On how plants keep Time.

Sun is THE MASTER CLOCK  for all  earthly beings, no doubt about that. (Of course having a clock and being punctual are two entirely different stories, we won't get into that now). We take a brief look at how living beings carry out their cellular functions punctually.  Mammals have a built-in super synchronizer  suprachiasmatic nucleus, (SCN) which coordinates and maintains a standard time for all cellular functions and set in motion the circadian rhythm. How do plants keep time? They directly receive their daily bread (via photosynsthesis) from the sun. But  apart from that   plants also have  short term and long term ( daily and seasonal ) rhythms. Some  flowers bloom with the early rays of Sun while others are literally  late bloomers; there are even those which spread their fragrance exclusively during the night. Mangoes and litchies arrive only in summer, while ripe oranges flood the markets  winter . So the question is do plants have a synchronizer? Or in other words, what is the SCN equivalent  in plants.?  Till now the general assumption has been that plants do have several built in  clocks but they all keep their own local time and are not exactly   synchronized. Sounds  a bit chaotic, but then there were no evidence to prove otherwise. And without proof scientists don't take decide one way or the other. 

20th November issue of Nature carries an interesting report by Endo et al  on the circadian clocks operative in plants. Endo and team proceeded to take a closer look at the  plant Arabidopsis thaliana. With a  short life span and  a  small genome (135mbp), arabidopsis thaliana is roughly  the vegetarian  equivalent of the guinea pig  in the lab. 
  

Endo et al sought answers at  molecular and genetic level on the circadian rhythms in arabidopsis thaliana.   The team  separately analysed three main cell lines in the leaf:  the epidermal cells on the surface ,  the   mesophyll cells underneath , which run  the photosynthesis factory and then the   vasculature cells  responsible for the plumbing system. This is important because, even when the solar factory is closed for the day, the plumbing system continues to do the logistics work  Endo and team  monitored the gene expression and  level of specific marker proteins  in vivo and also   in vitro for  these three types of tissues. It was  found that the mesophyll and vasculature clocks function independently but are not altogether uncoupled. Plants have two loops of cellular activity, the day loop and the night loop. The genes responsible for rhythmic behaviour in the mesophyll tissue are active during day time and those in the vasculature  tissues  report for duty during the evening hours. The day partollers must be leaving telltale signs for the night patrollers. The team also found that the vasculature clock has the upper hand and controls the physiological responses of the  plant as a whole. They suggest that the vasculature and mesophyll clocks are akin to the central and peripheral clocks in mammals  or evening and morning cells in drosophila
Tailpiece  
Acharya Jagadish Chandra Bose was one of the first to suggest  that plants have life and that they responded to various stimuli including light and dark cycles through  electrical impulses. In 1902  Bose compiled his  experiments, observations and conclusions   and published   Response in the living and non-living . This book  (currently  available  an e-book  in public domain, thanks to the Project Gutenberg),  carries complete details of the simple,  elegant and extensive  studies.

 References:

1. Response in the Living and the non-Living : J.C. Bose
2. Time specific clocks in Arabidopsis show assymmetric coupling.  Endo et al Nature,       20th Nov. 2014 p419-422.
3. Spontaneous spaciotemporal waves of gene expression from biological clocks in the leaf : Wenden B et al  Proc. Natl. Acad. Sci.(USA),109, 6757-6762 (2012)
4. The circadian clock in Arabidopsis is a simplified slave version of the clock in shoots.James, A.B. et al  Science 322, 1832-1835(2008)

Science and the Society : The TWAS-Lenovo Science Prize 2014

Sultanate of Oman hosted the 25th  annual meeting of The World Academy of Sciences (TWAS) at the capital city of Muscat from 26 till 28th of October. The venue was  one of the most scenic locations of Muscat, the Barr Al Jissa resort. 

 Quarraisha Abdool Karim 

This year, epidemiologist  Dr Quarraisha  Abdool Karim  was awarded   the  most prestigious TWAS-Lenovo Science Prize  for her relentless work in the area of HIV/AIDS prevention. Her research work  which  has few parrallels in terms of the socio-medical strategies and human impact has  helped set guidelines for patients infected with HIV  and doctors treating them.  It was in 1989 that Ms Karim joined  Aids Research Program of South African Medical Research Council' after obtaining a post graduate degree in Public Health  from Columbia University, USA. She soon realized that sociology is an integral part of epidemiology. She says "AIDS brought together two separate things for me; I saw the convergence between advocacy work and science ". The  extensive surveys she conducted in sub-Saharan Africa  brought to light not only the alarming statistics  but also  the plight of helpless and ignorant  adolescent girls    in a male dominated society.  Public health data showed that in South Africa alone an estimated 6.1 million people suffer from HIV infection, more than any other nation in the world. Women who are younger than 24 years are at  a greater risk than men in the same age group. Could there be a way to protect the women from HIV infection that didn't call for cooperation from their male partners? That is the question Karim and her team asked aloud. 

