Insulin Resistance: The Fishy Side

Astyanax  mexicanus also known as Mexican tetra is a small fish not more than 12cm in  length.  However the species  has attracted the attention of evolutionary biologists since  the time of Darwin. The natural habitat of  A. mexicanus are   dark caves and crevices in  the rivers of Texas  and    eastern Mexico.   This aquarium fish  is not just blind;  it has no eyes at all.  According to Darwin the species would have started out as eyed variety then over  millions of  generations  the  dark habitat could have bestowed  the evolutionary advantage of blindness.  After all what use are eyes when the surroundings is pitch dark ?  The uptown river dwelling cousins of A.mexicanus are blessed with eyes.   Darwin's wrote in Origin of Species (1859) :  

By the time that an animal had reached, after numberless generations, the deepest recesses, disuse will on this view have more or less perfectly obliterated its eyes, and natural selection will often have affected other changes, such as an increase in the length of antennae or palpi, as compensation for blindness.  

Astyanax mexicanus, Characidae, Blind Cave Tetra; Staatliches Museum für Naturkunde Karlsruhe, Germany. courtesy: wikipedia 

29th March issue of Nature, carries another  astounding piece of information about A. mexicanus  reported by  Riddle et al.  For as yet unidentified evolutionary  reason,  the cave dwellers  maintain very high blood glucose level and are  insulin resistant.   What is even more  intriguing is that  insulin is a growth hormone too and blocking its pathway   should have resulted in stunted growth and  low body fat. Also  high glucose level in blood should have led to extensive glycation of proteins  and thus irreparable   tissue damage.  But whichever way you look at   their  health report  card, A. mexicanus  populations are not in the  least  affected.  They grow to a full length of 12cm,  are  very fatty,  live upto a ripe old age of 14 years,  and show no  tissue damage whatsoever. There are enough evidences to suggest that  insulin resistance is a genetic disorder.   Using CRISPER-Cas gene editing technique, the team found out about  a mutation in  insr gene (insulin receptor gene). The   INSR gene codes for a specific protein chain  which eventually shapes itself as the   insulin receptor on the  surface of cells-  part of it inserted inside  and the other part as stub protruding  outside which  binds  insulin.  Because of the mutation in the gene,  the  protein chain  is improperly formed  thus rendering it incapable of  binding insulin.  Such a state, described in mammals as  insulin resistant Type II diabetes  is  a major health hazard for humans. Precisely for that reason A mexicanus  has now captured the attention of  biomedical researchers.   

Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1) which in turn starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis (4), glycolysis (5) and fatty acidsynthesis (6).Courtesy: wikipedia

Glucose enriched blood could have evolved as an instant-food-reserve trait to compensate for the food scarcity in the dark recesses. But how is  insulin resistance  decoupled from the debilitating consequences of high blood sugar? Answer to this question will be a boon to mankind.   

References:

1. The complex origin of Astyanax cavefish

2. Blind Cave fish beat back Diabetes symptoms that would kill people

3. Insulin resistance in cavefish as an adaptation to a nutrient-limited environment: Riddle et al Nature: 29th March 2018. Vol.555, pp647-651

4. Genetic basics of insulin resistance and its role in type 2 diabetes pathology

Eat Less - To stay young, to live long

Metabolic slowing and reduced oxidative damage with sustained caloric restriction support the rate of living and oxidative damage theories of Aging.  That is the  title of a recent   paper in Cell Metabolism (1).  Well it is the scientific way of saying   eat less and you may stay young and healthy for a long time.     

Currently there are two accepted  hypotheses concerning mammalian aging.  In 1928 Raymond Pearl advocated the concept of Rate of Living, which essentially stated that the length of life depends  inversely on the rate of living; in other words faster the growth, shorter the duration of life.  Thirty years  later  Denham Harman proposed  Aging: A theory based on Free radical and Radiation Chemistry  which is  currently known as the Oxidative Damage  Theory of Aging.  Food is digested by an oxidative pathway and  the process naturally spews out Reactive Oxygen Species (ROS) - superoxide, hydrogen peroxide and hydroxyl ion- as byproducts. Unless removed from the system  by antioxidants,  ROS can chemically hurt proteins, lipids, and DNA. This chemical damage manifests itself as the  phenomenon of Aging.  Club the two hypotheses together and the recipe  for  extending  youth and longevity.   
  
Redman et al conducted a rigorous study spanning two years. Of the 435 healthy normal individuals  screened initially,  73  (male and female) were finally enrolled for the experiment. They were divided into two groups the CR (Calorie Restriction) group and the other AL (Ad Libitum) group. The CR group ate prescribed meals as per protocol, while members of the  Ad Libitum group true to its label were allowed to eat as they please.  For the CR group calorie intake was gradually reduced by 15% without compromising on the essential nutrients.  The CR group registered an  average  weight loss of  8.7kg, while the AL group gained 1.8kg in the same time frame.   The excretion of  Isoprostanes, found in urine  are the markers and mediators of oxidative stress  which was found considerably reduced in the CR group. 

