From the cover of a memoir by Emory mathematician Ken Ono, recently published by Springer.
Quanta Magazine interviewed Emory mathematician Ken Ono about his new memoir, “My Search for Ramanujan: How I Learned to Count,” which he co-authored with the late Amir Aczel. The book describes how Ono grew up under such relentless pressure to succeed that he developed a crippling fear of failure that caused him to drop out of high school. He eventually found his way to the path of a successful math career, guided by various mentors and by the story of Indian math genius Srinivasa Ramanujan, who endured struggles of his own.
As Ono explains in the Quanta interview:
“For whatever reason, we live in a culture where we think that the abilities of our best scientists and our best mathematicians are somehow just God-given. That either you have this gift or you don’t, and it’s not related to help, to hard work, to luck. I think that’s part of the reason why, when we try to talk about mathematics to the public, so many people just immediately respond by saying, ‘Well, I was never very good at math. So I’m not really supposed to understand it or identify with it.’ I might have had some mathematical talent passed through my father genetically, but that was by no means enough. You have to be passionate about a subject.
“At the same time, I want it to be known that it’s totally okay to fail. In fact, you learn from your mistakes. We learn early on if that you want to be good at playing the violin, you’ve got to practice. If you want to be good at sports, you practice. But for some crazy reason, our culture assumes that if you’re good at math, you were just born with it, and that’s it. But you can be so good at math in so many different ways. I failed my [graduate-school] algebra qualifications! That doesn’t mean I can’t end up being a successful mathematician. But when I tell people I failed at this, nobody believes me.”
Detail from a poster for "The Man Who Knew Infinity," starring Dev Patel as Srinivasa Ramanujan and Jeremy Irons as the British mathematician G.H. Hardy who mentored him. "The Spirit of Ramanujan Math Talent Initiative" aims to spark similar collaborations, to drive progress in math and education.
Ono recently launched the initiative in conjunction with the Templeton World Charity Foundation; Expii.com – an open, personalized learning platform; and IFC Films and Pressman Film, producers of the motion picture “The Man Who Knew Infinity.”
The Spirit of Ramanujan initiative invites people to join in solving a series of mathematical puzzles at expii.com/ramanujan. “These puzzles are challenging but fun,” Ono says. “Expii is an instrument for people of all ages and walks of life, from all over the world, to become more engaged in math. Anyone with a computer or a smart phone can access the site and participate.”
The Templeton grant will support further enrichment for participants in the initiative who show great mathematical promise, including tailored educational opportunities for as many as 30 students and up to 10 Templeton-Ramanujan Summer Fellowships.
The initiative is inspired by the life of Srinivasa Ramanujan, the subject of the film “The Man Who Knew Infinity,” starring Dev Patel as Ramanujan and Jeremy Irons as British mathematician G.H. Hardy. In 1913, Ramanujan, a poor Hindu college dropout who was self-taught in mathematics, reached out to Hardy, who was so impressed by Ramanujan’s theories that he invited him to Cambridge to study and collaborate. Hardy’s mentorship burnished Ramanujan’s brilliant insights and brought them to a world stage, changing math and science forever.
“My character in the film, G.H. Hardy, states very directly that Ramanujan’s genius was not discovered because of his teachers, but because of Ramanujan’s own imagination and intuition,” Irons says. “I’m delighted that ‘The Man Who Knew Infinity’ has shared the story of this miraculous figure, inspiring this initiative. Hopefully we will be able to discover new minds, that in turn, will lead to continued progress in the world of mathematics.”
Ono served as the mathematical advisor and an associate producer of the film. Ono’s research as a number theorist and his personal life are also deeply interwoven with the story of Ramanujan. He recently published a memoir entitled “My Search for Ramanujan: How I Learned to Count,” which he co-wrote with the late Amir Aczel.
“Everything about traditional education is fairly inelastic,” Ono says, “which is contrary to the story of what made Ramanujan successful. The Spirit of Ramanujan initiative aims to break the mold and find brilliant outliers who may not be thriving in the system so we can match them up with the resources they need. It may take 30 to 40 years to measure the success of this initiative. It can take humanity a long time to catch up with the ideas of outliers.”
The Spirit of Ramanujan Math Talent Initiative is headed by Ono with an advisory board of other mathematicians, including Manjul Bhargava (Princeton), Olga Holtz (Berkeley), Po-Shen Loh (Carenegie Mellon) and Sujatha Ramdorai (University of British Columbia).
A model of the new catalyst. "We've designed a catalyst that provides a huge shortcut for how chemists can turn a simple, abundant molecule into a much more complex, value-added molecule," says Emory chemist Huw Davies.
By Carol Clark
Chemists have taken another major step in the quest to use carbon-hydrogen bonds to create new molecules, a strategy that aims to revolutionize the field of organic synthesis.
