Wednesday, July 5, 2023

Speuler Alert

Have you ever wondered how different some fundamental force fields, like gravity and magenetism, really are from each other? I wanted to elucidate the provenance of these basic physics principles. To help me with that, I asked ChatGPT4 to provide a conversation between 19th century physicists. Then I started to troll them.

Me: Does gravity curve space?

Yes, according to Einstein's General Theory of Relativity, gravity is not just a force as described by Newton's law of universal gravitation, but rather it is the curvature of spacetime caused by mass and energy. The more mass an object has, the more it bends the space around it. This curvature of spacetime tells objects moving within that space how to move, which we perceive as gravity.

This revolutionary concept is often illustrated with a rubber sheet analogy. If you place a heavy object on a stretched rubber sheet, the sheet will curve downwards where the object is. If you then roll a smaller object onto the sheet, it will move towards the heavier object not because of a direct force applied, but because of the curved path it follows on the bent sheet. This is a rough two-dimensional analogy for the four-dimensional spacetime curvature in our universe.

Me: Does a magnet curve space?

Magnetism, like any form of energy, does contribute to the total energy-momentum of a system, and according to Einstein's General Theory of Relativity, the energy-momentum of a system will cause spacetime to curve. In this way, a magnetic field can indirectly contribute to the curvature of spacetime.

However, the effects of this would be extremely tiny, far smaller than those caused by mass, for two reasons:

  1. The energy contained in even a strong magnetic field is relatively small, especially when compared to the energy equivalence of mass (given by E=mc^2).
  2. The General Theory of Relativity is a nonlinear theory, meaning the effects of different types of energy on the curvature of spacetime don't simply add up.

It's also worth noting that unlike gravity, which always attracts, magnetic fields can both attract and repel depending on the orientation of the magnetic moments. This makes the relationship between magnetism and spacetime curvature even more complex. In practice, the effects of a magnetic field on the curvature of spacetime are usually so small that they can be neglected in all but the most precise calculations. For most practical applications, it's sufficient to think of magnetism in terms of Maxwell's Equations, which describe how electric and magnetic fields interact with each other and with charges and currents, but do not involve the curvature of spacetime.

Me: If small magnet A is translating fast along a path, and passes by another much larger magnet B (assuming their attractive poles were oriented toward each other) , it's path curves toward magnet B, but let's say it had enough momentum to still keep on going onward after passing magnet B. Was magnet A's path dictated by the spacetime curvature of magnet B?

The curvature of a magnet's path when it passes by another magnet is generally understood in terms of the classical electromagnetic force between the magnets, as described by Maxwell's equations. This force can pull the magnets together or push them apart, depending on the orientation of their poles, and it's this force that would cause the path of a moving magnet to curve as it passes by another magnet.

In this case, the smaller magnet (A) would be attracted towards the larger magnet (B) due to the magnetic force between them. If magnet A had enough momentum, it would continue to move forward, but its path would be curved due to this attraction.

While it's technically true that the energy in the magnetic field contributes to the total energy-momentum of the system, and thus to the curvature of spacetime according to the General Theory of Relativity, this effect is typically so small that it can be neglected. For all practical purposes, the behavior of magnets can be accurately described using classical electromagnetism without considering the effects of spacetime curvature.

In short, while magnet A's path would be affected by magnet B, this is almost entirely due to the classical magnetic force between them, rather than any spacetime curvature caused by magnet B. The influence of spacetime curvature in this scenario would be incredibly tiny and almost impossible to detect.

Me: What is the origin of classical magnetic force - which is to say what is the physical nature by which magnetic force is imparted from one magnet onto another magnet.

The classical magnetic force has its roots in the movement of charged particles. At a fundamental level, magnetism is a force caused by electric charges in motion. For example, in many materials, including iron (a common component of magnets), atoms have electrons which are moving or spinning in coordinated ways, creating a net magnetic field.

Maxwell's equations, which are the foundation of classical electromagnetism, govern the behavior of electric and magnetic fields. One of these equations, Ampere's law (with Maxwell's addition), states that magnetic fields are produced either by electric currents (which are simply moving electric charges) or by changing electric fields.

When two magnets come into proximity, the magnetic field lines emanating from one interact with the other. The way these magnetic field lines interact with each other results in a force between the two magnets.

The force between two magnets is an example of a "field force," meaning it's a force that can act over a distance without the need for the objects to be in physical contact. The field itself — in this case, the magnetic field — is the entity that carries the force from one object to another.

In the case of magnetism, the magnetic field lines can either attract or repel depending on the orientation of the magnets. If you bring together two magnets, the north pole of one will attract the south pole of the other and vice versa. But the same poles — north-north or south-south — will repel each other.

It's important to note that our understanding of electromagnetism has been refined by quantum mechanics and quantum electrodynamics, which give a more fundamental picture of these phenomena in terms of the exchange of virtual photons. However, the classical picture I've outlined above is often sufficient for everyday situations and provides a good first approximation to the true behavior.

1. Provide me a resource to understand 'virtual photons' better.
2. What is the fundamental nature of a 'field force'.

Virtual Photons: Virtual photons are a concept from quantum electrodynamics (QED), which is the quantum field theory of electromagnetism. In this theory, forces are described in terms of the exchange of "virtual particles." For electromagnetism, these particles are virtual photons.

If you're interested in learning more about virtual photons, here are a few resources:

"QED: The Strange Theory of Light and Matter" by Richard Feynman. This book is a classic, accessible account of QED by one of the theory's key architects. It covers the concept of virtual particles in some detail.

