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February 19, 2016

A packet of time in a rock, or what rocks tell us 

A rock is not just a rock, but a fragment of the history of our planet. And to excel at reading that history, it is necessary to have a good understanding of not just geology but physics, chemistry and biology. That was just one small thing of the many that we learnt from Professor Pincelli Hull, at the most recent Tilde Cafe discussion.

Professor Hull started the afternoon with an introduction to rocks, a subject that not everyone is familiar with. We were introduced to three types of sedimentary rocks, and were lucky that we got a chance to touch and feel samples of sandstone, fossiliferous rock and laminated rock, each a consequence of unique processes. 
While on sandstone you can see and feel the marks left by waves, fossiliferous rock is a delicate fusion of shells over time. Laminations are a result of cyclic changes in sedimented materials, and are best preserved under anoxic conditions.

With that thumbnail sketch on rocks, we were introduced to mass extinctions. Mass extinctions are, as the name suggests, when large numbers of species become extinct in a short period. There have been five mass extinctions in the history of the earth, and the most dramatic one occurred 250 million year ago when 90-96% of living species became extinct. The most recent mass extinction occurred 66 million years ago, and one that wiped out about 75% of then existing species. That extinction is attributed to a catastrophic impact by an asteroid that was about 10-14 km or 6-9 miles in diameter. That's about the distance between New Haven and Branford where we meet for our cafes. So, in the context of the diameter of the earth 12,742 km or 7,900 miles relatively small. But, the asteroid came hurtling from space and is estimated to have been equivalent to 100 teratonnes of TNT or approximately 220.462 quadrillion pounds. That is roughly 8 billion times stronger than each of the bombs that hit Hiroshima and Nagasaki. To appreciate the scale of this impact, consider dropping a small bead in a cup of flour, and observe what happens - or just watch this video on Youtube of a ball bearing being dropped on sand - https://www.youtube.com/watch?v=ISr4hM-_jlE. The weight of the ball bearing in the video is likely less than a fifth of the weight of penny, and less then a fifth of the penny's diameter! 

The question of whether we are in the middle of the sixth mass extinction is debated by geologists. Perhaps an extremely simplistic way of trying to understand this very complex debate is that you really don't know if you are in a valley until you get out of it! But there's no denying that species continue to become extinct whilst we are in this valley. Studying rocks and fossils then helps shed light on the kinds of events that occurred that caused extinction of the creatures that are now fossilized. However, the vast majority of organisms don't become fossils, because to become a fossil the organism should exist in large numbers, and then when it dies, it should be in a place that is susceptible to the changes that permit fossilization. Dying in arid regions, for example would have a much smaller likelihood of the organism becoming fossilized, because arid areas experience significant erosion. 

I think all those who were present will now look at cliffs and rocks with a different eye and wonder what fragment of time is captured in them. And on that note, a poem from Ogden Nash:


At midnight in the museum hall
The fossils gathered for a ball.
There were no drums or saxophones
But just the clatter of their bones.
A rolling, rattling, carefree circus
of mammoth polkas and mazurkas.
Pterodactyls and brontosauruses
Sang ghostly prehistoric choruses.
Amid this mastodonic wassail
I caught the eye of one small fossil.
Cheer up, sad world, he said, and winked -
It's kind of fun to be extinct.

If you missed this wonderful cafe discussion, here's what the room looked like
Many thanks, Professor Pincelli Hull for a riveting afternoon.

January 17, 2016

Rubber-bands, nails, bridges and networks* 

It's January, and thankfully we weren't slipping on the sliding ice when we congregated at Blackstone Library to learn about networks from Professor Daniel Spielman.

A collection of connected elements (people/internet sites/computers/proteins - pretty much anything that can be connected) forms a network. For example, one is all too familiar with the concept of social networks; similarly, in biology there are networks connecting proteins; in engineering there are electrical networks. Each element in the network is called a node or a vertice, and the connection between two elements is called an edge or a link. If you know the characteristics of an element, you can predict the characteristics of other elements connected to it, which is why if you have a LinkedIn profile or a Facebook profile, you may be prompted with suggestions to connect with specific individuals. These predictions are based on refined algorithms that have been developed to make rapid calculations behind the scenes. What is particularly fascinating is if you looked at a particular social network, while connections exist because of some shared features between individuals, many other features may be divergent. Very complex networks that look like a pot of cooked angel hair pasta can be simplified into manageable clusters and then further studied. For example in a network of high school classmates, political views may span the spectrum. Each classmate has his or her own network.The question is, can you make a reasonable guess about the political views of someone who you don't know directly in this complex social network? Mathematicians study these networks (they refer to them as graphs), and develop elegant algorithms to yield fast and clean answers to such questions. Such algorithms can be applied to understanding and interrogating networks in general.

Dan took us through a captivating afternoon where we learnt about the history of the field of networks and how even map coloring played a role in the field - you may have encountered your school geography teacher telling you that you could use only four colors to color a map, and adjacent countries should have distinct colors. While the topic of networks and how mathematicians and computer scientists develop methods to understand them may seem daunting, Dan simplified it for us in a manner that can be broadly understood and shared with us how he is trying to continually improve existing protocols to study and understand networks. It definitely gave us a greater appreciation of the under-the-hood contributions of mathematicians to making the world a little more manageable!

Professor Heeger started the afternoon with telling us about subatomic On a note related to networks, Lewis Carroll had developed a game he called Word-links or Doublets, where two words were connected to each other through a number of steps, and each step involved the change of a single letter in the word; each new word had to be a word in the English dictionary. Perhaps the most famous Doublet challenge is this - can you evolve ape to man in five links?

Solution: APE - ARE - ERE - ERR - EAR - MAR - MAN
There is of course a shorter link:
Solution: APE - APT - OPT - OAT - MAT - MAN

For a compilation of Lewis Carroll's Doublets, visit - http://www.explorethemidwest.com/Doublets__a_word_puzzle__by_Lewis_Carrol.pdf 

Note that he ends the preface to the book as follows:

"I am told that there is an American game involving a similar principle. I have never seen it, and can only say of its inventors, "pereant qui ante nos nostra dixerunt!

I had to check what the Latin translated to, and according to Merriam-Webster, it is this: "may they perish who have expressed our bright ideas before us." Brilliant! 

Thank you, Dan, for an informative afternoon. It was worth the wait! 

In closing, a network joke - 

 Q: What kind of network does a Hobbit have? 
A: A Tolkien-Ring network.



*Check video below for context to subject line

November 7, 2015

Facts and theories are different things

Pop quiz: What do Johannes Kepler (1571-1630), James Ussher (1581-1656) and Isaac Newton (1642-1727) have in common?
  1. They were all physicists
  2. They were all natural philosophers
  3. They all estimated the origin of the universe dated to around ~4000 B.C.

If you chose option [c] as your answer, then you are right. This was one of the many things we learnt at the most recent Tilde Café discussion led by Professor Salman Hameed from Hampshire College. Although we had a smaller than usual gathering on a brisk fall afternoon, it was nice to welcome new faces.

Professor Hameed started the afternoon with a different pop quiz with two pictures - the exterior of a natural history museum; and the interior with a mastodon skeleton – which museum was this? The person with the correct answer would receive a DVD on Evolution, produced by PBS. After many guesses, we had a winner – it was the Pakistan Museum of Natural History, an institution overseen by the theocratic state. This then highlighted the question about whether Muslims accept biological evolution, and led into more than an hour long conversation and discussion about evolution in the context of religions and cultures, among other things.

In the course of the afternoon, we heard and perhaps considered some matters for the first time – for example the words ‘science’ and ‘scientist’. In Professor Hameed’s research, when surveying medical professionals who are Muslim in Pakistan, with regards to evolution, he found a mixed response. While the majority acknowledged that humans are products of evolution, a subset of these also noted that in the context of their religion it was not the case. Without going into the details here of his extremely interesting research which he described and which you can catch on the video of the café (click link below), it is clear that Muslims, like any other religious group, are variegated in their acceptance and opinions on biological evolution. 

And regarding the word ‘scientist’, it is a fairly new term coined
 by William Whewell, in 1833. Even the venerable publication Nature accepted it only 60 years after its inaugural issue; until then those who studied science were mostly called ‘natural philosophers’ or even 'sciencers'. You can search the internet for "Nature scientist substitute word" to see some of the spirited arguments for and against the word in that journal, reflecting the upheaval it caused at that time. Here's an excellent essay about this topic from science historian Melinda Baldwin - https://thonyc.wordpress.com/2014/07/10/the-history-of-scientist/

Despite scientific evidence, there seems to be no lull in whether or not the topic of evolution can be included in school textbooks; and included without caveats. Perhaps Stephen Jay Gould has put it most eloquently in saying “…facts and theories are different things, not rungs in a hierarchy of increasing certainty. Facts are the world's data. Theories are structures of ideas that explain and interpret facts. Facts do not go away when scientists debate rival theories to explain them. Einstein's theory of gravitation replaced Newton's, but apples did not suspend themselves in mid-air, pending the outcome. And humans evolved from apelike ancestors whether they did so by Darwin's proposed mechanism or by some other, yet to be discovered.” (http://www.stephenjaygould.org/library/gould_fact-and-theory.html). Another resource that distinguishes scientific fact from scientific theory can be found at the National Academies website and is worth sharing with     those who may conflate the non-scientific use of the word "theory" with the scientific one (http://www.nas.edu/evolution/TheoryOrFact.html). At least in light of the clarity of this, one wonders why there is any debate at all.


September 19, 2015

(In)Tangible to binary - a superb overview of digitization projects by Holly Rushmeier

Greetings and welcome to the first day of autumn!

Tilde Cafe's eighth season opened on the last Saturday of summer, with excellent weather in place and a riveting story thanks to Professor Holly Rushmeier. We heard about gathering fragments of past cultures and stitching them together in forms that would allow an observer to gain a greater understanding and appreciation of our collective story - human civilization's story.

Professor Rushmeier's work showed us how science has enabled opening doors into art history, archaeology and also ancient texts, enriching our ability to experience them. In all the projects that she talked about, there was either an unsolved mystery (the destruction of the Florentine Pieta of Michelangelo); or difficulties in deciphering handwritten manuscripts from the past (Books of Hours); or piecing together Dura-Eurpos from sketches and photos; or developing 3-D renderings of King Khufu and King Khafre's statues, and King Tutankhamen's throne. Each of these digitization projects had unique requirements. Thinking outside the proverbial box was essential to design equipment and technologies for the specific digitization process, while needing to exercise exquisite care in handling the objects to be digitized.

For those in attendance who had a limited knowledge of ancient history (such as myself), this cafe was an outstanding opportunity to get a brief look into the past, while also gaining an insight into the challenges that historians and archaeologists are faced with in trying to interpret and also maintain works and sites. Using three-dimensional scanning, multi-spectral imaging and other technologies, advanced computing has begun to make precious works and sites more accessible to scholars, because, as Prof. Rushmeier said, "Digitizing and making numerical models of things is just a means to an end". One end being making these works accessible not only to scholars, but also to the public. To see how wonderfully accessible some of this work is, visit http://www.eternalegypt.org/ from the comfort of your favorite internet connected device!

