The Tall and Short of it.....

How tall can a plant grow? When will it flower?  How soon the fruits will ripen ?  Well  Gibberellins, the plant hormones   hold all the answers.   Adequate levels of gibberellin  in the system boosts  internodal elongation and plants   grow tall. Since all gibberellins are  diterpenoid acids, GA is the general abbreviation used for this class of hormones.    Deficiency   or total  absence of  GA renders the plants  short and stalky. In fact  GA ( or to be more precise its deficiency) revolutionised the  horticulture industry in the sixties. The rice semi-dwarf1 (sd1) and wheat Reduced height-1 (Rht-1) were the foot-soldiers  which successfully  ushered in the Green Revolution.  Initial studies indicated that a defect in one of the  GA genes, which adversely affected GA biosynthesis,  is responsible for dwarfism.

1. A plant lacking gibberellins  has an internode length of "0" as well as it is a dwarf plant. 

2.  A plant with a moderate amount of gibberellins and an average internode length. 

3. A plant with a large amount of gibberellins has a much longer internode length.

(Courtesy: wikipedia)

All gibberellins are diterpenoid acids

The life cycle of a rice plant, since germination goes through   3 stages:  the vegetative stage, the reproductive stage and the ripening stage.  It is during vegetative stage that GA builds up in the system and  internodal elongation begins. The plant grows in size,  sprouts leaves and ultimately  tillers (special grain bearing branches) develop. Focusing on two specific rice varieties,  the flood resistant deep water  tall variety C9285  and the shallow water  dwarf variety T65,  a group of Japanese scientists recently investigated how gibberellin  regulates stem growth and internodal elongation. 

Nagai et al studied the behaviour of both plants in shallow water (~5cm) as well as in deep water(~100cm) conditions.  Shallow or deep, internodal elongation was conspicuous in C9285 throughout  the vegetative stage, in conformity with ample concentrations of GA in the system.  However  in  T65 plants  endogenous gibberellin didn't appeared  during the stem growth phase but  only much later during the   transition from vegetative to reproductive stage. As a result  the plants got completely submerged in deep water during vegetative phase and got destroyed.  Even  with exogenous supply of  GA during vegetative phase T65 failed to elongate  while  C9285 exhibited the  added advantage.  

 

The fact that T65 didn't respond to  exogenous supply of GA, gave the indication that there are other factors  that work in concert with GA to promote/retard stem elongation.  Nagai et al  carried out  the DNA profiling of both plants. They located two genes in chromosomes 3 and 12 respectively of  C9285 which responded to the presence and level of GA antagonistically.   The  gene in chromosome 3 ,  was activated by GA and the protein it coded for   facilitated internodal elongation. This gene is aptly named Accelerator of  internode Elongation, ACE1 and the protein product as Accelerator.  The corresponding  ACE1 gene in T65 was found  mutated and nonfunctional.  And that explains why T65 didn't respond to exogenous GA.  However    the 68kb  gene  in chromosome 12 behaves differently.   Exogenous GA or deep water conditions  suppressed the activity of this gene in C9285 but not in T65 in either situation.  Follow up studies demonstrated that this gene codes for a protein that decelerates stem elongation. Nagai et al calls his gene DEC1, short for Decelerator of internode Elongation 1.   It could be  that the tug of war between  ACE1 and DEC1  is an evolutionary trait, a  survival tactic to facilitate the selection  of  shorter plants  in shallow waters  and taller  varieties in  deepwater  conditions.

Tailpiece:

The Dutch seem to be  the tallest people on Earth, according to a recent report,  with an average height of 182.5cm  for the male and 168.7cm for the female.  So is there a gene associated with height in humans?  It is accepted that genetic factors greatly influence height,  however  but multiple genes and their variants are implicated.  In addition nutritional and environmental factors also play very prominent roles. 

REFERENCES:

1. A Century of Gibberellin Research: 

2. Semidwarf (sd-1) "green revolution" rice contains a defective gibberellin  20-oxidase gene

Speilmeyer et al., Proc.Natl. Academy of Sciences 2002 99 (13) 9043-9048.