Tenofovir :courtsey Wikipedia

The team took a relook at   tenofovir an antiretroviral   drug used in HIV treatment   and developed it into a topical gel to be applied to genital areas.  In a study  spread over 3 years,  Karim and her team demonstrated that application of 1% tenofovir  gel  reduced infection in women by ~40%.   Follow up studies and mathematical modelling have indicated that tenofovir gel has the potential to  prevent millions of new infections. Currently  the gel is undergoing rigorous clinical trials. By the end of  2015  it would  move into licensing, manufacturing and distribution stage. 

Dr Karim is an associate professor of epidemiology at the Columbia University medical Center  and associate director of CAPRISA ( short for Centre for the AIDS program Research in South Africa).  The TWAS-Lenovo prize comes with a an award of 100,000 US$ provided by Lenovo.

Tailpiece: 

TWAS delegates were pleasantly surprised to  receive  a small (4cm long) Omani Khanjar  as memento . While fiddling with it,  it suddenly unleashed  a pendrive!

References: 

• Qurraisha Abdool Karim wins TWAS-Lenovo Prize 
• Globalization, Ethics, and AIDS Vaccines  Salim S. Abdool Karim-Science 23 June 2000: 2129

• Simon V, Ho DD, Abdool Karim Q HIV/AIDS epidemiology, pathogenesis, prevention, and treatment Lancet. 368 489-504 2006
• Woodsong C, Abdool Karim Q    A model to enhance informed consent: experiences from the HIV Prevention Trials Network American Journal of Public Health 95 412-419 2005
• Q.A Karim et al Effeciveness and Tenofovir Gel an antiretroviral microbicide for the prevention of HIV infection in Women Science 3 September 2010:1168-1174

Now you see it; Now you don't

Hiding in plain sight is a common theme  in sci-fi or horror movies. Sci-fis show some respect for the rules of physics, or hypothesize  new ones ; but ghosts spurn  all laws and do as they please. And  Man? Man definitely knows ways and means to play with the laws, bend them, hoodwink them, and even  find loopholes. Light is an electromagnetic radiation(EMR) and hence one way to hide from light will be  to design a cloak using a special fabric with unique electrical  and magnetic characteristics (electrical permittivity and magnetic permeability to be precise).  Such a fabric will be able to bend and curve light  in every which way we want.  Not that we haven't been successful in this attempt; lo and behold! we have created metamaterials. These man-made materials, by virtue of their patterned structure can manipulate light very effectively. Thus metamaterial cloaking could  bestow invisibility on an object.  Yes cloaking indeed; precisely and literally covering up. The wrapper will gently and smoothly guide light that falls on it as if there is no solid object underneath.Though as of now a definite possibility, metamaterial cloaking  is not yet  a reality but  a field of intense research activity.  Inspired by the powerful and versatile attributes of the  binary system (0,1) of digital electronics, Giovampaola and Egheta have suggested the  concept of  Digital metamaterials  using just two elements of unique permittivity  as bits  to design a series of unique and versatile  metamaterial bytes  to suit any application. Still have miles to go in that direction. 

Peacock in the woods,
Painting by Thayer  Courtsey wikipedia

Bradypodion taeniabronchum
Courtsey : Wikipedia

We need to pause here and ask an important question: what exactly do we mean by being invisible? Please ignore the philosophical tone in the question and consider it  purely in the  practical context. Invisibility is neither abstract nor absolute in practical terms,  it is  always relative- relative to the ambiance, or the background. For example chameleons change color and merge with the ambiance and go undetected; Abralia, a variety of   mid-water squid, uses counter illumination to camouflage itself against the ocean glow. Likewise  Thayer with deft strokes of  brush  concealed his peacock in the woods.

Since light can't be fooled in a straight fight,  Schittny et al  decided to try   concealing objects in  in diffused  ambience such as mist, smoke, fog or  turbid liquids(1). In a murky medium photons gets tossed around, scatter and diffuse.  Hence its behavior is  best described by Fick's Law  of diffusion  and not by Maxwell's equations. The diffusivity of the ambience (D0), the object (D1) and  the wrapper(D2) assume significance.  Schittny et al caught on this point. How about negating the diffusivity  of the object to be hidden   with an equal but opposite diffusivity of a wrapper? 
  
In the July issue of Science Schittny et al demonstrate how an object can  be effectively hidden  in diffused light. They chose  hollow stainless steel cylinder and sphere as test objects to be concealed.  Since light doesn't  pass through steel these objects have zero diffusivity (that is D1=0). Based on the mathematical relationship that  linked  the dimensions of the object and  thickness of the  wrapper to D0 and D2 they could  formulate the conditions for perfect concealment (2).  Armed with these results they first coated the object with a very thin layer of white acrylic paint to ensure efficient diffusive reflection. For wrapper they chose polydimethylsiloxane (more popularly known as PDMS) doped with 10 micron size melamine resin particles.  To give a feel for the sizes involved : the cylinder (and the sphere) had a diameter of little more than 3 cm,  and in each case  the wrapper  thickness was less than 4mm. The objects were immersed in a rectangular transparent plastic  tank filled with deionized water containing  a small amount of white dispersion paint. The paint particles imparted the required turbidity to the medium. One side of the tank was illuminated by the glow from a computer screen. The monitor provided the flexibility of adjusting the incident light.  Images were captured using a digital camera positioned on the opposite side. Experiments were carried out with the cylinder as well as the sphere,  both  could be completely hidden from view.  The results are highly significant on two counts:  The omni-directionality of the phenomenon  and validity throughout the visible spectrum.

