Now, social justice in organic chemistry class

March 28, 2021 • 9:30 am

There is seemingly no academic field—not  even in the sciences—that’s immune from being forced to board the social-justice juggernaut. The latest is organic chemistry, and I found out about it from the letter below that just appeared in Science (click on screenshot). The letter is by Melissa McCartney, Assistant Professor in the Department of Biology and the STEM Transformation Institute at Florida International University.

So of course I had to look up the original article in the Journal of Chemical Education, which is free online (click on screenshot, pdf here).  The authors teach organic chemistry at Reed College in Oregon, a private liberal arts school that is among the five or six wokest colleges in America (think The Evergreen State College format). Do be mindful of that when you read about the student approbation for infusing social justice into the second semester of the class.

There are several ways they infuse social justice into the class, one of which seems harmless. The others, however, hijack the class to teach the students not only the social history of organic compounds, but to clearly impart to them an ideology based on Critical Theory.  The introduction shows the social motivations for the class:

Without engagement with equity issues, the standard curriculum produces students who may lack civic mindedness in their approach to science. We believe that young scientists should be invited to contemplate their work with a “systems thinking approach” and consider chemistry’s potential impacts beyond intention. Unfortunately, progressive discourse regarding these shortcomings in chemistry curricula is often overlooked, perhaps due to the misperception that science is somehow intrinsically “good”.

There’s nothing wrong with mentioning the social impact of various chemical compounds, but there is something wrong with using the class to foster “progressive discourse”, which in this case means Critical Theory discourse.  Not only does that constitute a form of propaganda for the teachers’ political views, but it also takes time away from learning chemistry itself. It’s clear from the article that the “social justice” implications aren’t just mentioned tangentially, but occupy 5-10% of the course, and will occupy more in the future.

The motivation continues:

In contrast to the dogma that science is “good”, chemists have historically produced compounds that are harmful to both humans and the environment. Examples of these harms are widespread and disproportionately affect economically disadvantaged areas. For example, over 30 years ago, an accident at the Union Carbide plant in Bhopal, India, was responsible for releasing poisonous gases into the local environment and atmosphere.(4) Reports described the release as containing 30–40 tons of methyl isocyanate and other toxic chemicals. Nearly 4000 residents of the surrounding tenements were killed immediately. For the remaining residents, the full long-term health consequences of the chemical exposure, including premature death, are still unknown.(5) Assessing the true costs of accidents such as the Bhopal disaster requires a full systems thinking evaluation. What were the early and late effects of exposure? What are the impacts of indirect contact? How have the toxic materials migrated and persisted in the local environment? Have these reactive compounds been transformed into other chemical entities with a new set of impacts and effects?

Seriously? The people who devised the synthesis of these compounds, and even that of Zyklon B (hydrogen cyanide), coopted to to kill Jews in Nazi concentration camps, didn’t aim to create harm (it was created to be used as a pesticide, which began in California in the 1880s). Harm was either due to the acts of bad people, a byproduct of the chemical’s poor storage, as in Bhopal, or an unintended consequence of drugs (the side effects of birth-control pills). Teaching this way gives the impression to students that science is “bad”, a general attitude of both postmodernism and Critical Theory, which dislike science because of its ability to find real truths.

But science itself isn’t “bad”: it is people who decide to use it in a bad way, or, when there are unintended side effects, it’s simply bad luck. Should they teach about the construction of gas chambers in architecture class to show that architecture is not “good”? Almost every discipline could be demonized in this way. Genetics could show that that science is bad by discussing how it was misused by the Soviet agronomist and charlatan Lysenko to derail Russian agriculture, which led to the starvation of millions.

And below is the goal of the professors: enhancing “equity”, which is proportional representation, not equal opportunity:

We aimed to briefly highlight how organic chemicals can be an instrument for enhancing equity, simultaneously stimulating awareness of the injustices and injuries that can be promoted by the misuse of chemicals.

How do they infuse social justice into Reed’s organic chemistry class? They talk about molecules that have social import—usually having a bad effect on minorities. These include birth control pills (has led to “serious environmental contamination”), antiretroviral drugs, and THC, active ingredient of marijuana. But whenever you can insert social justice, even if it’s not relevant to learning organic chemistry itself, they do. Here are the lessons they impart:

For antiretroviral drugs:

In a recent study, 35% of the countries with available data reported having a majority of people (over 50%) with “discriminatory attitudes” toward those living with HIV. This prejudice persists despite the fact that current antiretroviral therapy is able to suppress viral loads to undetectable and below transmittable levels. The stigma and discrimination against people living with HIV leads to marginalization (social, economic, and legal), which in turn can cause poor social, emotional, and physical well-being. These negative impacts on general well-being are correlated with lack of treatment.