The journal Nature is publishing the workby chemists at Emory University. They demonstrated the ability to selectively functionalize the unreactive carbon-hydrogen (C-H) bonds of an alkane without using a directing group, while also maintaining virtually full control of site selectivity and the three-dimensional shape of the molecules produced.
“The catalyst control we have found goes beyond what has been achieved before,” says Huw Davies, an Emory professor of organic chemistry whose lab led the research. “We’ve designed a catalyst that provides a huge shortcut for how chemists can turn a simple, abundant molecule into a much more complex, value-added molecule. We hope this gives people a fundamentally new view of what can be achieved through C-H functionalization.”
The first author of the Nature paper is Emory chemistry graduate student Kuangbiao Liao.
The streamlined process described in the paper holds tremendous potential for the synthesis of fine chemicals, such as those needed for the development of pharmaceuticals.
“Organic synthesis is all about simplicity,” Davies says. “It may lead to a sophisticated outcome, but it has to be simple to carry out in order to have practical applications.”
Davies is also director of the National Science Foundation’s Center for Selective C-H Functionalization (CCHF), which is based at Emory and encompasses 15 major research universities from across the country, as well as industrial partners.
The CCHF is leading a paradigm shift in organic synthesis, which has traditionally focused on modifying reactive, or functional, groups in a molecule. C-H functionalization breaks this rule for how to make compounds: It bypasses the reactive groups and does synthesis at what would normally be considered inert carbon-hydrogen bonds, abundant in organic compounds.
Watch a video to get a 3-D view of the dirhodium catalyst:
The fact that multiple C-H bonds are commonly present in a single organic molecule, however, presents a significant challenge to this new type of chemistry. Chemists experimenting with C-H functionalization normally use a directing group – a chemical entity that combines to a catalyst and then directs the catalyst to a particular C-H bond.
“The directing group has to be introduced and then removed,” Davies explains. “It works fine but the process is cumbersome.”
The Davies lab bypassed the need for a directing group by developing a series of dirhodium catalysts encased within a three-dimensional scaffold. The scaffold acts like a lock and key to allow only one particular C-H bond in a compound to approach the catalyst and undergo the reaction.
“We had already demonstrated that we could do site selectivity of C-H bonds in molecules where C-H bonds are fairly activated,” Davies says. “Here, we’ve gone for the ultimate challenge – the extremely unreactive C-H bonds of alkanes.”
Alkanes are the simplest of organic molecules, consisting only of hydrogen and carbon atoms. In chemistry, the original name for alkane was paraffin, which is Latin for “lacking reactivity.”
“Alkanes are cheap, plentiful raw materials that are considered non-functional, or unreactive, except in uncontrollable situations, such as burning them,” Davies says. “Our work, however, shows that it is indeed possible to efficiently functionalize an alkane in a controlled manner. We’ve actually changed the way that the description of alkanes in organic chemistry textbooks needs to be written.”
In addition to controlling site selectivity, the scaffold of the dirhodium catalysts developed by the Davies lab controls the chirality of the product produced in the reaction.
A graphic image demonstrating the chirality of an amino acid. A chiral molecule comes in two forms, like left and right hands that have a thumb and fingers in the same order, but are mirror images and not the same. (NASA)
Chirality, also known as “handedness,” refers to a property of three-dimensional symmetry. Just as the human hand is chiral, because the right hand is a mirror image of the left, molecules can be “right-handed” or “left-handed.”
The handedness of a molecule is important in organic chemistry, since this 3D shape affects how it interacts with other handed molecules. When developing a new drug, for instance, it is vital to control the chirality of the drug molecules because biological molecules recognize the difference.
Thalidomide is the most notorious example of the handedness problem. During the late 1950s, thalidomide was sold as an over-the-counter drug for pregnant women suffering from morning sickness.
“It’s difficult to make molecules with one mirror image, so many older drugs were a mixture of both,” Davies explains. “It was thought that one mirror image would be biologically active, and the other wouldn’t matter.”
In the case of thalidomide, however, while one mirror image cured morning sickness, the other turned out to cause birth defects.
Today, pharmaceutical makers must either limit a drug’s molecules to a single chiral shape, or go through the extra time and expense of testing the safety of a mixture of left-handed and right-handed molecules.
The new C-H functionalization catalyst may pave the way to a whole new realm of materials for drug discovery research.
“The starting material we used, pentane, is as cheap as gasoline, but we are able to efficiently generate a sophisticated product in a single step and control which mirror image is formed,” Davies says.
The process is also more sustainable than traditional organic synthesis, which typically involves the use of many reagents, and can produce toxic, inorganic byproducts.