Tailpiece:

Dr Luigi Fontana   says  what is important is  an healthy life style that includes  nutritious diet and  adequate  exercise;  nothing in the extreme.  "Don't make your life miserable by counting every single calorie" he adds.   

Also see earlier columns  " Blame it on Food" and  "Ageing Gracefully" 

References:

1. Metabolic slowing and reduced oxidative damage with sustained caloric restriction support the rate of living and oxidative damage theories of Aging.  
Redman et al Cell Metabolism 27,1-11 April 3 (2018 )

2. Calorie restriction in humans: an update 

3. The Hunger Gains: Extreme Calorie -Restriction Diet shows anti aging results : Scientific American February 2017.

In health and in disease - living together with microbes

Trillions of diverse microbes reside in our gut,  the gastrointestinal tract and as a community  collectively influence our state  of  health as well as  disease. This symbiosis  is not a recent phenomenon, says scientist Andrew Moeller who investigated the evolutionary histories of hominid gut microbiota for his doctoral thesis.  By the way microbiota  is the currently used terminology for a diverse microbial community in a given ecosystem and gut is one such ecosystem.  Acknowledging  the significant role of microbiota in human life, NIH, the National Institutes of Health, USA, initiated the ambitious Human Microbiome Project in 2008.   Microbiome is the word for the genomes of the microbial community in a given ecosystem.   Abbreviated as HMP, the project aims at, much like the earlier Human Genome Project, generating a   complete catalogue of the genomes of microbiota living in association with human body and analyse their role in human wellness and illness. 

  

Human digestive system: courtesy : wikipedia

Several very interesting pieces of information have come to light with regard to gut microbiota. Neonates beget a minimal share of maternal repertory, which gets enriched in diversity and proportion as the child grows and by  age 12 resembles the adult profile. Beyond age 70, there seems to be a decline in the  diversity and functional capabilities of the microbial community. Nature and nurture contribute to the diversity and functional capabilities  of microbiota. For example scientists suggest that the high fat high salt diet of the affluent west   and overuse of antibiotics elsewhere will leave telltale signs on the  gut microbial community Now the most important point:  the diversity and relative proportions of  microbiota is unique to each individual. In other words each of us have a unique microbial signature, a unique microbial identity.  According to experts this explains, to some extent,  individual preference / tolerance/intolerance  towards food/drug type.   

Thus by age 12 we achieve a unique balanced  microbial population in our gut.   Dysbiosis, that is  perturbations of this  balance   has been implicated in several intestinal and extra-intestinal disorders. For example in  a recent research paper Imhann et al reiterated  the role of dysbiosis  of  the gut microbiota  in inflammatory bowel disease (IBD). Others have found possible evidences to link allergy, asthma, metabolic syndrome, and even obesity. But the good news is that beneficial  microbial communities can be generated, cultivated and maintained  by consuming appropriate food. Probiotics which are fermented food items such as yoghurt, cheese, pickle etc. and prebiotics  fibre rich vegetables, fruits, cereals which ferment in the gut seem to aid this process greatly. 

TAILPIECE:
Does that mean gut feeling is just microbial biochemistry?

  

References:
1. Human intestinal Microbiome in health and disease:The New England Journal of Medicine:2016; 375:24
3. Diversity of the human intestinal microbial flora Science:2005; 10:1002-14
4. Gut microbiota composition correlates with diet and health in the elderly: Nature 2012, 488: 178-84 Claesson et al.
5.Diet rapidly and reproducibly alters the human gut microbiome: Nature 2014;505:559-63 David LA et al
6. The Gut microbiota in host health: a new clinical frontier: Gut 2016;65:330-9 Marchesi,JR et al.
7. Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity:J.Clinical Invest. :2014:124:3391-406. Chen Z et al
8. Interplay of host genetics and gut microbiota underlying the onset and clinical presentation of inflammatory bowel disease. Gut: 2018; 67: Imhan et al

When pushed to the extreme

Freezing, arid  terrain with sweeping winds: that is Antarctica, the southernmost continent on Earth.   Since the sighting of the ice mass in the first half of the nineteenth century by marine explorers,  Antarctica has attracted umpteen   expeditions. During the second half of twentieth century  extensive aerial surveys of the continent  were conducted mostly by the United States. Airplanes    carrying scientists and radar equipments criss-crossed over the icy continent. From the radar data   thickness of the ice cover  and presence of liquid water below the sheet could be estimated.   While those  old maps provide information on what the terrain was like "Then",    modern satellite imaging techniques yield detailed   "Now" images.