For THC:

The dark side of the cannabanoids is that they have been used to systematically incarcerate African-Americans. During the “War on Drugs” in the 1980s, drug-related arrests rose 126%. African-Americans account for 35% of drug arrests, 55% of convictions, and 74% of people sent to prison for drug possession crimes. The incarceration rate is 13 times higher than that of other races, despite African-Americans only comprising 13% of regular drug users. Furthermore, there are collateral consequences to drug arrests. Many states will suspend the driver’s licenses of offenders for at least six months, irrespective of if a car was involved in the crime.

If this has anything at all to do with chemistry, it defies me. And I’m absolutely positive that Reed students have the chance to learn this kind of material in many other classes. What the professors are doing here is using chemistry as a convenient excuse to discuss oppression and marginalization.

Now the okay part of using these particular molecules is that they can be enlisted to demonstrate real principles in organic chemistry, but of course other molecules may do that, and do it even better. Here’s one innocuous quiz question that follows the social-justice indoctrination (they could hardly ask about social justice itself on chemistry tests). It’s about an antiretroviral drug used to treat AIDS:

 

Finally, surveys of students at the end of the course show that many or most of them think that it’s important to learn about the social justice impacts of chemical compounds, that so this material makes them “into more responsible scientists”, makes the material more relevant, and keeps the students engaged. Of course, using other molecules can create the same relevance (e.g., caffeine, penicillin, alcohol), but those molecules can’t be used to teach social justice.

And of course the Critical Theory material helps the students learn exactly what social justice is—at least, the conception that their professors hold:

We were interested to find that in the first lecture a majority of the class felt familiar with social justice as a concept; 75% agreed or strongly agreed with the statement “Social justice is a familiar concept.” However, only half of the class (53%) agreed or strongly agreed with, “I can write a definition of ‘social justice’.” We were very pleased to find that after exposure to only three lectures with social justice content, 91% of respondents agreed or strongly agreed that “learning about the social justice impacts of chemical compounds is important.” Similarly, 91% agreed or strongly agreed with the statement “teaching students about the social justice impacts of chemicals could make them into more responsible scientists.” Furthermore, a majority of students (76%) agreed or strongly agreed that the discussion of social justice themes made the material more relevant to them (15% neutral).

Note that there is no “control” class in which socially important molecules like antibiotics or caffeine are used instead of ones that can be tied to oppression. More important, there is no assessment of whether students exposed to this kind of political material turn into better organic chemists or learn the course material better. All we have is the self-report of students who are mostly self-selected, by going to Reed, to be on the “progressive Left.”

But wait! The social-justice bit is going to expand:

In the future, we hope to address other timely issues such as the use of ethanol as biofuel, which was intended as an environmentally friendly alternative, but instead increased the risk of air pollution deaths relative to gasoline by 9% in Los Angeles. An entire class could be dedicated to addressing the impact of another supposedly sustainable biofuel, palm oil. While palm oil production has driven economic growth in Central and South America, “the methane produced by a typical palm oil lagoon has the same annual climate impact as driving 22,000 passenger cars.” We also would like to include a systems thinking approach to evaluating medications, as many of them can have harmful effects on animals and the environment upon excretion from the body.

Perhaps they might want to talk about the positive social effects of organic chemistry as well! Why is that left out? Because they want to show the students the bad effects of science, not the good ones. And few fields have had a more positive effect on human well being than organic chemistry.

While I have no objection in talking tangentially about molecules important to people in their everyday lives, this is not what’s going on here.  Rather, the lessons are used to impart the Critical Theory view of hierarchical oppression to students.  I have no doubt that almost any academic subject can be hijacked in this way. But is that how we should be teaching our students? Not only infusing everything with politics, but a particular view of politics?

Has the problem of protein folding been solved?

December 1, 2020 • 1:00 pm

One of the biggest and hardest problems in biology, which has huge potential payoffs for human welfare, is how to figure out what shape a protein has from the sequence of its constituent amino acids. As you probably know, a lot of DNA codes for proteins (20,000 proteins in our own genome), each protein being a string of amino acids, sometimes connected to other molecules like sugars or hemes. The amino acid sequence is determined by the DNA sequence, in which each three nucleotide bases in the “structural” part of the DNA sequence codes for a single amino acid. The DNA is transcribed into messenger RNA, which goes into the cytoplasm where, connected to structures called ribosomes, and with the help of enzymes, the DNA sequence is translated into proteins, which can be hundreds of amino acids long.

In nearly every case (see below for one exception), the sequence of amino acids itself determines the shape of the resultant protein, for the laws of physics determine how a protein will fold up as its constituent bits attract or repel each other. The shape can involve helixes, flat sheets, and all manner of odd twists and turns.  Here’s one protein, PDB 6C7C: Enoyl-CoA hydratase, an enzyme from a bacterium that causes human skin ulcers.  This isn’t a very complex shape, but may be important in studying how a related bacterium causes tuberculosis, as well as designing drugs against those skin ulcers:

And here’s human hemoglobin, formed by the agglomeration of four protein chains, two copies each from two genes (from Wikipedia):

Knowing protein shape is useful for many reasons, including ones related to health. Drugs, for example, can be designed to bind to and knock out target proteins, but it’s much easier to design a drug if you know the protein’s shape. (We know the shape of only about a quarter of our 20,000 proteins.) Knowing a protein’s shape can also determine how a pathogen causes disease, such as how the “spike protein” or the COVID-19 virus latches onto human cells (this helped in the development of vaccines). Here’s the viral spike protein, with one receptor binding domain depicted as ribbons:

And there are many questions, both physiological and evolutionary, that hinge on knowing protein shapes. When one protein evolves into a different one, how much does that affect shape change, and can that change explain a change of function? (Remember, under Darwinian evolution, gradual changes of sequence must be continually adaptive.) How do different shapes of odorants interact with the olfactory receptor proteins, giving a largely one-to-one relationship between protein shape and odor molecules?