This article from titled "What are virtual particles?" provides a succinct overview of the concept:

The Stanford Encyclopedia of Philosophy also has an in-depth entry on quantum field theory, including a section on virtual particles:

Field Forces: A field force is a type of force that does not require physical contact between the interacting objects. Instead, an object creates a "field" — an entity that permeates the space around the object — and other objects feel the force of this field.

For example, in the case of gravity, an object like the Earth creates a gravitational field that extends out into space, and other objects (like the Moon, or an apple falling from a tree) feel a force because they're within this field.

Electromagnetic forces are also field forces. Charged particles, for example, create an electric field around them. Another charged particle in this field will experience a force, with the direction and magnitude depending on the charge and the distance from the source.

The concept of a field is fundamental in physics. It's a way of describing how forces can act at a distance, without the need for the interacting objects to be in direct contact. The mathematical description of fields allows physicists to calculate the effects of forces in a wide variety of situations, and forms the basis for our understanding of many natural phenomena.

Me: Compose a multi-party conversation with the relevant physicists of the 19th century and turn-of-the-19th-to-the-20th-century trying to make sense of the apparent similarities and yet stark differences between electrostatic fields, magnetic fields, and gravity fields, in trying to unify them into a cohesive conceptual framework.

(The setting is an imaginary meeting room. In attendance are James Clerk Maxwell, Michael Faraday, André-Marie Ampère, Albert Einstein, and Isaac Newton. While Newton is not from the 19th or 20th century, we've invited him for the purpose of this thought experiment.)

Maxwell: Gentlemen, I've called this meeting to discuss the nature of the fundamental forces we've studied. We're all familiar with the work we've individually done—Newton on gravity, Ampère and Faraday on electromagnetism, and my own efforts to formalize electromagnetic theory. Einstein, your work on special relativity has recently opened new doors. I hope we can find some common ground.

Newton: Well, gravity is a force acting at a distance. Objects attract each other in proportion to the product of their masses and inversely proportional to the square of the distance between them.

Faraday: My studies in electromagnetism have shown something similar. Charges also interact at a distance, inversely proportional to the square of their separation. However, unlike gravity, they can either attract or repel.

Ampère: Correct, Faraday. And moving charges, or currents, produce magnetic fields, which have their own rules. This adds a layer of complexity.

Einstein: And there is where my theory of special relativity comes in. It unites the concepts of space and time into a single entity—spacetime. Moreover, it implies that the laws of physics, including the laws of electromagnetism, should look the same to all observers, no matter their state of motion. This inherently links the electric and magnetic fields.

Maxwell: Indeed, my equations describe how electric and magnetic fields interact and how they propagate through space as waves. I also noticed their speed matches the speed of light, which leads me to believe that light itself is an electromagnetic wave.

Einstein: Precisely, Maxwell. And I've started to think about gravity in a similar way to electromagnetism. In my general theory of relativity, which I'm currently developing, gravity isn't just a force acting at a distance. Instead, it's a curvature of spacetime caused by mass and energy. This might open a door to the unification of these forces.

Newton: I see, then my force-based interpretation might be just an approximation to a more profound reality, similar to how Euclidean geometry is a simplification of a more complex, curved geometry.

Faraday: But the real challenge remains unifying electromagnetism with gravity. Both have similarities, such as action at a distance and inverse square laws, yet the fundamental differences, like gravity's always attractive nature and electromagnetism's dual character, pose a problem.

Einstein: Agreed, Faraday. These are challenges for future generations of physicists. Perhaps quantum mechanics, still in its infancy, will provide us with the tools to merge these forces into a single, cohesive framework.

Me: That's a great cast of characters. Let's add Minkowski into the cast of characters. The subject of heated discussion at hand is whether all field forces acting at a distance represent curvature of space/spacetime or some other concept altogether.

(The setting remains in the imaginary meeting room. Hermann Minkowski has joined the group.)

Maxwell: Gentlemen, I'd like you all to meet Hermann Minkowski, a mathematician whose work has significantly contributed to our understanding of spacetime. He has some intriguing insights into our current discussion.

Minkowski: Thank you, Maxwell. To jump right in, Einstein, I find your theory of general relativity fascinating, and I believe my geometric interpretation of special relativity could fit into this nicely. I've proposed that the events of the universe occur not separately in space and time but within a unified four-dimensional "spacetime."

Einstein: Precisely, Minkowski. Your interpretation has been immensely helpful in shaping my thoughts on general relativity. When we incorporate gravity, it's not space or time alone that's affected, but this unified spacetime. Massive objects cause it to curve, and this curvature dictates the motion of other objects.

Minkowski: If I understand correctly, then, gravity is not a force in the traditional sense, but a manifestation of the curvature of spacetime.

Newton: Then, could it be that my theory of gravitation is just an approximation for low energies or large distances, similar to how the rules of classical mechanics approximate the laws of quantum mechanics at macroscopic scales?

Einstein: Exactly, Newton. And following this line of thought, could it be possible that other field forces, such as electromagnetism, might also be manifestations of some form of spacetime structure or curvature?

Faraday: An interesting proposition, but electromagnetism has characteristics that are starkly different from gravity. It's not always attractive like gravity—it can also repel. How would a curvature account for such a phenomenon?

Ampère: And let's not forget, electromagnetism is inherently a quantum phenomenon. Photons, the force carriers of the electromagnetic interaction, are quantum mechanical in nature.

Einstein: Those are valid points, Faraday, Ampère. It seems clear that a simple generalization of the curvature concept won't suffice to encompass electromagnetism, given its distinctive features.