While each project described was unique, perhaps what may present the most significant challenges is digitizing handwritten manuscripts particularly because of the uniqueness and variations in how text characters are transcribed. Unlike OCR (optical character recognition) that one has become accustomed to using when scanning and reviewing printed documents, handwritten documents bear little uniformity across pages, never mind from person to person. Consequently, Professor Rushmeier's current work on digitizing medieval manuscripts in the Beinecke Rare Book & Manuscript Library particularly the Books of Hours, is resulting in the development of new methods that could be applied to digitizing other similarly handwritten manuscripts.

It’s difficult to underscore the importance of computing in moving into the future, but it is equally difficult to underscore its significance in ensuring we have a record of our very rich past. Thank you Holly, for making us all sit up and be fascinated and absorbed on a perfect Saturday afternoon at Tilde Cafe.

June 8, 2015

There's a "butterfly" in your DNA

Conceptually and structurally, every time you go out into the sun without sunscreen, you are likely to acquire mutations in the cells on your exposed skin. Most of these mutations occur because of an ultraviolet light induced chemical reaction that changes some of the building blocks that make up your DNA. In Texas, an hour of sun exposure at noon (without sunscreen) can result in up to 10,000 of these chemical reactions per cell. You probably recall from Professor Tom Pollard's cafe discussion back in 2009, that DNA is made up of four fundamental building blocks - A (adenine), G (guanine), T (thymine), and C (cytosine). A and G belong to the group of chemicals called purines; T and C belong to the group called pyrimidines. Pyrimidines, when exposed to UV light, undergo a chemical change within picoseconds, resulting in a new chemical - a cyclobutane pyrimidine dimer (CPD) - part of whose structure resembles the shape of a butterfly. If this UV induced alteration in your DNA isn't repaired by the cell's DNA repair enzymes in a timely manner, the change is passed on to the next generation of cells, and repeated cell divisions over the years can now result in a mass of cells that carry the mutation, and this mass could become either a benign or malignant tumor. Thanks to an extremely sophisticated and efficient DNA repair system, a very small number of alterations go unrepaired

Sunlight includes light that encompasses a wide spectrum of energies. The human eye can't see light on either ends of the spectrum - ultraviolet is at the low end of the spectrum (and has high energy); infrared is at the high end of the spectrum (and has low energy). Although the ozone layer protects us from almost 99% of the UV radiation from the sun, the balance that reaches earth will be responsible for some of the 80,000 new skin cancer cases this year in the US. The most serious form of skin cancer develops in melanocytes, cells that produce melanin -  the pigment that gives skin its color. While melanin has been known to confer some protection from sunburn and skin cancer, Professor Brash's recent research has demonstrated that the sun's UV radiation damages not only DNA at the time of sun exposure, but also affects the susceptibility of melanin to highly reactive chemical intermediates, resulting in melanin fragments that work like energy reservoirs. His research suggests that the fragmented and energized melanin transfers the energy to nuclear DNA, resulting in chemical changes in the DNA similar to those when directly exposed to the sun's energy.This latter process of DNA distortion that occurs in absence of sunlight, the dark reaction, is much slower: direct sunlight damage occurs in picoseconds (there are 60 trillion picoseconds in 1 minute). It is conceivable that with further research, currently available sunscreen can be supplemented or complemented with agents that might inhibit the DNA damage that continues even after the end of direct sun exposure.

This last talk of the seventh season competed with wonderful weather in Branford and a strong temptation to be out in the sun; we hope that those who were unable to attend were well protected from the UV rays! Thank you, Doug, for shedding light on the dark reactions occurring in our melanocytes. Something to consider for the summer then - if you're going to spend a lot of time out in the sun and you missed the cafe, you can view the video at the cafe channel in the next couple of days. And through the summer, please consider what Sid the Seagull tells Aussies to do - Slip, Slop, Slap, Seek & Slide. Australia has the highest incidence of skin cancer, with 2 out of 3 Australians being diagnosed with some form of skin cancer by the time they are 70 years old, so Sid should know.

May 16, 2015

The answer is >>>42

For those who are familiar with the Douglas Adams Hitchhiker series, 42 is the Answer to the Ultimate Question of Life, the Universe, and Everything. But the answer to the question of how much does it cost to create a new drug with the best medicinal chemists working at the problem, is closer to 800 million. Dollars. 

Almost a year after our last discussion led by Dr. Daniel Broom relating to pharmacology, Dr. Kevin Currie talked about the complicated yet exciting processes involved in coming up with a new drug. The path to creating a successful drug is littered with failures, red herrings and PAINS (Pan-Assay Interference compoundS - promiscuous molecules). Which is why Structure-Activity Relationship (SAR) studies are at the heart of drug discovery and drug design, and medicinal chemists are critical to this process. SAR studies strive to achieve a balance between an ideal structure of a molecule and the biological effect of that molecule, so that PAINS can be minimized. Typically, the chances of success in drug discovery are about 1-2 % before going to clinical trials, and it can take up to 6-8 years before a drug is available for clinical trials. The entire process from start to approval and access of the drug to patients, has a success rate of 0.1-0.2%. With these low rates, collaboration is key to the process and medicinal chemists work in partnership with computational chemists, computational biologists, x-ray crystallographers, and other specialists, to increase success and reduce the number of PAINS. 

The science of drug discovery and medicinal chemistry is complicated by the fact that biological systems are complex. Despite information on the human genome being publicly available, drug discovery for specific diseases continues to be an extremely difficult and expensive process. The human genome is not a linear beast - products of the genome interact with each other in multiple pathways, not all of which have been characterized. Consequently, it is not uncommon to find that what at first, second, and even nth glance appears to be a perfect drug, must be rejected in clinical trials because of unpredicted and undesirable outcomes. 

But the issues faced by a medicinal chemist much earlier in the process of drug discovery are what can be both financially demanding and intellectually challenging to surmount. The medicinal chemist is unique in the drug discovery process because chemistry is a science which endows its practitioner the ability to synthesize molecules to order, as long as the laws of physics are obeyed! After an initial understanding of the region to be focused on in a target protein, a medicinal chemist gets to work synthesizing molecules that would fit into that region. Using computer graphics, in some cases it is possible to visualize how the synthesized molecule would align along the target protein, and based on these results medicinal chemists then modify the synthesized molecule further to reach optimal alignments. Other challenges in the discovery of oral drugs include how to package the synthesized molecule so that it can withstand the acidic environment in the stomach and still not lose its structural and chemical integrity, and then make its way through the digestive tract and finally out into the blood stream from where it must pass muster through the vigilant liver, before it is let loose to roam the body and find its target protein! How's that for multiple challenges to a small molecule that came into existence thanks to the assiduous efforts of a team of medicinal chemists and their collaborators? 

In general, the likelihood of a molecule becoming a successful oral drug is encapsulated in the Rule of 5 - criteria that include the minimum number of certain types of chemical bonds and atoms in a molecule. However, as with all rules, there are exceptions such as in the blockbuster drug Lipitor. Even so, using these rules as a rough guideline can make the drug discovery process slightly more efficient and narrow down the possibility of PAINS and red herrings. On the bright side, drugs that don't make it to patients despite all the efforts and dollars invested, can be screened and sometimes re-purposed for another disease. As discussed in a cafe led by Dr. Zeldis, the re-purposing process is faster, because the molecules have overcome initial tests for safety. 

Thanks, Kevin, for being our guide on a lovely spring afternoon - even if the answer is >>>>>42! 

The cartoon below is from the brilliant cartoonist Roz Chast who will be in New Haven next month - http://artidea.org/event/2015/1865 - like Tilde Cafe discussions, it's going to be a free event! 

April 11, 2015

In the cold light of day - yet another espectacular* Tilde Café afternoon

And once again, our Café afternoon coincided with a wonderful sunny day - there are those who've been suggesting we team up with local meteorologists to bolster their prognostications! The few, the proud, the Tilde Café die-hards, descended on the James Blackstone Library to hear Professor Iwasaki tell us about viruses and managing our relationship with them.

"Microbiome" is a word that Tilde Café attendees will be familiar with, thanks to Paula Kavathas telling us about the human microbiome a little over five years ago, in March 2010 (https://www.youtube.com/watch?v=mmTiUDBBNBk). If you did a PubMed search for published scientific articles that use the phrase "human microbiome", you'd see that until 2010 March there were only 50 articles (the earliest article using this phrase was published in 2002); fast forward to the period between that cafe and today, and that phrase appears in 545 articles published in 5 years. The attention the human microbiome is getting is clearly remarkable. While we have 23,000 genes, this number pales in comparison to the total number of genes (more than 1 million) we carry around with us thanks to the microbes that inhabit us. The NIH Common Fund Human Microbiome Project (HMP) was established in 2008, "with the mission of generating resources that would enable the comprehensive characterization of the human microbiome and analysis of its role in human health and disease." Viral genes, including genes from bacteriophages - viruses that infect bacteria - have been identified as part of human DNA through detailed sequencing efforts across the globe. Because viral replication depends on the host cell it infects, a viral genome (or parts of it) can sometimes remain integrated in the host genome even after an infection. This then propagates and the sequence remains relatively unchanged since the human genome acquires mutations at much slower rates than stand-alone viral genomes. Studying these pieces of stably integrated viral genomes is central to the specialized field of paleovirology. A very brief introduction and review of paleovirology can be found in an article by Aris Katzourakis.

Professor Iwasaki gave us a quick tour through the two arms of the immune system, perhaps one of the most complex parts of our physiology - innate and adaptive immunity, and the manner in which each of these systems propel into action in response to a virus. Innate immunity is the body's first line of defense. Type I interferons, produced at 37 Celsius when a virus infects a cell, play a critical role in quashing a virus via innate immunity - a relatively nonspecific, broad and short-lived response to an attack. Adaptive immunity on the other hand is more complex and longer lived, and can also be conferred via vaccines.

To establish an infection, most viruses need to replicate at 37 Celsius (98.6 F). As recent work from Professor Iwasaki's lab has shown, "most" does not equal "all": the rhinovirus, the perpetrator of the common cold, is able to successfully replicate at the lower temperature (33-35 C or ~91-95 F) in the upper respiratory tract. because the innate immune response cannot be adequately mounted at temperatures below 37 C. While it has been known for some decades that the rhinovirus replicates at these lower temperatures, how it evades the long arm of the immune system has now finally been elucidated by this work. So in winter, keep that nose warm so your cells can make type I interferons to keep you from sniveling!

As a result of years of time and money spent on researching many viral diseases, we now have vaccines for a few of them. Keeping up with vaccination regimens throughout one's life is critical to the health of our species, enhances overall life expectancy, and reduces healthcare costs in the long run. In fact with global mobility on the rise, keeping up with vaccination regimens becomes even more important. Thank you, Professor Iwasaki for a marvelous peek into your research, and showing us that despite a complex and fine tuned physiological system, there are enormous barriers that must be crossed to develop a strategy to overcome viral infections; encapsulating it all in an email is challenging!

Thank you also for your patience in responding to the seemingly innumerable questions from all in attendance. The footage of the afternoon will be posted on the youtube channel later this week.

*We're going to look for superlatives in other languages, since we seem to be running out of them in the English language. Send us your suggestions.

January 19, 2015
"There was a young lady named Bright" - A summary of "A Brief History of Light", relatively speaking

The first cafe of 2015 could not have been more interesting and well attended! And those present were particularly lucky, because thanks to technical issues, the video of the afternoon is slightly abbreviated. 

