In Search of a Universal Antivenom

Courtesy: World Health Organization 

July 16  happens to be World Snake Day.  A day dedicated to highlighting the role of snakes in maintaining ecological balance and  biodiversity.  Some species of snakes indeed near extinction  which necessitates focused conservation steps.  However  in parallel  is the undeniable  reality of death and deformity inflicted upon  humans by  snakebite.    World Health Organization lists  snakebite as one of the  Neglected Tropical Diseases because antivenoms are not only very species specific but also  in acute short supply.  A  few  monovalent formulations that work against  single snake species  available in market are  grossly inadequate to meet the requirements. Because in  most of the envenomation cases, the exact species  of the snake  responsible for the bite remains  unknown.  Polyvalent formulations  which  can  provide broader coverage against a wide range of venomous snake are  the need of the day.  While the complexity and  diversity of the biology and chemistry  of  venom are indeed the scientific  road blocks in the development of universal  antivenom,  there is an economic  barrier   too.     Snakebite is part of the lifestyle of the poor   in the third world  who can ill afford costly treatments.    Any kind of drug development requires huge  investments in terms of time and money  so  if  profit margins do not  look  attractive  who will venture? 

Typically any snake venom is  a concoction of a variety of short chain neurotoxins (SNX),  long

Courtesy Haggstrom, Wikipedia

chain neurotoxins(LNX), enzymatic toxins such as Phospholipase2 (PLA2) plus a low proportion of other compounds.  LNX  is  the most  lethal component,  SNX less so.  Phospholipase2 breaks down phospholipids, disrupting cell membranes and leading to muscle necrosis, neurotoxicity, and inflammation.  The chemistry , composition  and potency of  venom  vary widely  within  and across snake species. Even geographical variations are seen.  For example  the Indian cobra's venom   primarily contains neurotoxins that disrupt nerve impulses, leading to paralysis. African spitting cobras have a higher proportion of cytotoxins compared to Asiatic cobras.  Some species in addition contain  cardiotoxins too.  Potential respiratory failure is  responsible for a higher number of fatalities.   Thus pathologically  snakebites can cause nerve and muscle dysfunction (neurotoxicity), bleeding and clotting problems (hemotoxicity), and/or localized swelling,  blisters,  tissue death (cytotoxicity) etc. 

Antivenoms are antibodies extracted from horses or camels.  Adhering to  strict protocols these animals are  injected with snake venom below  lethal threshold. Their immune system swings into action and produces antibodies against the venom. Antibodies are extracted from the blood serum,  purified,  processed  and packaged.  Worldwide there are only a handful of antivenom formulations available  in the market  and as mentioned earlier  for effective medication it is important to know which  species  of snake caused the bite. What  if  we could  develop an Universal Antivenom Formulation?  That is the question  Jacob Glanville ,immunoengineer and chief executive of biomedical firm Centivax in South San Francisco, California, asked  and  he found the answer in   Tim Friede. 

Tim Freide an American citizen  has been living  dangerously  for the past almost  two  decades.  A truck mechanic by profession  and a snake collector by hobby, he has been bitten about 200 times by a variety of snakes accidentally and has intentionally  injected himself with snake venoms for about 600 times. Not that he hasn't  had set backs: once he was   knocked  off into a comma for 4 days.   He took it all  because he is a snake lover and want to be immune  to their stings.  A rather bizarre  wish, one would think.   But then  that  exactly is his claim to fame : An individual  hyperimmune  to  envenomation of any kind. 

Glanville saw the videos uploaded by  Freide  in the Youtube  and immediately  contacted   Prof Peter Kwong  at Columbia University. The  duo lost no time  to get  in touch with  Friede  and a research project was born.  They  were literally after  Friede's blood.  Friede agreed. Friede's  blood was subjected  to systematic analysis  by the research teams at Centivax and Columbia University.  As expected  Friede's hyperimmune blood indeed had an  abundance of antibodies against LNX and SNX neurotoxins. 

Over the  years   having encountered  envenomation   from  diverse  species from   black mambas to   king cobras and kraits, Friede's     immune system had  adapted  and evolved  broad spectrum  antibodies that could counter multiple toxins from various species.   The researchers identified  the  gene  that encoded for these antibodies and then   using a technique called  Phage Display  that involves several intricate   steps, generated and harvested    two broad spectrum  antibodies SNX-B03 and LNX-D09 that can neutralize  LNX and SNX neurotoxins from a wide variety of snakes including black mamba, King cobra.   

