Making Scents of it All

 Sense of Smell: Reubens &  Jan Brughel (1617) 
courtesy:wikipedia

In 2022, the Prado Museum, in Madrid ran a special event called “The sense of Smell. An Olfactory Exhibition”. The exhibition included the famous painting The Sense of Smell by Reubens and  Jan Brueghel the Elder.  To enhance the viewing experience  museum authorities adopted a novel technique: they filled the ambience with selected fragrances.  And the result?    Visitors lingered in front of the painting for 13 minutes, compared to the average 32 seconds.

Fast forwaed to 2026.  The Grand Egyptian Museum at Cairo is all set to  replicate the experiment.    “Because the ancient Egyptians used so many aromatic compounds, oils and resins,.... a lot of the original smell still remains,” says Matija Strlič  analytical chemist involved in  this project.  Strlič  is currently  lead scientist at the Heritage Science Laboratory, University of Ljubljana in Slovenia and prior to this  he was  deputy director at  the Institute for Sustainable Heritage at University College, London. He  has devoted his career to  the field of heritage science.  Much of his work focused on the preservation and reconstruction of culturally significant scents.  Being a multidisciplinary research project his team  uses  sophisticated   tools of  chemistry, ethnography, history and other disciplines to document and preserve olfactory heritage.

As we inhale the aroma of a steaming  cup of coffee, or sniff the  fragrance of a rose,  a swarm of  odorant  molecules enter our nose.  Inside the nose, these molecules  bind to specialized proteins  called receptors sitting on  on the  tiny, hair-like cilia of  the olfactory sensory neurons.  The total number of olfactory sensory neurons in our nasal cavity could be  about  10 million and    roughly every 30 to 60 days they regenerate.  Each neuron  sports around 500 different types of odor receptors. It is not that the receptors recognize an odorant molecule as a whole; only certain features of the molecule are recognized. In other words  multiple receptors can respond to the same compound and a single receptor can recognize multiple odors. This recognition act  triggers an electrical signal within the neuron. This signal travels along nerve fibers (axons)  to the olfactory bulb, a structure situated in the lower part of the frontal lobe of the brain. The olfactory signals are sorted out and refined here and  transmitted to  the olfactory cortex which is responsible for  identification  of smells.  Hippocampus and amygdala are integral part of the olfactory system and thus  smells are associated with specific contexts, emotions, and memories.  In his voluminous novel  In search of Lost Time, Marcel Proust  alludes to specific aromas rekindling  memories of childhood experiences.  Also, Agatha Christie's   beloved detective Hercule  Poirot  takes the aromatic route  to   solve more than one murder case. 

But as yet  we don't know  how brain  processes  signals from a mixture of aromatic molecules and creates the perception of a unique smell.  For example let us get back to  our morning coffee.  The unique  aroma of coffee arises from over 1,000 volatile compounds which   include sulfur compounds (2-furfurylthiol), pyrazines (nutty/roasty), furans (caramel), and aldehydes (which act as  enhancers).  Drs. Elizabeth Hillman and Stuart Firestein at Columbia University imaged olfactory sensory neurons in mouse nose tissue to unravel this mystery.    Hillman says their results  indicate   “ that scent molecules can mask other scents, not by overpowering them, but by changing the way cells respond to them”  More details are awaited. 

TAILPIECE:    

The Odeuropa Smell Explorer  is a rather unusual  website put together painstakingly by a global team of  computer scientists, AI experts and humanities scholars.  With   an  archive of  300 years of  European smell,   the website is searchable and claims to  provide an olfactory    perspective of  European  history !!!