2015 is not only the International Year of Light and Light Based Technologies (celebrations are in progress in Paris at the time of writing this), but it is also the 100 year anniversary of Einstein's equations for General Relativity. While humans have known about light in some form from the beginning of time, understanding it and being able to harness its properties took an inordinate amount of time and effort, and was not without controversy. Although one may have heard the names of some of the physicists who profoundly influenced our understanding of light, the details are mostly known only to "insiders". On Saturday, thanks to Professor Stone, Tilde Cafe attendees got a chance to peek into this relatively arcane realm, and get a sense of the breadth of the scientific contributions of these individuals, and also a little about the process of their discoveries. More importantly, an appreciation of the relationship between theoretical and experimental physics was evident - it's what contributed to recognizing the dual wave and particle properties of light. 

Doug Stone's recent research is focused on lasers and their novel modifications and applications, for which he and his colleague Hui Cao received the Willis E. Lamb award for Laser Science and Quantum Optics just last week. A poorly appreciated fact, but one which long time Tilde Cafe attendees might have recalled from Steve Girvin's talk in 2010, is that Einstein laid the foundations for lasers, the acronym for light amplification by stimulated emission of radiation. What few will have known before this cafe, is that lasers which produce light by themselves are actually oscillators and not amplifiers, rendering the acronym for them as LOSER - however, due to this unfortunate acronym, "laser" is used more broadly! 

Many thanks, Doug, for an informative and entertaining afternoon. It was wonderful to see such a great turnout and while the video has been posted on the youtube channel, it doesn't hold a candle (pun intended) to having been there that afternoon - https://www.youtube.com/user/tildecafe 

Recapitulating such a riveting afternoon any more than this, can be dangerous and/or ridiculous, as Scott Adams has so excellently shown in this cartoon! 

To make up for the footage lost to posterity, we close the circle from the subject line for this email, with this limerick: 

There was a young lady named Bright 
Whose speed was far faster than light; 
She set out one day 
In a relative way 
And returned on the previous night. 
- A. H. Reginald Buller (from Punch, 1923)

December 14, 2014
Looking at the wheel (molecule) differently

While the plural of anecdote is not data, there definitely is a trend where weather eases up for Tilde Cafe events! Yesterday was a sunny, precipitation free, but cold day and we had a good number of people come in to learn about drug repurposing.

In September 2000, 189 member nations of the UN pledged to free the world from extreme poverty and multiple deprivations; the pledge was charted out as eight millenium development goals to be met by 2015 (MDG 2015). One of these goals, goal 6, is to "Combat HIV/AIDS, Malaria, and Other Diseases by 2015". This is not a small task, and with a little over a year left until the end of 2015, a deeper understanding of the molecular mechanisms of the diseases can lead to a more thoughtful approach to curing and preventing them. There are 17 diseases on the list of "other diseases", and perhaps those that are of greatest concern are malaria, tuberculosis and dengue so efforts are underway towards targeting them.

Broadly speaking, diseases can be targeted using drugs that are either small molecules (such as aspirin or acetylsalicylic acid), or larger molecules like proteins (such as Avastin or bevacizumab). Most pharma companies have enormous libraries of compounds that never made it as drugs for the intended purpose - according to some reports, only 1 in 1000 molecules make it to the final stage where they are approved by the FDA for human use. Some of those that did not meet approval may have also gone through clinical trials but were rejected due to not meeting the expected levels of efficacy. So what can one do with this arsenal of molecules that never made the cut? Enter drug repurposing. In all likelihood, some of the abandoned small molecules - the 99.9% that didn't make it to the market for the intended disease, can be reviewed for their effect on the diseases listed in Goal 6 of the MDG 2015.

&By segregating the sidelined small molecules based on a variety of criteria such as shape or charge, and using them based on the molecular processes that are impacted by these diseases, it is possible to test large numbers quickly in a laboratory setting, and to narrow them down to the most promising few to proceed to clinical trials and approvals. Further, since some of the 17 diseases also occur in animals, lessons learned from current treatment of affected animals can be applied to focusing on the most effective therapies for the human disease - something which was discussed in the last cafe on dogs; the converse is also possible.

With a concerted effort involving academia, industry and non-profit organizations even more vigorously than before, achieving MDG 2015 goal 6 is not necessarily a pie-in-the-sky, because it is much easier and probably more effective to put existing resources to other and/or better use, than to develop resources from scratch. Thank you, Jerry, for a thought provoking afternoon - and for driving down from New York, expressly for Tilde Cafe!

October 18, 2014
Distinct yet similar: dogs and humans - a recap of Tilde Cafe #50

Today was a milestone for Tilde Cafe, with it being the 50th cafe discussion since 2008! Keeping our sights on bringing you eminent scientists to speak on a panoply of subjects, dog-lovers in particular were treated to an absorbing afternoon about the intricacies and potential of canine genetics. 

While humans and dogs have roughly the same number of genes, 23,000, these genes are spread over 23 chromosomes in humans, and 39 chromosomes in dogs. A working draft of the human genome was published in 2000; a working draft of the dog genome was published in 2004, using DNA from a female boxer, Tasha. With information on both genomes now available, previous observations of similarities between diseases of dogs and humans have been confirmed in many instances. This makes it even more compelling to understand and treat the shared diseases in dogs and humans. 

All breeds included, dogs suffer from more than 300 genetic disorders, many of which resemble human conditions. The most common diseases among purebred dogs include cancer, epilepsy, heart disease, allergies, retinal disease, and cataracts, and current treatment provided is not very different from that provided to humans. With this in mind, and the fact that although 365 days define a year in the life of both dogs and humans, and that a dog's physiological age is on an average 7-9 times that of a human's, finding appropriate interventions for pathological conditions in dogs can have a direct bearing on treating similar human conditions. For example, the Canine Longevity Consortium is undertaking a significant collaborative effort funded by the NIH's National Institute on Aging to study aging in dogs - the Canine Longitudinal Aging Study. Although aging has been studied in laboratory animals, the studies have been conducted under controlled conditions that don't mimic the environments we inhabit. Enter, the normal life cycle of Canis lupus familiaris who shares our living environments and thus experiences the same environmental stresses and benefits that we experience! Because of the rapidity of canine aging, results from novel ways of treating dogs in this difficult period of their lives, can likely be swiftly translated to helping humans through similar discomforts. And, as dog lovers would say, this would be yet another instance of a dog being man's best friend! 

 For those who are interested in supporting efforts to discovering the links between canine and human cancers, the 2 Million Dogs Foundation is organizing fundraising walks around the US. Please visit http://www.2milliondogs.org/walks/upcoming-walks/ to find a walk in your area. If you are close to the Connecticut shoreline, there's a walk on November 9 at Hammonasset. 

 Here's a take on what Orhan Pamuk said in My Name is Red, "Dogs do speak, but only to those who know how to listen": dog genetics will speak, and we will benefit from listening. Let's listen! Thanks Mark, for giving us a quick walk through the field and the potential it holds for both dog and human health.

May 11, 2014

Confidentially speaking, it's all in the liver - almost all

The most recent Tilde Cafe discussion, "Pharmacology Confidential" paralleled the 1997 film "L.A.Confidential" only in that there were intertwining stories about drugs, just as the movie had intertwining stories about three detectives!  This was Dr. Daniel Broom’s second café discussion in three years. Thank you for coming back to talk to us, Dan. He started with the very basics on a Saturday afternoon that was alternately sunny and overcast:  what is the difference between pharmacology and pharmacy; between a drug and a medicine, things that many people think they know, but in reality are not clear about.
In order for a drug to be considered as a viable candidate for the market, its performance must be assessed using strict criteria. ADME - or absorption, distribution, metabolism, and excretion are the four criteria that must be rigorously evaluated for every new drug molecule. 
Intravenous and oral routes are the most common methods of administering drugs. Oral drugs have to pass muster of the liver before getting out into the blood stream and thence to the site where they are needed. This means the drug has to pass across multiple cell membranes, which are rich in lipids (fats). Consequently, the drug must be reasonably fat soluble. But it must also be reasonably water soluble, since the interior of a cell is largely aqueous. This covers absorption and distribution criteria.
Upon reaching its destination and doing its job, the drug must be metabolized and excreted. Once again, it passes through the liver where it is broken down and detoxified and finally excreted in urine. The liver is equipped with a battery of enzymes which break down the drug to smaller components that are often highly reactive and potentially toxic and must therefore be quickly modified before excretion. However, since there isn’t a never ending supply of this machinery – there is a constant turnover – overdosing with drugs as innocuous as acetaminophen (Tylenol) can wreak havoc on ones liver.
As you might have guessed, this café discussion was excellent, and would have gone on much longer but for the fact it was near closing time for the library! To explain how drugs work, Dan used fascinating examples of drugs that are quite common and I will wrap-up this email with just one of the (more than) three examples he discussed. You can catch them all on the video that will be available later this week.
Did you know that although morphine and loperamide both bind to μ-opioid receptors, the drugs have very different structures, and very different effects? The one on the left is morphine, and on the right is loperamide.

Morphine2DCSD.svg   File:Loperamide.svg

While almost everyone knows about what morphine does – relieves pain by acting on the central nervous system, loperamide’s effect is relatively unknown - until you hear the trade name "Imodium" - the anti-diarrheal over-the-counter medication you can buy at your local drugstore. Loperamide binds to μ-opioid receptors along the intestinal tract and effectively reduces diarrhea by reducing peristalsis; morphine binds to μ-opioid receptors in the central nervous system and reduces pain. The similarity in terms of what they bind to is also what leads to some side effects – extended use of morphine can cause constipation. So the collateral benefit of learning how drugs work, was learning why there are side effects of drugs. Suddenly one can be a slightly more informed and educated patient, all thanks to Pharmacology Confidential, courtesy Dr. Daniel Broom!
Thank you, Dan, for making this sound less complicated than it really is, and fielding all our questions patiently on what was probably the first glorious Saturday we’ve had in a long time. I think we're all going to look at drugs and medicines in a very different light after this cafe.

April 8, 2014 

Music in numbers

While the inextricable connection between music and maths has been discussed extensively by musicians, mathematicians, neurobiologists, psychologists and others, computation has seldom been included in the discussion. Thanks to Professor Paul Hudak, Tilde Cafe attendees saw the confluence of the triad come to life beautifully on April 5, at the Willoughby Wallace Memorial Library (video posted at https://www.youtube.com/user/tildecafe). 

Professor Hudak's research includes the areas of functional programming and computer music; in fact he is one of the principal designers of the language Haskell. Functional programming differs from other programming in that it is based (primarily) on algebraic principles and algebraic structures. Using Haskell, his lab has developed Euterpea to compose music with complex rhythms and electronically generated sounds, as well as develop musical representations of conventional instruments. With an open ended PVC tube in hand, Paul demonstrated how all these developments also take into account fundamental principles of physics, such as the sinusoidal pattern of sound waves and the multiples in which they travel and the resulting overtones that one can hear from some instruments (see video around 12:30). In several subsequent examples we heard what could have been clearly mistaken as a flute, but which was in fact the output of an iterative series in Euterpea to fashion the sound of a flute - breaths and all included!