Until now, determining protein shape was one of the most tedious and onerous tasks in biology. It started decades ago with X-ray crystallography, in which a protein had to be crystallized and then bombarded with X-rays, with the scattered particles having to be laboriously interpreted and back-calculated into estimates of shape. (This is how the shape of DNA was determined by Franklin and Wilkins). This often took years for a single protein. There are other ways, too, including nuclear magnetic resonance, and new methods like cryogenic electron microscopy, but these too are painstakingly slow.

Now, as the result of a competition in which different scientific teams are asked to use computer programs to predict the structure of proteins that are already known but not published, one team, DeepMind from Google, has achieved astounding predictive success using artificial intelligence (AI), to the point where other technologies to determine protein structure may eventually become obsolete.

There are two articles below, but dozens on the Internet. The first one below, from Nature, is comprehensive (click on screenshot to read both):


This article, from the Deep Mind blog itself (click on screenshot), is shorter but has a lot of useful information, as well as a visual that shows how closely their AI program predicted protein structure.

 

In a yearly contest called CASP (Critical Assessment of Structure Prediction), a hundred competing teams were asked to guess the three-dimensional structure of about a hundred sections of proteins (“domains”). The 3D structure of these domains were already known to those who worked on them, but was unknown to the researchers, as the structures hadn’t been published.

The method for how Deep Mind’s AI program did this is above my pay grade, but involved “training” the “AlphaFold” program to predict protein structures by training the program with amino-acid sequences of proteins whose 3-D structure was already known. They began a couple of years ago in the contest by training the program to predict the distance between any pair of amino acids in a protein (if you know the distances between all pairs of amino acids, you have the 3D structure). This year they used a more sophisticated program, called AlphaFold2, that, according to the Nature article, “incorporate[s] additional information about the physical and geometric constraints that determine how a protein folds.” (I have no idea what these constraints are; the procedure hasn’t yet been published but will be early next year.)

It turns out that AlphaFold2 predicts protein structure with remarkable accuracy—often as good as the more complex laboratory methods that take months—and does so within a couple of hours, and without any lab expenses! In fact, the accuracy of shape prediction wound up being about 1.6 angstroms—about the width of a single atom! AlphaFold2 also predicted the shape of four protein domains that hadn’t yet been finished by researchers.  Before this year’s contest, it was thought that it would take at least ten years before AI could be improved to the point where it was about as good as experimental methods. It took less than two years.

Here’s a gif from the DeepMind post that shows how accurately DeepFold 2 predicted two protein structures. The congruence of the green (experimental) and blue (AI-predicted) shape is remarkable.

There aren’t many cases where computers can make a whole experimental program obsolete, but this appears to be what’s happening here.

There is one bug in the method, though it’s a small one. As Matthew Cobb pointed out to me, in a few cases the sequence of amino acids doesn’t absolutely predict a protein’s shape. As he noted, “Sometimes the same AA [amino acid] sequence can have different isoforms [shapes that can shift back and forth], which can have Very Bad consequences—think of prions, in which the sequence is the same but the structure is different.” Prions are shape-shifting proteins that, in one of their shapes, can cause fatal neurodegenerative diseases like “Mad cow disease”. These are fortunately rare, but do show that the one-to-one relationship between protein sequence and protein shape does have exceptions.

Here’s a very nice video put out by DeepMinds that explains the issue in eight minutes:

We’ll have to wait until the paper comes out to see the details, but the fact that the computer program predicted the shapes of proteins so very well means that they’re doing something right, and we’re all the beneficiaries.

Doudna and Charpentier win Chemistry Nobel for CRISPR/Cas9 method of gene editing

October 7, 2020 • 6:15 am

This year’s Nobel Prize in Chemistry was long anticipated, for the CRISPR/Cas9 system of gene editing was a tremendous accomplishment in biology and chemistry. It promises a lot, including curing human genetic disease (see the first five posts here). Remember, Nobel Prizes in science are designed to reward those who made discoveries potentially helping humanity, not those who just made general scientific advances.