Minkowski: We must remain open to the possibility that the fabric of spacetime might be more complex than we currently understand, able to accommodate these differing phenomena. Or perhaps, these forces exist in distinct yet interwoven realms of a more intricate framework.

Maxwell: Regardless, this discourse has made it clear that our pursuit is not just to unify forces, but to deeply understand the geometric and physical properties of our universe. The path ahead is exciting and full of intriguing challenges.

Einstein: Well said, Maxwell. The quest to reconcile gravity and electromagnetism—these fundamental, yet profoundly different aspects of nature—is indeed the grand challenge that awaits future generations of physicists.

Me: A physicist walks into the room to participate in the discussion. Let's call him Speuler. Even though Speuler is unknown to history, the other physicists in the room know him by reputation and respect his prestige. Of course, like any physicist, he can be wrong too. He comes in to challenge each set of physicists - to Maxwell and Ampere, he comes in with an assertion that the 'fields' of their electricity and magenetism forces are curvatures of a kind of spacetime. To Einstein and Minkowski, he comes in with an assertion that gravity is imparted by a hitherto undiscovered particle with characteristics comparable to the photon (of electricity & magnetism fame). Lorentz also accompanies him, though they are not necessarily friends, just colleagues.

(The door to the meeting room swings open, and a man named Speuler walks in, followed by Hendrik Lorentz. The room, already brimming with lively discussion, grows momentarily quiet.)

Maxwell: Ah, welcome, Speuler! I've heard of your alternative ideas. Please, do share them with us.

Speuler: Thank you, Maxwell. Let's start with electromagnetism. You, Ampère, and Faraday have all done impressive work on the concepts of electric and magnetic fields. Yet, I've been pondering—could these "fields" be manifestations of a curvature in some kind of spacetime, much like Einstein's gravity?

Ampère: That's a curious thought, Speuler. But how would you account for the unique behavior of electromagnetic forces—the duality of attraction and repulsion? Can a mere curvature capture this?

Speuler: An excellent question, Ampère. Our understanding of "curvature" might need to be expanded or modified. Maybe, the spacetime which hosts these fields could possess additional dimensions or properties, leading to complexities like attraction and repulsion.

Faraday: But the quantum nature of electromagnetism poses its own challenges. How would you reconcile that with the continuum of spacetime?

Speuler: This would indeed require careful consideration. Now, turning to Einstein and Minkowski, I have a different proposition—what if gravity were imparted by a particle? Like the photon carries the electromagnetic force, what if there were a 'graviton' carrying gravitational interactions?

Einstein: Interesting, Speuler. The idea of a gravity-carrying particle is certainly appealing. However, it would need to fit within the framework of general relativity, which describes gravity as a geometric property of spacetime, not a force in the conventional sense.

Minkowski: And if gravity is mediated by a particle, it should be a quantum entity. Then, we'd have to marry quantum mechanics and general relativity—a formidable challenge.

Lorentz: I would add, Speuler, that your proposed 'graviton' would also have to explain the observed equivalence of inertial and gravitational mass—an integral part of Einstein's theory.

Speuler: You all raise valuable points. We are certainly on the frontier of our understanding. I believe that regardless of whether we are speaking of spacetime curvatures or force-carrying particles, we are grappling with the same fundamental question: the nature of reality itself.

Maxwell: Indeed, Speuler. It's exhilarating to ponder these possibilities, and it's discussions like these that continue to drive our understanding of the universe forward. Our theories may change and evolve, but the quest for understanding remains the same.

Me: Make them less collegial with each other. They have grants riding on the validity of the respective theories being borne out, and they collaborate / corroborate others only insofar as their theories & frameworks aren't incompatible with their own. They particularly like physicists whose theories & frameworks actively support their own. Speuler, being independently wealthy to fund his lab's research, has no need for such grants. Speuler kick-starts the conversation.

(The mood in the meeting room is tense as Speuler, who is independent and wealthy, enters.)

Speuler: Gentlemen, I've been closely observing your work and, I must admit, I see some glaring oversights. Allow me to challenge your perspectives.

Turning to Maxwell and Ampère, I find your notion of electric and magnetic fields intriguing, but couldn't these fields be interpreted as manifestations of curvatures in a higher-dimensional spacetime? This would put electromagnetism on the same footing as Einstein's gravity.

Maxwell: Speuler, I respect your courage in challenging established concepts, but you seem to overlook the fundamental nature of electromagnetism. It's not simply a force acting at a distance. It's a dynamical entity that evolves and propagates through space and time.

Ampère: And let's not forget, Speuler, how different electric forces are from gravity. Electric forces can repel and attract, unlike gravity. How would a simple spacetime curvature capture this dual character?

Speuler: I expected such resistance. But, it seems to me that we might need to consider spacetime to be more complex than we currently imagine. Perhaps additional dimensions or properties could explain these phenomena.

Maxwell: Interesting idea, Speuler, but you'll have to provide compelling evidence to convince the rest of us and the scientific community.

Speuler, moving on to Einstein and Minkowski, continues: And as for you two, what if gravity isn't merely a curvature of spacetime but is mediated by a particle, analogous to the photon in electromagnetism?

Einstein: Speuler, that's a bold statement. While a particle carrying gravity might fit nicely into a quantum framework, it doesn't neatly align with general relativity's geometric description of gravity.

Minkowski: Einstein is right. Gravity as we understand it in the context of spacetime doesn't need a particle to mediate it. It's an intrinsic quality of the universe, not an exchangeable quantity.