Antarctica with ice shelves marked-Courtesy Wikipedia

   

United States' National Science Foundation funds several projects on various aspects of Antarctica. Project Midas undertaken by UK    focuses on stability of Larson C ice shelf in West Antarctican coast. In addition to these two countries several others have  permanent research stations  there.  

Limacina Helicina Courtesy: Wikipedia

Not only penguins, blue whales and krill, Antarctica accommodates life in many other forms.  The terrain as such  is hostile; with  global warming and consequential increase in the acidity of the ocean   would it become even more inhospitable?   Tiny marine snails, Limacina Helicina (also called sea butterflies because evolution equipped them with wings rather than feet) have already devised a counter measure. Acidic ocean can leach out the protective coating on their outer shell. They have learnt to repair this damage not by regenerating the coating but by thickening the innerside of the shell by appropriate secretions. In the picture alongside, the white rectangle marks  the area where the effect of ocean acidification was studied. The antarctic fish Emerald rockcod too has braced itself against warming and acidity of the ocean, although it can take on only one at a time. 

  

Prof. Belinda Ferrari from the Australian Centre for Astrobiology recently recorded the ability of certain microbial communities to "live  on air alone".  These microbes  belonging to phyla Actinobacteria, can survive by oxidising trace amounts of atmospheric hydrogen and carbon monoxide, present in the atmosphere. Detailed genetic and biochemical studies showed that the microbes possess three very important enzymes: high-affinity hydrogenases, to  catalyse the reversible oxidation of hydrogen, carbon monoxide dehydrogenases to  facilitate the conversion of carbon monoxide to carbon dioxide and  CO2 fixation enzymes of the  RuBisCO family to   "fix" inorganic carbon into organic carbon. 

 Tailpiece:
Antarctic tourist season is from November to March, the summertime in southern hemisphere. 2016-17 clocked more than 44,000 visitors!

Blood Falls: Iron oxide stains the water flow
blood red in Taylor glacier
Courtesy:Wikipedia

References:
1. Flying lab to investigate Southern Ocean's appetite for carbon
2. Coping with climate stress in Antractica
3. Sea butterflies patch up shell damage from ocean acidification
4. Pteropods counter mechanical damage and dissolution through extensive shell repair
5. Scientists find antarctic microbes that live on air alone

Shocking Experiments!!!!

Professor Kenneth Catania is indeed a brave man. He let himself be stung by an electric eel ten times.  During this experiment  his arm remained  coupled with a  measuring device  so that  the intensity of the shock could be measured. In science one data point is inclusive and hence  10 times!.  After all repeatability and reproducibility are the hallmarks of Science.  All 'In the Name of Science' Washington Post commented. The research paper(see ref.2) appeared in the Sept. 25th(2017) issue of  Current Biology. Catania had selected a smal, juvenile  electric eel for the experiment, and  the mild shock of  about 40-50mAmp, generated acute short term pain, but no long-lasting injuries. An eel can deliver two types of shocks, low voltage when they are linear  and high voltage when they curl up. 

Electric Eel  Courtesy wikipedia

Major part of the eel's body, almost 80% is a powerhouse.  Electrocytes, the electricity producing cells are compacted in parallel stacks inside the electric organ. Neurotransmitter acetylcholine is the messenger  that signals the cells to  align and get activated. As Na+  K+ ion channels open and close in a synchronous fashion a voltage across the anterior and posterior membranes of the cell is developed.  Each cell contributes a tiny amount of electricity but when linked in series the output  adds up.  In an airborne attack, that is when the eel leaps out of water  the blow could be stunning.  

Voltage development across a cell membrane
courtesy: wikipedia

As described in Ref 4

The electric eel inspired Schroeder and colleagues too, but in a rather different way. They viewed the eel as the apt  model for designing and developing a biocompatible  " soft power source".  In many  medical applications the need for a soft pliable energy device  has long been felt.  Schroeder and his team set out to bridge that gap.  They selected  hydrogels as the basic material to design the electrocytes. Hydrogels are materials with 90% water and 10% biological or synthetic polymer. Their design is shown in the picture-   a cation selective gel, separated from an  anion selective gel with an intervening low salt gel and the whole assembly sandwiched between two high salt content  gels. In resting state gels are separated with no current flowing, but when they are brought into contact, ionic gradients result in voltage development.    This is just the beginning; Schroeder's team is hopeful that next generation devices  will  " open the door to metabolically sustained electrical energy powering implants, wearables and other mobile devices". 

References:

1 Biologists reaches into electric eel tank, comes out with equation to measure shocks 
2. Power transfer to a Human  during an Electric Eel's Shocking Leap
3. Watch an electric eel zap a biologist in the name of Science 
4. An electric eel inspired soft power source from stacked hydrogels.

