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

• 
  

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