Next the team  made  a cocktail of SNX-B03 , LNX-D09 and Varespladib  a known phospholipase2 inhibitor. This  formulation was    tested in mice  against 19 diverse  and intense venoms of the elapid group, classified as most lethal by World Health Organization.  The formulation  provided  full protection against 13  and partial protection against the remaining 6.  Glanville is  excited: “That, for me, was a very exciting moment.  A universal antivenom is now tractable, within reach, and we have the tool, and we just need to keep turning the crank to find it.”   

Glanville is hopeful that   philanthropic societies, governments  and  pharmaceutical companies will collectively provide the necerssary financial support.  Thus the  road to designing an universal polyvalent antivenom is clear. However making it available/accessible  to the victim  on the spot  remains a challenge.

REFERENCES:

1. Snakebite envenomation turns again  into a neglected tropical disease.

2.Snake venom protection by a cocktail of varespladib and broadly neutralizing human antibodies.   Glanville et al.,  Cell (188) 3117-3134, 2025.

3.Thoughts, observations and experiments on the action of snake venom on the blood : with an appendix by George B Halford

 

Genomic Editor goes Personal

Decades long intense  research  of Jennifer Doudna and Emmanuelle Charpentier  culminated  in  Nobel Prize  in Chemistry in 2020.  The duo had hit upon a simple yet very accurate  way of editing the DNA chain  precisely at a given location.   Famous now as  CRISPR Cas-9 technology, this editing tool consists of an  RNA strip that guides  the razor sharp  bacterial enzyme Cas-9 to the exact location to do the correction work. Two books A crack in Creation and The Code Breaker  provide   detailed description  and analysis of this revolutionary technique.  

The medical implication of the discovery was  immediately obvious: that the DNA repair kit can search, find, delete/replace  faulty genes, thus making gene therapy a reality.   Indeed  FDA, USA  has  approved standard procedures  for a few  inherited diseases such as sickle cell anemia, thalassemia, cystic fibrosis, lukemia,  hemophilia, Huntington's disease  spinal muscular atrophy etc.  It takes years and money  to develop  genome editor kits, but  if pressed for time the whole process can be fast forwarded.    A recent issue of  New England Journal of Medicine  reports   how this tool was  customized to suit  a single recipient, racing against time.  

Baby KJ  now nearly 10 months old,  was born with a rare and serious  genetic  defect, termed  CPS1 deficiency.   CPS1, short for  Carbamoyl phosphate synthetase 1  is a key enzyme in the urea cycle  responsible for  converting ammonia into urea which  is then excreted through urine.  In  KJ's case both copies of  the CPS1 gene,  paternal and maternal  that he inherited  were found defective.    KJ was just 2 days old when this was diagnosed. As a temporary solution the baby  was immediately put on renal replacement therapy (RRT) to remove waste products, excess fluid, and electrolytes from the bloodstream.  Because for such patients the only curative option is  liver transplantation and   KJ was too young to undergo that.   The other option was to design  personalized gene therapy .  Normally this  would take years, but  KJ had no time to wait. 

Doctor  Rebecca Ahrens-Nicklas, is  a pediatric geneticist and Director of  Gene Therapy for Inherited Metabolic Disorders Program, at the Children's Hospital, Philadelphia and   Dr  Kiran Musunuru,  a cardiologist, geneticist and gene editor at Perelman School of Medicine, University of Penn. They with   their research teams  took up the challenge. The team  worked  at lightening speed. The first step was  analyzing  KJ's  genome to pinpoint  the exact nature and location of the defect.   This exercise   revealed   a  mutation at position 335 in the paternal copy and at position 714 in the maternal copy  of the CPS1 gene.  In both these positions   a stop codon  prematurely truncated   the formation of the  CPS1 enzyme.  The team decided to focus on the paternal copy. 

The  next step was to put together   a precise gene-editing tool.   A modified version of CRISPR, called base editing, which allowed the alteration of single DNA "letter" in the sequence was  chosen. Within 2 months  the repair kit nick named K-abe  loaded into lipid nanoparticles  was  ready  for trials.  First  the efficacy of K-abe was tested  in mouse and monkey models.  This was necessary to assess safe dosage  levels in terms of tolerance and toxicity.  In six months  the therapeutic kit was all set complete with all toxicological, safety and regulatory protocols.   KJ was slowly weaned off  the dialysis unit  and put on nitrogen scavenging medication and minimal protein diet.  

Doctors decided to start with   very low initial dose of K-abe , then later  hike up the dose  slowly and steadily.   KJ was 7 months old when he received  the first infusion.  Lipid nanoparticles carried the correction scheme to  KJ’s liver.  Dr Musunuru  sums it up  :  “CRISPR, a gene editor, enters the nucleus of the cell.  In this case, we programmed it to go to the site of the genetic variant that was causing the disease in KJ.”    As of  now KJ has had 3 infusions and he is doing very well. There is no ammonia build up in his system and his protein intake has been steadily  increased. He is growing up hale and healthy and his first birthday is fast approaching. 