3. Antagonistic regulation of the gibberellic acid response during stem growth in rice 

Nagai et al Nature 2020 (584) pp109-114

4. Why are the Dutch  so tall?

5. Is height determined by genetics?

 

From Bayer's Aspirin to Roche's Hemlibra

Meadowsweet shrub(Spiraea Ulmaria)

Pharmaceutical industry  made its debut  with  Bayer's  Aspirin. This was way back in 1899.  However, aspirin was not exactly a new drug discovered painstakingly through intense research. It had an illustrious past.   Ancient Sumerians,  Egyptians, Greeks, and Chinese  had known that  chewing the bark and leaves of willow tree (Salix in latin) gave relief from pain and fever. It was much later in  1763, that the  Royal Society of Chemistry published a comprehensive study by clergyman Edward Stone  on the medicinal effects of the dried, powdered willow  bark.  Six and a half decades  later  Professor Joseph Buchner at the Munich University identified the active ingredient to be  salicylic acid and named it salicin, giving credit to the salix tree.  Later it was  discovered that the shrub meadowsweet (Spiraea Ulmaria) is also a rich source of salicin.

However   pure salicylic acid was not easy on the stomach and caused  serious side effects such as nausea,vomiting and at times even bleeding.

Aspirin: Acetyl Salicylic acid

Towards the last decade of the nineteenth century, chemists at Bayer led by Felix Hoffmann  perfected the science  of  converting salicylic acid to its acetyl form which alleviated almost all of the undesirable side effects.  Bayer marketed the drug under the the name Aspirin;  A  for acetyl,  Spir  for spiraea, the shrub  and in  a tag used in general for medicines. Thus Aspirin initiated the  rush for isolating and identifying active ingredients in  folk and traditional medicines.  But scientists were still in the dark on how and where  exactly these drugs work in the human body. 

Revisiting the progress made by pharmaceutical industry  over the last 120 years since the introduction of aspirin,  Raymond  Deshaies, states that  the Rational Drug Design  was the next revolutionary leap that  redefined the industry. This was made possible in the 1970's because of the rapid advances made in the interdisciplinary fields such as    chemistry/biochemistry/pharmacology/medicine  and related areas.  Scientists now knew the chemistry and three dimensional structure of the target site and accordingly they could design suitable drug molecule to latch on. This idea known as  "Lock and Key" or one Target one Drug (1T1D) concept, ushered in the era of  rational  drug design.  And this trend continued  when  Recombinant DNA Technology   opened new vistas   with biomolecules as drugs.   In 1982  first  drug in this category  Humulin  (short for Human insulin)  hit the market. And then followed a series of  therapeutic  mAbs(monoclonal antibodies) for immunotherapy.  In all these endeavours,  drug design fundamentally still retains the  1T1D approach. 

However in parallel now  the idea  of   Multispecific Drugs (MDs) is catching up fast.   As the name  implies  these moieties  could have two or more docking points. Two types  of  MDs are being developed.  The first category are  drug carriers, which  would dock in close proximity to the target site and then release the drug molecule, thus improving specificity and reducing effective dosage. The second category is a more ambitious plan of  biological matchmakers  that will coax   two  entities  to come together and interact.  A typical example is hemlibra  now in market for haemophilia A.  Haemophilia is the inability of blood to clot.  Blood clotting involves a series of steps, each  requiring specific interaction between biological entities known as Factors.

Courtesy: wikipedia

There are 13 such factors. People with hemophilia A lack Factor VIII, which is necessary for bringing together Factors IXa and  X. Conventional treatment so far has been to supply the missing factor VIII. However  Hemilbra acts differently. It is a bispecific mAb that selectively and  exclusively latch onto Factors IXa and X and pull them to proximity so that they interact. 

TAILPIECE:

During  1970's, Professor John Vane, at the Pharmacology department, University of   London,  discovered  that aspirin interrupts platelet aggregation and thus prevents blood clotting. Professor  Vane together with  Sune Bergstrom and Bengt Samuelsson won Nobel Prize for physiology/medicine  in 1982 for their pioneering work on prostaglandins.

Bayer now  lists a variety of  Aspirins  such as  low dose,  regular dose,  chewable and genuine in  its product list.  The website states  effective on Pain. Prevention for recurrent heart attack, and clot related (ischemic) strokes. 