REFERENCES:

1. The Essence of a Painting: An Olfactory Exhibition Museo del Prado

2. Ancient Egyptian Mummified Bodies: Cross-Disciplinary Analysis of Their Smell

3. Making Sense of Scents: 3D Videos Reveal How the Nose Detects Odor Combinations

When Panic becomes Pandemic

A  pandemic is  the worldwide spread of an infectious  disease. The outbreaks of  severe acute respiratory syndrome coronavirus (SARS-CoV) in early 2003  the more recent COVID-19  are typical examples of such  catastrophes  descending on  humankind. In a pandemic there are  three basic factors involved : the agent , the host and the environment. The agent (A)  is the infectious microorganism (a pathogen)  that causes disease, the host (H) is the person/ organism that is susceptible to the agent and the environment (E) is the ambience  in which the agent  and the host  interact.    There  might as well be  a vector involved  an animate or inanimate carrier of the disease, such as  mosquitos or contaminated water.  

Epidemiological models take into account several  of these variable parameters  and   subject them  to rigorous analysis using  mathematical, statistical, and computational tools.   Critical parameters are individually and collectively evaluated using appropriate equations.  Based on  logical verification and  quantification  forecasts are made.   Even so, one should bear in mind that  these models are  simplified representations of a real complex  phenomenon  because  only selected parameters and  properties deemed essential  to the process are included.  A sure way to avoid any bias in this exercise is to include  as many  parameters as possible, even remotely connected.  

Almost a century ago Kermack and McKendrick  developed the   SIR model of  infection dynamics.  The model is elegant in its simplicity.  It divides the population into 3 categories:  the Susceptible, the Infected and the Recovered.  A recent refined version  includes the re-Infected too and becomes the SIRI model.  Either way the  model  allows  real-time monitoring of the progression of the pandemic. The susceptible group  represents the portion of the population that has not yet been exposed nor infected with the disease but could be infected in the future. The infected group represents the portion of the population that is both infected  and infectious. The recovered  group represents the portion of the population that has recovered from infection and developed immunity to reinfection. Differential equations  represent the rate of change of each group over time and allow the computation of the transmission as well as recovery rates.  

The Third Estate(Common man) carrying the load of
First(Clergy) and Second(Aristocrats) 

But what happens if the  pathogen  is a rumor and the disease is panic among the population? Will the SIR model hold good?  In a recent issue of Nature, Zapperi et al do just this exercise.  They dissect the brief period of   Grande Peur  (The Great Fear)  in French history when panic gripped the peasantry. It all began with a rumor that aristocracy is  conspiring against them, the lesser mortals.  Poor harvest, food shortage, unemployment, political turmoil etc. worsened the situation further.   Based on eighteenth century French maps of  roads, waterways, postal routes and  riot onset dates  Zapperi et al  classified towns  into susceptible, infected and recovered compartments.  Then they pinned  the  nodal points and retraced the trajectories of unrest    substantiating  that  rumor spreading  is indeed amenable to epidemiological models.  

But what of that?  Grande Peur  maybe   past history, however the pathogen is still very much around:   as AI empowered Fake News,  spreading at lightning speed.   What we need urgently is an effective tool to  counter that. 

REFERENCES:

1.  Epidemic models: why and how to use them

2. The Great Fear of 1789 : Rural panic in Revolutionary France 

4.  Epidemiology models explain rumour spreading during France's Great Fear of 1789 Zapperi etal Nature 646 pp358-365 (2025).

5. Real-time fake news detection in online social networks: FANDC Cloud-based system

About Ghosts, Corpses and Witches

Monotropastrum humile CourtesyWikipedia

Halloween  being just a few  days away  this is an ideal time to talk about ghosts, corpses and witches, but among  the Flora.

Ghost flowers? Yes, these are actually beautiful   translucent  blossoms on  pearly white  stalks.   These plants  lack  chlorophyll  and that explains their deathly pallor.   No  chlorophyl means no need for sunlight and  hence they flourish in the darkest corners of  forests, adding to their ghostly glow. Also called monotropes, there are  several closely related varieties and all  belong to  the  monotropoideae  subfamily. These are plants alright, but    without  chlorophyll and access to sunlight how do they fix their dinner? How do they get energy to survive?   

