotations include,
- “Each morning when I awake, I experience again a supreme pleasure, that of being Salvador Dalí.”
- “At the age of six I wanted to be a cook. At seven, I wanted to be Napoleon. And my ambition has been growing steadily ever since.”
- “I don’t do drugs. I am drugs.”
- “There is only one difference between a madman and me. The madman thinks he is sane. I know I am mad.”
Other notable Dalí quotes include:
- “Have no fear of perfection—you’ll never reach it.”
- “Intelligence without ambition is a bird without wings.”
- “I do not paint a portrait to look like the subject, rather does the person grow to look like his portrait.”
Sigmund Freud was Dalí’s hero and he considered his art to be an expression of Freud’s theory of the unconscious. Freud and Dalí met in 1938 although there are no notes to document what they talked about. After the meeting, Freud confided to a friend, “That boy looks like a fanatic. Small wonder that they have a civil war in Spain if they look like that.”
There is a play titled Hysteria (which I’ve seen) written by British playwright Terry Johnson, which imagines how this encounter between Freud and Dalí must have gone. It premiered at the Royal Court Theatre in London in 1993.
In the alternative reality of Danielle: Chronicles of a Superheroine, Claire has been nominated for the Award for Best Screenplay at the Sundance Film Festival but is edged out by (a fictional) author Adolpho Cayetano for his screenplay titled Passing Passion, based on Cayetano’s popular erotic novel of the same name. Cayetano begins his acceptance remarks by calling his own book and screenplay “brilliant,” and goes on to defend his hubris by comparing himself to two other Spaniards: Juan Belmonte, who was also not shy about bragging about his bullfighting skills, and Salvador Dalí, who bragged about his artistic skills.
See entry for Juan Belmonte.
As explained in the entry for Drug cocktail, the typical response of a pathogen infestation (such as a bacterial or viral infection or cancer tumor) to an antipathogen medication (such as an antibiotic for a bacterial infection) is that the medication wipes out almost all of the pathogens but a small fraction survive (for example, 1 in 10 million). As explained in the entry for Asymptoting logarithmic response curve, the surviving pathogens are resistant to the medication and grow back. This new infection can be worse than the original because the pathogens are now all descendants of a resistant (and often heartier) form.
A key strategy to combat this issue of residual resistance is to use a cocktail of drugs. If the drugs in the cocktail all work using the same mechanism, then pathogens resistant to one of the drugs will likely be resistant to all of them, which is not what we want. For this strategy to work, the drugs in the cocktail need to use different (sometimes called orthogonal) approaches. A cocktail of three to five drugs with orthogonal mechanisms is often enough to destroy every single pathogen and thus prevent the infection (or tumor) from returning.
One way to visualize this concept is to consider a graph showing the impact of drugs on various parameters. For example, one drug may increase acidity which could destroy a pathogen that prefers alkalinity. Another drug may increase vulnerability to T cells. If we created a multidimensional graph showing the impact of these different drugs on these different parameters (acidity, vulnerability to T cells, etc.), we would see that the two drugs in this example move the resulting parameters in orthogonal directions, that is at right angles to one another. If two different drugs move the resulting parameters in the same direction (for example, they both increase acidity), then taking the two drugs would have a similar effect to taking more of either one of the drugs. Moving the parameters in orthogonal directions can overcome drug resistance provided that both directions inhibit the pathogen.
In the alternative reality of Danielle: Chronicles of a Superheroine, Danielle invents a treatment for cancer that involves two drug cocktails, one to combat cancer cells and the other to combat cancer stem cells, which are the progenitors of the cancer cells. She is concerned that millions of people will die of cancer unnecessarily given the amount of time it would take to get not one but two drug cocktails through the approval process. She decides instead to do an end run around the FDA and nearly brings down the US Government in the process.
DNA encodes the information defining all biological life on Earth. Each strand of DNA is comprised of a chain of nucleotides of which there are four types: adenine, cytosine, guanine, and thymine, abbreviated as A, C, G, and T. The nucleotides are matched with an complementary type (adenine with thymine and guanine with cytosine) in the opposing strand.
All living organisms on Earth use a similar process of DNA replication which produces two identical DNA molecules from one original, and is the basis for the inheritance of biological traits. During replication, the two strands are separated and the now-disconnected nucleotides are matched up with their opposing types thus recreating the double helix.
In addition to providing the basic mechanism for reproduction, the double helix design of DNA provides for a means of error correction because each nucleotide is matched with a corresponding one. The reproduction of the DNA strand codes as well as the proofreading and error correction are all performed by biological molecular machines. The ability of molecular machines to perform these intricate tasks can be considered an existence proof of “nanotechnology,” that is creating machines out of atoms that are capable of performing computations as well as intricate manipulations of other atoms.
A molecule called DNA polymerase creates the new strand. It also performs the first stage of proofreading and error correction. Other molecular enzymes are responsible for a second pass of error correction after the strand has been created. The error rate by the DNA polymerase in creating the strand is 1 error out of 108 (1 in 100 million) nucleotides. The second phase correct 99 out of 100 of these errors so the overall error rate is 1 error out of 1010 (1 in 10 billion) nucleotides. These errors are called point mutations and are generally of little consequence.