We had an opportunity to hear examples of the different compositional strategies that Paul's work considers when developing programs (see video around 25:29). One of the many compositional techniques used in generating computer music is a process of training the program to learn the grammar particular to a genre of music. Paul showed us some results from his graduate student Donya Quick's doctoral dissertation, where she has developed a system called Kulitta that automatically composes music based on a number of criteria including grammar. We heard four different short pieces of music and tried to identify which two were by Bach, and which two were generated by Kulitta - as it turns out, many in the room were fooled (see video around 46:55)! And, as Paul told us, professional musicians have also been fooled! 

The afternoon resulted in some really interesting discussions on music and computation, that few had probably considered before this. Thank you, Paul, for sharing with us your absolutely fascinating research. How perfectly well-timed this talk was with April being Mathematics Awareness Month - punctus contra punctum?

With April also being National Poetry Month, it's hard not to end with this quote attributed to Einstein: "Pure mathematics is, in its way, the poetry of logical ideas" - and dare I say, music!

February 23, 2014

A liver cell walks into a bar....

...and orders a gin and tonic. The bartender says with a sneer, "We don't serve liver cells here." The liver cell replies: "Oh, yeah? Well, what about that cell over there?" and points to a neuron lounging on a bar stool nearby. Says the bartender: "What about her? That's a brain cell. She's got connections." (orig. Kyle Kirkland).

Yes, a neuron does indeed have connections. Lots of them. And they're called synapses. With close to 100 billion neurons, each of which can make as many as 1000 connections, there are estimated to be trillions of synapses in the human brain. That's more stars than there are in the Milky Way. And it's more than 500 cups of sand (assuming 20 grains of sand line up to 1 cm, and a cup = 250 ml).

Professor Sreeganga Chandra broke down this enormously complicated topic for Tilde Cafe attendees who had chosen to take a break from the single good day we've had weather-wise, in a very long time. We had more than 50 people commenting and asking questions! Providing a historical background by telling us about Ramon y Cajal's 1890s drawings of various parts of the brain down to substructures of neurons, Professor Chandra introduced the group to the salient structures of a neuron and described and illustrated how a synapse functions. The exquisite and inconceivably rapid orchestrations of sequential electrical and chemical changes that occur along the path of a neuron are what enable you to move your toe - the most distant part of your body from your brain.

There were many new concepts we were introduced to this afternoon, and still others that we'd heard in this most recent season of cafe discussions - we'd heard of neurotransmitters, and axons and dendrites before, but they were in the context of specific functions and diseases of the brain. This time, we had an opportunity to appreciate these in greater detail, and understand how something as small as a synapse helps your tick - a synapse is about 20 nm wide; a sheet of paper you use in your printer is almost 5000 times thicker! At perhaps a more practical level, this cafe discussion also helped us understand what exactly is happening when your physician knocks your knee with a reflex hammer, and your leg jerks slightly in response: upon being hit on the knee, the neuron that innervates the quadriceps transmits an electrical signal (action potential) via its axon and then releases the neurotransmitter glutamate at the synapse; this causes the motor nerve that is responding to the glutamate to now cause the quadriceps to contract via an action potential, and then at the same time other neurons are activated to get an inhibitory neurotransmitter into play so that the hamstrings relax. It's the reflex arc. Complicated, eh? Well, try to remember this and maybe even quiz your physician the next time your knee-jerk reflex is tested! Here's a nice demonstration of it - http://neuroscience.uth.tmc.edu/s1/chapter06.html.

Thanks, Sreeganga, for taking time out of the one lovely day we've had in weeks! The video for the afternoon will be posted on the youtube channel in the next week. Batten down those hatches - the weather is boomeranging into more snow this week. We'll be meeting next on April 5. Watch this space for news. And enjoy pi-day on 3.14!

January 12, 2014 

It comes like a thief in the night - Parkinson's Disease 

Despite the torrential downpour on Saturday (certainly better than the polar vortex precipitation from a few days ago), Dr. Duarte Machado spoke to a packed room of Tilde Cafe enthusiasts. It may well be the largest crowd we've had since we started in 2008!

While one hears a lot about Parkinson's disease (PD), Dr. Machado showed us how little many of us know about PD and its progression. According to current understanding, earliest signs of PD are found in the enteric nervous system (made up by neurons that help regulate your intestines), the brain stem (the part of your brain that regulates sleep, among other things), and the olfactory bulb (the part of the brain responsible for smell perception), resulting in non-motor symptoms such as constipation, sleep disorders, and a loss of a sense of smell. The disease progresses slowly and largely unnoticed even though it can cause significant disruptions in sleep patterns, because of which it is often called the thief who came in at night. It is much later in the trajectory of PD that the substantia nigra, home to almost all of the approximately 400,000 dopaminergic (dopamine producing) neurons, is affected. It is at this stage, when greater than 50% of the dopaminergic neurons fail to function, that movement/motor symptoms begin to appear.

Until recently, research, as well as clinical intervention, has been focused on the later stage of PD, when motor symptoms become apparent. However, with a wider recognition of earlier non-motor symptoms, efforts are being directed to understand these and also hopefully identify reliable biomarkers for disease progression. In 2010, The Michael J. Fox Foundation for Parkinson's Research undertook a massive study to understand the link between smell loss and PD (https://www.michaeljfox.org/get-involved/smellsurvey-screen.php). In fact, the Institute for Neurodegenerative Disorders located in New Haven (http://www.indd.org/index.htm) is one of 23 clinical sites that is participating in this study. Data collected in this study is still being analyzed.

While there is little specific information on what causes PD, advances in understanding the mechanism of its progression continue to be reported. Briefly, some of the factors include issues relating to the misfolding of a protein (alpha-synuclein) that causes it to aggregate/form clumps as part of Lewy bodies in the brain, compromising the functioning of those areas; prion like behavior of the misfolded alpha-synuclein; loss of mitochondrial function/integrity. It is impossible to capture the complexity of the underlying causes for PD in a short email, so keep an eye out for the video of the afternoon - it will be posted at http://youtube.com/user/tildecafe in a few days.

For those who want to learn more about PD, an excellent resource is a book published by the Parkinson Creative Collective - "The Peripatetic Pursuit of Parkinson Disease" - http://www.amazon.com/The-Peripatetic-Pursuit-Parkinson-Disease/dp/0989326608/ref=sr_1_1?ie=UTF8&qid=1389567593&sr=8-1&keywords=peripatetic+pursuit+of+parkinson+disease. Written by nine authors, it is in a sentence "For those with Parkinson* Disease (PD), (it's) a support group between two covers; and for everyone else, it's a window into the world of living with PD."

Almost 200 years ago, in 1817, James Parkinson published "An Essay on the Shaking Palsy". An excellent site that pays a tribute to his contributions can be found here - http://www.movementdisorders.org/james_parkinson/essay.html

The next cafe will be on February 22, details for which will follow soon.

Thank you, Duarte, for coming in on a rainy afternoon and sharing with us not just the details of PD, but also describing how you help patients who suffer from the disease.

December 8, 2013 

To be a simple Trilobite In the Silurian seas!*

Hope you had a wonderful Thanksgiving break and are immersed in the last stretch of 2013. So that you can get the most of this last stretch, we have scheduled zero cafes for the month of December. That's right, zero cafes this month. Which is also nice considering the significant amount of information we will continue to process from the last cafe led by Professor Briggs. We had a magnificent turn out on that day with attendees ranging from 8 years to 80 years - a remarkable age spectrum for a topic of the ages! If you were unable to attend the cafe, consider checking out the video at https://www.youtube.com/user/tildecafe (ambient lighting was kept low to permit a better contrast of slides on the screen). Although we ran into some technical problems initially, the afternoon was peppered with oohs and aahs upon seeing some of the phenomenal pictures of research findings by Professor Briggs and his colleagues - findings ranging from trilobites, fossilized squid and dinosaurs to mosquitoes! 

 There is an inverse relationship between the information one can get from the different types of biomolecules, and their chemical stability. Thus, while nucleic acids (DNA) encode a tremendous amount of biological information, they are extremely unstable. Structural biopolymers such as bone on the other hand are much more stable, but encode limited information. Which is why although there are a large number of fossils that have been discovered over the ages, extracting more detailed information from them has been relatively difficult. Enter squid ink sacs and melanosomes (the organelle that makes melanin) in fossil records. By studying electron micrographs of ancient melanosomes it has been possible to reconstruct color patterns in fossil feathers, and Professor Briggs showed us reproductions of his work that revealed a colorful feathered dinosaur, with a rufous crown! The afternoon was rounded off with recent results from the first fossil of a blood-engorged mosquito preserved for almost 46 million years in northwestern Montana - all thanks to the stability of iron-stabilized heme from hemoglobin. This work was conducted by a collaboration between labs in the US, Sweden and England; Professor Briggs has written a commentary on it which you can access here - http://www.pnas.org/content/110/46/18353.extract 

Thank you, Professor Briggs for telling us about your work, and also for considering a request o show us around your lab. Yes, that's right folks - if you are interested in visiting Professor Briggs' lab., send me an email and we will try to organize a group visit in the near future. 

In closing then, two additional things to note: 

The next cafe is on January 18, 2014 - details to follow  

With Nelson Mandela's death on December 5, Tilde Cafe followers might be interested in a dip into the cafe's past. Back in 2009, when Professor Himla Soodyall from University of Witswaterand, South Africa had talked to us about genetic ancestry, she had shown us a short video clip of her conversation with Mr. Nelson Mandela where she told him the results from her sequencing his DNA. The sequencing was part of a project she'd undertaken to interrogate what our DNA sequences tell us about our history. You can see that clip here - http://www.tildecafe.org/Home/video-clips. The entire cafe discussion can be viewed at - https://www.youtube.com/watch?v=VNHhp1PAm98&list=PL207DFABCC38673B3

And the subject line to this email is from a little poem by May Kendall, an English poet and social reformer. Apparently, she wrote it to satirise the kerfuffle that resulted when Darwin published "On the Origin of Species" - 154 years to the day of Professor Briggs cafe discussion.

Lay of the Trilobite  

I wish our brains were not so good,
I wish our skulls were thicker,
I wish that Evolution could
Have stopped a little quicker;
For oh, it was a happy plight,
Of liberty and ease,
To be a simple Trilobite
In the Silurian seas!

November 4, 2013 

Secrets of the swarm 

On yet another sunny and brisk Saturday afternoon, we had a highly interactive Tilde Cafe discussion about insect behavior and the incredible diversity of things we can learn from their behavior. (An aside: we are keeping count of these matched occurrences here at Tilde Cafe headquarters, and we will eventually develop a meteorological model correlating Lovely New England Saturday Afternoons, and Superb Tilde Cafe Discussions). This cafe discussion was one of the 40 Innovations Cafes organized nationally in support of the recent Making Stuff series on PBS. 

Professor Ouellette talked about his work on the swarming behavior of the non-biting midge Chironomus riparius (http://www.arkive.org/midge/chironomus-riparius/). These insects resemble mosquitoes and like mosquitoes, tend to swarm at dusk. Although qualitative aspects of swarms have been described for decades, the quantitative parameters that underlie swarming are only now being recognized, thanks in no small part to exquisitely enhanced imaging technologies. Using stereoimaging, Nick has recorded the movement of single insects as well as swarms. Quite unexpectedly, we saw that a single insect can sometimes describe motion not unlike that seen in a swarm. Which brings up the fundamental question of how a swarm is defined (here we are distancing ourselves from rigorous dictates of collective nouns). 