Lorentz, who has been listening attentively, finally interjects: Besides, Speuler, any proposed 'graviton' would need to accommodate the observed equivalence principle—an essential part of general relativity.

Speuler: These are all good points. Still, I insist that whether we are talking about spacetime curvatures or force-carrying particles, our ultimate goal is to uncover the true nature of reality.

The room falls into a tense silence, everyone mulling over Speuler's words. It's clear that the path to truth isn't always harmonious. But even in this challenging environment, the shared pursuit of understanding keeps these physicists firmly bound to their mission.

Me: Speuler asks each physicist in turn to itemize the primary assumptions / frameworks their respective theories are based on.

Speuler: Gentlemen, if we are to truly grapple with these concepts, it would be beneficial to make explicit the primary assumptions and frameworks upon which your theories rest. Newton, would you please begin?

Newton: Of course, Speuler. My theory of gravity rests on three primary assumptions:

  1. Gravitational force is universal. It acts between all particles of matter and is always attractive.
  2. Gravitational force is directly proportional to the product of the masses of the two interacting objects.
  3. Gravitational force acts along the line joining the centers of the two masses and is inversely proportional to the square of the distance between them.
Speuler: Thank you, Newton. Faraday, Ampère, your turn.

Ampère: My theory of electromagnetism can be summarized as follows:

  1. An electric current in a wire produces a magnetic field in the space around it.
  2. The magnetic field is circular, centered on the wire, and its direction depends on the direction of the current.
  3. The strength of the magnetic field is directly proportional to the magnitude of the current and inversely proportional to the distance from the wire.
Faraday: Building on Ampère's work, I have further assumptions:
  1. A changing magnetic field induces an electric field.
  2. This electric field can drive an electric current in a conducting material.
  3. The magnitude of the induced electric current is directly proportional to the rate of change of the magnetic field.
Speuler: Maxwell, can you describe your framework?

Maxwell: Certainly, Speuler. I have consolidated the works of Faraday, Ampère, and others into a set of four equations, known as Maxwell's equations. Here are their primary implications:

  1. Electric field lines originate on positive charges and terminate on negative charges, and their divergence gives the charge density.
  2. Magnetic field lines are always closed loops, and their divergence is always zero.
  3. A time-varying magnetic field induces an electric field.
  4. An electric current or a time-varying electric field produces a magnetic field.

Speuler: Einstein, Minkowski, your assumptions?

Einstein: In the special theory of relativity, my assumptions are:

  1. The laws of physics are the same in all inertial frames of reference.
  2. The speed of light in a vacuum is constant and independent of the motion of the light source or the observer.

In the general theory of relativity, I add:

  1. Gravity is a manifestation of the curvature of spacetime caused by mass and energy.
  2. Objects move along geodesics, which are the shortest paths in the curved spacetime.
Minkowski: My work builds on Einstein's special relativity, interpreting it in a geometric framework:
  1. Spacetime is a four-dimensional manifold, with three dimensions of space and one of time.
  2. Events in the universe can be described by a set of four coordinates (x, y, z, t).
  3. The spacetime interval, an invariant quantity under transformations, provides a natural metric for the geometry of spacetime.

Speuler: Lorentz, your turn.

Lorentz: My work primarily relates to the transformation of physical quantities between different frames of reference:

  1. The laws of physics, including Maxwell's equations, have the same form in all inertial frames.
  2. The time and space coordinates of an event change when observed from different inertial frames, according to what we now call the Lorentz transformations.

Speuler: Thank you all. Understanding these foundational assumptions will be crucial as we continue to question, refine, and potentially unify our theories.

Me: Into this situation we introduce the fact that each physicist holds identical sensors that can sense the minute attraction or repulsion of objects from each other, no matter how slight. From one of his pockets Speuler pulls out a 'gravitic dipole'. The dipole's 'north' pole attracts all of the objects in the room just as much as objects in the room attract each other, per ordinary familiar gravity. The objects in the room, however, are repelled by the dipole's 'south' pole.

(The room grows quiet as Speuler reveals a 'gravitic dipole' from his pocket. As he holds the dipole up, the scientists can feel the slight pull and push on their bodies and the sensors in their hands.)

Speuler: Gentlemen, observe this. I call it a 'gravitic dipole.' The 'north' pole of the dipole attracts all objects just as gravity ordinarily would. But the 'south' pole repels them. How do your respective theories account for this?

Newton: If this is a form of gravity, then it contradicts the universality of gravitational attraction that I assumed. It suggests the existence of a new kind of force or an alteration to our understanding of gravity.

Faraday: Speuler, this is intriguing. Could there be a connection to electromagnetism? After all, we see similar attractive and repulsive effects in magnetic dipoles.

Ampère: Yet, gravity and electromagnetism operate on different scales and principles. The quantum nature of electromagnetism allows for duality in attraction and repulsion. Can the same be said for gravity?

Maxwell: Indeed, Ampère. The principles that govern electromagnetism are significantly different from those of gravity. Speuler's device would require a considerable expansion or modification of our current theories.

Einstein: A repulsive force in gravity? That contradicts the principle of equivalence, the cornerstone of general relativity. We might need to rethink gravity as not just a geometric property of spacetime but potentially a property that can be manipulated.

Minkowski: The existence of such a dipole would be a profound departure from our current understanding of spacetime. This might hint towards a more complex structure or even the possibility of additional dimensions.

Lorentz: Whatever the explanation, Speuler, this 'gravitic dipole' certainly presents a challenge to our current understanding of fundamental forces.