There is also DNA in the mitochondria, which are organelles responsible for energy production. The mitochondria are actually descendants of ancient bacteria that were engulfed by ancient predecessors to the (eukaryotic) cells that comprise our bodies. The mitochondria have only 37 genes organized in a circle. We inherit our mitochondrial DNA only from the mother. The mitochondria use only single-stranded DNA and use a completely different molecular machinery to reproduce. Thus they do not have the error checking and correction capability. Error rates in mitochondrial DNA reproduction are much higher as a result, about 1 in 105 (1 in 100,000), higher than nuclear DNA by a factor of about 100,000.
Cancer stem cells (the progenitors of cancer) have yet another DNA reproduction method and machinery. They use a DNA-RNA duplex and its reproduction does not have error correction, so its error rate is similar to mitochondrial DNA. This is a factor in the genesis of cancer. See the entry of Cancer stem cells for a full explanation.
In the alternative reality of Danielle: Chronicles of a Superheroine, Danielle explains to Claire the fact that these different types of cells have different molecule machines (enzymes) for reproduction and therefore need different drug cocktails to combat them.
In the alternative reality of Danielle: Chronicles of a Superheroine, Danielle explains to Claire that chemotherapy drugs typically kill cancer cells by depriving them of oxygen, but that cancer stem cells thrive in anaerobic (that is, oxygen deprived) conditions. This is another reason that combating cancer stem cells requires a different drug cocktail than one used to kill cancer cells. Many types of stem cells gain their energy from glucose (sugar) without the need for oxygen.
Chemotherapy is a common type of cancer treatment using one or more drugs, usually a cocktail, that combat cancer cells. Most chemotherapy drugs work by interfering with the reproduction of cancer cells. These drugs are systemic, meaning they circulate throughout the body, not just in the known region of a cancer tumor. This can be beneficial in that they may combat small metastatic cancer tumors that have not yet been detected. On the other hand, chemotherapy drugs usually cause harm to noncancer cells since both cancer cells and normal cells are similar eukaryotic cells.
Because chemotherapy drugs generally target cell reproduction, they can be harmful to cells that divide rapidly such as cells in the bone marrow, digestive tract, and hair follicles resulting in such common side effects as decreased production of blood cells, inflammation of the digestive tract, and hair loss.
Chemotherapy can be curative in a small number of cases such as certain leukemias, but can be ineffective for cancers such as most brain tumors.
There is a new category of chemotherapy called immunotherapy that is creating a great deal of excitement as this book is being written. This approach involves boosting the immune system to combat cancer and to overcome the strategies that cancer uses to defeat it. Cancer usually strikes later in life, and the immune system, which evolved many thousands of years ago, did not optimize for long life as it was not in the interest of the species thousands of years ago for people to live beyond raising their children.
The body contains “checkpoint inhibitors,” which inhibit the immune system to prevent it from attacking normal cells. Cancer tumors have learned how to activate and strengthen these natural brakes to prevent the immune system from attacking cancer cells. One category of immunotherapy inhibits the checkpoint inhibitors. The first drug of this category, Bristol-Myers Squibb’s Yervoy, which was approved in 2011, disables the CTLA-4 checkpoint inhibitor and has been effective for metastatic melanoma.
Another category of immunotherapy drug known as TNF receptor agonists, now in clinical trials, stimulates the immune response which is generally too sluggish to combat cancer tumors. Another approach is to modify a patient’s T cells (by grafting a new receptor onto the T cell called a “chimeric antigen receptor”) to recognize certain molecules found uniquely on the surface of cancer cells and then to attack these cells.
Immunotherapy is regarded as a very promising approach because it specifically targets cancer cells and therefore causes less or no harm to healthy tissue.
In the alternative reality of Danielle: Chronicles of a Superheroine, Danielle points out to Claire that most chemotherapy drugs kill cancer cells by depriving them of oxygen and therefore cause anaerobic (oxygen-free) conditions which are ideal conditions for cancer stem cells to thrive. She argues, therefore, that we also need a cocktail of drugs to defeat cancer stem cells to defeat cancer.
A eukaryote is an organism whose cells contain organelles, which are structures within each cell surrounded by a membrane. One special organelle in a eukaryotic cell is the nucleus which contains the chromosomes carrying the organism’s DNA. Another important type of organelle is the mitochondria which are responsible for energy production and also contain DNA with a simpler form of reproduction.
A prokaryote is an organism in which the cells do not have organelles and, in particular, whose DNA is contained in the cell protoplasm without a membrane surrounding it. Most prokaryotes are single-celled organisms although some are multicellular. Bacteria, which are generally prokaryotes, may have cellular compartments with protein based membranes which may be considered as primitive organelles. Prokaryotes were the original life form on Earth for hundreds of millions of years until the more advanced eukaryotic cells evolved.
The bulk of cancer cells are eukaryotic cells similar to the eukaryotic cells that comprise the bulk of human cells containing human DNA. There are only subtle differences between normal human eukaryotic cells and human cancer eukaryotic cells. These differences are exploited in cancer treatments, especially the newly emergent cancer immunotherapies (see entry on Chemotherapy drugs).