Plants with chlorophyl are autotrophs. Auto means self and trophos means food/nurishment.   They generate their own food through photosynthesis. Heterotrophs  depend on others for food.   The Monotropoideae are mycoheterotrophs, as they depend on mykos   (fungi) for food.  To put it simply  ghost plants  thrive as  parasites on fungi.  This fungal dependence is  highly specific  with different plant genera associating with different groups of  fungi. Such  specialized associations are a crucial factor for  their survival and distribution. 

Fungi, on their part  are indeed a hardworking lot. They  form  underground networks (mycorrhizal networks) to forage through the soil to collect phosphorous and other mineral nutrients.  They then trade these with  trees in exchange for sugars, a  win-win situation for both partners. The  ghost plants stick on to the fungi and  appropriate part of the fungal food reserve.    An abundance of ghost plants indicate   robust fungal network underneath and fertile soil.  The ability of  ghost plants  to exploit the tree-fungi food chain is considered  an ingenious adaptation and evolutionary strategy. 

Rafflesia arnoldii  courtesy : wikipedia

Corpse lilies are so named ,because of their repulsive stench of rotten flesh.  Belonging  to the  Rafflesiaceae    family  there are at least 40 varieties and they produce  world’s largest flowers.  Among them    Rafflesia arnoldii  is one of the   National Flowers of Indonesia.  The Flower's foul smell  attracts swarms of carrion flies which  facilitate  pollination.  There are no known uses  and not much research has been done on these plants/flowers.   

Striga Plant Courtesy: Randy Westbrooks Wikipedia 

The ghost and Corpse plants  are parasitic  they  do steal food from their  hosts  but  never cause any  harm 

In  Latin  Striga,  means witch and that is the genus name for witchweeds.    There are at least 30 species  and they all belong to the Orobanchaceae family.  Though  innocuous looking, striga  is  a killer weed and  a major threat to  crops like sorghum, corn, sugarcane and rice.  It attaches itself  to the roots of the host and  sucks off   all the nutrients and water.  As a result the host plant wilts and dies.  Striga's  seed pods can  hold  billions  of microscopic seeds which can hibernate in the soil for decades. 

 

REFERENCES:

1. A review on subfamily  Monotropoideae (Ericaceae) for Thailand 

2. Developmental origins of the world’s largest flowers, Rafflesiaceae  

3. Witchweed (Striga Asiatica)an overview of management strategies in the USA 

4. The genus Striga : a witch profile 

 

TAIL PIECE

There is a popular legend  among  the Cherokee Indian  tribe in North America. They believe that when friends and relatives quarrel  ghost plants flourish in their neighborhood. Because   once upon a time  two chieftains had a disagreement, they met to settle the issue, but instead  they smoked tobacco pipes and continued to  quarrel   stubbornly  for 7days.    This  annoyed the  Spirit and  he turned them into  ghostlike flowers with drooping heads  and  long stems.  

On Ophelia's depression and Hamlet's despair

It is ancient wisdom  that  human brain and gut are in constant communication.  An upset   stomach disturbs one's mood and when  in foul mood everything tastes bitter.  Add to this  the gut feeling about someone or something which at times  proves right.    The   concept  of  a gut-brain axis (GBA)  took shape during the 19th century  which  now   stands scientifically proven.   Follow up studies have  established  that  the gut has its own nervous system and it  can function  autonomously.  In other words we do have a  second brain in the gut.  

courtesy:wikipedia

The brain in the head and the one in the gut are in tune with each other  and this perfect  harmony  keeps us hale and hearty.   That  this  harmony  is modulated/enhanced/modified by the infinitely diverse microbial community  (also  called microbiota ) flourishing in the gut,  is a rather recent discovery.  

