Coronavirus news & views

SpaceX AND BioX Do It Again!!

“In science one tries to tell people, in such a way as to be understood by everyone, something that no one ever knew before. But in poetry, it's the exact opposite.

--Paul Dirac (1902-1984)

                                                                 

Backstory: Yup. SpaceX did it again. They landed a rocket booster on a bullseye; even catching it in the air with large mechanical arms they called “chopsticks.” The Brewers would love to have an outfielder like that!

BioX also did it again, following its last year’s Nobel Prize win for the mRNA technology that led to the very effective COVID vaccines. Just a few days before the SpaceX catch, it was announced that BioX won the 2024 Nobel Prize for using a computer, or artificial intelligence, to decipher the structure of ALL known proteins, and for using similar technology to create whole new functional proteins that promise to remediate environmental contamination and treat diseases. We are in a new brave world of science.

For those new to these pages, “BioX” is what I earlier dubbed the new, post-molecular biology (mobio) science that has been absolutely amazing. And I speak as a molecular biologist who now feels like a scientific dinosaur. What we learned from the old-school mobio is now being fed into computers which do all the work for us. Much tedious lab work has now become obsolete, which means that we are learning about our bio-world at an unbelievable pace. It also means that we are translating all that information into useful tools, such as better vaccines and medicines, and into making new proteins that do what we wish—like digest plastics contaminating our environment.

The science of molecular biology began in the 1920s with really basic questions. Swedish chemist and Nobel Prize winner, Theodor Svedberg, developed the ultracentrifuge in 1924, which was then used to determine the size of biomolecules—the first major question in molecular biology. The centrifuges were also used to separate different cell components, which played a huge role in discovering how cells function. The ultracentrifuge was a major tool used by only a few of the most advanced labs at that time. Now, pretty much every bioscience department has at least one ultracentrifuge.

Three decades after the advent of ultracentrifuges, Jim Watson, an American, and Francis Collins, a Brit, at Cambridge University, reported on their seminal discovery of the structure of DNA, which unleashed a storm of research into how it functions and deciphering the genetic code. That in turn led to much research into the other nucleic acid molecules found in cells, RNA. And that guided research into the structure and function of proteins, the things that make cells function. All that mobio research led to many, many Nobel Prizes. All that information provides the basis for the new post-mobio science of BioX.

Current story: All this background is mentioned in order to introduce the latest Nobel Prize for Chemistry, announced October 8. Three BioX chemists share the award. Demis Hassabis and John Jumper of Google DeepMind used AI to decipher the structure of millions of proteins. David Baker of the University of Washington used similar computer software to invent new proteins. It is possible that none of them ever purified DNA from a cell culture, sequenced DNA, cloned a gene, inserted a gene into cells to determine its function, etc. All of that is mobio—old stuff. These post-mobio scientists showed us we really do not need to that anymore if you can use a computer. Boy, does that make me feel old.

It used to take decades and many thousands of dollars of high tech equipment and an army of lab techs, students and post-docs to learn how a single protein, like hemoglobin, was structured and functioned. Now it takes minutes and a lap top. Computers can be used to predict the structure of any protein in the human body, which can inform researchers how other molecules will bind or physically attach to it. This is the new path for drug discovery.

These are the 2024 BioX Nobel Prize winners:

Demis Hassabis was born in London, where his parents—one a Greek Cypriot, the other Singaporean—ran a toy store. At one time, he was the second-highest-ranked chess player under 14 in the world. He began designing video games professionally before attending college. After completing a computer science degree at the University of Cambridge, he founded a video game company then returned to academia for a PhD in neuroscience. He and a fellow academic, Shane Legg, and a childhood friend, Mustafa Suleyman, founded an AI start-up called DeepMind in 2010. About four years later, Google acquired it for $650 million.

DeepMind’s goal was to build an artificial machine that can do anything the human brain can do. It also explored other technologies that could solve particular scientific problems. One of those technologies was AlphaFold, the program used to solve the structure of millions of proteins and for which the Nobel Prize was awarded. AlphaFold is built using a mathematical system called a neural network. With neural networks, computers can analyze vast amounts of data to learn to perform many tasks that were once beyond their capacity.

John Jumper, the youngest chemistry laureate in over 70 years, was born in the United States. After finishing an undergraduate degree at Vanderbilt University and a master’s degree at the University of Cambridge, he earned a Ph.D. degree in theoretical chemistry at the University of Chicago.

He joined Hassabis at DeepMind as a researcher in 2017 after Google had acquired the technology. He soon began work on AlphaFold. In 2020, Google researchers unveiled an update of the AlphaFold technology and showed that it had fully cracked the problem of predicting shapes of proteins with an accuracy that rivaled physical experiments and made lab rats like me obsolete. Sigh....

With AlphaFold, the Google team was able to calculate the structure of all human proteins, and then, according to the Nobel committee, it deciphered “the structure of virtually all the 200 million proteins that researchers have so far discovered when mapping Earth’s organisms.” Holy moly!!