BodyNET: Sixth Sense in the Making

A new concept, On skin body area networks  abbreviated as bodyNET is all set to revolutionise the way we  communicate. In a  recent  report in Nature, researchers  Bryant Chu,   William Burnett, Jong Won Chung and  Zhenan Bao of the Stanford University     foresee not too distant a future when bodyNET will enable us "to sense and communicate with    others and the surroundings  in new and sophisticated ways beyond the  existing 5 senses".  In that context bodyNET will indeed function as the sixth sense.  Imagine  wearing your smart phone as a digital tattoo or a patch on your skin.   Exactly five years ago   a write up on medical tattoos ( Time for Medical Tattoos ) appeared here; now the umpteen possibilities of the concept are being explored.  

True; as of now  bodyNet is not yet ready, it is still in the developmental stage. Central to the design of bodyNET is the class of materials known as elastronics.  These are materials which can stretch like elastomers (rubber) and can be  embedded with the necessary electronics. The electronic circuits must be stretchable too in everywhich way without compromising on their performance. This indeed is the first challenge. Then follow the need for suitable sensors, energy sources etc.  There are additional requirements- of miniaturisation,  of biocompatibility (since the devices will be worn on skin or implanted), of durability  in  a variety of physiological and climatic conditions and above all cost.  Global demand for  such ensembles  is expected to peak by 2023.

Samsung Gears and Apple Watches are wearable smart devices  currently in the market. Team bodyNET has much more ambitious plans for their first generation product.   Subsequent  versions will have the capability to interact with  digital networks as well as decode physical and biological signals which are otherwise invisible.   But these capabilities also raise   uncomfortable  questions of privacy threats and data security. Chu et al are aware of these challenges and are confident that the necessary  legal checks and balances will also come into force in parallel. 

TAILPIECE:
On the flip side, if you opt for a decorative conspicuous patch, then you might  be displaying your moods for the whole world to see; permitting everyone into your personal space. 


REFERENCES:
1. Bring on the bodyNET
2. Global Stretchable electronics Market

Herceptin- A case of Perseverance in Drug Development

From concept to commercialisation,  drug development takes decades.  The process demands a concerted, multi-disciplinary approach involving several agencies.  The time span is too long for   people and management  to remain committed to the cause. That almost happened to  Herceptin,  the best drug now available  in the market for HER2 positive  breast cancer.  Now in living tissues   HER-2 protein is the  biochemical signal for  cells to grow and multiply.   When the levels of   HER-2, become abnormally high, cells are  provoked  to  mushroom at an alarming rate and that is cancer. This type of cancer is also referred to  as HER2 positive.  Herceptin moieties  attach themselves to HER2 receptors and suppress them. The uniqueness of  herceptin  is that it doesn't have the debilitating side effects of either chemotherapy or radiotherapy. 

Herceptin,  has the generic name Trastuzumab which in WHO nomenclature is loaded with information. While Tras is a euphonic prefix,  tu stands for miscellaneous tumours, zu for   humanised and mab for   monoclonal antibody.  This drug was  developed jointly by  scientists at the biotech company  Genentech and the University of California,Los Angeles.  Axel Ullrich of Genentech and Dennis Slamon of UCLA were at the helm in the beginning. When Ullrich moved to Max Planck Institute of Biochemistry, it fell on Slamon to see the project through.  In retrospect, the timeline presents a hazzle free smooth roadmap, as easy as connecting the dots: for example  the seventies provided  the concept of monoclonal antibodies; by the eighties  the HER2 gene was cloned  and its role in   breast cancer  established; beginning of  nineties saw the  design and creation of herceptin and by 1998 the FDA approval was in place.  But it wasn't a smooth sail at all.  Science journalist Robert Bazell tells the story in great detail in  his book  Her-2 :The making of Herceptin, a revolutionary treatment for breast cancer. Scientific hurdles apart, there were parties with vested interests. 

New England Journal of Medicine in its review described the book  as  the story of the triumph of an inspired clinician against great opposition, which included his own colleagues, grant-awarding agencies, and pharmaceutical companies. Robin M. Henig , wrote      in    The New York Times     : Populated with single-minded scientists, clueless biotech company executives and women stricken with a particularly vicious form of breast cancer -- one that rages so fiercely that it can erupt along the fault lines of a mastectomy incision even before the scar heals -- ''Her-2'' is about the making and marketing of an entirely new kind of cancer therapy. 
Later the book was made into a telefilm " Living Proof" 

REFERENCES:

1. Genentech Her2 Story

2. HER-2: The making of Herceptin, a Revolutionary Treatment for  Breast cancer by Robert Bazell, Random House 1988 ISBN 13: 978-0812991840