Schittney et al  conclude their paper with the suggestion " one could insert metal bars which are almost as thick as glass into bathroom frosted-glass window to prevent burglary. Usually these bars would be visible via the diffusive  shadow they cast. By adding thin diffusive cloaking shells around the metal bars, the window would again appear as a homogeneously bright milky glass".  

Tailpiece:
What does invisibility portend for Man? 

Almost 2400 years ago Plato cautioned  that invisibility will completely shatter   man's fragile morality mask;  he gave the parable of   Gyges of Lydia (The Republic  Plato -Book 2 : Story of Ring of Gyges). 

Nor did   Griffin  have a happy ending. For him invisiblity was a power tool to usher in reign of terror.( Invisible Man - 1897 novel by H.G Wells )

References:

1.Invisibility cloaking in diffusive light scattering medium Schittny et al Science 25th July 2014 Vol 345, pp 427-429
.
2. Fick's second Law  transformed: One path to cloaking in mass diffusion  Guenneau  and Puvirajasinghe,   J. Royal Society Interface 10 20130106 (2013) 

Revolutions : Of the Biomedical Type

Ambitious research programs in the bio-medical field are set to bring in revolutions: not imminent  but sure enough.

DARPA (Defense Advanced Research Projects Agency, U.S.A)  is asking a  rebellious question  about RAM; no it is not about  the familiar Random Access Memory, but Restoring Active Memory.  Or in simpler terms the question is can we reverse memory lapse? In soap operas sudden memory loss of a key character  is a trick  to raise TRP when the story reaches a cul-de-sac.  But DARPA has more serious concerns. Its focus is on soldiers who have suffered severe traumatic brain damage and as consequence lost memory. Many in the scientific fraternity are skeptical but a  few are optimistic and would like to give it a try. Research teams at University of Pennsylvania and University of California @ Los Angeles have decided to jump in. The first step of course will be neuronal mapping of the brain and both teams  feel it will be advantageous to start with epileptic patients.  Ultimately  DARPA  wants tiny implantable devices that can RAM. 

In matters of heart the attempt is to get away from the implantables and  substitutes. Could we browse around in body's own toolkit and come up with mix and match tricks? Cardiomyocytes are heart muscle cells.  It is known that the human development Factor T-box-18, (a gene necessary for the development of pacemaker cells in the heart)  has the power to reprogram ventricular cardiomyocytes to pacemaker cells. Hu et al  are exploiting this possibility, a biological alternative for an implantable pacemaker. In a recent report they indicate that this indeed is possible. Hu and team have conducted experiments on pigs with induced cardiac block.  Using   a specially designed   catheter they directly delivered the gene concoction via an intravenous injection to the left ventricle. Though the test animals registered improved performance, a lot more follow up studies are pending. 

On a parrallel highway, as a part of stem cell therapy,  Organoid technologies are being actively pursued. Organoid means organ-like . Pluripotent sem cells can turn into any cell line, liver cells or spleen cells, kidney cells, intestinal cells ....etc.  And the amazing thing is when coaxed into such specialized  cell lines, the cells organize themselves exactly  as in that tissue. And if we can let them grow on appropriate   Extra cellular matrix (ECM)    then   we would  have a great organ model  to study the progress of  and possible remedies  for   diseases. The significance and value of such studies multiply infinitely if the patient's stem cells are used.

Tailpiece
Birbal was going ga-ga about the advantages of having a flying horse.  Finally Akbar relented and agreed to fund the project. But  on one condition: if  the flying horse doesn't become a reality in 25 years, Birbal will be executed.  Birbal agreed; his well wishers chided him. But Birbal was undaunted: he said "In 25 years a lot of things can happen. For example the emperor might die, I might die . And who knows even the horse might fly" 

Of course, it took centuries,but  it did fly , didn't it? And how elegantly! 
  

Pegasus in Greek Mythology

Concorde Supersonic

Albatross II 1868

Courtsey : Pictures from wikipedia 


1.Direct conversion of quiescent cardiomyocytes to Pacemaker cells by expression of Tbx-18

2.Y.F.Hu et al: Sci.Transl.Med. 6, 245ra94(2014)

3.Organogenesis in a dish: Modeling development and disease using organoid technologies

  M.A. Lancaster & J.A. Knoblich   Science: 345, 1247125(2014)

4. Decellularized matrices for cardiovascular  tissue engineering 

Water Stories

Any discussion on water slips into the domain of philosophy. Most mundane at  the same time most sublime, scientific aspects of water are equally fascinating. Chemically water is an innocuous molecule, with the simple formula H2O. Alas! don't be fooled by the simple formula, because it conceals incredulous  complexities that made Life itself possible on this planet. The chemical formula shows one oxygen atom linked two hydrogen atoms, but in reality  there is extensive  sharing of hydrogen atoms. Hydrogen bonding. is the term chemists would prefer. Hydrogen bonding is a very fast  dynamic process,  breaking and making  happens in a jiffy,  in picoseconds (10 -12 second).  Almost all  the unusual properties that water exhibits, have been be linked to hydrogen bonding. For decades Ander Nilsson and his team  have been investigating the weirdness of water. In his opinion Water is the strangest liquid known. His .Public Lecture Water The Strangest Liquid  is a nice refresher on the uniqueness of water. 