A prize for developing the editing system was, then, almost inevitable. The only question was “who would get it?”, since several people contributed to the work that led to CRISPR/Cas9.  It turns out that the Prize—in Chemistry—went to the two frontrunners, Jennifer Doudna of UC Berkeley and Emmanuelle Charpentier at the Max Planck Institute for Infection Biology in Berlin.  Other serious contenders were George Church of Harvard, Virginijus Šikšnys at the Vilnius University of Biotechnology, Francisco Mojica of the University of Alicante, and Feng Zhang of the Broad Institute (the dispute was largely over whether those who developed ways to use the method in human cells also deserved the Prize). There will be a lot of kvetching today, but if I had had to pick two to get the prize, given that only three can get it au maximum, it would be Doudna and Charpentier. (They could have awarded up to six prizes if they’d split the CRISPR award between Physiology or Medicine and Chemistry.)

The press release from the Nobel Foundation says this:

Genetic scissors: a tool for rewriting the code of life

Emmanuelle Charpentier and Jennifer A. Doudna have discovered one of gene technology’s sharpest tools: the CRISPR/Cas9 genetic scissors. Using these, researchers can change the DNA of animals, plants and microorganisms with extremely high precision. This technology has had a revolutionary impact on the life sciences, is contributing to new cancer therapies and may make the dream of curing inherited diseases come true.

Researchers need to modify genes in cells if they are to find out about life’s inner workings. This used to be time-consuming, difficult and sometimes impossible work. Using the CRISPR/Cas9 genetic scissors, it is now possible to change the code of life over the course of a few weeks.

“There is enormous power in this genetic tool, which affects us all. It has not only revolutionised basic science, but also resulted in innovative crops and will lead to ground-breaking new medical treatments,” says Claes Gustafsson, chair of the Nobel Committee for Chemistry.

As so often in science, the discovery of these genetic scissors was unexpected. During Emmanuelle Charpentier’s studies of Streptococcus pyogenes, one of the bacteria that cause the most harm to humanity, she discovered a previously unknown molecule, tracrRNA. Her work showed that tracrRNA is part of bacteria’s ancient immune system, CRISPR/Cas, that disarms viruses by cleaving their DNA.

Charpentier published her discovery in 2011. The same year, she initiated a collaboration with Jennifer Doudna, an experienced biochemist with vast knowledge of RNA. Together, they succeeded in recreating the bacteria’s genetic scissors in a test tube and simplifying the scissors’ molecular components so they were easier to use.

In an epoch-making experiment, they then reprogrammed the genetic scissors. In their natural form, the scissors recognise DNA from viruses, but Charpentier and Doudna proved that they could be controlled so that they can cut any DNA molecule at a predetermined site. Where the DNA is cut it is then easy to rewrite the code of life.

Since Charpentier and Doudna discovered the CRISPR/Cas9 genetic scissors in 2012 their use has exploded. This tool has contributed to many important discoveries in basic research, and plant researchers have been able to develop crops that withstand mould, pests and drought. In medicine, clinical trials of new cancer therapies are underway, and the dream of being able to cure inherited diseases is about to come true. These genetic scissors have taken the life sciences into a new epoch and, in many ways, are bringing the greatest benefit to humankind.

I haven’t looked it up, but I think this is the first time that two women have been the sole recipients of any Nobel prize.(Correction: I should have said “Prize for Science”, for, as a reader pointed out below, two women shared the 1976 Nobel Peace Prize: Betty Williams and Mairead Corrigan. Their achievement was organizing to suppress sectarian violence during the Troubles in Northern Ireland.

Here are Doudna and Charpentier from the Washington Post (the paper’s caption):

FILED – 14 March 2016, Hessen, Frankfurt/Main: The American biochemist Jennifer A. Doudna (l) and the French microbiologist Emmanuelle Charpentier, then winners of the Paul Ehrlich and Ludwig Darmstaedter Prize 2016, are together in the casino of Goethe University. The two scientists were awarded the Nobel Prize for Chemistry 2020. Photo: picture alliance / dpa (Photo by Alexander Heinl/picture alliance via Getty Images)

Here’s the live stream of the announcement from Stockholm. The action begins at 11:45 with the announcement in English and Swedish, and the scientific explanation starts at 19:10.

Once again, although seven people, including Matthew, guessed the winners in our Nobel Prize contest (here and here), nobody got the Chemistry or Physics prizes. Given your miserable failures, I may have to have contest for the literature prize alone.

Matthew was also prescient in his book, Life’s Greatest Secret (2015), which includes this sentence:

“Whatever happens next, I bet that Doudna and Charpentier—and maybe Zhang and Church—will get that phone call from Stockholm.”

In 2017, I reviewed (favorably) Jennifer Doudna’s new book on CRISPRA Crack in Creation, for the Washington Post. (Samuel Sternberg was the book’s co-author). The book is well worth reading, but I did have one beef connected not with the narrative, but with where the dosh goes for this discovery. Here’s what I wrote then:

. . . this brings us to an issue conspicuously missing from the book. Much of the research on CRISPR, including Doudna’s and Zhang’s, was funded by the federal government — by American taxpayers. Yet both scientists have started biotechnology companies that have the potential to make them and their universities fabulously wealthy from licensing CRISPR for use in medicine and beyond. So if we value ethics, transparency and the democratization of CRISPR technology, as do Doudna and Sternberg, let us also consider the ethics of scientists enriching themselves on the taxpayer’s dime. The fight over patents and credit impedes the free exchange among scientists that promotes progress, and companies created from taxpayer-funded research make us pay twice to use their products.