The gastrointestinal tract ( or GI tract for short), irreverently referred to as the gut, is a muscular tube that stretches  from the  esophagus to the rectum.  The ingestion, digestion, absorption, egestion processes  happen  in stages  aided by  the enzymes  secreted by  the  stomach, pancreas, and liver etc.  The inner wall of this tract is lined with a fine mesh of millions of nerve cells. This meshwork called the Enteric Nervous System (ENS)  independently  ensures and coordinates the efficient functioning of all the biochemical and muscular activities in the gastrointestinal tract.  Hence  ENS is  referred to as the gut brain or the second brain.   The ENS communicates with the main brain  via a two-way hotline called  the vagus nerve. The vagus nerve,  one of the longest nerves in the body,  begins at the brainstem and stretches down to the abdomen, exchanging  information  with various organs all along its  path.   

The term microbiota refers to the collection of trillions  of   bacteria, fungi, archaea and viruses etc. residing in the gut.    Microbial colonization in the human GI tract begins right after birth.  By age of  six a  child will have a thriving colony  of heterogenous  good, and  bad    microbes.  These minute inhabitants are  not passive observers  of  the happenings in the GI tract.  They aid in the breakdown down of complex carbohydrates and tough fibrous matter. They  have other    responsibilities too:   facilitating the development and modulation  of immune system, enabling the production of certain essential amino acids and vitamins,  helping to  maintain the integrity of the gut barrier,  protecting the body from pathogenic organisms. etc.  

The power  of the microbiota  lies in  its diversity and number.     More than 2000 known species  totaling   trillion plus are living in the human intestinal tract.  Collectively they  contain more than 100 times the human  genomic DNA .  In healthy individuals there is a fine balance between the  good  and bad microbial communities.  When this balance  is upset ( this is referred to as dysbiosis)  a variety of  maladies including  mood disorders, depression, anxiety,  etc. manifest.  Because  many of the microbial  metabolites and secretions are potent neurotransmitters such as serotonin, dopamine, oxytocin, short chain fatty acids (SCFA), tyramine, acetylcholine, norepinephrine and many more.   These molecules are  the main propellants of  various brain functions like  emotions, learning, and memory.  However  these neuroactive  molecules generated in the gut  don't reach the brain instead they  modulate/manipulate  the communication  along  Gut-Brain Axis and  thus indirectly exert influence.   Imbalances in the microbial diversity  and  in  the level of  neurotransmitters have been detected in the gut of  patients afflicted with neurological and psychological disorders such as Alzheimer's and Parkinson's diseases, autism , anxiety and depressive disorders.

As a correction mechanism   attempts are on to enrich the microbial diversity  by   including  food rich in  probiotics (beneficial live microorganisms), prebiotics (substances that promote beneficial bacteria growth), and  postbiotics (microbial metabolites) in the  diet. Indications are that  a microbial  approach to the management of   mental health  might soon evolve.  If only   Ophelia's depression and Hamlet's  despair  had  a microbiological cure.

The communication along  the  Microbiota-Gut-Brain Axis, (MGBA for short)  is  bidirectional hence the brain can as well  drive changes in the gut and alter the microbial composition.  “The complex interplay between our microbiome and brain is a testament to the body’s remarkable interconnectedness. It’s not just about gut health or mental health; it’s about how each influences the other in profound ways,” says Sean Spencer, MD, PhD, Gastroenterologist and Physician Scientist at Stanford University. 

TAILPIECE

Dr Jake M. Robinson poses a relevant question: If neurotransmitters and hormones secreted by microbiota can influence the emotional status of the host  then  why not explore the microbiology of Love?  