This cafe discussion came right after the Making Stuff Wilder episode (http://video.pbs.org/video/2365105192/) where we saw a swarm of little robots, designed to move and reconfigure their motion not unlike a swarm of insects which might encounter a physical obstacle (or even a predator). So those of us who had seen the episode were primed for Nick's Tilde Cafe discussion. If you missed it, you can catch it at http://youtu.be/IJPL2WF-7DE

 And if you'd like to listen to an interesting Science Friday piece about swarms, visit - http://www.sciencefriday.com/segment/09/10/2010/swarms.html 

Thank you, Nick, for an excellent Saturday afternoon - not only are we all going to think more carefully when we throw around the phrase "herd instinct", we are also going to have to review our knowledge of collective nouns! 

September 22, 2013

It's all about the receptor - and location, location, location!

Distilling and conveying the complexity of the effects of nicotine on the brain and behaviour into an hour is exacting enough when speaking to a homogeneous group; it is an order of magnitude (if not greater) more demanding when speaking to a mixed group of individuals that make up a typical Tilde Cafe audience. Thank you, Professor Marina Picciotto, for laying out the story so patiently, and untangling the misconceptions that exist.   That smoking is addictive has been borne out by innumerable studies, and has been captured in almost as many cartoons. But other than those studying nicotine and its effects, not many have an idea of the underlying intricacies. While nicotine is a plant alkaloid, we (and even the electric eel and insects, among other organisms) have nicotinic acetylcholine receptors where nicotine can bind. The native molecule that binds to this receptor is acetylcholine. But we have two types of acetylcholine receptors, both of which respond very differently when acetylcholine binds to them, so in order to distinguish them, they are referred to as either nicotinic (binds nicotine) or muscarinic acetylcholine receptor, binds muscarine, which is also not native to our bodies. 

Broadly, nicotinic acetylcholine receptors while located primarily in the nervous system and skeletal muscles, they are found almost everywhere in our bodies. More specifically though, the details of the receptor makeup varies with where the receptor is located, and consequently, when nicotine binds to it, the receptor response is dictated by its makeup. Further, the receptor is not a single protein, but made up of multiple subunits, and nicotine does not bind all the subunits, only some, and with varying degrees of affinity – the highest affinity binding subunit (beta-2) is a component of the receptor found in the brain, in the specific regions that are part of the reward circuitry. And from reward circuitry, a term one sees associated with excessive eating, we also learned a little about how chemicals that resemble nicotine have been shown to play a role in reducing food intake – and for the rest of the story, check the footage of the afternoon at – http://youtu.be/jlJQNx6cV_4 

One aspect of the nicotine/nicotinic acetylcholine receptor story that is quite exciting is research that is attempting to modulate the activity of the receptor as a possible means of treating nervous-system disorders such as Parkinson’s disease, Alzheimer’s disease, schizophrenia and depression. 

Thank you, Marina, for a wonderfully informative afternoon!

Please don't forget to tune your TV to your local PBS station, to catch the Making Stuff series hosted by David Pogue - http://www.pbs.org/wgbh/nova/tech/making-more-stuff.html

The next cafe session will be on November 2, 2013 - details will follow.

May 18, 2013

Water, water, every where, and all the drops did spring*

Tilde cafe discussions always bear the promise of good weather, and so it was this past Saturday. Stony Creek was definitely the place to be, not only because of the wonderful weather, but because Professor Mark Johnson gave us a glimpse into The Wild World of Electrified Water. Chemistry graduate students Arron Wolk and Andrew Deblase played a supporting role and showed us a simple experiment (go to the 19 min point in the video of the afternoon, located at http://www.youtube.com/user/tildecafe) on how water can conduct electricity - but only when it contains other materials in it, such as salt. Using a simple observation like this, John Fenn, a former Yale professor with ties to Branford, developed a technique that finds wide use today in the analysis of proteins, carbohydrates and nucleic acids - electrospray ionization. For developing this method, Professor Fenn was awarded the Nobel Prize in Chemistry in 2002, along with Koichi Tanaka and Kurt Wuthrich. Using high voltage, a liquid can be rapidly dispersed as an aerosol (see http://www.tildecafe.org/Home/video-clips), and through various devices thereafter the composition of the dispersed material can be analysed. The technique has also been applied to depositing nanoparticles (http://faculty.uml.edu/jtherrien/Research/nanodep.html). In fact, the applications of the technique are probably only limited by the trajectory of one's imagination! Through the course of the afternoon we learned not just about this fascinating technique, but also how it came to be - the back-story, something you won't find neatly collated elsewhere. Thank you Mark, for bringing it all together for us. Tilde Cafe will be on pause over the summer and we will reconvene in September 2013. It's been a glorious five years - thank you for your continued support.

April 15, 2013

Stress happens!

Once again Tilde Café supporters had to struggle with deciding between immersing themselves in fantastic weather and immersing themselves in an absorbing afternoon on the ramifications of stress on your brain and overall health. A difficult choice, indeed, and for those who came to the café discussion on Saturday, perhaps you feel empowered by your choice. And it was a twofer! Professor Sinha surprised us by bringing along a colleague, Dr. Ania Jastreboff who talked about the role of food in compounding how stress ravages our bodies, and ways to stymie that process. The human brain has evolved to handle and respond to a number of different stimuli, many of which one is quite literally not aware of.  Through evolution, wje have retained the functions of the “primitive” brain (evolutionarily speaking). This region controls functions basic to one’s survival. And then, the prefrontal cortex that is just behind your forehead is like a control center that is the “responsible” region – it confers in us the ability to rationalize and make decisions and judgments based on evidence, rather than on emotion or impulse. For the most part, in the world we live in today, we have relatively fewer challenges from our surroundings, but every so often we experience situations that put the “primitive” brain into high gear, muting the role of the prefrontal cortex. This, in short is what stress does to your brain – it galvanizes the primitive brain and undermines and mutes the prefrontal cortex. At the biochemical level then, this results in an enormous change in cellular responses and Rajita showed us some marvelous pictures of how branches from neurons respond to stress, and to the removal of the stressful stimulus. Removal of stressful stimuli can restore neural structure. Here is an excellent broad representation of “your brain on stress” from Rajita and her colleagues - http://www.nature.com/scientificamerican/journal/v306/n4/box/scientificamerican0412-48_BX1.html. So, managing stress can enhance one’s life multifactorially. One of the ways to manage stress is called Mindfulness-based Stress Reduction (MBSR), and Rajita led us through a couple of exercises in MBSR. To supplement the information from this most recent café, you might want to check a panel discussion hosted by the Nour Foundation, on the science of mindfulness - http://www.nourfoundation.com/videos/becoming-conscious-the-science-of-mindfulness.html


And for an introduction to the brain, here is a nice interactive site -http://its.sdsu.edu/multimedia/mathison/limbic/index.htm


Stress happens - it's how we manage it that keeps our cerebral balance! 

March 10, 2013

An Aha! experience for Tilde Cafe attendees

The café discussion on what felt like the first day of spring, was quite illuminating. Dr. Pradeep Mutalik, a physician by training, whose avocation is all things puzzles, elaborated on the unique traits that distinguish humans from other species. Significant among these traits is cognition. Mastering higher order cognitive skills activates distinct regions of the brain, including the hippocampus, which in fact is probably the first region of the brain that is affected in Alzheimer’s patients. Pradeep got us to think about similarities and differences between puzzles and problems, and it became clear that a puzzle is actually a special sort of problem: puzzles have a known solution; problems need not. Solving a puzzle leads to a deep satisfaction because it results in a sudden insight called the “Aha! Experience” or “Aha! Effect”. According to Pradeep, solving a puzzle results in a decrease in cognitive entropy, and all is well with the world. The more elegant the solution, the greater the Aha! Experience. And indeed it is - until you pick up the next puzzle. And solve it. In most cases, the intensity of the Aha! is likely to be directly proportional to the amount of time and energy spent on arriving at the solution. Either you've experienced it yourself, or seen someone look a little happier and more alive when they've completed a puzzle of any kind. So, as we start observing Brain Awareness Week (March 11-17, 2013), this might be just the time to get your hands on the next puzzle and get a taste of a great Aha! Experience – because you’re human!

Thank you, Pradeep, for helping us look at puzzles and the process of solving them in a whole new light, and giving us the opportunity to try out puzzles that are available at the Museum of Mathematics.


January 21, 2013 

The Universe and diseconomies of scale - a consequence of expansion 

To summarize a cafe discussion on dark energy seems almost like a Sisyphean task, not only because of the burden of what is still unknown about the topic, but also the complexity of what is known. Professor Nikhil Padmanabhan ignited the interest of those attending this most recent Tilde Cafe discussion. He shed light on the topic quite effortlessly and gave us some appreciation of the magnitude of the questions he and his peers are attempting to answer through their research efforts. That the Universe was expanding was known for almost a century, but it has been only in the last two decades that there has been evidence of an acceleration of this expansion. And this new evidence comes from the field of dark energy. Although the term "dark energy" was coined only in 1998 as a consequence of then puzzling results, the 2011 Nobel Prize in Physics went to three scientists who "helped to unveil a Universe that to a large extent is unknown to science." Dark energy constitutes about 70%of the Universe; dark matter - 25%; we constitute barely 0.03%! Perhaps one aspect that makes it harder for those of us who aren't devoted to studying dark energy appreciate the field, is the fact that while there is evidence of the existence of dark energy, it's composition remains largely unknown. After introducing us to some basic concepts, Nikhil described what goes into a typical survey of the skies, right from collecting images, to how spectra are collected from the objects observed - check the video from the afternoon at - http://www.youtube.com/watch?v=xGxU1uRCx1I&feature=youtu.be (55 min mark). Despite the relative opaqueness of the topic, we had almost twice the number of people than we'd expected, which is always welcome and a treat, so thank you all for coming out on a lovely Saturday afternoon. This was the first cafe discussion for many, and I hope it has helped to whet their appetites - watch this space for many more engaging discussions. 

From the press release by the The Royal Swedish Academy of Sciences -  ".....dark energy [is] remains an enigma - perhaps the greatest in physics today", and Nikhil helped us get a peek at that enigma on Saturday afternoon. Thank you, Nikhil.

November 6, 2012 

A cell is a cell, is a cell, and then some 

The oldest meaning of the word "cell" according the Oxford English Dictionary, is "A dwelling consisting of a single chamber inhabited by a hermit or anchorite", with the etymology traced to the second half of the 11th century. It was only in the 1600s that Robert Hooke used it to describe what he saw when he observed cork through a low resolution microscope. As stated in the OED: "the modern understanding of the cell is usually taken to begin in the early 19th cent. with the work of J. B. Purkinje and other (mainly French and German) botanists and anatomists". But when Professor Larry Rizzolo asked us what the word "cell" conveyed to us, almost all responses were about a structure that contains a nucleus and other organelles. However, using the “primitive” meaning of the word, Larry illustrated the uniqueness of each cell type: in a house with rooms defined only by walls and nothing else, the function of each room is not immediately obvious; it is only after the rooms are equipped with furniture that one can discern the function of each room. Similarly, in a biological system, cell types/lineages (rooms) are identified by their unique proteins (furniture). Using equally illustrative metaphors, Larry described various stages in biological development, and the potential of cells at each of these stages to be different kinds of stem cells: totipotent, pluripotent and multipotent.