Speuler: Indeed, gentlemen. This might well be an indication that we are merely at the precipice of our understanding of gravity and the fundamental forces of nature. Perhaps the theories we hold so dear will need to be re-evaluated in the light of such anomalies.

Me: Each physicist in turn contributes their perspective on how they think the gravitic dipole works.

Speuler: So, gentlemen, how might your respective theories explain this 'gravitic dipole'? Newton, would you care to start?

Newton: Well, if this is indeed gravity we're dealing with, it goes against my understanding of the force being universally attractive. It might imply gravity is not as simple as I thought and could involve more complex principles. We may need to contemplate a dual nature of gravitational force, similar to how magnetism operates.

Speuler: Fascinating, Newton. Faraday, your thoughts?

Faraday: From an electromagnetic standpoint, it's tempting to draw parallels with magnetic dipoles. Yet, gravity and electromagnetism are fundamentally different. However, we could explore the possibility of an underlying unified force that manifests as both gravity and electromagnetism, depending on certain conditions.

Speuler: Interesting perspective, Faraday. Ampère?

Ampère: I agree with Faraday. Our understanding of forces and fields may need to be expanded. Perhaps there is a hidden layer of reality where gravity and electromagnetism share a common origin, and this 'gravitic dipole' is a glimpse into that reality.

Speuler: Thought-provoking, Ampère. What about you, Maxwell?

Maxwell: The existence of a repulsive aspect to gravity, as seen in this dipole, demands a thorough rethinking of my equations. It could mean gravity isn't just about mass curving spacetime, but also about how matter responds to this curvature. The repulsion could be a kind of resistance to spacetime curvature.

Speuler: That's an interesting idea, Maxwell. Now, Einstein?

Einstein: The presence of a 'gravitic dipole' might indicate the need for modifications to general relativity. One possibility could be the inclusion of some form of quantum mechanics, as the concept of repulsion is inherent in quantum theory. The graviton, if it exists, may have properties we haven't considered yet.

Speuler: An intriguing concept, Einstein. What about you, Minkowski?

Minkowski: This gravitic dipole could suggest that the geometry of spacetime is more complex than we've imagined. Maybe we have more than four dimensions, or perhaps our understanding of how matter influences spacetime needs a revision.

Speuler: Very insightful, Minkowski. Finally, Lorentz?

Lorentz: As a theoretical physicist, I see this as an opportunity to propose new mathematical descriptions of the universe. This 'gravitic dipole' may imply that our physical laws transform differently between different frames of reference. If this is the case, we'll need new transformation laws that go beyond my current transformations.

Speuler: Thank you all for your input. It's clear that the 'gravitic dipole' challenges our current theories and invites us to think outside the box. The road to understanding the true nature of the universe is indeed full of surprises.

Wednesday, June 14, 2023

ChatGPT reinvents the UFO

In light of recent UAP revelations, I decided to see if AI could help reverse-engineer, extrapolate, and propose a research program to determine how they work. Here is that conversation, abridged.

Thursday, June 4, 2020

Tu YouYou's speech at the 2002 China-Africa Forum on Traditional Medicine

There is a famous person who really should be a lot more famous, even after having earned the Nobel Prize in Physiology or Medicine in 2015. Her name is Tu YouYou.  She discovered artemisinin, which is now the first line malaria medication for infected cases.  What's even more interesting and perhaps more deserving of fame (in light of the result of course) was that she did so by mining traditional medicine systems, in this case Traditional Chinese Medicine, to find this therapeutic.  This is one of those medications that are probably most easily and appropriately termed a 'cure', although the medical profession looks down at that term for anything because of the expectations it instills in the patient and their loved ones (and there's always an exception, complication, or side effect in some small number of patients relative to the total number of treated).

Anyway I was at the KEnya Medical Research Institute hq the other day, in their Traditional Medicine Research department.  There was a binder there from 2002 with the agenda and speeches from an Africa-China traditional medicine research convocation in Beijing.  There was a speech of hers inside, and I was given permission to transcribe it.  Here it is:


China-Africa Forum on Traditional Medicine convened from 20-22 October in Beijing

Qinghaosu [ed. note: Artemisinin] - the Crystal of Traditional Anti-malaria Chinese Medicine

Tu Youyou
Director, Research Center for Qinghao and Qinghaosu, China Academy of Traditional Chinese Medicine, Beijing, 100700, China

I am a researcher from the China Academy of traditional Chinese medicine.  Traditional Chinese medicine (TCM) with its unique theory is shaped from the long history of medical practice and experiences accumulation of the Chinese nation.  TCM protects the development and multiplication of the nation.  THe flourishing of TCM today is based on the continuous invention nad innovation in its history.  In 11th century BC, anatomic terms of human body and descriptions of a number of diseases were recorded by inscriptions on bones and tortoise shells.  The Yellow Emperor's Internal Classic (Qin dynasty and Han dynasty) and Treatise on Diseases (by Zhang Zhongjing, East Han dynasty) establish the theoretical basis of TCM, and guided the clinical practice of the medicine.  Medicine and drugs are inseparable.  Chinese herbal medicine has a long history as the one of TCM.  Over a hundred of herbal medicines and treatment and/or prevention for dozens of diseases are registered in Canon of mountains and Sea (3rd century BC). Historical Record carries the following message " Shen Nong (the god of agriculture) tasted hundreds of herbs and initiated the medicine".  Shen Nong is certainly a legend character.  However, Shen Nong's Herbal Classic is a reality.  It carries 365 kinds medicines from herbal, animal and mineral origins.  The newly-revised Materia Medica (659 AD) was implemented in Tang dynasty. In 1578 , the well-known Compendium of Materia Medica was completed by Li Shizhen of Ming dynasty, and printed the cut blocks in 1593. After founding of new China, the Academy of Traditional Chinese Medicine, affiliated to the Ministry of Health, was set up in 1955. In 1983, seven WHO collaborating centers for TCM in China were established. The Institute of Chinese Materia Medica, China Academy of TCM is one of them.