KJ  with his tiny hands has pushed open the door to personalized gene therapy.   However  challenges remain:  such as  prohibitive  cost, complexity, safety etc.  and above all  ethical concerns abound.   

REFERENCES:

1. Patient-Specific In Vivo Gene Editing to Treat a Rare Genetic Disease    

2.  World's First Patient Treated with Personalized CRISPR Gene Editing Therapy at Children’s       Hospital of Philadelphia

3. World’s first personalized CRISPR therapy given to baby with genetic disease

                      

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Whom Pressure wouldn't squash , Fire wouldn't burn

Tardigrade 
Courtesy:
EnWikipedia 

Spineless  and tiny  it maybe,  but  the Tardigrade has shot into fame. Readers of the Guardian have  voted it  to be  the  invertebrate  of the year 2025.    Popularly  known as water bear or moss piglet,  tardigrades are like tiny elongated pouches  less than a millimeter in length. But don't dismiss them  just because  of  their size.   They are  omnipresent and practically  indestructible.  They  can withstand  subzero temperatures  and  the  volcanic  heat , intense radiation pressures upto 600 MPa and even vaccuum.  In other words  they are extrtemophiles with mind boggling resilience.   When confronted with  such adverse  ambience they simply  withdraw into  cryptobiosis, a desiccated state in which  bodily functions are bare minimum.   They  can survive in this state  for decades.  The organism resuscitates itself  from the dormant  state, when conditions become favorable.  It presumed that it has survived through the  5  five apocalyptical  planetary extinction events.  The  earliest  which happened 440 million years ago wiped out most of the marine species due to global cooling.  The latest which occurred 66 million years ago saw to the end of non-avian dinosaurs.  So what is so special about the tardigrade? 

Anatomy of Tardigrade: Courtesy En Wikipedia

Tardigrade is a simple uncomplicated organism. Its body cavity is filled with a colorless fluid  hemolymph which   facilitates oxygen and nutrient transport. It  has eight stubby legs which it can move individually or collectively. Its nervous system too is  very elementary.  A cerebral ganglion on the head serves as the  brain from which  two nerve cords  run under the belly along the whole length of body connecting smaller local nerve centres.  Neurons may not exceed  200 in number. With such simple arrangement tardigrade can swim, walk or glide as it pleases, the speed and gait depending on the terrain on which it moves. It has a mouth for food intake and anus for waste removal. The eyespots, sensory whiskers and chemoreceptors collectively function as sensory organs.  Above all they can multiply sexually or asexually.  Enough for existence  as well as subsistence.

Scientists irrespective of the   disciplines  they work,  are   enamored  with this tiny yet resourceful organism.   For example  oncologists  have long been  frantically looking for ways and means to reduce collateral   damage to healthy tissues of patients  receiving  radiation therapy.  And here is this simpleton who can withstand  intense doses of radiation.  Research has revealed  that  tardigrades have a special protein  called Dsup (short for Damage Suppressor Protein)  in their genetic makeup.   Dsup is a  disordered polypeptide  chain of   445 amino acid residues most of which are  positively charged.  These positive charges  facilitate it  to wrap around   the negatively charged  DNA as a protective cover.   When  Dsup gene  is incorporated  into the  genome  of  laboratory mouse, the protein is expressed and  the   mouse exhibits  radiation tolerance.   

The ultimate in biomedical electronics  is nanotattooing  of biosensors and control devices on the patient's skin itself.  As of now this happens only in science fiction.   Nano lithography (or nanopatterning) as the process is called, is well standardized  for inert surfaces and  a variety of techniques are available to choose from.  However   none is  suitable for live biological tissues  because the  processes involve several harsh steps  such as   intense  radiations, wet/dry etching, high temperature  curing,  toxic solvent wash, vacuum etc.  Recently   a group of  scientists  from the School of Engineering, Westlake University, Hangshu  and Institute  for Optoelectronics, Hangshu, China. decided o take advantage of the cryptobiotic behavior of tardigrades.  The   organism  was cooled to subzero temperature, goading it to go into  cryptobiotic stage.  While in  that state, it was given a protective coat of  anisole.  A  nanodesign  was tattooed  on the ice layer formed over the anisole coat  using an electron beam.  Wherever the beam impinged,  anisole reacted to leave a biocompatible mark.  The unreacted anisole layer was then vacuum evaporated.   When  brought back to room temperature the organism displayed the nanotattoo.    

A  batch of tardigrades in the dormant state of course,  flew  to  the moon in an Israeli spaceship,  Beresheet in 2019.  Unfortunately  the spaceship  crash landed   on the lunar surface. It is presumed that the  crash as well as the unfriendly ambience of the moon would have been too much for the tardigrades  to survive.  But who knows, perhaps future holds that secret. 