. . . . Finally, let us remember that it was not so long ago that university scientists refused to enrich themselves in this way, freely giving discoveries such as X-rays, the polio vaccine and the Internet to the public. The satisfaction of scientific curiosity should be its primary reward.

I’m not sure how the legal battle between the participants (via Berkeley and MIT) has shaken out, and can’t be arsed to look it up, but surely a reader or two will know

Nobel Prize in Chemistry goes to three who developed lithium ion batteries

October 9, 2019 • 7:00 am

From the Swedish Academy of Sciences, we have today’s Prize announcement (click on screenshot to go to page giving the details):

And the tweets:

The winners get only about $300,000 each, but of course the cachet exceeds that by far. Still, that’s probably about two years’ salary for these guys. The Swedish Academy should ante up more!

 

Here’s the official announcement, which will be live and is coming up:

This year’s Nobel Prize in Chemistry goes to three people

October 4, 2018 • 8:00 am

I’m a day late to the party for this one, especially because one prize went to a woman who worked in “directed evolution”. The Nobel Prize in Chemistry for 2018 was awarded to three people: Frances H. Arnold (half share), George P. Smith (quarter share) and Gregory P. Winter (quarter share). Arnold is a professor of chemical engineering, bioengineering and biochemistry at the California Institute of Technology in Pasadena; Smith is an emeritus professor of biological sciences at the University of Missouri, and Winter a biochemist at the M.R.C. Laboratory of Molecular Biology in England.

Arnold is the fifth woman to earn the Chemistry Prize, but I’m hoping that as women enter the sciences more, it won’t be remarkable enough to single them out as the “xth woman to win the Prize.” I thought, as did some readers, that it might go to Jennifer Doudna and her collaborator Emmanuelle Charpentier, but it wasn’t their time. But that will come, even if CRISPR doesn’t prove to be a useful tool in genetically engineering humans.

Here’s the New York Times article about the Prize.

The Nobel press release is more specific:

One half of this year’s Nobel Prize in Chemistry is awarded to Frances H. Arnold. In 1993, she conducted the first directed evolution of enzymes, which are proteins that catalyse chemical reactions. Since then, she has refined the methods that are now routinely used to develop new catalysts. The uses of Frances Arnold’s enzymes include more environmentally friendly manufacturing of chemical substances, such as pharmaceuticals, and the production of renewable fuels for a greener transport sector.

The other half of this year’s Nobel Prize in Chemistry is shared by George P. Smith and Sir Gregory P. Winter. In 1985, George Smith developed an elegant method known as phage display, where a bacteriophage – a virus that infects bacteria – can be used to evolve new proteins. Gregory Winter used phage display for the directed evolution of antibodies, with the aim of producing new pharmaceuticals. The first one based on this method, adalimumab, was approved in 2002 and is used for rheumatoid arthritis, psoriasis and inflammatory bowel diseases. Since then, phage display has produced anti-bodies that can neutralise toxins, counteract autoimmune diseases and cure metastatic cancer.

We are in the early days of directed evolution’s revolution which, in many different ways, is bringing and will bring the greatest benefit to humankind.

For a closer look at the work of Dr. Arnold, here’s a writeup in Science from 1994 by the journalist Faye Flam, which, although somewhat dated, does explain the main thrust of this work: the application of Darwinian evolution to molecules. At that involves mutating genes that produce enzymes (often with the enzyme engineered into bacteria) and then using a selection process to get to the molecule you want.

Nobody was even close to guessing the winners of this year’s three science prizes, so, as usual, there will be no winner of my contest.

Nobel Prize in Chemistry goes to Jacques Dubochet, Joachim Frank, and Richard Henderson (and another contest)

October 4, 2017 • 12:15 pm

I’m not keeping track on who’s guessed correctly on the biology, physics, chemistry Nobel Prizes, but we may already have a winner. (If you were the first to guess at least one winner in two of those categories, let me know). As announced by many venues this morning, including the New York Times, this year’s Nobel Prize in Chemistry went, not to those who developed the CRISPR/Cas9 system of gene editing, but to Jacques Dubochet of the University of Lausanne, Joachim Frank of Columbia University in New York, and Richard Henderson of the MRC Laboratory of Molecular Biology, in Cambridge, UK. Their award was for developing high-acuity methods for visualizing biomolecules.

The Swedish Academy of Science’s press release is here, and it’s a good place to see a summary of the research and some of the computer-processed images that have resulted from their cryogenic methods. (For a longer and more technical explanation, go here.) Here’s part of their summary, which explains the contributions of each of the three winners:

Researchers can now freeze biomolecules mid-movement and visualise processes they have never previously seen, which is decisive for both the basic understanding of life’s chemistry and for the development of pharmaceuticals.