In 1960's, malaria was epidemic when Vietnam was in the flames of war. It has been an urgent need for new antimalarial drugs due to the problem of chloroquine-resistant strains of P. Facliparum. Globally, hundreds of millions of people were annually suffered from the disease, and the mortality was increased sharply. A large scale screening for antimalarial drugs was carried out home and abroad at that time, without satisfactory results. Our project for developing new antimalarial drugs was set up under the above mentioned situation in 1969. Malaria is a common disease for the world, and recorded in a medical literature (12 century, BC) in China.  I graduated from the Department of Pharmacy, Beijing Medical College, and systematically studied TCM after employed.  I firmly believe that TCM with this long history is a great treasure-house, and efforts should be made to explore its essence. On the basis of collection and analysis of traditional prescriptions, over two hundreds of herbs and three hundreds and eighty abstracts from them were screened by malarial models of mouse or monkey.  The screening showed positive results in October, 1971. We isolated and purified the effective compound from the traditional Chinese herb, Artemisia annua L, in 1972. It was named Qinghaosu after the herb's pronunciation in Chinese. Qinghaosu showed 100% inhibition to malaria parasites for monkey and mouse.  In 1973, clinical trials verified the efficacy of Qinghaosu. A new antimalarial drug was finally appeared. Qinghaosu is a compound of sesquiterpene lactone with a peroxide. It is just what we were looking for - the antimalarial drug with totally new chemical structure. The antimalarial effect of Artemisia annua L was firstly described in "The handbook of prescriptions for emergencies" compiled by Ge Hong (281-340 AD), the physician and alchemist in East Jin dynasty. The invention of Qinghaosu is benefited from TCM. It is a good illustration of the treasure and essence in TCM and the potential for contribution to the world medicine. Qinghaosu is a drug with high efficacy, fast-action and safe. In October of 1981, I delivered a talk on the chemical research of Qinghaosu during the international symposium of Qinghaosu held in Beijing. The talk evoked great attention. Qinghaosu was appreciated as "a new antimalarial drug with importance of pointing direction for drug synthesis and design". New drug certificate for Qinghaosu was issued as the first category drug in 1986, and the one for dihydro-Qinghaosu later on. Dihydro-Qinghaosu is a derivative of Qinghaosu with two hydroxides. It provides basis for further development of derivatives of Qinghaosu. The achievements gained the National Invention Award and the Top Ten National Award for Progress in Science and Technology accordingly.

For our good wishes, the 21st century should be a better one with magnificent prospects. Although we can roam in the heavens, and the world is connected closely by the internet, but we still have to face the cruel facts of local wars and life-threatening diseases.  Malaria is still a dangerous enemy to mankind in the new century. An airplane crash may kill hundreds of people, and results in an impact of shake and grief for the living people for a long time to come.  However, we sometimes neglect the significant tragedy. Malaria, as the tropical disease, is cruelly killing the poor people in the developing countries. Some 500 million infections are globally reported, and some 3,000 children are killed daily in Africa only.  The simple figures tell us that ten abuses [editors note: Airbuses probably] full of children were crashed every day. What a nightmare to the mankind! We get to fight back. "Roll back malaria" is the fighting target for the new century setup by WHO. I believe Qinghaosu and its derivatives are the right weapons for the combat. We sincerely hope that the invention of Qinghaosu will save thousands of endangered people from the verge of death daily. Research Center for Qinghao and Qinghaosu was established at the China Academy of TCM due to the invention of Qinghaosu. The center carries out systematic researches on Qinghaosu, and gains new progresses in compound prescriptions with better therapeutic efficacy ( increased 7.6 folds ) and in new applications of Qinghaosu.  We are looking forward to cooperating with our African colleagues. I heartily hope that Qinghaosu will contribute more for the benefit of human health in the 21st century and for the bright future of mankind.


Thursday, April 30, 2020

45 Flavonoids vs. SARS-CoV's 3CLpro under Autodock Vina

In Silico effect of Flavonoids on SARS-CoV 3CLpro progressively targeting A and B-chains' HIS41-CYS145 interfaces


So while I've been a very strong proponent of Hesperidin based on in vitro results. benign cytox values, inherent known safety, and wide suppy availability, this Autodock Vina docking study shows stronger hits in 1. Hinokiflavone, 2. Luteolin-O-7-rutinoside, 3. Eriocitrin, 4. Sulcatone A, and 5. Amentoflavone.
As amentoflavone is the only one of the above with known outperforming in-vitro efficacy demonstration on SARS-CoV 3CLpro, while showing two orders of magnitude margin for cytotoxicity on Vero cells, I advocate that in vitro trials targeting phytotherapies focus on amentoflavone as applied to (e.g. e.coli-expressed) SARS-CoV-2 3CLpro proteins.