“In contrast, our catalyst speeds up a reaction but is not used up in a reaction,” Davies says. “Only a tiny amount of the catalyst is needed to produce a lot of product. And the only byproduct is nitrogen, which is innocuous.”
While the Nature paper “opens the door” to a new method for C-H functionalization, more work is needed, Davies says. “We need to understand how to use it predictably and demonstrate its use in complex target applications.”
“The center is much better known since we started in 2009,” Davies says. “We now have a world presence through virtual symposia on C-H functionalization that we give three times a year.”
Anyone can join the symposia live, as they are broadcast on YouTube, or access them later via the CCHF web site. The most recent symposium drew a live audience of more than 1,300 chemists from 45 countries. “C-H functionalization is an important new way of thinking about synthesis, and we have leading speakers in the field giving talks on it, so there is a lot of interest,” Davies says.
Additional co-authors of the Nature paper include Solymar Negretti and John Bacsa (from Emory’s Department of Chemistry) and Djamaladdin Musaev (from Emory chemistry and the Cherry L. Emerson Center for Scientific Computation).
A 3-D rendering of a fluorescence image mapping the piconewton forces applied by T cells. The height and color indicates the magnitude of the applied force. (Microscopy image by Yang Liu.)
By Carol Clark
T cells, the security guards of the immune system, use a kind of mechanical “handshake” to test whether a cell they encounter is a friend or foe, a new study finds.
“We’ve provided the first direct evidence that a T cell gives precise mechanical tugs to other cells,” Salaita says. “And we’ve shown that these tugs are central to a T cell’s process of deciding whether to mount an immune response. A tug that releases easily, similar to a casual handshake, signals a friend. A stronger grip indicates a foe.”
T cells continuously patrol through the body in search of foreign invaders. They have molecules known as T-cell receptors (TCR) that can recognize specific antigenic peptides on the surface of a pathogenic or cancerous cell. When a T cell detects an antigen-presenting cell (APC), its TCR connects to a ligand, or binding molecule, of the APC. If the T cell determines the ligand is foreign, it becomes activated and starts pumping calcium. The calcium is part of a signaling chain that recruits other cells to come and help mount an immune response.
Scientists have known about this process for decades, but they have not fully understood how the T cell distinguishes small modifications to the antigenic ligand and how it decides to respond to it. “If you view this T cell response purely as a chemical process, it does not fully explain the remarkable specifity of the binding,” Salaita says. “When you take the two components – the TCR and the ligand on the surface of cells – and just let them chemically bind in a solution, for example, you can’t predict what will trigger a strong or a weak immune response.”
The researchers hypothesized that mechanical strain might also play a role in a T cell response, since the T cell continues to move even as it locks into a bind with an antigenic ligand.
To test this idea, the Salaita lab developed DNA-based gold nanoparticle tension sensors that light up, or fluoresce, in response to a miniscule mechanical force of a piconewton – about one million-millionth the weight of an apple.
The researchers designed experiments using T cells from a mouse and allowed them to test ligands containing eight amino acid peptides that had slight mutations.
“We swapped out the fourth amino acid position to create really subtle chemical changes in the ligand that would be very difficult to distinguish without a mechanical component,” Salaita says.
Some of the mutated ligands were given a firmer anchor to give them a tighter “grip” to the moving TCR.
Through the experiments, captured on microscopy video, the researchers were able to see, record and measure the responses of the T cells as they moved across the ligands.
“As a T cell moves across a cell’s surface and encounters a ligand, it pulls on it,” Salaita explains. “It doesn’t pull very hard, it’s a very precise and tiny tug that is not sustained. The T cell pulls and stops, pulls and stops, all across the surface. It’s like the T cell is doing a mechanical test of the ligand.”
During the experiments, the T cells did not activate fully when they encountered ligands with weak anchors. In contrast, when a T cell encountered a ligand with a firm anchor, the T cell became activated, showing that it experienced a piconewton level of resistance.
The amount of force that was applied by the T cell was mapped by using tension probes of different stiffness. Probes that responded to 19 piconewtons did not fluoresce, while softer, 12-piconewton probes produced high signal.
Following the fluorescence of the probe, the T cells switched on their calcium pumps and increased the calcium concentration within the cell, indicating that the T cells were mounting an immune response.
“We were able to map out the order of the cascade of chemical and mechanical reactions,” Salaita says. “First, the T cell uses a very specific and finely tuned mechanical tug to distinguish friend from foe. And when it senses a precise, piconewton level of force in response to that tug, the T cell realizes that it has encountered a foreign body and gives the signal for attack.”
The discovery could help in the search for treatments of auto-immune diseases and the development of immune therapies for cancer.
“Cancer cells have an extra molecule that can make T cell security guards ‘drunk’ or ‘sleepy’ so that they are not able to function properly,” Salaita says. “Learning more about the mechanical forces involved in an effective immune response may help us develop ways to evade this defense system of cancer cells.”