David Baker’s work preceded the emergence of these AI models and focused on creating novel proteins. A Seattle native, Baker earned his undergraduate degree from Harvard in 1984 and in 1989, a biochemistry PhD from the University of California, Berkeley. He now serves as the director of the Institute for Protein Design and is a professor of biochemistry at the University of Washington (the other UW). In 2003, Baker and his colleagues created the first entirely new protein: a molecule called Top7. The molecule was useless but symbolic.

Since then, the researchers have used a computer model called Rosetta, which searches databases of existing proteins to find a sequence that might create a desired structure. Baker realized that if he could create a novel protein structure, he should also be able to create proteins “that actually do things,” like break up the amyloid fibrils that are thought to cause Alzheimer’s disease. Or digest plastic bottles. Or oil contamination from spills.

So far, his lab’s novel proteins—created with a more advanced iteration of Rosetta—have already been the basis of several potential medical treatments, like an antiviral nasal spray for Covid-19 (on which I will soon blog) and a medication for celiac disease. A Covid-19 vaccine, SKYCovione, based on his one of his lab’s proteins, was approved for use in South Korea in 2022.

Baker is also a co-founder of more than 20 biotechnology companies.

Congratulations, BioX! Stay tuned, more is sure to come.

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Coronaviruses, Colds And COVID: And Cool Immunology

“The most exciting phrase to hear in science…is not ‘Eureka!’ but ‘That’s funny…’”

–Issac Asimov

 

Background. Your run-of-the-mill common cold virus is sometimes related to its more infamous relative that caused the world all sorts of consternation between 2020-2023, and still demands respect like an aging rock star who might still have some chops left. I, of course, allude to SARS-CoV-2.

Yup, the now infamous family of deadly human coronaviruses, which includes the original bat-borne SARS-CoV-1 (which caused the first SARS pandemic in late 2002), its Middle-Eastern camel-riding cousin (that caused MERS in June 2012), and the recent, much more traveled, durable, and concerning SARS-CoV-2 (origins so far unknown and the cause of COVID-19), have some lesser known, ne’er-do-well cousins that have long traveled among us. I refer to certain viruses that visit us often and are as unwelcome as a distant cousin who arrives unannounced needing a place to crash for a few days. This is the “common cold virus” which actually is several different kinds of viruses. Cold viruses are all as irritating and inconvenient as said uninvited distant cousin, and about as enjoyable as a hangover; but seriously debilitating or life threatening? They are not.

The common cold is mostly caused by one of three families of viruses; rhinovirus (not related to any large mammal), adenovirus, or a coronavirus. Yup, a distant cousin to that bug that caused so much serious illness and death across this blue orb during the COVID pandemic also is one of the causes of the mostly benign, but very annoying common cold. In fact, there are four different types of coronavirus cousins that cause 15-30% of the “common colds” in adults. Isn’t it interesting that one coronavirus, like SARS-CoV-2, can kill you, but its cousins just make you sneeze and your nose run like a leaky faucet, but that is all. Aren’t viruses fascinating?

Facts. Just as between unwelcome distant cousins, there are genetic similarities between the dangerous CoV-2 and its nettlesome coronavirus kin that just cause colds. And recent studies found that infection with one of these coronavirus cousins can indeed confer some immune protection to the other distant cousins. In other words, if you were infected with CoV-2, you likely had a much milder cold, if you caught one at all. And vice versa! But the funny thing is that vaccination against COVID did not also protect you against a cold like an infection would. What??

This stuff makes viral immunology so much fun.

To confirm all this, one study showed that this cross protection only occurred in people who had a definite bout of COVID caused by the coronavirus, and the reduced incidence of colds only occurred for colds also caused by a coronavirus, and not for a cold caused by unrelated rhino or adenoviruses. Clearly prior exposure to a different member of the coronavirus family conferred some immunity to other members of that family, even to distant cousins. Also, just being vaccinated to the CoV-2 spike protein did not confer this sort of protection to future coronavirus-caused colds. Wow! This kind of discrimination and specificity gets immunologists salivating like a Pavlovian dog to a ringing bell. I know—I am wiping secretions off my keyboard as I type.

Vaccines to just the spike protein quickly generates antibodies that neutralize the virus and thus prevent serious disease. But, that only offers short term protection to just that coronavirus from whence the spike protein sequence came. The viruses quickly mutate their spike surface proteins so the viral cousins cannot be recognized by the spike protein alone. That is why anti-spike immunity and the vaccines are not very good at protecting against re-infection for very long and why the vaccines don’t confer immunity to distant coronavirus cousins.

However, the immune system is a multi-layered security system. Besides these short-lived neutralizing antibodies that target the coronavirus spike protein (or similar surface proteins in other viruses), other layers of the immune security system can also be generated to other molecules across the SARS-CoV-2 genome following infection with the whole virus (see here and here). These other genome sequences are often more conserved and less likely to change between distant coronavirus cousins, than the highly variable spike protein sequence. This means that any immune response generated to one of these more boring, unchangable sites on a given coronavirus, can also recognize similar sequences on distant cousin coronaviruses.