Source data:

PDB File: 2duc.pdb

Ligand Files: PubChem 3D Conformers

Yu Wai Chen, Chin-Pang Bennu Yiu, Kwok-Yin Wong, (Hong Kong Polytechnic University)
Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like protease (3CLpro) structure: virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidate”, F1000Research, 2020

O. Trott, A. J. Olson,                                        
AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading, Journal of Computational Chemistry 31 (2010) 455-461 DOI 10.1002/jcc.21334  

Lin, Tsai, Tsai et al. (China Medical University)
Anti-SARS coronavirus 3C-like protease effects of Isatis indigotica root and plant-derived phenolic compounds", Antiviral Research, Volume 68, Issue 1, October 2005, Pages 36-42.

Ryu, YB et al. (Korea Research Institute of Bioscience and Biotechnology)
"Biflavonoids from Torreya nucifera displaying SARS-CoV 3CL(pro) inhibition.", Bioorg Med Chem., 2010 Nov 15; 18(22):7940-7.
DOI 10.1016/j.bmc.2010.09.035

Michel F. Sanner.
Python: A Programming Language for Software Integration and Development. J. Mol. Graphics Mod., 1999, Vol 17, February. pp57-61

Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S. and Olson, A. J. (2009) Autodock4 and AutoDockTools4: automated docking with selective receptor flexiblity. J. Computational Chemistry 2009, 16: 2785-91

Wednesday, April 29, 2020

SARS-CoV-2 3CLpro- Flavonoids - (Autodock 4)

So I've been doing a lot of flavonoid in silico docking runs on SARS-CoV-2's 3CLpro (pdb file 2duc) protein. Posting results here for posterity.


Monday, April 13, 2020

One instance of research papers permalink list

(for storing, not for reading)

Saturday, March 28, 2020

I failed my first Intro Chemistry course, only barely passing my second. And this is my literature review on coronavirus.

For the tl;dr, scroll to the bottom.

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So with the coronavirus pandemic going on, like everyone else I've been stuck home with little more to do outside of work than to read up on this beast with the minor privilege of being able to ask friends who are more competent in such matters than me about it.  When I see friends and family in my hometown of San Francisco who work in ER wards and nearby county clinics posting their stories and PPE fundraisers on Facebook, I know that something is very wrong, and so in spite of my lay credentials ( I failed chemistry my first semester in university, only to pass within an inch of my life the 2nd semester), feel compelled to post what I've learned about it.

I'm going to describe by way of outlining my learning progression, because I want it to be clear how I got from A to B to C.

As the epidemic in China was starting to wane, but picking up elsewhere, my anxiety grew.  Seeing reports that an HIV antiviral Kaletra (lopinivir and ritonavir) was showing early anecdotal success in patients in China, I asked my Chinese b-school classmates for links to scholarly papers gaining currency on the topic in China, simply so that I could try to reduce my anxiety. 

One of the papers they identified was this, a preprint from Hong Kong Polytechnic University cleverly using Python tools and a drug database to do a drug-docking study:

In-silico drug screening against SARS-nCoV-2:

I remembered from a UCSF biotech researcher I roomed with two decades ago that proteins are capable of interacting if they have a 3D structural match and complementary chemical bonds at their active sites - like two puzzle pieces fitting together -  so I appreciated the approach and marveled how far the technology had come in 20 years that anyone with Python could do such simulations.  These simulations are called 'in silico', to distinguish themselves from 'in vitro' (testing a compound on actual animal cells, typically in a petri dish), and 'in vivo', (testing the efficacy of a compound in a live animal or even a live human population).

Reading that paper sensitized me to the proteins that are being targeted by drug designers during this epidemic.  For example, there is the protein that makes the virus's spikes. There are other proteins required for the virus to enter a cell and begin replicating itself using the cell's machinery.  Altogether there are some 20-30 unique proteins that make up this coronavirus, which is technically called SARS-CoV-2.  (Side note: A lot of papers out of China were calling the virus 2019-nCoV, so make sure to use that keyword if you ever want to research papers out of China especially from the early period of the pandemic).

The protein the researchers from Hong Kong Polytechnical University were targeting is called 3CLpro.  They usefully compare it to the coronavirus from the 2003 outbreak:

" All 11 3CLpro sites2 are highly conserved or identical (Extended data7, Table S1), inferring that their respective proteases have very similar specificities. The 3CLpro sequence of SARS-CoV-2 has only 12 out of 306 residues different from that of SARS-CoV (identity = 96%)."

They map the 'in silico' efficacy of FDA-approved prescription drugs, and they also study other non-prescription compounds that are typically plant-derived.  They use the binding energy as the figure of merit for the efficacy of a drug or compound to affect the 3CLpro protein.  The logic goes, if you can bind most strongly to one of the virus' protein sites, then you're probably inhibiting the virus' performance somewhat.

Since I could see there was already a lot of scholarly work happening on the approved presription antivirals, such as lopinivir/ritonavir and remdesivir, I began searching on 3CLpro with regards to the non-prescription compounds that ranked quite highly in the HK Polytechnic U researchers' study -specifically hesperidin and diosmin.  Hesperidin and diosmin are found prevalently in orange peels and orange juice, and hesperidin is also found prevalently in peppermint.

On performing the search, one of the earliest hits was this:
which is a 2005 paper out of China Medical University in Taiwan covering in-vitro drug testing on SARS-nCoV using Vero cells.