Cancer cells are descendants of cancer stem cells. According to the cancer stem cell thesis of MIT scientists Elena Gostjeva and Bill Thilly, the cancer stem cells have a DNA organization that is between that of prokaryotic cells and eukaryotic cells, thus they have dubbed them “metakaryotes.” The metakaryotic cancer stem cells use a DNA-RNA duplex (unlike the dual-DNA duplex used by normal human eukaryotic cells) whose reproduction does not have error correction so its error rate is high and similar to mitochondrial DNA. This is a factor in the genesis of cancer. Since the reproductive machinery of cancer stem cells is different, different drugs are needed to kill them or interfere with their reproduction. (See the entry for Cancer stem cell.)
In the alternative reality of Danielle: Chronicles of a Superheroine, Danielle explains that her cancer cure uses a different drug cocktail to disrupt the cancer stem cells than the one used for cancer cells.
The Food and Drug Administration (FDA) is a US federal agency responsible for regulating the safety of food, dietary supplements, drugs (both prescription and over-the-counter), medical devices, and related products. It was first organized as the Food, Drug, and Insecticide Administration in 1927 and then renamed the Food and Drug Administration in 1930.
It was the 1959 thalidomide tragedy that resulted in the FDA gaining the extensive powers it holds today. Frances Kelsey (1914–2015) was an FDA reviewer and refused to authorize the drug because of concerns about its safety. When it came to light that thousands of babies in Europe had been born severely deformed to mothers who had taken the drug, the Kefauver-Harris Amendment to the Food, Drug and Cosmetics Act was passed in 1962 which vastly expanded FDA authority. The thalidomide disaster has since been frequently cited as a justification for the FDA’s strict approach to the approval of drugs.
Undoubtedly FDA regulations prevent unsafe medications from reaching patients, but having a life-threatening disease is hardly risk free. In my view, there is an inadequate attempt to balance risks. FDA regulators are rarely if ever brought to task for delaying approval of a medication or a drug trial, but are often severely censured for approved drugs or drug studies that go awry.
Consider the example of gene therapy research. Around the year 2000 gene therapy research was just getting started. In 1999, eighteen-year-old Jesse Gesinger suffered from a rare metabolic disorder called ornithine transcarbamylase (OTC) deficiency, and volunteered for a gene therapy trial, which resulted in a massive immune response and his death. In 2002, a three-year-old boy with a condition called Severe Combined Immune Deficiency (SCID) received an experimental gene therapy which appeared to cure his SCID but he then developed a condition similar to leukemia, which scientists suspected was related to the treatment. The medical merits of these particular incidents can be and have been extensively debated, but the result of these and several other incidents was a multiyear slowdown of gene therapy research, with the authorities in some countries banning the research for a period of time.
Gene therapy is now saving lives and is providing promising new approaches to controlling major diseases. There have been promising results for gene therapy treatments for leukemia, patients are now successfully treated for SCID with gene therapy, replacement organs are being grown which use gene modification, and it is having an impact in many other cases.
I have made the point that one could do a master’s thesis demonstrating that hundreds of thousands of people may have died due to the resulting delays in gene therapy research around 2002, but we can never be sure of the exact number and we cannot identify who these people are, unlike the actual patients who died from these early trials. The delay in the early 2000s of gene therapy research is just one example of many. Delaying trials and drug approvals is rarely criticized, even though such delays invariably result in suffering and death. Such losses can simply be attributed to diseases that have been around for a long time, whereas losses from a new treatment generate a much more certain condemnation. In my view, there is a substantial bias, therefore, on attributable risks (risks that can be attributed to action such as administering a drug) versus the unattributable and inherent risks of disease. This is a misinterpretation, in my opinion, of the Hippocratic oath, “First of all do no harm.” If we really wanted to do no harm (that is harm from active intervention), then we should fire all the doctors and close all the hospitals.
The public appears to agree with this view, at least by a modest plurality. A poll sponsored by the research group Research!America and conducted with help by Zogby Analytics polled about 1,000 adults. 38 percent said that the FDA should approve drugs “more quickly in order to get new treatments to patients, even if means there may be risks,” whereas 25 percent said they wanted the FDA “to act more slowly in order to reduce risk, even if this means patients may wait for treatments.”
I have spoken to a number of FDA leaders who also agree that greater risks should be taken to initiate drug trials and to approve drugs more quickly, but the reality of negative press and public and congressional reactions to actual problems puts enormous pressure on regulators to be overly cautious.
The regulatory situation is especially stark with regard to patients who have terminal diagnoses and therefore do not have the time to wait for the slow pace of the approval process. It is common sense that the risks of an experimental treatment should have much lower weight than the almost certain risk of death from an untreated terminal condition. The FDA does provide a program for this situation called Expanded Access (often referred to as Compassionate Use) which allows experimental drugs to be used for terminal patients in certain situations. However, there are severe restrictions on this program and burdensome requirements, including demonstrating that the treatment can be given safely outside of a clinical trial (as if the terminal condition itself were safe), that no other therapy is available, that providing the drug or therapy will not interfere with ongoing experiments, and that the drug developer agrees to provide access to the therapy. These are formidable requirements and most terminal patients are not in a position to navigate this process. I have had experience trying to assist friends and colleagues to access experimental drugs for terminal conditions only to find the requirements overwhelming. In several cases, the drugs were approved shortly after these colleagues passed away from their conditions having been unable to utilize the Expanded Access program.