Electron microscopes were long believed to only be suitable for imaging dead matter, because the powerful electron beam destroys biological material. But in 1990, Richard Henderson succeeded in using an electron microscope to generate a three-dimensional image of a protein at atomic resolution. This breakthrough proved the technology’s potential.

Joachim Frank made the technology generally applicable. Between 1975 and 1986 he developed an image processing method in which the electron microscope’s fuzzy twodimensional images are analysed and merged to reveal a sharp three-dimensional structure.

Jacques Dubochet added water to electron microscopy. Liquid water evaporates in the electron microscope’s vacuum, which makes the biomolecules collapse. In the early 1980s, Dubochet succeeded in vitrifying water – he cooled water so rapidly that it solidified in its liquid form around a biological sample, allowing the biomolecules to retain their natural shape even in a vacuum.

Following these discoveries, the electron microscope’s every nut and bolt have been optimised. The desired atomic resolution was reached in 2013, and researchers can now routinely produce three-dimensional structures of biomolecules. In the past few years, scientific literature has been filled with images of everything from proteins that cause antibiotic resistance, to the surface of the Zika virus. Biochemistry is now facing an explosive development and is all set for an exciting future.

Here are two photos of how it’s done and how the images are analyzed, courtesy of the Swedish Academy site:

Here are images of three molecules visualized by the method:

(From Swedish Academy summary, as is the following picture): Over the last few years, researchers have published atomic structures of numerous complicated protein complexes. a. A protein complex that governs the circadian rhythm. b. A sensor of the type that reads pressure changes in the ear and allows us to hear. c. The Zika virus.

Here’s another molecule, glutamate dehydrogenase, in which the improvement of resolution by the new method can be seen:

Fig. 9. The resolution progression of cryo-EM, illustrated by a representation of glutamate dehydrogenase with an increasing level of detail from left to right. For a protein of this size, 334 kDa, the 1.8 Å resolution to the right (38) could only be achieved after 2012/13. After an image by V. Falconieri (see ref. 38). Illustration: © Martin Högbom, Stockholm University.

And the winners:

(from the NYT) From left, Dr. Dubochet, Dr. Frank and Dr. Henderson. Credit From left: University of Lausanne, Columbia University and Cambridge University, via European Pressphoto Agency

The Nobel Prize in Literature will be announced on Thursday in Sweden; the Nobel Peace Prize will be announced on Friday in Norway; and the Nobel Memorial Prize in Economic Science will be announced on Monday in Sweden. If you want to guess, go ahead. Here’s another offer: if you guess who gets the literature prize, I’ll send you an autographed copy of either of my trade books. You can’t be the other winner, and you get only one guess. (Don’t you think it’s time Salman Rushdie got the Prize? Or Richard Dawkins?)

Google Doodle honors peppermeister Wilbur Scoville

January 22, 2016 • 8:45 am

Today’s Google Doodle, an animation (access it by clicking on the screenshot blow), honors the 151st birthday of Wilbur Scoville (1865-1942), an American chemist. In 1912, Scoville devised the “Scoville Organoleptic Test,” a way to quantify the spiciness of chile peppers. Now, of course, breeders all over the world compete to grow the spiciest chiles with the highest Scoville rating.

Screen Shot 2016-01-22 at 6.46.20 AM

Here’s a video of the animation; Google’s story about the making of the Doodle is here.

In 2013 the New Yorker had a nice article, “Fire-Eaters” (free online) about breeders’ informal competition to grow the hottest chile. It ends with the teaser that Butch Taylor, a Louisiana plumber who breeds chiles as a hobby, was producing a really wicked one:

Before we came inside, Taylor had shown me his greenhouse, where he tends his most precious plants. A single bush dominated the small hut. Hanging from its branches were an assortment of pods, some of them deep red and some of them a faint green. The plant, which was not yet stable, was the third generation of an accidental cross of a 7-Pot Jonah and, most likely, a Trinidad Scorpion Butch T. Taylor was calling it the WAL—the Wicked-Ass Little 7-Pot. He shook a branch, unleashing a swarm of flies, and picked a pod from the stem. “Just off the top of my head, the first one I tasted, I’d say two million Scovilles,” he said. “But it may just be a freak of nature. You get those now and then.”

Below is Wikipedia’s diagram of the Scoville scale, with the Carolina Reaper still holding out over the Trinidad Scorpion Butch T pepper. Here’s how the ratings are achieved, a combination of objective methodology and subjective assessment (unavoidable when it comes to matters of taste perception):

In Scoville’s method, an exact weight of dried pepper is dissolved in alcohol to extract the heat components (capsinoids), then diluted in a solution of sugar water. Decreasing concentrations of the extracted capsinoids are given to a panel of five trained tasters, until a majority (at least three) can no longer detect the heat in a dilution. The heat level is based on this dilution, rated in multiples of 100 SHU.