Co-authors on the study include Yang Liu, Victor Pui-Yan Ma, Kornelia Galior and Zheng Liu (from the Salaita lab); and Lori Blanchfield and Rakieb Andargachew (from the Evavold lab).
"Our detailed data proves a much sharper view of the actual dynamics of the troposphere," says theoretical chemist Joel Bowman. In this NASA photo of the space shuttle Endeavor, silhouetted against Earth's atmosphere, the troposphere is the orange layer. The white layer is the stratosphere and the blue is the mesosphere.
By Carol Clark
Chemists have identified a cascade of reactions for how mysterious molecules known as Criegee intermediates generate hydroxyl radicals – an oxidant that helps remove pollutants from the lower atmosphere.
Nature Chemistry is publishing the findings, a collaboration of Emory University and the University of Pennsylvania.
“We’ve solved another piece of the puzzle in the formation of hydroxyl radicals, by zooming in to see all the steps of the reaction in much finer detail than ever before,” says co-author Joel Bowman, a theoretical chemist at Emory. “This kind of detailed data is important to atmospheric chemists trying to make predictive models for how the atmosphere will respond to climate change.”
The theoretical work revealed that a Criegee intermediate first produces highly energized vinyl hydroperoxide, or VHP, then rapidly decomposes to hydroxyl radicals, along with vinoxy byproducts.
In 2014, Lester’s lab was the first to observe the creation of a hydroxyl radical by a Criegee intermediate in a laboratory setting. Many questions remained about the process, however, since it occurs so rapidly in the lab, as well as in the troposphere.
The turbulent troposphere, the lowest layer of Earth’s atmosphere, is where the weather happens. It’s like a giant washing machine filled with molecules – hydrogen, oxygen and nitrogen and all the other chemical byproducts of plant, animal and human activity that float up and mix with solar energy.
Hydroxyl radicals are sometimes called the detergent in this mix because they are extremely reactive to many common pollutants and greenhouse gases. When a hydroxyl radical encounters a molecule of sulfur dioxide, for instance, it steals its electrons and oxidizes it. Both the hydroxyl radical and the sulfur dioxide vanish, turning into an innocuous aerosol.
The troposphere, the lowest layer of Earth's atmosphere, is where the weather happens.
Most hydroxyl radicals are produced during the daytime as sunlight breaks down ozone, releasing oxygen atoms that react with water vapor and become hydroxyl radicals. About a third of the troposphere’s hydroxyl radicals, however, are produced through a more mysterious process that can even occur at night.
German scientist Rudolf Criegee proposed a hypothesis in 1949 for this process. He predicted the existence of another radical, known as the Criegee intermediate, as a step in the chain of reactions needed to produce hydroxyl radicals from ozone, without daytime solar energy.
“Alkene ozonolysis is a fancy term to describe the process Criegee proposed,” Bowman says. “The Criegee intermediate, or carbonyl oxide, is one of the stepping stones in the process, but it has a lot of energy so it breaks up right after it forms. The Criegee intermediate was certainly possible – it followed the rules governing how bonds form and rearrange – but for decades it remained hypothetical.”
It was not until 2012 that researchers managed to create a Criegee intermediate in a laboratory setting. That discovery was followed by the Lester lab’s 2014 work: Actually tracking a Criegee intermediate through the reaction that results in a hydroxyl radical, using a technique known as infrared action spectroscopy.
For the current Nature Chemistry paper, the Lester lab teamed with the Bowman group to combine its experiments with theoretical modeling.
As theorists, the chemists in the Bowman group can slow down time, in a sense, to study and measure a reaction in more detail. “We have developed sophisticated algorithms and software codes that allow us to study chemical reactions at the ultimate level of detail,” Bowman says. “Running the calculations for a reaction that occurs in picoseconds requires days of computer time, and we have to run it over and over again. The result is a mind-boggling data set, made up of billions of pieces, that we then have to analyze.”
The theoretical results both extended the experimental work and were validated by them, giving an unprecedented insight into the multi-step cascade of reactions.
“What actually happens in the wild is so much more complicated than in a controlled laboratory setting,” Bowman says. “Our detailed data provides a much sharper view of the actual dynamics of the troposphere.”
Sophisticated experimental techniques, high-powered computers and powerful new algorithms are driving advances faster than ever before, he adds.
“A lot of science done prior to 50 years ago, before computers, involved brilliant people, like Rudolf Criegee, doing hypothetical work that they could not prove,” Bowman says. “They would be bowled over by our capability now to actually settle many of these questions.”
Additional authors on the paper include Emory chemist Xiaohong Wang and University of Pennsylvania chemists Nathanael Kidwell and Hongwei Li.