REFERENCES:

1. The Gut-Brain Paradox :  Steven R Gundry,  Harper (2025);  ISBN-13 ‏ : ‎ 978-0063471252

2. The Mind-Gut Connection: How the Hidden Conversation Within Our Bodies Impacts Our Mood, Our Choices and Our Overall Health : Emeran Mayer :‎ HarperCollins (2016) ISBN-13 ‏ : ‎ 978-0062376589

3. How gut bacteria are controlling your brain

4. Does microbial-endocrine interplay shape love -associated emotions in humans?  A hypothesis 

5. The gut microbiome connects nutrition and human health

6 .Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases

Lets go for the 3 Rs

“Plastic,  would create a world brighter and clearer than any previously known […] a world free from moth and rust and full of colour”.   “A world in which man, like a magician makes what he wants for almost every need….” (From a book on Plastics written in 1941)

We woke up to the dangers of plastic waste accumulating around us during the  seventies.  Packaging  and single use plastics  make up the major chunk of plastic waste.  But remember single-use plastics  are also  essential  for healthcare applications such as personal protective equipments, syringes, sterile packaging,  life support equipment, etc. In brief we have gotten so used to the convenience of the disposable plastics that we cannot live without them. Of course   there have been attempts to  contain plastic waste.  Biodegradable alternatives have  proved to be too costly to adopt.  Also  there are legitimate concerns about their performance.   Now attempts are on for popularizing the 3Rs;  Reduce, Reuse, Recycle.  This again  is not a smooth path forward.  It is a pity that   The  Intergovernmental Negotiating Committee on Plastics Pollution  which   met  from  5 to 15 August 2025  in Geneva, Switzerland  failed to arrive at an international legally binding resolution.  Because India, United States,  China and several Arab countries  don't want  any curb on plastics production. 

Courtesy: Wikipedia    

But now an associated  major  concern is looming large.  The discarded plastic items weathered by water, wind, sunlight or heat  or even by  tearing and friction,    disintegrates   yielding   smaller particles which are of micrometer or  nanometer in size. Collectively called MNPs (Micro&Nano Plastics)  these  have become ubiquitous: they can enter our body through the air we breathe,  through the food we eat, and drink.  MNPs have been found in  human saliva, blood, breast milk and  in  the liver, kidneys, spleen, brain and even  bones. There was a time when  specially designed  microbeads were added to formulations such as toothpaste and scrubbing creams to enhance  abrasion, a practice which has since  been discarded. In a recent podcast, Professor Matthew Campen, University of New Mexico  cautions us: Beware of tiny plastic particles, these are invading  our  bodies  including the brain and  organs.    In a study conducted on postmortem liver, kidney and brain samples, MNPs were detected in higher concentration the brain  than in the liver or kidney. The brain samples of  dementia patients registered higher MNP content.  In another  study conducted in Netherlands, 17 out of   22 volunteers had MNPs in their blood samples. 

We are now faced with a key question: Human body has a robust clearing  process. Generally if we inhale or swallow anything  unwanted/undigestible/alien, our  body gets rid of them all, through cough,   through urine or feces.  Then  how do MNPs escape  this clearing process?   To answer   we need   a standardized  approach across laboratories  to quantify and analyze  MNPs in biological tissues/organs.  To begin with   uniform  well defined, reproducible  protocols  for  human tissue collection,  precautions  for minimizing contamination and robust  controls, detection methods  etc should be adopted.   With these guidelines in place   biological processes such as absorption, metabolism, transportation, and accumulation of MNPs  as well as  their ability to  cross biological barriers  should be monitored. This will facilitate comparing  results from across the globe  and allow conclusions to be drawn. Currently comprehensive  epidemiological studies on  MNPs are lacking.

That  leads us to the next more critical  question:  how exactly  are MNPs messing up our health? Unfortunately here again  we don't have clear answers  as of now.  What we have are speculations and possibilities which are alarming.   There is general consensus  that  MNPs could cause serious  biological  complications for us  in the long run.  Perhaps it might take a generation or two for  manifestation.  For the time being the best  policy will be to rely on the 3Rs: Reduce, Reuse, Recycle.

TAIL PIECE:

Courtesy: wikipedia

REFEREMNCES:

1. How microplastics are invading our bodies

2. Bioaccumulation of microplastics in decedent human brains 

3. Microplastics: A Real Global Threat for Environment and Food Safety: A State of the Art Review

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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