Another controversy regarding the FDA is what many observers, including myself, regard as interference with the First Amendment right of free expression. The FDA only allows “medical claims” if they approve them, and the FDA will only approve claims if a claimant goes through the FDA’s extensive process and pays the FDA for its expenses. The overall cost of a claim is usually in the hundreds of millions to billions of dollars. This process is generally not feasible for natural substances that cannot be patented, so there are almost no claims allowed for nutritional supplements even if there is substantial research supporting such claims. If a maker of a nutritional supplement even quotes a scientific paper demonstrating efficacy in its communication about that supplement, that may be a federal crime unless the FDA has approved the claim. Under Federal Law, the FDA is supposed to approve efficacy claims of nutritional supplements on its own, but with a very small number of exceptions it has failed to do so, and there are almost no approved claims. That is why if you look at the aisle of nutritional supplements in your health food store or supermarket, virtually none of them will state what they are supposed to be used for. Even citing scientific research on the website of a nutritional supplement manufacturer is taking the risk of a criminal sanction.
Danielle makes the point that it is almost impossible to get FDA approval for a drug cocktail, despite the fact that drug cocktails are usually needed to overcome the natural resistance of pathogens (such as bacteria, viruses, and cancer cells) to any one drug. Although the FDA rules do not explicitly rule out cocktail drug approaches, it is almost impossible to gain approval for a cocktail therapy in a single cycle. Since each cycle can take five to ten years, this makes approval for cocktail approaches impractical in a reasonable timeframe. The FDA will allow testing and approval of one drug at a time, but this means that each drug has to show efficacy on its own which may not be feasible.
In the alternative reality of Danielle: Chronicles of a Superheroine, in the case of AIDS, the key breakthrough in turning an AIDS diagnosis from an almost certain death sentence to a difficult but usually manageable condition was the advent of the AIDS cocktail. Claire asks Danielle about the AIDS cocktail as contradicting her assertion that the FDA is not sympathetic to drug cocktails. Danielle replies, “Since the AIDS activists were already orphaned from society and were allied with like-minded doctors and lawyers and knew exactly what they wanted, they rammed it through with very forceful political, legal and extralegal tactics. If only the cancer patients were as alienated and aggressive.” Danielle subsequently thinks better of being critical of cancer patients.
Danielle invents a treatment for cancer that involves two drug cocktails, one to combat cancer cells and the other to combat cancer stem cells, which are the progenitors of the cancer cells. She is concerned that millions of people will die of cancer unnecessarily given the amount of time it would take to get not one but two drug cocktails through the approval process. She decides instead to do an end run around the FDA and nearly brings down the US Government in the process.
In the early 1920s, a hunter or vendor of bushmeat (the meat of a monkey or ape) in Kinshasa, the capital of the Democratic Republic of Congo, cut himself while handling or butchering an animal infected with Simian Immunodeficiency virus (SIV), and became infected himself (or herself). The SIV virus subsequently mutated into what we now call HIV. This HIV infection was slowly passed on from human to human, most likely through sexual transmission by people with untreated venereal diseases (as most such diseases were not treated in Sub-Saharan Africa). Fifty years later, the infection had spread to five continents (North and South America, Europe, Africa, and Australia) and was deemed an epidemic in the early 1980s.
The above is a popular and plausible (although not proven) story of the origin of the HIV epidemic. Infection with HIV has few or no symptoms until late in the progression of the disease in a stage known as Acquired immunodeficiency syndrome (AIDS) characterized by a greatly weakened immune system allowing opportunistic infections and cancers to emerge.
HIV infection spreads through the sharing of bodily fluids, especially blood. In the early and mid-1980s, HIV infection spread rapidly in Africa through heterosexual intercourse, again because of untreated venereal sores, through sharing needles by drug addicts, and through unprotected homosexual anal intercourse by homosexual men. It is estimated that about 300,000 people were infected by 1980. In the early 1980s, the syndrome of AIDS began to be reported which included a severe lung infection called Pneumocystis carinii pneumonia (PCP) and an aggressive cancer called Kaposi’s Sarcoma. By the end of 1981, 270 gay men had been diagnosed with this new syndrome and 121 of them had died. By 1982, the syndrome was named Gay-related immune deficiency (GRID) but was renamed “AIDS” by the US Center for Disease Control in 1982. By the end of 1983, about 3,000 people in the US had been diagnosed with AIDS of which about 1,300 had died. By the end of 1990, over 300,000 cases of AIDS had been officially reported in the world with the actual number estimated to be about a million, and eight to ten million people were estimated to have been infected with HIV.
It was in 1990 that the FDA approved the drug zidovudine (AZT) first to treat children with AIDS, and subsequently adults. AZT was the first drug to provide hope for AIDS patients. It was not a cure but it did slow down the progression of AIDS. HIV is a retrovirus which means that it works in the opposite fashion from most viruses. A typical virus consists of a DNA strand which is transcribed into RNA, and is subsequently translated into proteins that do the destructive work of the virus. In a retrovirus like HIV, it consists of an RNA strand which is reverse-transcribed into DNA, which then inserts itself into the host cell’s (the human cell’s) DNA. Once it has inserted its reverse-transcribed DNA into the normal human DNA of a cell, the DNA will generate proteins along with the usual proteins produced by the cell’s normal DNA. AZT is a reverse-transcriptase inhibitor, meaning it inhibits the reverse transcriptase enzyme that HIV uses to copy its RNA into DNA, thus thwarting the virus from forming harmful proteins.