Tailpiece:

Cosmo Sheldrake 's  song   If I were a tardigrade.....  ends  like this :

If I shed all my liquid and let myself dry out

I'll shrivel and sleep for some 15-odd years

I'd wake up, come water, and get on with living

With time in my pocket to pass by the day

  ------------------------------------------------

REFERENCES:

1.It’s heroic, hardy and less than a millimetre long: meet the 2025 invertebrate of the year

2. The biomedical potential of tardigrade proteins: A review

3. Patterning on living tardigrades: Yang et al  Nano Lett. 2025, 25, 6168−6175 

Babes in the Digital Woods

 "Lucid, Memorable, Galvanizing". That is how The Wallstreet Journal  described  the   book : The  Anxious Mind- How  the great  rewiring of the  childhood is causing  an epidemic  of mental illness.  This book  has been on the  2024 Best seller list  for several weeks and has been discussed at length  by parents and experts.  The author Jonathan Haidt  is a  professor at New York  University  Stern School  of Business  who  specializes  in  social psychology.

Haidt  laments  that with the advent  of smartphones,  today's adolescents ( 10-20 age group)  are lost in the  dark labyrinths of the digital world.   They  are drawn irretrievably  to the  friends and friendships of the virtual world rather  than the solid  realities  of the physical  world.  True,  adults are equally   addicted  to and influenced  by  the  social media platforms. But,  Haidt  argues adolescents are  more at risk, more vulnerable  to the charms extruded by the  virtual  world.  They could be permanently scarred, leading to the possibility of mental illnesses.  Haidt suggestions  for  "a healthier  childhood in  a digital world" include No smart phones before   high school, no social media before16  and  phonefree  schools"  

Why adolescents are at risk?  Though thankfully brief, adolescence, an essential  phase of growing up, is indeed a  very difficult time for both boys and girls.    Hormonal influx  initiates hitherto unexperienced  and novel changes   in the body and the child within  struggles to come to terms  with awareness of  sexuality.  Anxiety, curiosity, apprehension, doubts and above all questions abound.  Overwhelming  majority of the  teenagers tide over  this  turbulent phase naturally  without any serious repercussion. However  there are exceptions. As  Silvers point out  " for some youth  adolescence marks the beginning or worsening of psychopathology characterized by difficulties with emotion regulation."   

During the transition  phase  more than parents/teachers/siblings, it is the peer group that becomes  trusted confidante.  To be accepted by them, to be like them, to be one of them  means a lot.  But  tragedy  is,  instead of  dealing directly with  real friends, in the real world, in real time,  today's adolescents opt for  the social media platforms to interact.    Where everything is easy and just a click away. To some extent parents are responsible for this trend, Haidt  argues.  Distrustful of neighbors and neighborhoods , paranoid  parents feel their wards are safer in the digital world. 

In a recent interview with  BBC,  Haidt  warned that  utter disaster is all set to descend on us in the form of   AI, the all powerful Artificial Intelligence.   As the boundaries between True and Fake tend  to blur ,  societal  set up  as we  know now may cease to exist. 

Or  who knows,  perhaps AI disaster might turn out to be a blessing in disguise. When nothing can be trusted in the virtual world,   innate human  intelligence  will  win.   Teenager might   shrug off the digital world  as easily and  naturally as a child discards  cartoons  as it grows.   

References

1. The anxious generation: how the great rewiring of childhood is causing an epidemic of mental illness

Haidt,J 

Penguin, New York, NY, 2024, ISBN-13 ‏ : ‎ 978-0241694909

2. Can childhood survive the smart phone?

Haidt to BBC

3.Do smartphones and social media really harm teens’ mental health?

Pearson 

Nature  2025 vol.640,pp26-28

4. The great rewiring,unplugged:  Is social media really  behind an epidemic of teenage mental illness?

Odjers  

Nature 2024  vol. 628, pp.29-30.

5.The age of adolescence

Sawyer,  et al.

Lancet Child Adolesc Health. 2018; 2:223-228

6. The teenage brain: Sensitivity to social evaluation. 

Somerville, L. H. (2013) 

Current directions in psychological science, 22(2), 121-127.

7. How social media affects teen mental health: a missing link

Orben, A ∙ Blakemore, SJ

Nature. 2023; 614:410-412

8.Adolescence as a pivotal period for emotion regulation development

Silvers, JA

Curr Opin Psychol. 2022; 44:258-263

9.Peer facilitation of emotion regulation in adolescence

Sahi et al 

Developmental Cognitive Neuroscience 2023,August Volume 62, 101262