A weakness of the Scoville Organoleptic Test is its imprecision due to human subjectivity, depending on the taster’s palate and their number of mouth heat receptors, which varies greatly among people. Another weakness is sensory fatigue the palate is quickly desensitised to capsaicins after tasting a few samples within a short time period. Results vary widely, ± 50%, between laboratories.

Notice that jalapeño peppers, which most people consider hot, come in at a wimpy 1000-4000 Scoville units.

Screen Shot 2016-01-22 at 7.28.52 AM

The active ingredient in chiles—the stuff that makes them hot—is the compound capsaicin, although other related compounds (“capsaicinoids”) contribute to the heat as well. Below is the diagram of a capsaicin molecule; it and its relatives probably evolved as protective compound in wild chiles, deterring attacks by herbivores and fungi. Humans have taken advantage of that protection by simply breeding for more and more of the hot metabolites.

Apparently birds, who disperse wild pepper seeds, don’t react to capsaicinoids, while mammalian herbivores, who would crunch the seeds and destroy the plant’s ability to pass on its genes, react adversely. This is probably not a case of true coevolution; I suspect that plants producing fleshy bits containing capsacinoids (seeds don’t themselves contain the compounds) left more genes than those that didn’t simply because birds already lacked the receptors for the compounds while mammals had them.

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Capsaicin

There is in fact, a Wikipedia article about Guinness’s Official World’s Hottest Pepper, the Carolina Reaper, also known as HP22B, bred in South Carolina and coming in at a scorching 1,569,300 Scoville units.  (One was rated at 2.2 million Scoville Units.) Here’s what they look like:

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You can buy seeds and Reaper Hot Sauce from the PuckerButt Pepper Company (sauce here; hottest seeds here). I dare any reader to try one of these (warning: do not ingest “Reaper Venum” directly):

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If you want something hotter, there are pure capsicum extracts, hotter than the hottest pepper available, here, as well as a panoply of hot sauces having various degrees of tongue-destruction.

Oh, and here’s Scoville himself, a man who had no idea what monster he’d created:

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A chemically-camouflaged frog

December 1, 2015 • 1:15 pm

By Matthew Cobb

Social insect colonies rely heavily on chemical signalling to identify members of the colony, and conversely to detect intruders. These communication systems are generally very effective, but as that great scientist Professor Ian Malcolm put it, ‘Life will find a way’. If there’s a locked system, somewhere a pesky but perspicacious parasite will find a way to crack it.

Caterpillars of the Maculinea genus – also known as Alcon butterflies – hatch on the ground near Myrmica ant nests, and are picked up by the workers. The ants take home what tastes/smells like one of their babies, except this is a carnivorous cuckoo that will munch its way through their larvae…

An unusual example of such chemical camouflage was discovered in 2013 by a group of German and Swiss researchers, led by Mark-Oliver Rödel of the Museum für Naturkunde Berlin. It’s unusual because, as the title of this post indicates, it involves a frog.

The West African Rubber Frog (Phrynomantis microps) is found throughout west Africa, and can often be found living in the underground nests of the ponerine ant Paltothyreus tarsatus (aka the African stink ant).

These are pretty aggressive ants about 2 cm long, which pack a nasty bite and an even more powerful sting. They can be found pretty much throughout sub-Saharan Africa, where they play a very important ecological role. Most ponerine ants have quite small nests of a few hundred individuals, but in a paper published in 2013 my pal Christian Peeters found that some P. tarsatus nests can be as large as 5,000 individuals.

Here’s a rather small picture of Christian with a box of these alarmingly large ants:

Although the ants are notoriously aggressive, they don’t seem to bother about the Rubber Frog, as shown by this photo:

You can see how the ants seem rather bemused by the frogs in this video stitched together from the Rödel paper by a YouTube user – the first part shows ants with an adult frog, the final section with a froglet:

Other frogs, and other arthropods, are immediately attacked by the ants when they encounter them. However, when dead mealworms or live termites were covered in extracts from the frog’s skin, they were generally ignored by the ants, or at least it took much longer for the first bite to be administered:

Figure 1. Time from first ant, Paltothyreus tarsatus, contact with termites (left; inlet A) or mealworms (right), coated with the skin secretion of Phrynomantis microps, until stinging (inlet B).
Figure 1. Time from first ant, Paltothyreus tarsatus, contact with termites (left; inlet A) or mealworms (right), coated with the skin secretion of Phrynomantis microps, until stinging (inlet B). Control groups are termites or mealworms coated with water. Boxplots show the median and the interquartiles of time from first ant contact with a termite or mealworm until stinging. Coated insects were stung significantly later than control insects. Taken from here.

When Rödel’s group examined the chemical composition of the frog’s skin, they found it contained two novel peptides – short proteins, each 9 or 11 amino acids long – with a proline-phenylalanine pair at the end. When termites were covered with either or both of these peptides, the ants took significantly longer to attack them, suggesting these are indeed the active ingredients on the frog’s skin:

Figure 3. Effect of the two peptides from the skin secretion of Phrynomantis microps applied to termite, Macrotermes bellicosus, soldiers and delaying the aggressive behaviour and stinging of Paltothyreus tarsatus ants.
Figure 2. Effect of the two peptides from the skin secretion of Phrynomantis microps applied to termite, Macrotermes bellicosus, soldiers and delaying the aggressive behaviour and stinging of Paltothyreus tarsatus ants. Maximum observation time was 20. Taken from here.