AZT was successful in slowing down the progression of AIDS symptoms, but the HIV virus was able to rapidly evolve around an AZT attack. As described in the entry on Asymptoting logarithmic response curve, it is typical that a drug or treatment that attacks a pathogen such as the HIV virus may destroy on the order of 99.999 percent of the pathogens, but the remaining pathogens will grow back exponentially, and all of these new pathogens will be descendants of ones that are resistant to the treatment. That is exactly what happened with AZT.
By the end of 1993, the number of AIDS cases worldwide had risen to 2.5 million.
In 1995 and 1996, several other reverse-transcriptase inhibitors were developed, including a variant called protease inhibitors which interfered with the creation of proteins needed for the HIV virus to reproduce. It became clear to AIDS activists, who include significant medical and legal talent, that a cocktail of drugs was needed with each drug working on different molecular targets. Public protests had started in the mid-1980s but were joined by medical and legal experts by the early 1990s. The protests specifically targeted the slow pace of the Food and Drug Administration, especially on the issue of approving drug cocktails.
In the early 1990s, Anthony Fauci, the director of the National Institute of Allergy and Infectious Diseases (NIAID) decided to reach out and establish a dialogue with the AIDS protestors. He had led AIDS research since the early days of the epidemic in the early 1980s. He credits this dialogue with transforming the treatment of AIDS. Here he recalls these interactions in a 2005 interview:
What had happened is that we were taking the brunt of a lot of criticism, the FDA and myself and the CDC. … But after a little while, I began to get beyond the rhetoric and theater of the demonstrations and the smoke bombs, to really listen to what it is that they were saying, and it became clear to me, quite quickly, that most of what they said made absolute sense, was very logical and needed to be paid attention to. But their confrontational tactics tended to put off the somewhat conservative viewpoint of scientists about not deigning to get involved with people who have a disease when scientists know best or regulators know best.
Interacting with the constituencies was probably one of the most important things that I had done in my professional career. … There was a demonstration in the early years here at the NIH, and we had everybody on campus—we had the Montgomery County [MD], police; we had the NIH police; we had the FBI; mounted police, everybody. I always remember looking out the window and seeing them demonstrating, so I asked our chief of police to go down and ask them to get five or six of their leaders to come up and talk to me about what it is that they were concerned about.
Well, that was a total shock to the constituents, because no one had ever asked them, “Were you interested in hearing what I have to say?” They were always pushing them away because of their theatrical and confrontational tactics. So I invited a group of them up to my conference room, and we spent a couple of hours talking about their concerns. Again, it just confirmed in my own mind that most of their concerns were really quite valid. Not everything—they were off base on a few things.
That was the beginning of the constructive dialogue between me and the activists. … We came to an agreement that “I’ll listen to what you have to say. If I see that there’s merit in it, we’ll pursue it, and if there really is no merit, I’ll try and explain to you why I think there’s no merit,” because they were on base on more things than they were off base on. …
If there was anything about all of this that was truly productive, it was that interaction between the activist community, because it really transformed the way we did things. You were trying to develop drugs and treatment protocols for a disease for which there was no treatment. At the same time that you had to do good science to get it right, you had to be sensitive to the fact that these people had nothing else and no other option. In a pristine world, you do the science first, and then you worry about everything else. You couldn’t do that. That’s how we came about with expanded access to drugs, how we came about with accelerating greatly the approval process and how we came about what was known as the parallel track.
A lot of people give me credit for coming [up with] the parallel track. It really wasn’t me. It was the activists who said, “Why don’t we try this?” And I said, “You know, that sounds like a great idea. I think I’m going to stick my neck out on this one and push it for you. …” There was a lot of concern on the part of the FDA that this would interfere with the integrity of the clinical trial process, so I took a deep breath and went out to San Francisco and said, “I’m not going to check this with anybody back in Washington.” I got up and I said, “I’m absolutely in favor of a clinical trial process under the parallel track.” It was one of those instances of it’s easier to beg forgiveness than to ask for permission. And I did it. There was a bit of a stir in Washington for a few days to a week after, but then everyone saw the potential advantage of doing it this way. The parallel track concept became accepted, and I think that went a long way to getting access to drugs for people who needed it at the same time as we had the integrity of the scientific process. …
The result was the approval in 1996 of the Highly Active Antiretroviral Therapy (HAAR), the first effective drug cocktail to treat AIDS and to prevent HIV infection from turning into AIDS, only about two years after it was proposed. By 1999, the death rate from AIDS had been cut drastically. Equally important, the rate at which HIV infection resulted in AIDS had also been cut dramatically. Further improvements in the cocktail were perfected in the early 2000s. HIV infection had been changed from a death sentence to a manageable condition for most people.
Anthony Fauci was clearly a hero of this story although he credits many other researchers. But it is clear that the AIDS protest movement, imbued as it was with a sophisticated knowledge of the medical requirements and the legal process, uniquely deserves credit. Demonstrations for other diseases such as cancer attempt to raise awareness and funding, but generally do not advocate a particular scientific approach.
The success of the AIDS drug cocktail has increased attention on the need for drug cocktails for other diseases such as cancer, but with the lack of an engaged patient population knowledgeable about the science of drug cocktails, the FDA remains very slow in considering this approach.