273K (more popularly known as  0 degree Celsius), is  the melting point of ice or freezing point of water. But under certain circumstances water can be cooled to well below 273K without ice formation. In other words water can be coaxed into a supercooled liquid state.  Here is the only catch : water should be  ultrapure,  and shoulld very carefully cooled. Till about 232K (-41 degree C)  water  remains a liquid and then homogeneous crystallization sets in.  This temperature referred to as TH, is the lowest temperature at which rate of crystallization of ice can be measured reliably. Below TH,  ice crystallizes in microseconds.  It must be mentioned that  experimental variations do affect TH by a unit or  two.  The pertinent question is what is the structure of  water below TH?.  

A very difficult question indeed. Because of experimental limitations  the domain   below TH  has so far remained a blackbox and is generally  referred to as No Man's land. There are indications that below TH   heat capacity and compressibility of water increase abnormally and several  structural models have been proposed to account for  these phenomenal changes. In the recent issue of Nature magazine(1) Nilsson's team at the SLAC National Accelerator Laboratory, Menlo Park, California report an  an elegant experimental platform with ultrafast X-rays as the probing eye which can  blink in femtoseconds, (Femtosecond= 10 -15 of a second) . Water droplets of diameters ranging from 9 to 37 microns  were cooled rapidly by evaporation as they  were propelled through vacuum.The team could detect liquid water  even at temperature as low as 229K  but noticed that  a crop of  ice crystals too appeared very quickly. The X-ray pattern suggested tetrahedrally coordinated liquid phase. which could  the trigger   homogeneous nucleation. 

When  experimental hurdles  block your way , the next best thing is   to resort to simulation and modeling.  In the same issue of Nature a group from  Princeton University, headed by Pablo Debenedetti report (2) Monte Carlo simulations of deeply supercooled water. They performed calculations on ST2 model of water  with  temperature fixed at 228.6K and pressure at 2.4kbar .  Profile of   the energy surface was monitored as a function of density and a structural parameter called Q6 . They propose that  the system oscillates between two liquid forms, High Density Liquid (HDL) and (LDL) with no inclination to crystallize, though a crystalline phase too is present.  

The same issue of Nature  carries a write-up on the scarcity of drinking water and unconventional methods  being used to address this challenge, such as construction of qanats as practised by  ancient Persians  and   the modern fog harvesting technique.

1.Ultrafast X-rayprobing of water structure below the homogeneous ice nucleation temperature : Sellberg et al: Nature 19 June 2014( Vol. 510, pp381-384)

2.Metastable liquid-liquid transition in a molecular model of water,  Palmer etal: Nature 19th June 2014 ( Vol. 510, pp385-388)

3.Water on Tap , Schiermeier:  Nature 19th June 2014 ( Vol.510 pp 326-328 )

Genetic Matchmakers?

Matchmaker, Matchmaker,Make me a match,

Find me a find, catch me a catch

Matchmaker, Matchmaker

Look through your book,

And make me a perfect match 

(Film :Fiddler on the Roof (1971))

Perfect 46 is a recent science fiction movie  by Brett Ryan Bonowicz,  centered around a personal genomics  company  named  Perfect 46. Perfect 46  symbolizes 23 pairs of  perfectly matching genes in a progeny. The Company counsels couple planning parenting hood and based on a unique algorithm suggest  a perfect match between a donor and a receiver. 

 Well, there indeed is an element of truth in the story;  given that the United States Patent Office has granted patents to this effect to two companies  GenePeeks  and  23andMe.     The GenePeeks patent lists 14 claims  and states  that  it addresses the   need for methods of assessing  the inheritance of such complex attributes prior to, or in place of, conception. and provides a pre-conception method for  predicting the likelihood that a hypothetical child of any two persons, of opposite sex,or same sex, who may or may not be fertile , will express any trait or disease that is subject of genetic influences that have been previously characterized , completely or partially.  This patent is the foundation of GenePeeks' Matchright™   Program. Perhaps 23andMe took a few more hasty steps  towards what looked like eugenics and designer babies,   but beat a quick  retreat when   USFDA  imposed certain restrictions.  

GenePeeks claims that its  services are limited to identifying the probability of inherited diseases;  as a screening tool to select suitable donor for a given receiver or vice versa . The CEO of the company Anne Morriss had to endure anxious moments   because her baby was born with a rare genetic disorder called the MCADD ( medium chain acyl CoA dehydrogenase deficiency) which meant the baby's enzymatic apparatus  couldn't digest fat.  It was only later that she found that she as well as the sperm donor she had chosen, both carried this rare genetic trait. There are several hundred inheritable diseases but the probability  of someone receiving defective genes from  both parents is rather low. The question Anne asked was could this have been avoided?  Sure, if she had prior knowledge of the genetic makeup of herself and the donor. That was the motivation for Anne Morriss and soon the company GenePeeks and the program Matchright™   became a reality   with the active participation of molecular biologist Lee Silver.  Matchright™   aims to completely eliminate the possibility of the Mendelian diseases in  assisted reproduction technology  by thorough genetic screening of the prospective donor/recipient pair for recessive genes.   For the time being the capability of Matchright™   is limited to single gene defects but  they hope to be able to confront in future more complex diseases such as diabetes, cancer, stroke etc.  where multiple genes are implicated.

References:

Gamete donor selection based on genetic calculations 
Method and system for generating a virtual progeny genome

World Cup 2014 : The Symbolic First Kick

For Professor Nicolelis  it is indeed a  Symbolic First Kick !

Watch out for the opening ceremony  of the World Cup 2014 in  at the Arena de Sao Paulo next week. Amidst the uproar and exuberance there would be a moment of complete silence. A paraplegic youth wearing a robotic suit with an EEG sensor cap will be wheeled into the stadium.  He will  help himself from the wheelchair , advance a few steps and kick a soccer ball. The brain behind the spotlight event is Professor  Miguel Nicolelis of the Duke University, Durham, N. Carolina. A renowned neuroscientist  with special interest in the area of  Brain- Computer interface. Prof. Nicolelis   wants to showcase the immense potential and promises that science and technology hold for human race.   Prof. Nicolelis is providing proof  for a concept called Shared Control  where the disabled  person has to imagine  movements to empower his robotic limbs. Prof Nicolelis explains :    "Part of the higher order decision is done by the brain and the low-level movement is enacted by the robot.  Higher order decisions include "start walking" , "stop walking", "accelerate", "slow down", "turn left", "turn right", "kick the ball". 

A minimalistc view of the  exoskeleton is as follows : 

• EEG sensor cap which will pick up signals from the brain, 
• Backpack that will carry a computer,  battery power and hydraulics; computer would translate the brain signals to the robotic limbs, battery and hydraulics together will empower the robotic limbs  
• Gyroscopes to keep balance 
• Sensors in the Footplates to monitor  steps and feed the info back into the system. 

In the meanwhile  US FDA( United States Food and Drug Administration) has just recently been approved  . the DEKA Arm . That means the product is now available in the market.   Designed to be of great help for  upper arm amputees, the project was conceived and conducted by the US Army Research Office  less than a decade ago.  Videos demonstrate   the capabilities of the prosthetic arm from picking up a tiny grape to more complex tasks. This bionic arm  is comparable to the human arm in size and shape but not in looks. The semitransparent outer cover retains the robotic look. The electronic package is a set of   EMG (electromyograph) electrodes together with additional assembly of switches, sensors etc.  The EMG electrodes pick up signals from muscle/device interface sends to a micro processor which ensures the desired movement. If you are wondering about the unusual name of DEKA for a bionic arm, well it stands for the inventor entrepreneur Dean Kamen.  He has about 400+ US and international patents to his credit and that is the recipient of several medals and honor including the National Medal of Technology and Innovation.  Dean Kamen shot into fame with  the personal vehicle Segway. 

1.Kickoff looms for demo of brain controlled machine : Science 6th June 2014, Vol. 344, pages 1069-70
2.A Brain-Machine Interface enables bimanual arm movements in monkeys. Ifft etal  Science Transl.Med. 6 Nov. 2013 Vil.5 pages 210ra154
3.FDA approves high-tech prosthetic arm Nature 15th May 2014 Vol.509 page 264

Blame it on Food!

There is no love sincerer than the  love of food  

-George Bernard Shaw, (Man and Superman, 1902)

We humans have a Love-Hate relationship with food. We love to eat ad libitum,  and then   bear a grudge against food for every minute ailment.  If there are TV channels   dedicated to cookery shows 24/7  and then there are  shows that  teach you  how to shed what you ate. And those who afford appoint  a personal dietitian.  New eateries crop up every day reducing the distance from home, why they even volunteer  home deliveries. Earlier one used to insist-  No MSG please, but now?  Low carb, no salt, no sugar, no trans fat, gluten free?  You name it and you get it.  Feasting or Fasting  food  opens up  great business opportunities.   Science can't be far behind can it? .  

Professor Valter Longo , director of Longevity Institute University of Southern California is interested in understanding the molecular biology of health and aging and longevity as a function of food(1,2).  He is of the opinion that fasting  is more advantageous  than dieting. Well, as he discusses CR(calorie restriction or dieting), IF (intermittent Fasting) and PF (periodic fasting)  we realize that there are  several   ifs and buts. He  points at  studies conducted  in mice and men.  His team monitored the changes in the levels of biological markers for aging and health : IGF-1, IGFBP1, glucose and insulin during fasting. Fasting for 3 days brought down the levels of the these by almost 30%.  IGF-1( insulin like growth Factor-1) and insulin have been strongly implicated in accelerated aging and cancer.   Longo and team contend   that studies  have in general established the beneficial effects of  fasting in cancer patients. Of course fasting  in combination with   chemotherapy; mind you  the two are not mutually exclusive.  It is suggested  that even from the perspective of looking good,  regular fasting is  an healthier alternative to cutting down on calories. Looks like we are on a path to rediscover the benefits of fasting. In any case several civilizations and religions have time immemorial been  encouraging  the  practice of fasting at varying frequencies for various reasons .    

March 2014 issue Cell Metabolism carries another paper from  Longo's group(3). This is a study aimed   to understand the link between the level and source of protein, amino acids aging, diseases and mortality.  This study  covered 6381  individuals of both sexes  in the 50+ age group.The epidemiological data from a US National Health Survey was corroborated with mouse and cellular studies. The team monitored the levels of  markers for biological aging such as IGF-1 well as  other vital and relevant parameters of the participants. The study obviously has its limitations, the researchers are aware of that. Nevertheless they conclude "our findings suggest that a diet in which plant based nutrients represent the majority of the food intake is likely to maximize health benefits in all age groups."  In the same issue of Cell Metabolism Solon-Biet et al (4)  provide further experimental evidence   that "low protein high carbohydrate diets are associated with longest lifespans".  They monitored the fluctuations of another marker mTOR, which is known to positively influence mice's lifespan. 

The papers though  interesting  were  intriguing.   Because  as mentioned before, these are conditional findings;  several ifs and buts   modify each  finding, and  complex  interlinked pathways and  phenotype and genotype traits   are at work.  
  
Tailpiece:
Here is a 440V jolt for all of us   by Libert etal (5).  

"Smell  is an ancient sensory system present in organisms from bacteria to humans. In the nematode C. elegans  gustatory neurons regulate aging and longevity. Using the fruitfly Drosophila  melanogaster , we showed that exposure to nutrients, nutrient derived odorants can modulate life span and partially reverse  the longevity-extending effects of dietary restrictions. .................................................................................olfactory regulation of life span is evolutionarily conserved. 

Soon this will be true for   mice and men!.      

Bon appetit

References:

1. Fasting Molecular mechanisms and clinical applications: 
    Longo and Mattson  Cell Metabolism-Vol.19, issue 2 p181-192, 4 Feb. 2014 

2. Fasting cycles restrict growth of tumours and sensitize a range of cancer cells to    
    chemotherapy.                                                                                                              Lee etal Science Translational Medicine  Vol 4, 124- 127, March 2012

3.Low protein intake is associated with a major reduction in IGF-1,cancer and overall       
   mortality  in the age 65 and younger but not older population                                             Levine etal Cell Metabolism  Vo.19 Issue 3 p407-417 March 2014

4. The ratio of macronutrients not caloric intake dictated cardiometabolic health, aging    and   longevity in ad-libitum fed mice- 
   Solon-Biet et al  Cell Metabolism Vol. 19 issue 3 p418-430, March 2014

5. Regulation of drosophila lifespan by olefaction and food derived odours 
    Libert etal Science 315, 1133 2007

Long Live Henrietta Lacks!

He La, the  play which won the Scottish Theatre Fringe Award for the best production at the Edinburgh Festival 2013,  ran to packed  houses in Jagriti Theatre. Adura Onashile the solo performer  unfolded the little known story of Henrietta Lacks, immortalized as HeLa, the  human cell line that defies death  and  grows in petridishes in the laboratory on which  medical and biological  research is done world over.   

It was in 1950 that Henrietta Lacks consulted Dr. George Otto Gey at the Johns Hopkins Hospital, Baltimore. The diagnosis :  cervical cancer. Dr. Gey had been seeing cancer patients for quite some time.  Hell bent on understanding the disease better and thus zero in on a cure, he routinely collected cancer cell samples from patients.  If only he could grow them  in the laboratory ! The collected samples were coded  with the first two letters of the patient's first and last names. And that is how Henrietta Lacks became HeLa. Of the several thousand samples collected,  only HeLa  demonstrated the unusual ability to survive and multiply   in petridishes. Thus the first   immortal human cell line HeLa was borne.  Since then for biomedical research  HeLa cells have  become the crucial and inevitable raw material. HeLa cells  standardized the  procedures and processes  for experimental  research. Scientists now could compare and contrast their results, repeat and reproduce their experiments  on a common platform: everyone was using HeLa cells.  