Having simplified a very complex biological entity - the stem cell - for café attendees, other inevitable questions that surface because of the politicized and therefore contentious nature of stem cell research were also discussed. Certainly a lot of food for thought for those who were there. We ended on a timely question, considering many will exercise their right to vote in a few hours: how will the outcome of the presidential election affect funding for stem cell research in the US. For the answer, check out the video tomorrow on the café youtube channel!

And here's a neat link for you to explore over the coming weeks: http://www.onezoom.org/. Absolutely brilliant resource! "OneZoom is committed to heightening awareness about the diversity of life on earth, its evolutionary history and the threats of extinction. This website allows you to explore the tree of life in a completely new way: it's like a map, everything is on one page, all you have to do is zoom in and out." 


Hope that the effects of Sandy are slowly ebbing, and the impending nor'easter will spare you. If you were at the café discussion this past Saturday, I’m sure you’ll agree that Professor Rizzolo laid out very eloquently the reasons for why we should care about what stem cells are, and their future. Thanks, Larry for an excellent afternoon – I know several people who were there simply had to get away from everything that had a hint of Sandy! 

September 18, 2012

Think before you ink!

What a lovely day it was to have the first cafe discussion of the new season, even if it was on the Ides of September! Over the preceding four seasons we've had truly fascinating discussions with more than 30 scientists telling us about their research and what motivates them to pursue it, so it was nice to have a science writer's perspective of science and scientists, to start this fifth season. 

Carl Zimmer is a renowned science writer, who whilst talking to scientists about their work, noticed that many wore their scientific passion on their dermis in relatively indelible ink. This led him to delve deeper into this casual observation, culminating in his recent book "Science Ink: Tattoos of the Science Obsessed", which was the topic of discussion on Saturday. We learned a little about the history and science underlying tattoos: for example, the oldest catalogued tattoo appears on Ötzi the Iceman - a 5400 year old natural mummy, discovered in the Alps on 19 September 1991; and tattoos remain relatively indelible because the material (ash, or "ink") used to create the tattoo is engulfed by fibroblasts and macrophages that lie right below the epidermis, limiting the ink from getting into your blood stream.

A little known fact is that today, tattoos are also used in medicine - for cosmetic as well as restorative surgery; for radiation therapy; some even use tattoos to alert others of existing medical conditions. There is also exciting research that draws on using tattoos, or principles underlying tattoos for applications as diverse as monitoring blood sugar, to monitoring dental hygiene.

But the take home lesson from the afternoon, is think before you ink - who knows, one might end up like Ötzi! And to all you tattoo aficionados out there - consider a celebration on 19 September for Ötzi's tattoos, the interpretation of which remains an enigma. The video of this discussion will be posted by Monday evening.

Thank you Carl, for providing a great start to a new season.

The next cafe will be on November 3, 2012, with Dr. Larry Rizzolo speaking about stem cells. Check www.tildecafe.org for more information.

June 12, 2012

Your Inner Tactus

Once again, Professor Ian Quinn led a riveting discussion that underscored the tight and often under-appreciated connection between the brain and music, this time though in the context of beats. Our ability to perceive sound is actually inextricably tied to silence. It is the ability to perceive silence between sounds that finally allows the brain to interpret those sounds into recognizable and interpretable fragments that can be stitched together to present various patterns that are speech or music, or even noise and cacophony. 

Beats are essentially a series of sounds that have a regular perceivable periodicity; a pulse. For the vast majority of us, 5 beats per second is the threshold at which we can distinguish between individual beats at regular intervals - in other words, each beat needs to be 200 ms (1/5 th of a second) apart. Slow it down a little further to 750 ms between each beat and you have 80 beats per minute, a rhythm that is very close to the heart rate of the average non-athletic adult, and one that it is very easy to align to. Still slower, when the distance between each beat exceeds 2000 ms (2s), the human brain can tend to be confused in appreciating the periodicity of beats. Tactus then, is the basic pulse that one can perceive unambiguously, and is typically around 80 beats per minute.

Professor Quinn engaged the audience in a series of clapping operations to demonstrate perception of beat, tactus, and how easily and unconsciously the brain's perception of beats tends to lead to an overall convergence of periodicity, in an originally irregular group-clapping operation. What also became evident is that the emphasis on beats can vary with social groupings and thus lend a distinctiveness to the music of each group. An absolutely fascinating afternoon, thank you so much, Ian.

April 21, 2012

Sure, they aren't truffula trees* but do we need them!

The desert may well seem an inhospitable place as depicted in this Jack Ziegler New Yorker cartoon from the July 11, 2011 issue, but if you were at the recent Tilde Café discussion led by Eric Larson, you’d know where to find that water, if not the tiny piece of pie!

Eric Larson came to the recent Tilde Café with lots of interesting information about desert plants and carnivorous plants, and also brought along a few examples that are zealously guarded at the Marsh Botanical Gardens at Yale University.  We got a thumbnail sketch about some of the adaptations that desert plants have evolved for arid conditions. For example, whereas C3 photosynthesis is the most common form of photosynthesis used by plants, desert plants are adapted to use C4 and CAM pathways. In C3 plants, during the day, carbon dioxide enters through open pores (stomata) on the leaves. Whilst this happens, the plant also loses some amount of water. However, in plants that are found in areas that are dry or that are particularly active during the summer, so as to minimize water loss, they undergo C4 photosynthesis, a pathway that is faster than C3 photosynthesis, thus requiring stomata to be open for briefer periods and reducing water loss.  CAM photosynthesis is unique to desert plants in several different ways. CAM plants are adapted to keep their stomata closed during the unforgiving hot day time temperatures; the pores open at night to take up carbon dioxide and store it for photosynthesis during the day (having got all the carbon dioxide it can, the stomata remain closed during the day when photosynthesis occurs). And, the best time to get that water from your friendly neighborhood cactus or succulent plant, if your stranded like the chap in this cartoon, is at night – during the day, the water tastes a little sour – a nifty tip from this café discussion.

Plants, like animals, have evolved to adapt to their environment, not only above the ground, but also in the kind of root structure they have. And while we could not really appreciate the latter when viewing the several samples that Eric had brought along for us to see, the adaptations and camouflage of some of them was absolutely amazing. I think the lithops were by far the most popular that afternoon – this is a genus of succulent plants that is native to South Africa, and can easily be mistaken for a pebble!  Visit the Marsh Botanical Gardens to see the amazing diversity in the plant kingdom - lithops included. For local plant diversity and tips for growing, Eric publishes a newsletter that you can subscribe to via a link on the website for the Gardens - http://www.yale.edu/marshgardens/index.html.

Thank you Eric, for a truly engaging afternoon, and an excellent tribute to Earth Day 2012. Every plant, even a prickly one or a carnivore, plays a vital role in maintaining a balanced planet, just like the Lorax told us!

March 18, 2012
Bric-à-brac mutations on BRCA1 and other genes....

....would you want to know if you have them? That was the central point that Ellen Matloff discussed at the most recent Tilde Cafe, on March 17.  Yes, it was a lovely (almost) spring day, and it was St. Patrick's day, and the first and third rounds of the women's and men's NCAA basketball tournament were underway, yet there were more than 30 people who came to engage in a discussion on a topic that is very much in the news. As information on the genetic basis of more diseases becomes available, the question that many people might be confronted with is whether or not to determine one's predisposition for a genetic disease. The emphasis for the afternoon was genetic testing for cancer predisposition and the difficulty and ease that surrounds handling a positive or a negative result.  

Some of the issues that had been touched upon in two earlier cafes came up again; particularly significant in the context of this discussion was the fact that only about 10-15% of cancers are hereditary. A number of risk factors can impact whether one is predisposed for a hereditary cancer. While tests may be available to ascertain one's predisposition for the cancer, the decision making process is fraught with questions because there are risks and benefits to being tested. However, some of the risks and benefits that one hears about genetic testing were clearly urban myths that Ellen debunked for us. What became very clear is that although genetic testing is offered by a number of laboratories, if interpretation of the results is done in the absence of genetic counselling, overall outcomes have the potential of being quite disastrous. In fact, genetic counselling prior to testing is equally, if not more, important.

And the cost of genetic testing is not insignificant, despite the fact that the cost of gene sequencing has reduced considerably. Much of the high cost of a genetic test can come from the gene to be tested having been patented, as in the case of BRCA1 and BRCA2, two genes that when mutated in specific regions are linked to certain breast, ovarian, prostate and pancreatic cancers. In fact, the US Supreme Court is considering hearing a case on the matter of patenting genes. You can read more about this case at http://yalecancergeneticcounseling.blogspot.com/2012_02_01_archive.html and http://www.aclu.org/take-back-your-genes
Thank you Ellen for a very thought provoking afternoon! I am certain some of those who attended will participate in the Take Back Your Genes project, and all will be following the case closely because the decision will have extremely wide ramifications.

Hey, that’s my gene! 

Not it’s not, it’s mine.

No, it’s not.

Yes it is.

How can it be yours?!

You didn’t invent it!

Neither did you.

Did so.

Did not.

Big fat liar…

Your genes are on fire.

 - from Gillian K. Ferguson "The Human Genome: Poems on the book of life"


February 6, 2012

February 4, 2012 was a good hair day!

The fat cells have it!  Yes, adipocytes, or fat cells, may well hold a, if not the key to getting ones hair looking lush, based on Professor Valerie Horsley's fascinating story of how hair growth is regulated. Although the details she described were all derived from her studies involving mice, Tilde Cafe attendees had an inordinate number of questions as this complex narrative unfolded, because until that afternoon, many of us probably listed hair growth as one of the multiple things one takes for granted. In doing so, until Saturday afternoon, we had missed appreciating the intricacies underlying a process as orchestrated and complicated as hair growth.  But not on the palms of your hand and the soles of your feet - the only two parts of your body's surface that are completely hairless. 

A hair follicle is a complex beast - there are about seven types of cells, including stem cells, calling it home, and each has a unique role in the three phases of the follicle's life cycle. The length of each phase of the cycle varies based on where the hair follicle is located.  For example, the life cycle of a hair from your eyebrows, is very different from the life cycle of a hair on your head. And those hair cells in your ears that play a role in your hearing and maintaining your balance, are very different - in the ear there are specialized cells that actually have their membrane protruding and tapering into something that looks like a hair.  More on this later.  Through her studies in mice,

Valerie Horsley's research group has revealed a hitherto unknown involvement of fat cells in regulating hair growth.  It turns out, stem cells that are necessary for the repeated turnover of the hair follicle, need to "talk to" fat cells that reside in the vicinity of the hair follicle in order to maintain proper cycling of the follicle. Tying together numerous exhaustive experiments, the whole story came together when Valerie's research group injected adipocyte precursor cells under the shaved skin of a mouse and new hair growth was seen in the injected area, compared to similar injections with other skin cells. A key future direction will be to look at whether the paradigm revealed in mice is mirrored in humans, bringing us that much closer to avoiding comb overs and their ilk!  And about those hair cells in the inner ear - these cells don't cycle - once destroyed (by loud noises, or even medications), that's it for them.  So speak softly and carry a big stick if you want to maintain your balance in addition to catching every word of all conversations!

Thank you Valerie for a riveting afternoon, and for patiently answering the multitudinous questions we had of you.  For those who missed it, to paraphrase LeVar Burton, don't take my word for it and check out the video for the afternoon at  http://www.youtube.com/user/tildecafe?ob=0 

January 7, 2012

The Dialectics of Cancer

Two weeks after the 40th anniversary of Richard Nixon signing into law the National Cancer Act of 1971, Tilde Cafe hosted a discussion led by Dr. Thomas J. Lynch, Jr., on his "Adventures in Lung Cancer".  Thanks to the background provided by Professor David Stern in the August 2011 discussion, we were primed for this discussion on an unseasonably warm January 7, 2012. 

Through an introduction that included a brief description of some very remarkable cases Dr. Lynch had treated over the years, the enormity of the problem that lies before us in sustaining unflagging efforts to design key diagnostics and treatments for various cancers was evident: what's good for the goose is not always good for the gander.  Because when it comes to cancer, every patient is unique. And it is unfortunate, that despite advances in genome and related technology, funding for cancer research in the US remains relatively static since 2000.  

 "Cancer affects everyone" is a well-worn cliche, and those who attended this cafe discussion benefited from hearing first-hand, a clinician's experiences treating cancer patients and his thoughts about the future of cancer treatment. Interestingly, imaging methods that are effective for one cancer are often not as useful for other cancers - for example, MRI, a useful imaging tool for breast cancers is an ineffective imaging method for lung cancers; CT scanning is currently the ideal imaging technique for lung cancers.  Almost 15% of lung cancer patients are individuals who have never smoked - lung cancer, like other cancers, can occur as a consequence of mutations acquired over the course of one's life.  Further, one of the reasons lung cancers are detected at more advanced stages is because of the very size of lungs - lungs being as large as they are, small tumors can be obscured and are usually larger at the time they are eventually detected.  Tom fielded a wide variety of questions from attendees. Questions ranged from occurrence, diagnosis, current and future direction of treatment of a variety of cancers; funding for cancer research; and even questions on the beneficial effects of commonly touted magic bullets like red wine and green tea.  While both green tea and red wine do contain components that are beneficial in allaying cancer, the volumes of these liquids that one would have to consume are simply impossible: drinking a swimming pool's worth of green tea every day would not work! 

Cancer is a consequence of either inherited or acquired mutations that disrupt normal biological processes. At the current rate of cancer research, it is conceivable that biological pathways that play a major role in precipitating most cancers will be fully identified very soon; however, interdicting those pathways to arrest or reverse the process is going to be more challenging, since what's good for the goose is not always good for the gander.  This is where personalized cancer therapies become extremely important, and the need to fund such research is critical.

Thank you, Tom, for a very informative afternoon.

The video for this cafe discussion is available at http://www.youtube.com/user/tildecafe 


November 21, 2011

Not coasting on the downward slope

While there is enough oil on this planet to sustain current consumption for about another century, much of it while being technically accessible, is economically not worth bringing to the surface – it would be a dreadful return on investment. On Saturday, after telling us about earlier methods employed in drilling for oil, Dr. Martin Cobern told us of the state-of-the-art technology used for locating and drilling oil wells. Some of this technology was developed right here in Connecticut, and has not only made the process a lot more efficient, but also increased the turnaround time from locating the oil to getting it to the surface. Turns out that back in 1956, geophysicist M. King Hubbert proposed that over the course of time, fossil fuel production in any region would follow a bell-shaped curve. The Hubert curve predicted that oil production would peak in the US in the 1970s. In fact, we see that is exactly what happened; we are now on the downward slope of the curve. And we are definitely not coasting 

with a price of >$100 per barrel of crude oil!

Despite advances in technology for drilling, it has become increasingly less economically prudent to drill in extant regions. This is primarily because of the tremendously reduced pressure that results after continual (repeated) accession of oil from these wells. So, although there is oil, the energy required to get that oil to the surface under the diminished pressures far outweighs the benefits of accessing the oil. Consequently, exploring other sources of energy is essential. In this context, back in September 2010, Professor Gary Brudvig had led a Tilde Cafe discussion entitled "Learning from Nature: how to use solar energy for renewable fuel production". Thank you, Marty for rounding off a very informative afternoon with a splendid show and tell, of equipment used in drilling as well as specimens from a few oil rich regions in the US. Thank you also to NOVA, for once again providing a DVD that went to a lucky cafe attendee. For those who were unable to attend, you can catch the video of Dr. Martin Cobern's cafe discussion later this week on the Tilde Cafe youtube channel.

October 25, 2011

Remembrance of Things Past  

Not only is the brain a very labyrinthine organ, the nomenclature system adopted to label its distinct parts is equally complex!  After gaining some understanding about the intricacies underlying how a brain is wired in September, the October Tilde Café was even more interesting than many had anticipated.  Professor Krystal’s big picture view for those of us who are not neurobiologists but know what it feels like to experience stress, was without a doubt informative; more so as one hears and reads about the extraordinarily high levels of stress people seem to be experiencing today.  

PTSD can be regarded as a consequence of the brain being unable to maintain traumatic events within their context - this can happen because biochemical pathways are either in overdrive, or under-performing. It is then that memories can play havoc and even immobilize individuals. What was clear from the afternoon, is that it is a misguided notion that PTSD is experienced only by those who have been exposed to war. And, it is important to note that individuals who appear resilient do in fact also experience stress – their resilience comes from their ability to cope with stress better than those who may buckle under it.

Over the course of the afternoon, we were introduced to specific regions of the brain that play a role in stress and resiliency, such as the amygdala, the hippocampus, and the winner of all names for the afternoon, the “bed nucleus of the stria terminalis”!  Each of these, and other regions of the brain, are finely tuned to recognize and respond to unpleasant stimuli. But there are instances where this fine tuning can be disrupted, or is not function optimally, leading to anxiety and stress that becomes difficult to cope with. With Professor Krystal’s extensive experience working with veterans in his capacity as Director of the Clinical Neuroscience Division at the VA National Center for PTSD, we had a front row perspective on the status of research being carried out to help PTSD patients.  Of the many novel approaches, a fascinating one related to Neuropeptide Y, one of the neurotransmitters we heard about in the September café. Neuropeptide Y has the ability to confer resiliency and thus the ability to cope with stress, and there is active research to determine how this can be harnessed in coping with PTSD and perhaps even pre-empting it.

One has to only look around to see how increased stress today has led to a burgeoning cottage industry that is trying to help people deal with stress, whether it is in the form of yoga, meditation or something else. Those who came to the Blackstone Library on Saturday to get a primer on the neurobiology of stress and the efforts in treating it were definitely lucky to learn from an expert.  Thank you, John, for an enthralling afternoon. The video and audio files of this recent Tilde Cafe afternoon will be available online by Friday, October 28.

To learn more about other research in treating depression and brain related clinical matters, you can also watch Ed Boyden's talk at a TED conference earlier this year http://www.ted.com/talks/ed_boyden.html

When it comes to the most traumatic events in our lives, we walk a fine line between remembering too much and remembering too little.” - Susan R. Barry

September 10, 2011

Trillions and trillions of connections later - a wired brain!

"As long as the brain is a mystery, the universe, the reflection of the structure of the brain, will also be a mystery" - Santiago Ramón y Cajal 


If you allow some poetic license in interpreting this quote from Santiago Ramon y Cajal, a pioneer in neuroscience, it is not difficult to appreciate the visual likeness between neuronal structures and the universe in the graphic pasted above.  The picture was taken from the New York Times repository, and before you visit the link for details and credits - http://www.nytimes.com/imagepages/2006/08/14/science/20060815_SCILL_GRAPHIC.html try to guess which graphic is related to neurons, and which one to the universe.  [Visit http://www.virgo.dur.ac.uk/index.php?subject=millennium to view one of the originals reproduced by NYT].

We opened the fourth season of Tilde Cafe with a captivating discussion led by Professor Thomas Biederer. He introduced us to a tremendously complex and complicated, yet fundamental area in neuroscience - how neuronal networks are established
and the centrality of synapses in establishing these connections. A conservative estimate of the number of synapses - a specialized junction via which neurons communicate - in a human cerebral cortex is 60 trillion; there are 10 billion neurons in the cortex, so a typical neuron in the cortex receives almost 6,000 synaptic inputs!  


The afternoon was highly interactive, with Professor Biederer very patiently addressing the many questions provoked by the information he was sharing with us. Indeed, the synaptic activity in the room was very high, and harnessing it might well have powered a pretty reasonable light bulb!  What clearly baffles the mind is the exquisite organization of these synapses, and the intricate parsing of inputs by each neuron via specialized molecules, so that it can decipher them and enable us to do even the most mundane tasks in our lives.  Which makes one wonder what the Wizard meant when he said the following to the Scarecrow in The Wizard of Oz:


"Why, anybody can have a brain. That's a very mediocre commodity. Every pusillanimous creature that crawls on the Earth or slinks through slimy seas has a brain. Back where I come from, we have universities, seats of great learning, where men go to become great thinkers. And when they come out, they think deep thoughts and with no more brains than you have."


Certainly, even pusillanimous creatures have a brain, but it is the elegant and succinct dialogue between neurons that is facilitated by synapses, which makes it a consequential brain. What is important to note is that over the course of ones life, synapses are pruned, leaving a matrix of more efficient synaptic communication.  Consequently, aberrant pruning of synapses, as well as aberrant synaptic organization can result in a variety of brain disorders.  If you missed this cafe discussion, you can view it on the cafe site by the end of this week. And for those keeping count of coincidences related to Tilde Cafe discussions, the journal Science published an article entitled "How Many Cell Types Does It Take to Wire a Brain?" a day before Professor Biederer's discussion.


Many thanks to Thomas Biederer for an absorbing afternoon. Thanks also to NOVA/PBS for generously donating an excellent DVD (http://www.pbs.org/wgbh/nova/body/how-does-the-brain-work.html) that went to a lucky attendee on Saturday.

August 13, 2011
How to stare down the emperor (of all maladies)*

"Any important disease whose causality is murky, and for which treatment is ineffectual, tends to be awash in significance...The disease itself becomes a metaphor.
" Susan Sontag 

On Saturday, August 13, 2011, not long after the peak of the Perseids, David Stern gave a simple and elegant introduction to how normal cells lose some of their exquisitely fine tuned functions and go down the perilous path of cancer. Cancer is a complicated disease, defined in the OED as a "an uncontrolled proliferation of cells, typically with invasion and destruction of adjacent normal tissue."  Normal cells have robust machinery to cope with errors that might occur when a cell progresses through the multiple steps required for it to successfully replicate.  Indeed, with the constant onslaught of a variety of environmental insults as well as the choices we make in things as mundane as food and drink, and the lives we lead, the fact that there aren't more cases of cancer than the million cases that are reported each year in the US alone, is testament to the almost infallible repair machinery with which are cells our cells are equipped.  And it is this cellular repair machinery that also handles the majority of random errors that might occur, errors that could lead to mutations that could potentially lead to a cancer. It is important to note that majority of the million odd cases of cancer are not hereditary; hereditary cancers are estimated to be between 10-20% of all diagnosed cases.