With the death rate from HIV/AIDS having been dramatically cut in the US, attention shifted in 2001 to the lack of availability of effective treatments in developing areas such as Africa. In 2001 the United Nations called for a global fund for such initiatives. Generic drug manufacturers began to provide certain HIV/AIDS drugs at significantly discounted prices. In November of 2001 the World Trade Organization (WTO) announced the Dona Declaration which allowed developing countries especially in Africa to manufacture generic HIV/AIDS medications at cost. In 2003, President George W. Bush signed legislation providing $15 billion over five years to fund HIV/AIDS treatments in developing nations.
As of 2016, 70 million people worldwide have been infected with HIV and about 35 million have died from AIDS, although the rate of HIV turning into AIDS and of people dying from AIDS has been significantly reduced in developing nations due to these worldwide initiatives.
In the alternative reality of Danielle: Chronicles of a Superheroine, Danielle comments on this situation, “Since the AIDS activists were already orphaned from society and were allied with like-minded doctors and lawyers and knew exactly what they wanted, they rammed it through with very forceful political, legal and extralegal tactics. If only the cancer patients were as alienated and aggressive. Instead most are passive, thankful for whatever tired and expensive crumbs the regulatory system will toss their way.”
She subsequently thinks better of criticizing cancer patients, “I’ll have to reword that,” Danielle said as an aside, “so I’m not insulting the patients.”
Danielle explains to Claire that she needs two drug cocktails for her cancer treatment, one for cancer cells and one for cancer stem cells, the progenitors of cancer. She points out that the cancer stem cells have different molecular machines (enzymes) for reproduction and therefore need different drug cocktails to combat them.
In 1864, William Worrall Mayo started a medical practice which was taken over by his son and was known as the Mayo clinic. Today, it is perhaps the world’s best-known hospital and is ranked number one in the 2016–2017 List of “Best Hospitals” by US News and World Report. It has been at or near the top of that list for 25 years.
The primary Mayo Clinic hospital is in Rochester, Minnesota, but it also operates campuses in Arizona and Florida with smaller clinics in other states. It is a nonprofit medical practice and research institute which employs over 4,000 doctors and scientists and over 57,000 health staff and spends over $600 million per year on research.
Among its many medical innovations, were the isolation of thyroxine, the principal hormone of the thyroid gland; the isolation of cortisone, a hormone of the adrenal gland (for which it shared the 1950 Nobel Prize); development of the first major treatment for rheumatoid arthritis; the establishment of the first American hospital-based blood bank; the advancement of the understanding of histamine in allergies leading to the development of antihistamines; the development of the first heart-lung bypass machine (which it used to perform the first series of successful open-heart surgeries); being one of the first institutions to use insulin in the treatment of diabetes; the introduction of the first computerized tomography (CT) scanner in North America; recently conducting research that demonstrated the ability to rejuvenate a heart damaged by a heart attack with stem cells; and many other advances.
In the alternative reality of Danielle: Chronicles of a Superheroine, Danielle develops an alliance with the Mayo Clinic to support her cancer cure. Danielle and the director of the Mayo Clinic begin to distribute it and are quickly arrested by the Food and Drug Administration.
Oliver Wendell Holmes Senior (1809–1894) was an American poet and physician. He was considered by his peers in the Fireside Poets (a group of nineteenth century popular American poets) as one of the foremost poets in America. He was friends with Ralph Waldo Emerson and Henry Wadsworth Longfellow.
In the alternative reality of Danielle: Chronicles of a Superheroine, Danielle, clad in her prison jumpsuit, performs a concert with her backing band to her fellow prisoners after she is arrested for distributing her cancer cure without approval by the Food and Drug Administration. Two billion people watch her concert on the Internet. She has painted a flower on her prison jumpsuit in keeping with her fashion statement of always wearing a flower.
“What flower is that?” a man in the front row with several missing front teeth asks. In response, Danielle paraphrases four lines of Holmes’ poem “The Flower of Liberty” and then begins to sing her own lyrics.
Barack Hussein Obama II (born August 4, 1961) served two terms as the 44th president of the United States. He is the first African American to hold the office.
He was born in Honolulu to a Kenyan father and an American woman of English ancestry. From the age of six to ten, Obama lived in Indonesia with his mother and went to school there. At age 10, he returned to Honolulu to live with his maternal grandparents and attended a private school.
He has an undergraduate degree from Columbia University and a law degree from Harvard Law School where he served as president of the Harvard Law Review. In 1992, prior to earning his law degree, he was a community organizer in Chicago, worked as a civil rights attorney, and taught constitutional law at the University of Chicago Law School through 2004. He was a state senator in the Illinois Senate starting in 1997.
He came to national attention in 2004. In that year, he became the Democratic nominee for United States Senator from Illinois in March. In July, he gave the keynote address at the Democratic National Convention to great acclaim. His oratorical skills quickly made him a star of the Democratic Party. He was elected to the Senate in November.
He launched his presidential campaign only three years later in 2007 and narrowly defeated Hillary Clinton to win the Democratic nomination for president in 2008. He defeated the Republican nominee John McCain and was sworn in as president in January of 2009. Nine months later he was named the 2009 Nobel Peace Prize laureate, largely based on the hope the Peace Prize committee felt that he had brought to world affairs.