When Dr Gey took samples from his patients, there were no laws  on medical  ethics in place. Dr Gey's intentions were purely scientific. He freely shared the samples with other researchers. He never attempted to patent them either.  In 1951 The Tuskegee Institute took up the responsibility of mass producing HeLa cells and supplying it for research,  this too was a non-profit mission. Necessity not only gives birth to invention (also called discovery) but also its twin brother Business.  As demand  grew  He La production  moved into the  hands of  profit-makers. Currently HeLa cell line is available from certain pharmceutical firms for a price. It is important to mention here that Henrietta's descendants never received any benefits from any of these business ventures.In fact  it was only in 1973, that they even came to know about the existence of HeLa cells and its true identity.  In fact  Rebecca Skloot  mentions that they are too poor to afford health insurance

In 1950, 30 year old Henrietta Lacks had  entered the Johns Hopkins Hospital and walked into the  ward set aside for COLOREDs in the Johns Hopkins  Hospital, because that was what she was- a woman of African American origin. Today, if alive she would have touched 84 and as it says in the play how  would she have felt  to know that anyone who has taken a pill stronger than aspirin owes it to  her?  

Immortal Life of Henrietta Lacks: by Rebecca Skloot (Reprinted by  Broadway Books 2011, ISBN-10 9768140005218). 

Henrietta Lacks

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Cancer Cure : Brave New Strategies

Cancer Ward  was first  published in 1967.  Its political implications  have  expired, but the emotional trauma of the terminally ill cancer patients continues still, worldwide. Pulitzer Prize winner (2011)   The Emperor of All Maladies   resonates with the  very  same despair-  If only ....... there could be a cure!   4th of February happens to be World Cancer Day. Most appropriate day for us to examine the latest  in the treatment of cancer.  Have we hit upon anything new? 

Recent issues of both  Nature and Science are unanimous in hailing  Immunotherapy as a paradigm shift in the treatment of cancer. What is so special about immunotherapy, that it tops the list of Newsbreakers of 2013?  The fundamental difference is that  till now all treatments, (whether the the hot ray or cold knife as Mukherjee puts it), focused on the cancerous tissue whereas  the new mindset  aims  to boost,  equip and train body's immune system to stand up against cancer cells. The thought process had begun  almost 125 years ago, when  William Coley,  a surgeon at the New York Cancer Hospital ( now part of Memorial Sloane Kettering Cancer Center), accidentally came across a cancer patient whose tumor had miraculously disappeared after a bacterial infection. Coley was excited and interested. He  was correct in assuming that the infection  was instrumental in the disappearance of cancerous growth and quickly began a series of  tests on other cancer  patients. Coley deliberately infected them with a similar bacterial concoction. Though proved successful, this line of treatment was soon discontinued for two reasons. One: clean and quick  radiation therapy entered the stage in early 1900s, second: standardized and reproducible procedures for infection therapy (actually vaccination therapy) were not yet in place, bacterial concoction had to be adjusted to suit each patient. Hundred plus years later doctors and scientists dug up Coley's records and came to the conclusion that  the bacterial infection might have rejuvenated  cancer patient's  immune system somehow.   And that is one of the anchoring points of  modern day immunotherapy : boost, equip and train body's immune system  to attack cancer cells. While there are several drugs to ensure the general  robustness and readiness of the immune system, how to train and equip them to attack the cancerous growth? 

The most remarkable  feature  about vertebrate immune system is adaptability. And it is this feature that is being  exploited extensively  in immunotherapy. Immune system, body's defense force, comprises of  white blood cells (also called  leucocytes). They are indeed organized as an army with  several cadres entrusted  with very specific and exclusive responsibilities.  Alert watchmen, the dendritic cells (DC)  are ever  on the patrol,  always on the look out for foreign intruders, enemies ( scientific term Antigen).  If they  spot anything new  they will grab  a sample and carry it to the soldiers' training center. Soldiers in training, the immature T cells,  will puff and sniff at the foreign body and recognize it as the enemy .  Memory T cells will  lock up the information in their data bank for present and future use;  helper  T cells will  produce  weapons (antibodies against the antigen), and killer T cells   will  go all out for the enemy. Regulatory T cells meanwhile will take care of the supply logistics. But here is the catch - the whole system is geared to work   against aliens.  Cell division is a natural process, only difference is that   in cancerous tissues this process  is unstoppable. When the enemy is unidentifiable how  can a defense strategy be set up ?  

Scientists are trying out various  tricks. One approach  is to empower the patrollers, the dendritic cells, to recognize the cancerous cells. Immature DCs are taken out of the patient's blood, differentiate and activate them in culture, load them with tumor specific antigens  and then inject the cells back into the patient"  explains immunologist Karolinska Palucka. The vaccine Provenge for the treatment of prostate cancer  falls under this category. Another approach is to nudge the killer T cells. Immune system has a number of checks and balances to ensure that  it doesn't turn suicidal, means it doesn't attack  body's own cells.  Several oncologists from various research hospitals individually and collectively  observed that tinkering with these checks and balances often proved helpful.  Dr James Allison noticed that  a protein identified as CTLA-4 is one such check point protein. It doesn't allow the killer T cell to demonstrate its full capability.  Allison argued  that if he can   turn off CTLA-4,  the killer T cell   would realize its full potential. Could it then be coaxed to   attack  the tumor cell?.  Allison used a specially designed protein, (a monoclonal antibody to be precise), in mouse models for melanoma (skin cancer) and got very successful results. After decades of intense studies and trials, Bristol-Myers-Squibb finally received   US FDA approval in 2011. Currently in the  market as Ipilimumab for treatment of melanoma , its  price tag is a whopping US$120,000 for a course and it isn't clear minimum how many courses one needs.  