But who, other than an immunology nerd really cares if having COVID protects you against a future cold? What about the reverse? Can having a cold caused by a coronavirus cousin generate some protective immunity to the nastier SARS-CoV-2 and protection from COVID and future coronaviruses that will emerge? Some, but not all research has indeed shown that people without prior exposure to CoV-2 do indeed show immune reactivity to the virus (see here and here). This means that folks who haven’t been infected with SARS-CoV-2 must have been exposed to another coronavirus that gave them a bit of cross protective immunity to the COVID virus. Other studies confirmed that prior infection with cold-causing coronaviruses can reduce COVID severity following infection with CoV-2 (here and here).

Bottom line.  What this means is that if you have been infected with some sort of mild coronavirus in the past, you just might be able to show some immunity to future infections with distant coronavirus cousins. Vaccination with the spike protein mRNA just doesn’t do the same. You need to be exposed to the whole kit and caboodle to enjoy all this immune goodness.

The responsible part of the immune system for this cross-over immune response is CD8⁺ T cells, also known as cytotoxic T lymphocytes, or CTLs. These immune cells are assassins that seek out other cells infected with a virus and they kill those cells. So, immunologists get all atwitter and think, “Hellz bellz, why don’t we make vaccines using parts of these boring, but conserved virus pieces that generate CTLs to different viral cousins, instead of the ever changing spike proteins to make vaccines? We could make one vaccine for all coronaviruses! Or flu, or whatever virus….”

It is a great idea and that research is well underway. The goal is to make a single coronavirus vaccine that would be long lasting and target many coronavirus cousins to prevent any future pandemic (believe me, another one is sure to come).

Back to earth. As interesting and hopeful as this sounds for making a single vaccine against multiple coronaviruses so we don’t have to continually try different boosters each year, don’t get your hopes up just yet. Similar immuno-optimism has been going on with influenza for decades and what do we have to show for that? We still have the annual guessing game of which flu strain will pester us each winter and then feverishly roll out millions of vaccines to try to nip that particular one in the bud. Meanwhile its flu cousins chortle and conspire in the Southern Hemisphere on how to mix and mutate their genes so they can surprise us again in the Northern Hemisphere the following year with a sufficiently new variation to vex us again.

But, flu, like coronaviruses also has important proteins that are not changeable, and very constant between distant flu cousins. These too can be seen by the immune system’s T cells. Flu immunology’s Holy Grail has long been to make a vaccine to a conserved flu virus genomic sequence so we can use just one vaccine to immunize against all flu strains once and for all for all time. A pan-flu vaccine.

Well, we are still trying to do that. This makes the idea of finding a pan-coronavirus vaccine using similar immunology daunting. Still, these recent studies showing that cross-reactive immunity between distant cousin coronaviruses does exist, just stokes an Immunologist’s stubborn resolve to solve the problem. As I have written before in these pages, amazing science advances have often come from the long, dogged pursuit of goals that very stubborn scientists believe they can see right in front of them, even when others cannot. It often takes a long time to prove what is so clearly obvious to one or two science visionaries yet so oblivious to the rest of us. That often is how science progresses. Thank goodness for these obstinate scientists who see things the rest of us cannot.

Once again, We will see.

Personal note. These anti-viral CD8⁺ or cytotoxic T lymphocytes are near and dear to this correspondent’s heart since I got my PhD in Immunology studying how these immune cells in mice recognize cells infected with viruses. It is a lot more complicated than you would think. In fact, in 1996 two immunologists, Peter Doherty and Rolf Zinkernagel were awarded the Nobel Prize for work they did on this problem in the early 70s, and that work drove my PhD research (and a lot more!).

Doherty and Zinkernagel discovered that T cells have to simultaneously identify two different molecules on an infected cell surface before they actually know a cell is infected with a virus. They made a head-scratching observation that turned viral immunology upside down. It was one of those observations that I bet made them say, “That is funny.” Basically, they found that your T cells that can recognize flu infecting your cells would not recognize flu infecting my cells or anyone else’s cells. And vice versa. You would think flu is flu and that a T cell that can see flu in an infected cell would not care whose cell it came from. But it does care. It turns out that T cells can only see virus within the genetic background from whence they came. They cannot see the same virus on a cell from a different genetic background! How strange is that? An antibody does not care where it sees a virus. T cells do. Picky little suckers.

It gets even crazier. Doherty and Zinkernagel, mapped this genetic restriction in virus recognition to the same genes that the immune system also use to determine whether a tissue or organ is its own or is foreign! For example, the genes your immune cells recognize as a password to determine friend vs foe in a skin graft (do we accept it or reject it?) are the same genes the immune cells use to help them know if your cells are infected with a virus! Tell me that doesn’t make you scratch your head and mutter, “That’s funny?” That is exactly how the world of immunology reacted to Doherty and Zinkernagel’s findings. It was a beautiful time for immunology science. That launched a tsunami of research, my PhD effort included.

This is personal note because I earned my PhD further probing the mechanism of what Doherty and Zinkernagel stumbled on. I used a large panel of mice that had been engineered to carry single point mutations in different parts of these genes that immune system used to ascertain tissue compatibility, and detect viral invasion. This helped us learn what part of these molecules the T cells recognized and how their folding was important for this recognition. It was a grand time!

Immunology is so doggone interesting!

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