He became president as the greatest economic crisis since the Great Depression of the 1930s was under way, now known as the Great Recession. He signed into law the American Recovery and Reinvestment Act and several other laws beginning a slow recovery which stretched into his second term.
He ended official US military involvement in the Iraq War at the end of 2011. The abrupt departure of American military without leaving a residual force was subsequently blamed by critics for creating a power vacuum leading to severe tensions between the Sunni minority and the Shiite majority and the rise of ISIS in Iraq and Syria.
He initiated an allied air campaign against the Qaddafi regime in Libya in 2011 (See the entry on Hillary Clinton).
On May 2, 2011, he ordered the Navy Seal Team Six operation that killed Osama bin Laden, which was widely celebrated in the United States and around the world.
A major Obama initiative during his first term was the passing of the Patient Protection and Affordable Care Act known as Obamacare. It made it illegal for insurers to drop people who become ill or to deny coverage based on preexisting conditions. It required every American to obtain health insurance and included a government insurance option. The estimated cost of the plan to the government was about a trillion dollars over ten years. The plans contained ideas that had been introduced by Hillary Clinton with her unsuccessful health care proposal as first lady known as Hillary Care. It also contained provisions introduced by Mitt Romney in Massachusetts when he was governor in 2006 in a program known as Romney Care. Obamacare was passed by Congress after a divisive national debate and signed by Obama in March of 2010.
After defeating the Republican nominee Mitt Romney in 2012, Obama was elected for a second term. In a major initiative during his second term, the Obama administration negotiated with Iran for two years on its nuclear program starting in November of 2013, which concluded with an agreement in July of 2015. The deal imposed strict restrictions on Iran’s nuclear program for ten years in exchange for the lifting of financial and economic sanctions. The deal resulted in Iran receiving about $150 billion of funds although this was Iran’s money that had been tied up by the bank restrictions that had been in place. The deal was hailed by the Obama administration, supported by Democrats, but severely criticized by Republicans and Israeli prime minister Benjamin Netanyahu.
Obama’s presidency was characterized by a stalemate in Congress between Democrats and Republicans which became acute during his second term. In response, Obama turned increasingly to executive actions, which the administration maintained did not require congressional approval. The most controversial of these was an immigration plan shielding as many as five million undocumented immigrants from deportation and allowing them to work legally. In June of 2016, the Supreme Court in a 4–4 tie blocked implementation of this plan.
During the last year of his presidency, he campaigned extensively for the Democratic nominee for president, Hillary Clinton.
In the alternative reality of Danielle: Chronicles of a Superheroine, Danielle’s arrest for distributing her cancer cure without approval by the Food and Drug Administration led to the largest demonstrations in American history and represented a political threat to the Obama administration. Obama was furious at his administration for stumbling into this crisis. “We can’t take on Danielle, that’s crazy,” he told his attorney general.
Near the end of Obama’s second term, Danielle addresses a joint session of Congress to help resolve a budget crisis, thereby preparing for her own presidential run.
The muon is an elementary particle, meaning it is not believed to be composed of yet simpler particles or any other internal structure. Like the electron it has an electric charge of –1, but is 207 times heavier. Also like the electron, which has an antiparticle with a positive charge called the positron, muons have an antiparticle called the positive muon.
Muons are far more capable of penetrating matter than electrons and therefore penetrate into the Earth more than electrons do. Because of their greater mass, when muons encounter electromagnetic fields, they do not accelerate nearly as much as electrons do. This acceleration emits a radiation called bremsstrahlung (German for braking radiation) which results in energy loss. As a result, even though more electrons are produced by cosmic rays hitting the atmosphere, the energy loss due to the radiation when encountering electromagnetic fields near the Earth results in relatively few reaching the surface. Muons generated by cosmic rays on the other hand reach the Earth to a far greater degree and have been detected in significant numbers in deep mines.
Muons can decay into an electron and muon neutrinos.
In the alternative reality of Danielle: Chronicles of a Superheroine, in one of her conversations with the Chinese physicist and democracy activist Cheng Liu, Danielle runs out of things to say and suggests that they talk about muons. She notes that there has been speculation that muon neutrinos can go faster than the speed of light. Liu replies, “Like us, Danielle?”
Hillary Diane Rodham-Clinton (born October 26, 1947) is an American politician and the first female candidate for president of the United States to be nominated by a major party in 2016. On November 8, 2016, she was defeated by the Republican candidate Donald Trump.
She was the first lady of Arkansas during her husband Bill Clinton’s governorship from 1979 to 1981 and from 1983 to 1992. She was the first lady of the United States during her husband’s presidency from 1993 to 2001. She was the junior United States Senator for New York from 2001 to 2009, and was the secretary of state for the United States from 2009 to 2013.
Clinton received an undergraduate degree from Wellesley College in 1969 and a JD from Yale Law School in 1973. She married Bill Clinton in 1975 and co-founded Arkansas Advocates for Children and Families in 1977. In 1979, she became the first woman partner at the Rose Law firm. As the first lady of Arkansas, she led an effort to reform the Arkansas Public Schools.