Tinkering with the immune system may not be without risks.  But as Couzin-Frankel concludes : "One book has closed, and a new one opened. How it will end is anyone's guess"

1. Cancer Ward : Alexander Solzhenitsyn
2. Emperor of All Maladies- A Biography of Cancer  : S Mukherjee 
3. Cancer Immunotherapy   Nature   504,(7480). ppS1-S1719/26 December 2013

4. Cancer Immunotherapy Science   342, p1432-1433, 20th Dec 2013

  

Taming Hydrogen :Enzymatically

New Year ushers in new hopes and sets aggressive targets. 2014 is no different.   Toyota, the Japanese auto giant unveiled  the  concept version  of a  hydrogen car  or the FCV (fuel cell vehicle)  at  the Consumer Electronics show  currently being held at Las Vegas. The cars will be marketed in California next year and even  the blueprint  for Hydrogen gas stations are ready The car, it is claimed   can reach a maximum speed of 100mph and accelerate to 60mph in 10 seconds.Moreover a fulltank run of about 300 miles is assured. Toyota didn't specify a price , but a humble guess is:anywhere between 50,000  -100,000 USD. (1). Hyundai and Honda motors are also fast catching up

Hydrogen,is the  simple, unassuming numero uno of  the periodic table.  Henry Cavendish, the eighteenth century chemist was the  first  to identify  this colorless odorless gas  and realize that upon combustion it yielded  water. That is why Lavoisier later named it   Hydrogen  that which yields water.  With just one electron and one proton, how complex can it chemistry get? Sure it is simple but  explosive too. It can burst into flames at the slightest provocation. Now combustibility is the hallmark of fuels, and naturally questions popped up among scientific circles. Could hydrogen be the ultimate fuel, because the product of its combustion is the benign and benevolent  Water. Can there be a greener fuel? However easy  combustibility, though highly desirable for a fuel, makes its storage and handling extremely difficult and dangerous.  Scientists have been trying  for decades to tame hydrogen. Indeed  there are success stories, but the price tags are  so exorbitant  that hydrogen as a fuel isn't a commercial success yet .If storage, handling and transportation of hydrogen become  cheaper and viable (on par with that of the crude oil,) then FCVs,  will soon be within common man's reach. Persistent efforts at all levels are on to tackle issues.  It is in this context that we must once again acknowledge help from the   lowly microbes.   

In a recent issue of Science magazine Schuchmann and Muller (Molecualr Microbiology and Bioenergetics, Institute of Molecular Biosciences, Wolfgang Goethe University Frankfurt Germany)  report (2,3)a clever way of  restraining this mischievous molecule. The method may even be economically viable.  Schuchumann and Muller  found a perfect ally in Acetobacterium woodii. These microbes thrive at room temperature , need no oxygen (or in more scientific terms they are anaerobic. It contains an enzyme Hydrogen Dependent Carbon dioxide Reductase,(HDCR) which can chemically link hydrogen (hydrogenase ) to carbon dioxide or peel them off (dehydrogenase) if necessary. In  other words the reaction is reversible. The reaction as depicted  below is quite simple, and devoid of the usual complexities of enzymatic catalysis. Earlier Reda et al(4) reported the use of an electroactive enzyme to bring about the reversible reaction of formate , but  hydrogen molecule did not play any direct role there.

                 

                         

Formic acid is a liquid,and  noncombustible which solves the problem of  storage , handling and transportation.  Schuchmann and Muller point out an  additional advantage; possibility of using  syngas, as the input  stream. Syn gas  is a mixture of  carbon monoxide, carbon dioxide and hydrogen. (CO, CO2 and H2,)  and is produced in bio gas generators. 

The concept of trapping hydrogen in carbon dioxide is not new (4,5). There are chemical methods to do  it, however  they all suffer in one way or the other either  by way of low yields, high temperature requirements or expensive catalysts.   Schuchumann and Miller are hopeful that their discovery  could be a biotechnological breakthrough.

But there are more  road blocks in the path of FCVs :for example   industrial scale manufacture of hydrogen  may not be so green. 

 References:

1. Toyota's Hydrogen car 2014

2.Direct and reversible Hydrogenation of CO2 to formate by a bacterial carbon dioxide:

   Schuchmann and Muller, Science Vol 342, p 1382-1385 , 2013 

3.An enzymatic route to H2 storage  Pereira Science 342, p,1329-30, 2013 

4.Reversible Interconversion of  Carbon dioxide and formate by an electroactive enzyme:   Reda et al Proceeeding of the National academy of Scienes (USA) Vol. 105(31)  pages  10654-10658, 2008

5..Reversible hydrogen storage using CO2 and a proton switchable iridium catalyst in   

   aqueous media under mild temperatures and pressures:  Hull etal  Nature Chemistry : 

   Vol.4,    pages 383- 388,  2012