REFERENCES:
1. From a tree, a miracle called 'aspirin'
2. Multispecific drugs herald a new era of biopharmaceutical innovation.
2. Multispecific Drugs: the fourth wave of Pharmaceutical Innovation 
3. A sea of change in drug design
4. Emicizumab a bisspecific factor IXa and Factor X directed antibody, for the prevention of  
    bleeding episodes in patients with haemophilia A

On Magic Blue

              

lapis lazuli rock ( Wiki)

"The most perfect of all colors", thus wrote Cennino Cennini in the 15th century,  about   azzurre oltre marine in his   handbook for artists.  This mesmerising, precious  blue popularly known as ultramarine was  worth its weight in gold.  For Renaissance painters,  there were several   blue pigments to choose from  such as azure della magna, indigo, lapis armenus etc., but ultramarine  was the most sought after blue pigment.  The mineral rock  lapis lazuli from which the blue pigment was extracted, had to be imported from  beyond the seas and hence the name ultramarine.    Ancient caves dotting the Sar-i-Sang region in  Afghanistan were and are still the sole yet rich source of   Lapis lazuli. In old latin lapis means stone  and  lazuli is a derivative of lazulum,  a word associated with colour  blue. During there medieval times, rich patrons who commissioned paintings would often specify in the contract that ultramarine pigment must be used.  Because the  blue pigment prepared  from lapis lazuli retained brightness and clarity  for ages  whereas the cheaper  lapis armenus   turned green over time. Though comparatively costlier, ultramarine had  excellent spreading quality minute amounts were enough to paint the flowing robes of Virgin Mary or royalty or the vault of the  sky.

 Virgin Mary and infant Jesus 14th century
(wiki)

Lapis lazuli was known to the ancient world and they fashioned it easily into artefacts such as jewellery and decorative pieces.  But the process of  extracting  the blue pigment from the  rocks was laborious. Cennini in his  handbook  on the  art and science of painting and paint formulations, describes the process in detail. He cautions that for high quality pigment, blue rocks with minimal grey areas  must be selected and   ground dry to as fine a  powder  as possible.  The fine powder was then intimately mixed with 3 times  its weight of melted bees wax and   plant resins such as mastic and pine. The dough so obtained was kneaded repeatedly while being left to age for several days. Later when  extracted with very dilute aqueous alkali the pigment settled as a fine colloidal  paste. 

From alchemists, at the turn of the 19th century, chemists inherited the  spell of utramarine blue. It was known by then that the lazurite component of lapis lazuli held the blue.  An intense competitive search for a synthetic substitute began in 1824 when a competition was 

announced in France  with a prize money  of 6000 francs.  French chemist Jean-Baptiste Guimet and German professor of chemistry  Christian Gemlin  at the Tubingen University succeeded in freezing the correct composition. The prize however was awarded to Guimet.  Gemlin as sorely disappointed. Guimet chose to keep his formula secret, Gemlin published his results  and paved the  way for the ultramarine pigment industry. 

ultramarine blue structure
courtesy PubChem CID71587188

  While it was known that  sulphur content was responsible for the blue colour,  it took a century and half to  conclusively prove that the blue color is due to trisulfur  radical anion. 


The cheap synthetic substitute had no business to retain the name ultramarine, but it did and  pushed out  the original from the artists' palette almost  for ever.  

Tailpiece

In 2015, an art exhibition "Lapis Lazuli: The Magic of Blue" was held in Florence.  On display were artefacts and paintings of unique beauty, spanning from antiquity to the  21st century. 
In 2018, an international highway, Lapis lazuli corridor was inaugurated connecting Afghanistan to Turkey, reminiscent of the old trade route.

REFERENCES:
1. A treatise on painting : Cennini,Cennio
2. Lapis Lazuli and the history of the "Most Perfect Color"
3. Color in Art: a brief history of blue pigment.

Demand and Supply : Dealing with aggressive customers

Bumblebee foraging on flowers
(courtesy: Wikipedia)

Bumblebees are very demanding customers; their demand is for steady supplies of pollen.   If pollen is in short supply, they register their protest, by injuring the suppliers.  A research team  led by De Moraes and Mescher  at the ETH, Zurich were surprised to find  this bizarre behaviour of the bumble bees and followed up with a systematic study. They were even more surprised to note that the damaged flora responded by flowering ahead of time.  Onset of flowering is known to be influenced by a variety of environmental factors such as sunlight, ambient temperature availability of water/nutrients etc., however direct bee intervention  is perhaps being reported for the first time.