As the first lady of the United States, she led a major initiative to enact the Clinton Health Care Plan of 1993, which would have required employers to provide health coverage to their employees. The plan became known as Hillary Care, although this term was largely used pejoratively by her political enemies. The plan was abandoned in September of 1994 despite the Democrats controlling both chambers of Congress. As a result, her approval rating fell to 35 percent at that time. Despite the failure and opposition her plan created, it did lay the groundwork for a national health insurance plan and contained many of the ideas that would subsequently be approved during the Obama presidency.
At the end of the Bill Clinton presidency, Hillary Clinton became the first US first lady ever to seek an elected office. She ran and won as the first female senator from New York. As senator, she voted for both the Afghanistan War and the Iraq War. She later said she regretted the vote for the Iraq war.
One of her major initiatives as secretary of state during the first term of the Obama administration from 2009 to 2013, was to be a strong advocate for US military intervention in Libya, leading an alliance of nations. Using air power and without ground troops, the regime of Muammar Qaddafi was overthrown. The US and its allies then abandoned Libya which as a result disintegrated into chaos with multiple governments, each with their own legislatures, and regions controlled by al-Qaeda and by ISIS. As this book is being written, there is a UN led effort to consolidate a single government, and ISIS is rapidly losing territory through a multinational effort.
As secretary of state, Clinton also led a diplomatic initiative to establish diplomatic isolation and sanctions against Iran, which during Obama’s second term led to a controversial agreement with Iran to limit its nuclear program for a decade.
As the 2016 Democratic nominee for President, her platform and speeches emphasized reducing income inequality, improving Obama’s Affordable Care Act (Obamacare), reforming campaign finance and Wall Street, allowing a path to citizenship for undocumented immigrants, expanding rights for women and LGBT persons, supporting paid parental leave and providing preschool for all children.
Her campaign was burdened by a scandal involving her use of a private email server for official emails while she was secretary of state in violation of State Department rules, and accusations that she gave preferential treatment in scheduling official meetings as secretary of state to donors to the Clinton Foundation, a private foundation run by the Clinton family.
In the alternative reality of Danielle: Chronicles of a Superheroine, ten-year-old Danielle has a different approach to Libya; she helps the anti-Qaddafi rebels overthrow the regime using software viruses she has written from her outpost in the Libyan desert. Unlike the Obama administration, she immerses herself in the post-Qaddafi era and helps establish a stable government. The Libyans erect a monument to her and Claire, showing them with their iPads in their desert outpost.
Twelve-year-old Danielle (along with the head of the Mayo Clinic) is arrested for distributing her cancer cure. National demonstrations threaten to bring down the Obama administration.
“How did we get in this corner?” President Obama asked his secretary of state, Hillary Clinton.
“You took your eye off the ball, sir.”
“So what do you recommend?”
“Don’t stand on pride. Just do what she is asking. You’ll be friends again, privately and publicly. I have assurances that she’ll quickly repair the damage. You’re on the wrong side of history at the moment, but she has provided a bridge to the other side.”
Later on, when Danielle is nineteen, she runs for president against Hillary Clinton. The Slate headline reads, “Pick a Gal for President.” Clinton makes an issue of Danielle’s age, but this does not go over very well given Danielle’s successful tenure as president of China.
See entry for President Obama.
A stock option is a contractual right to purchase shares of stock of a company at a set price, called the exercise price. If at the time a stock option is granted the exercise price is the same as the then fair market price of the stock (in a public company that would be the public price at that time), then the grant of the stock option is a tax-free transaction. Stock options are a popular way to provide a form of stock ownership to employees in new companies because there are no taxes due when the grant is made.
An incentive stock option (ISO) is a type of stock option that only can be granted to employees (not consultants) and carries certain tax benefits in the United States. Specifically, when the stock option is exercised (to purchase the underlying shares), the individual does not have to pay taxes at that time. If the person holds the stock for at least one year from the date of exercise and two years from the date of grant, then the profit made on the sale of the shares is taxed at the long-term capital gains rate (which is generally about half the rate of regular income). However, the person may have to pay the “alternative minimum tax” when exercising the shares. Persons who are not full-time employees (such as consultants) and who do not meet other requirements can be issued nonstatutory stock options (NSOs) rather than ISOs. The issuance of NSOs is also nontaxable upon grant, but when exercised there is a tax due on the difference between the then fair market value and the strike price (the price actually paid based on the right granted by the NSO). This tax is not at the long-term capital gains rate, even if the option was held for a long time, but at regular income tax rates. Usually the holder of an NSO will “flip” the NSO rather than just buy shares, meaning the holder buys the shares at the strike price and immediately sells them at the market price, and then owes taxes for the difference at regular income tax rates. By selling the shares immediately, the person has the cash to make the tax payment.
Around 2014, the tax code put significant new restrictions on the use of ISOs making it difficult to obtain these tax benefits, so that ISOs have become less popular, and many companies issue NSOs to employees as well as consultants.
In the alternative reality of Danielle: Chronicles of a Superheroine, Danielle offers Martine Rothblatt a position on the board of another new Danielle company, Danielle Stem Cell, which is intended to commercialize her cancer cure based on destroying cancer stem cells. Danielle explains to her that she cannot just issue Martine stock in the company because the company already has significant value, so granting stock would immediately incur a large tax bill. She tells her that “the equity will have to be nonstatutory stock options.” Danielle goes on to explain that she is giving 90 percent of her own stock to her foundation, which is named Danielle.