Appreciating the genetic diversity of the human species, and the fact that cancers are a consequence of mutations in DNA, acquired mostly randomly and sometimes inherited, brings into greater clarity why it has been so difficult to "find a cure" for cancer. Unlike most other diseases, manifestation of cancer can vary tremendously between patients, even if the organ affected is identical.  On August 5 1937, the National Cancer Act established the National Cancer Institute to "to support promising research projects on the causes, prevention, diagnosis, and treatment of cancer; collecting, analyzing, and disseminating the results of cancer research conducted in the United States and elsewhere; and training and instruction in the diagnosis and treatment of cancer." Almost seventy-five years later, we have come a long way in diagnoses and treatments, but cancer will soon overtake heart disease as the leading cause of death in the US. This despite what Richard Nixon said in his State of the Union address in January 1971: "I will also ask for an appropriation of an extra $100 million to launch an intensive campaign to find a cure for cancer, and I will ask later for whatever additional funds can effectively be used. The time has come in America when the same kind of concentrated effort that split the atom and took man to the moon should be turned toward conquering this dread disease. Let us make a total national commitment to achieve this goal."

After introducing us to the basics of how cells replicate and the many ways this replication can go awry, David Stern took us through a brief history of how cancer therapies have 


  reached the point they are at today: from the traditional paradigm of surgery-chemotherapy-radiation, to examples of cancers like some breast cancers having benefited from research that has developed targeted therapies like Herceptin.  With this as a backdrop, he gave us a glimpse into what lies ahead for cancer treatments and cures, in the context of the uniqueness of each tumor.  Much of this is propelled by the enormous advances in technology that have now permitted sequencing  DNA from patient's genomes, allowing identification of mutations in the tumor DNA . This information then has the potential to allow for the design of specific therapies, which would hopefully also have fewer side effects that are typical of traditional therapies. 

“A good designer must rely on experience, on precise, logical thinking; and on pedantic exactness. No magic will do.” - Niklaus Wirth 

Thank you, David, for a window into the challenges and complexities underlying designing better treatments and cures for cancers.

*Apologies to Siddhartha Mukherjee. This cafe was an exercise in learning about the ways in which we could stare down this Emperor of All Maladies that Siddhartha Mukherjee has so eloquently written of.

May 16, 2011

If not for Henrietta Leavitt, we would not have "The Realm of the Nebulae", the 1935 Silliman lectures presented by Edwin Hubble at Yale University.  And were it not for those lectures where Hubble described his observations on the expansion of the universe, relying largely on Henrietta Leavitt's earlier findings, we would likely not have a telescope named Hubble.

Over the course of the most recent Tilde Café afternoon, Moshe Gai regaled attendees with the contributions of a number of scientists who have enabled us to gain fascinating insights into what comprises the cosmos. His narrative was extensive and absorbing, and abbreviating here will not do it justice.  Worth noting here though, is that those who had participated in previous cafe discussions on dark matter and dark energy got an excellent historic perspective of the fields.  The footage from the afternoon will be available by late May 16, 2011 at http://www.youtube.com/tildecafe

"Ms. Leavitt did view many plates
And studied the images’ traits;
She found a Cepheid variable
Later used by Edwin Hubble,
And now we get telescope updates."

Thank you Moshe, for an enjoyable afternoon.

April 16, 2011

Turns out that morphine, mint and chili peppers do share some things in common.  As Mortimer Snerd would have said, “Who’d have thunk?!”  Dr. Daniel Broom gave Tilde Café attendees who’d braved gusts of 40 mph winds and rain, a primer on how neurons respond to painful stimuli, and how this neuronal response is transmitted to the brain via electrical signals that travel at up to 22-23 mph.  To put this in some perspective, if a person 5 feet tall stubbed her toe, her brain would receive that information and she would respond, perhaps with a scream, in about a tenth of a second.  Which is just as well, because if it were a graver stimulus that her toe received, she would definitely need to respond very fast.  And this is where the role and perception of pain becomes important.  

 “A neuron who sensed some strain
Said "This is really a pain",
It said to its friend,
"This must really end",
So a message was sent to the brain.”

As became evident through
what Dan shared with us, the ability to perceive pain is essentially an aspect of survival.  We were also introduced to two conditions of abnormal pain perception viz. hyperalgesia and allodynia, both of which are not entirely uncommon. Using response to temperature as an example of a pain pathway, we learnt that there is a family of proteins that are gatekeepers or channel guards located at one end of a neuron, and respond to temperature. These proteins are called ion channels and their main job is to maintain the correct balance of specific ions, i.e., chemical entities that carry a positive or negative charge, inside the neuron; an imbalance of ions results in the generation of an electrical charge which gets transmitted through the length of the neuron. Interestingly, there are defined ranges of temperature assigned to each family member; for example, TRPV1 (read as Trip Vee one) is an ion channel that responds to temperatures greater than 43 Celsius or 109 F – the temperature of a fairly hot shower. When exposed to the appropriate temperature, the ion channels physically reorient themselves permitting ions to pass through, resulting in an ionic imbalance which translates into a rapid electrical signal being transmitted to the brain, The Decider of what action to take!  

Neurons have specialized proteins that respond to specific stimuli. It quickly became clear that electrical conductance through the neurons to the brain is one of the key mechanisms underlying our ability to sense pain. The electrical signal is conveyed by the “first responder” neuron to specific areas in the spinal cord, from where another neuron picks up the electrical information and conveys it to the brain.  From there, a series of hand-offs of information occur, leading to one being actually cognizant of a noxious agent.  In general then, the gatekeeper proteins and their neighbours, are very important in pain perception and ensuing responses.  Morphine’s binding to specific proteins (opioid receptors; often located not very far from ion channels) on neurons allow pain perception to be blunted.  Similarly, menthol from mint, and capsacin from chili peppers also bind to specific proteins on neurons, affecting the ability of the proteins to act as effective gate-keepers, resulting in altered concentrations of charged chemical entities in the neuron, and generation of an electrical impulse that is conveyed to the brain for appropriate action by you!  

This synopsis does no justice at all to the content of the afternoon which you can access at http://www.youtube.com/user/tildecafe in the next day or so.  Thank you, Dan, for a very illuminating afternoon – and for the samples of Wasabi peas and Mentos too – for those did not attend, they were excellent examples of perceived temperature changes by way of other stimuli!  He did bring along some chili peppers too, but we took his word on the effect of capsacin, the substance that renders a pepper hot. Incidentally, the hottest chili pepper according to the Guinness Book of World Records is the Naga Viper Chili as of Feb.2011.

March 5, 2011

You can't take 3 from 2; 2 is less than 3* - an afternoon spent with Amanda Folsom

"I'll tell you once, 
and I'll tell you again. 
There's always a prime 
between n and 2n." 
— Paul Erdos

Professor Amanda Folsom drew Tilde Café attendees, only a few of whom had a robust background, into her world of pure mathematics.  And what a fascinating world that is!  True to her original assurance that she would not engage us in mathematical operations beyond simple addition and subtraction (and a touch of multiplication) that is taught in elementary school, she introduced us to concepts that few were familiar with.  And then proceeded to astonish us with how beguiling simple, yet inherently complicated/complex is the puzzle that has engaged mathematicians for almost a century. After showing us a short series of (small) numbers, she asked us to predict the next number and thus figure out a pattern; while all our answers held for at best the next number, it quickly became clear that the series was more complicated!  She then told us that the series we were looking at was that of partitions of numbers going sequentially from 1 to 8, and then using a $5 bill explained the concept of partitioning of numbers - how many ways can you arrive at the number 5 - seven ways.  The number of partitions of a number goes up dramatically, from 42 partitions for 10, to 190,569,292 partitions for the number 100!  Around 1918, Srinivas Ramanujan presented mathematicians with a formula to calculate the number of partitions an integer can have; however, he appended a cryptic comment that has been finally decoded by Professor Folsom and her colleagues. Their finding sheds a new light on how to look at partitioning. The February 2011 issue of Scientific American has an excellent article (http://www.scientificamerican.com/article.cfm?id=mathematics-ramanujan) about their findings which were presented at a specially convened symposium at Emory University on January 21, 2011. Tilde Café attendees were privileged to hear of these very new results directly from an author of research that presents a heretofore unappreciated fractal view of partitions. For those who are keen on reading the original paper, it is posted on the American Institute of Mathematics website (http://www.aimath.org/news/partition/folsom-kent-ono.pdf).  And the fact that Professor Folsom is at Yale is indeed a happy convergence of events, since the term “fractal” was coined by the late Benoit Mandelbrot who was in the Department of Mathematics at Yale.  He coined the term when he was at IBM’s Thomas J. Watson Research Center. 

I think everyone who attended Amanda’s café will look at numbers very differently henceforth – the patterns she described, including those that follow Benford’s Law! Check out a wonderful audio link on the applications of the pattern described by this law - http://www.radiolab.org/2009/nov/30/from-benford-to-erdos/. Thank you Amanda, for nudging our mathematical curiosity, and for helping us get a better appreciation of what keeps a pure mathematician excited. The excitement is indeed infectious as evidenced by the response from those present.

The footage of this café will be posted in the next couple of days. 

 *Apologies to Tom Lehrer, and BBC's TW3 - taken from his song "New Math".

January 23, 2011

Rosie, R2-D2, C3-P0 and 3Ds

“We are survival machines -- robot vehicles blindly programmed to preserve the selfish molecules known as genes.” -RICHARD DAWKINS, The Selfish Gene


The common thread in the title here is robots/robotics: Rosie (from the Jetsons), R2-D2 and C3-P0 (from Star Wars); however, 3Ds is really not a robot but the three “D”s that drive the field of robotics to some extent. If a task is Dangerous, Dirty or Dull, designing a robot may well be considered for it.  When Professor Aaron Dollar began his conversation with a large number of Tilde Café attendees, he asked, "if you had a robot, what would you like it to do?"  Interestingly, most of the responses fit into either the Dull, Dirty or Dangerous categories.  It was clear that our general understanding of robots and robotics is guided by the three Ds.  However, the potential of the field extends well beyond these three Ds.  And this is where Aaron Dollar’s research becomes really important.  One of his focuses is designing a prosthetic hand that has a soft-touch – a prosthetic hand that comes close to that of a human hand, and can handle tasks as diverse as picking up a delicate egg, to handling a rigid object.

Designing a hand that recapitulates a human hand requires taking into account multiple factors, such as the number of joints (more than 30), the extensive network of nerves and muscles that are profoundly efficient, ability to make accurate decisions based on object to be manipulated, and the weight and cost of the prostheses.  An exquisite integration of all these factors, to yield the desired prosthetic hand requires a knowledge of areas as diverse as material science, biomechanics and psychology. Indeed, by the end of the afternoon we had a greater appreciation of the amazing teamwork that is required in designing an efficient robot, and although robotics has made inroads in routine jobs like assembling cars, its application to refining prosthetics is still a young field.


If you visit the GRAB lab website - http://www.eng.yale.edu/grablab/ you will find links that tell you more about Aaron Dollar’s research.


Many thanks to Aaron Dollar for an enthralling afternoon, and to NOVA/PBS for their support of it. 

Please visit http://www.crisp.yale.edu/index.php/Education_Outreach#Connecticut_Making_Stuff_Outreach_Coalition for additional events planned through the CT Making Stuff Outreach Coalition.  

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