This finding is doubly surprising – most instances of chemical camouflage involve cuticular hydrocarbons, which many arthropods use for communicating (for example, these are involved in the case of the Alcon Blue caterpillars described above). In the case of Phrynomantis microps, not only were novel peptides involved, no hydrocarbons could be detected on the frog’s skin, even though the animals were living in a hydrocarbon-rich environment in the ants’ nest.

What’s in it for the frog? Protection from predators (you’d have to be very foolhardy to take on the ants) and possibly protection from dessication during the dry season. They may also eat some of the ant larvae, although that is speculation on my part.

What’s in it for the ants? Probably nothing. If the frogs found a way to hack their chemical communication system, but at low or zero cost to the ants, then it won’t matter. If there’s a substantial cost to the ants, then you would expect a chemical arms race to begin – any ant nest that used a slightly different system of communication would not sustain the cost of the frog in the room.

The final point about this rather neat piece of biology, which flowed from a field observation, is that it’s opened up a new area of study in chemical communication in ants, and potentially a way of placating aggressive insects.

You see, Professor Malcolm was right:

 

Rödel M-O, Brede C, Hirschfeld M, Schmitt T, Favreau P, Stöcklin R, et al. (2013) Chemical Camouflage– A Frog’s Strategy to Co-Exist with Aggressive Ants. PLoS ONE 8(12): e81950

Peeters C, U. Braun U & Hölldobler B (2013) Large Colonies and Striking Sexual investment in the African Stink Ant, Paltothyreus tarsatus (Subfamily Ponerinae) African Entomology, 21(1):9-14. (Abstract)

You won’t believe these pictures of molecules!

November 30, 2015 • 9:30 am

Well, I just wrote my first clickbait headline as a test to see if it attracts readers. I’m referring here to a 2.5-year-old paper that just came to my attention; I call it to yours because although the chemistry is complicated, the pictures are lovely. The work in question is by Dimas de Oteyza et al. and appeared online in Science Express in March of 2013 (reference at bottom; free download). There’s also a blurb at the campus news site at UC Berkeley, where the work was done.

The research was an attempt to synthesize large structures of “graphene“, a honeycomb of hexagonal carbon structures that has a lot of practical uses. But rather than detect the products of their reaction through chemical analysis, they decided to do it visually using non-contact atomic force microscopy (nc-AFM; see below). They started with reactant 1 below, heated it and chilled it on the visualization surface (this stops molecular motion cold), and looked at the products.

The figure below shows the outcome. The chemical structures are at the bottom, the top row gives the visualization from coarser scanning tunneling microscope (STM), which uses a fine metal tip that moves across the sample.

But look at the second row, which shows the improved resolution with nc-AFM. You can see the chemical bonds themselves and the hexagonal carbon structures with double bonds. When I was a kid, I used to say that all our evidence for atoms and molecules is indirect: based on prediction and observation on the macro level. It’s astounding to me that humans have now developed the technology (and I emphasize that all of this technology comes from raw elements and molecules found on Earth) to see individual atoms and molecules.

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(From UC Berkeley figure): Non-contact atomic force microscope (nc-AFM) images (center) of a molecule before and after a reaction improve immensely over images (top) from a scanning tunneling microscope and look just like the classic molecular structure diagrams (bottom).

Here’s the amazing way they visualized these molecules: an nc-AFM appartus that scans the surface of the plate using a single carbon monoxide molecule as the probe, which moves back and forth over the molecule—not touching it—on the chilled plate. The CO molecule’s interaction with the big carbon molecules is detected by displacement of the plate, which is then converted into images by a laser hitting the plate, producing a readout of displacements in all three dimensions:

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An atomic force microscope probes a molecule adsorbed onto a surface, using a carbon monoxide molecule at the tip for sensitivity.

Ain’t humans smart?

According to the authors, this isn’t just a neat trick, for they say they’ve gotten insight into the precise chemical mechanisms,induced by heat, that convert the molecule on the left to the three molecules on the right; and they give a detailed scenario (of interest only to chemists) of what has happened. For our purposes, we can just gape in awe at what we can see happening, and the fantastic apparatus that helps us see it.

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Oteza, D. G. et al. 2013. Direct imaging of covalent bond structure in single-molecule chemical reactions. Science 340: 1434-1437

An interactive periodic table

May 26, 2015 • 2:45 pm

TED-Ed has created a nice interactive periodic table of the elements. If you click on the screenshot below, you’ll go to the site, and then just click on the element of your choice for a several-minute video that explains it. (Alternatively, if you click on “get full lesson” below the video, you’ll go to a page with even more information.)

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h/t: Elibeth