Bumble bees are social creatures. Spring is the time  when they start new colonies. New colonies mean hive  full  of hungry larvae. Pollen is the  only food given to the larvae and that means there should be flowers in abundance. If for some ecological or anthropogenic reason flowering is delayed, then the bumble bee community  will have to starve to death. It is to avert   such circumstances that  worker bees  puncture   leaves of flowering plants with their proboscises and mandibles.  Plants and trees on their part, can't and don't blacklist these violent customers because bumble bees are the most important group of pollinators in the ecological symbiosis.  

De Moraes's team  noted that bee damaged  plants  flowered several weeks  ahead of undamaged control plants. Curious, they included another set of plants whose leaves were manually injured  with forceps and razor. Manual damage didn't accelerate flowering. The team alludes to the possibility that  bees must be lacing the wounds with a chemical cue.  Such behaviour, that of chemical signalling either within same species and/or between different species  is  well known in the realm of  symbiosis. Pheromones , allomones and kairomones  are classic examples. Aptly enough  these  are collectively called semiochemicals (semion in Greek means signal).  The Zurich team's next step will be to identify the chemical that the bumble bee leaves behind on the leaves.  And perhaps that might usher in the era of unseasonal flowers. 
  

REFERENCES:

1. The role of plant sensory perception in plant-animal interactions :  Journal of Experimental Botany 2015,  66(2) 425-33: Mescher, MC and De Moraes C 

2. Identification of an insect-produced olfactory cue that primes plant defenses. 

3. Bumble bees damage plant leaves  and accelerate flower production when pollen is scarce : Science 2020,  368, pp881-884 Pashalidou et al
4. Stress induced flowering in Pharbitis

When Enemy is Unknown

We humans have to be ever on  alert to combat  new, as yet  unknown pathogens. That is why WHO,  the World Health Organisation included Disease X in its list of most dreaded pandemics.  There was a brief explanation  along side which  read: " Disease X represents the knowledge that a serious international epidemic could be caused by a pathogen currently unknown to cause human disease, and so the R&D Blueprint explicitly seeks to enable cross-cutting R&D preparedness that is also relevant for an unknown “Disease X” as far as possible.  WHO has officially named the virus responsible for the  current viral outbreak in China  as COVID-19, (short for Corona Virus Disease 2019).  Is this the much dreaded Disease X? Opinions differ on this point.

Hemagglutin spikes on the viral particle(blue)
latching on to host  cell membrane(pink)

Forewarned is indeed good, but that doesn't make us exactly forearmed. How do we design weapons against an unknown pathogen? In an answer to this question a global collective has been formed called CEPI( Coalition of Epidemic Preparedness and Innovation).  Registered in Oslo, Norway CEPI is an independent organization which will facilitate collaboration among medical doctors and researchers.  A non-profit organization, CEPI will work closely with WHO  to speed up remedies for pandemics.  CEPI's ambitious plan is to build on the existing knowledge  and reduce the time span from gene sequencing of the virus to clinical testing of the vaccine to 16 weeks.   A tough task indeed given the fact that it usually takes years to develop vaccines. 

The genetic map of the COVID-19 virus , a single stranded  RNA of 29674 bases has been decoded. Scientists have also modelled its three dimensional folding pattern and identified possible niches where a drug molecule can bind and thus prevent the virus from replicating.  Currently several drugs  Flavipiravir, an antiviral drug proved efficient against a variety of viral infections and Remdesivir proven efficient against MERS and SARS in animals   are  in the pipeline.  In the meantime, China has adopted a multiprong approach  to fight the disease. From HIV drugs and  stem cells to ancient and  traditional Chinese medicines are being  tested as possible drugs. WHO authorities are making sure that strict protocols are followed in each trial.  Some of the results are indicative but not yet proven.   

But the gravest question is what if the virus is susceptible to frequent  mutations?  So far the virus hasn't exhibited any such tendency. But doctors and scientists are ever on the alert.
  
References:

1. Prioritizing diseases for research and development in emergency context
2.Therapeutic  options for the the 2019 novel coronavirus 
3. The road to a coronavirus vaccine runs through Oslo
4. More than 80 clinical trials launch to test coronavirus treatments
5. US begins trial of Gilead' Remdesivir in Covid-19 patients