This 2005 paper performed in the wake of the original SARS epidemic describes the compounds they tested against the 3CLpro protein in a type of standard animal cell test called "Vero" cells. (These are cells that come from African Green Monkeys, and have been used since the 1950's as a standard cell test that researchers could easily replicate findings against)

The 2005 Taiwan paper also tests compounds that the HKPU study didn't even look at, like Indigo and Sinigrin.  Evidently they didn't even have the benefit of in silico screenings, as their motivation for testing these choices of compounds was based on:

"Isatis indigotica root and phenolic Chinese herbs were frequently used for the prevention of SARS during the SARS outbreaks in China, Hong Kong, and Taiwan"  and "In addition, several herb-derived phenolics aloeemodin, hesperetin, quercetin, and naringenin have been accredited with antiviral effects against poliovirus, vesicular stomatitis virus, Sindbis virus, herpes simplex virus types 1 and 2, parainfluenza virus, and vaccinia virus" (with trailing citations)

As the authors acknowledge, it turns out that hespiritin performs well in inhibiting 3CLpro's cleaving action, which is otherwise necessary for the virus to propagate, at relatively low concentrations compared with the other compounds, at 8 micrograms per mL.

Finally, and usefully, the Taiwanese researchers looked at what upper limit of quantity of the compounds under test would actually kill the test cells.  Lots of compounds kill viruses in a petri dish, but you want to know which of those compounds doesn't also kill the cells they are intended to protect.  As they say after all, "the dose makes the poison."

So hespiritin starts to look interesting, but so does sinigrin, because ostensibly it is so benign to the test cells that it is beyond the top of their scale in terms of ability to harm the cells.  Sinigrin is common in many green vegetables such as brussels sprouts and collard greens.  It's also what gives horseradish its unique test.

Also at this point, note the slightly different spelling hesperidin -> hesperitin.  This will become relevant later, but essentially hesperidin is the naturally-occurring compound, and hesperitin is what the human body metabolizes hesperidin into.

So I started to think about possible administration routes of these compounds.  The two that stand out are 1) ingestion, because it's the easiest and most popular form of taking medication, and 2) (since this manifests as a respiratory and pulmonary infection . . . inhalation.

But then I felt stuck.  Things are looking up, but I don't know what to do next, or even if my approach to reviewing the research is valid.  On the advice of a friend who has a PhD in Systems Biology and practicing in the pharmaceutical industry, he suggested I look up the safety of these administration methods with regards to these compounds.

After a lot of cited online research later, I learned that Sinigrin all-too-easily becomes poisonous at high ingestion (and inhalation (!) ) doses!  Anyone who's ever taken a deep whiff of horseradish or sushi wasabi can speak to this.  So this literature review helpfully enabled ruling it out, leaving Hesperidin as the only remaining candidate to show high in vitro efficacy at accessibly low concentrations.

Then we naturally want to learn how can this compound be had in therapeutically effective doses?  For this I did a bit of math based on the Taiwan paper.  The Taiwan researchers identify the effective concentration for hesperidine to be 2.5 micrograms (mcg or μg) per mL (presumably aqueous).  Taking simple orange juice as the most available vessel for this, and treating the human body as having the same density as water (1 kg per litre) and assuming uniform concentration of the ingested compound in the body, then a 100-kg person, (say a heavier male) would need 250000 μg, or 250 mg, of hesperidine maintained over some period relevant to the virus' generation cycle.

According to this really helpful database of concentrations of various compounds in foods, we find that production orange juice contains 26 milligrams / 100ml of hesperidin.  Hesperitin is about half the molar weight of hesperidin, so we need to treat this as an effective 13 milligrams / 100ml of hesperitin.  So how much OJ does a 100-kg person have to retain without excreting any through urine, in order to reach the dose level indicated by the Taiwan study?  The simple math answer is 1.9 litres.  The average human's weight, 62-kg, would need about 1.2 litres.

While there are many questions remaining that, absent further expert advice, could affect the efficacy of orange juice on either prophylactically protecting against a coronavirus infection, or tamping down a nascent existing infection, considering the universally-accepted safety of orange juice consumption in the world, the choice to drink orange juice is essentially a zero-cost option.  It doesn't pose a health-risk anywhere close to these quantities (the equivalent of having passed phase-1 clinical trials for pharmaceutical drugs), its cheap for developed country consumers, and its widely available, and in all likelihood is sitting inside your fridge as I write.

Don't like drinking all that orange juice?  Well hesperidine (paired with diosmin, which is anyway also naturally prevalent in the same orange juice) is manufactured in pill form, with the hesperidine component typically dosed at 100 mg a day.  In the US, while they can't be advertised for treatment of a disease, instead the FDA regards these constituent compounds as GRAS ("Generally Regarded As Safe") via FDA's published GRAS certifications on Orange Pomace and Orange Extract.

That was all regarding the oral ingestion route.  The inhalation route, of course, should be of particular interest for acute cases, but the downside risk is just this side of dicey that I'd prefer not to speculate on a public forum about it; suffice to say that if this OJ oral ingestion is found to have merit, I'd be happy to share with medical professionals the learnings I've assembled so far on the inhalation route. (Suffice to say that it doesn't involve orange juice).

So I close with a request: If you've gotten this far, I would really appreciate if you can poke holes in this analysis, and to particularly include same in the comments below so that others can evaluate.  In particular, I'd love a qualified answer to the question, "If these are qualified research paths, then which researchers are in the process of studying them?"

Please consider yourself warmly-welcomed to troll, call me a snake-oil peddler, or whatever, but just put some reasoning behind your concerns so that the reasoning can be shored up or thrown out as appropriate.  Disclaimer that I have no financial interest in any company, venture, or trading position associated with the above - I just want to get back to normal-life again.

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Drink extra orange juice.  And don't gain a false sense of security from doing so.

Update 2 April: I 'professionalized' up this post into a Medium post that I'm feeling relieved has been getting attention from appropriate places: