Contributions of Organic Chemist in Pharma and Agro

S. ChandrasekharCSIR-Indian Institute of Chemical Technology

Hyderabad, 500 007Email: srivaric@iict.res.in

International Crop-Science Conference & Exhibition(ICSCE 2018)Goa

20th November 2018

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“Science is a personal activity. Withvery few exceptions, scientiststhroughout history have plied theircraft not through a lust for glory ormaterial reward, but in order to satisfytheir own curiosity about the way theworld works.”

Science and Scientists

• Definition of Science– the intellectual and practical activity encompassing the

systematic study of the structure and behaviour of the physical and natural world through observation and experiment.

– "the world of science and technology"

• Who is a Scientist?– A scientist is a person who works in and has expert

knowledge of a particular field of science.– Or, more generally, any person who studies or works in a

scientific field.

• The Different Fields of Science– Fields of science are commonly classified along two major

lines:– Natural sciences, the study of the natural world, and– Social sciences, the systematic study of human behavior and

society.

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Science

Physical Sciences

Biological Sciences

Earth Sciences

Physics

Astronomy

Geology 4

Scientists: Not Poster boys

Isaac Newton and Albert Einstein

Watson & Crick and Alexander Fleming

A P J Abdul Kalam and C N R Rao

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The Beginning

• The first scientific observations were of the sky, stars, planets, comets and supernova– Copernicus (1473-1543)

• Described ‘Revolution of Celestial Bodies’ establishing revolution of planets

– Giordino Bruno (1548-1600)• Stars are distant suns• There is no centre to universe

– Tycho Brahe (1546-1601)• Called ‘naked eye astronomer’• Refuted belief of unchanged universe• Precise measurements identified supernova of 1572 (stellae

novea)

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The Pathbreakers

• Scientists who contradicted the scriptures– Johannes Kepler (1571-1630)

• Laws of Planetary Motion• Invented improved version of Refracting Telescope• Helio-centric geometrical model of the Universe• Treated Astronomy as Universal Mathematical Physics• His mother faced trial as witch

– Galileo Galilei (1564-1642)• Father of Observational Astronomy• Built telescopes• Championing of ‘Heliocentric universe’ was controversial• Had to face inquest• Was under house arrest for contradicting ‘geocentric’ view• After recanting his theory that Earth moves around Sun, he said “and yet it moves”• Identified 3 moons of Jupiter• Observed ‘Milky Way’

• Telescopes and lenses were the tools for development of this branch

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Start of Biological Sciences

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▪ Born in 1635 he was not expected to survive

▪ His diet was milk, milk products and fruits

▪ He had a weak constitution▪ Developed a pronounced

malformation of his body at 16 years▪ He developed expertise in making

tools▪ Studied coloured patterns produced

by thin layers of materials (wings of insects, oil spilled on water)

▪ Wrote ‘Micrographia’ concerned with microscopy

▪ Most famous discoveries are:▪ Cellular structure of slices of cork▪ Microorganisms in droplets of water▪ Sperm cells (he called animalcules)▪ Structure of feathers ▪ Nature of butterfly’s wings▪ Compound eye of a fly

Human Body • Andreas Vesalius (1514-1564) (the grave robber and dissector)– Founder of human

anatomy– Published 7 volume “On

the Fabric of Human Body”

• Gabriele Fallopio (1523-1562)– Studied inner parts of the

ear– Worked on understanding

path of nerves to face and structures that lie in their path

– Developed neuroanatomy

• William Harvey (1578-1657)– Circulation of blood– He doctorined omne

vivum ex ovo (all life comes from the egg)

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Temperature studies

• Studies of variations in temperature• Melting of ice and generation of steam• Establishment of Fahrenheit scale• Start of Chemistry as a Scientific Discipline

James Watt and his steam machine

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Identification of Elements

• John Black– Discovery of carbon dioxide by heating ‘white magnesia’

• Carl Scheele– Air is a mixture of two gases

• One prevents combustion and other supports it

– His work was not published till 1777

• Joseph Priestley– Air is a mixture of gases– Heated red calx of mercury (mercuric oxide) and the gas generated

was better than air for respiration– Identified 10 gases

• Ammonia, hydrogen chloride, nitrous oxide, sulfur dioxide etc.

• Henry Cavendish– Identified presence of hydrogen– Water is not an element but a compound– Noticed presence of Argon (as called today) but did not

characterise it

• Antoine-Laurent Lavoisier– Diamond is combustible– Sulfur gains weight on burning– In collaboration with Pierre Laplace proved that respiration is a

combustion, admittedly very slow but similar to burning of charcoal.

– Renamed elements and published ‘Elements of Chemistry’

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Periodic table

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150 Years of Periodic Table

• THE UNITED NATIONS PROCLAIMS THE INTERNATIONAL YEAR OF THE PERIODIC TABLE OF CHEMICAL ELEMENTS

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Modern Chemistry

• Wilhem Roengent (Nobel 1901)– X-Rays

• Becquerel & Marie & Pierre Curie– Radioactivity (coined by Marie Curie)– a, b, g-Rays– Marie died of aplastic anemia due to

exposure to radiation – Her notebook is protected as it is still

radioactive

• Rutherford– Model of atom

• Max Plank– Black body radiation

• Niels Bohr– First quantum model of atom

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Life Expectancy

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10

20

30

40

50

60

70

80

Life Expectancy at Birth in Years

Life Expectancy at Birth in Years

❖ Oldest confirmed recorded age is 122 years❖ Hindu belief is 120 years is the life span of humans

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• 10 Happiest Countries– Norway– Denmark– Iceland– Switzerland– Finland– Netherland– Canada– New Zealand– Sweden– Australia

• Parameters of Happiness– GDP per capita– Healthy years of Life expectancy– Social support– Trust (absence of corruption in Govt.

& business)– Freedom to make life decisions– Generosity

• India ranked 122

World Happiness Index

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Health

Agriculture

Energy

Industrial Revolution

• 1760-1840 (1820)– Began in Great Britain

• Salient Features– Machines instead of hand production– Chemical Manufacturing– Use of Steam Power-Railways– Rise of Factory system– Iron making– Textile industry– Urbanisation

• Chemical industry– Sulfuric acid– Sodium carbonate– Bleaching powder– Cement– Dyestuffs (eventually lead to discovery of chemotherapy)

• Agriculture– Mechanical seeder– Iron plough– Threshing machine

• Environmental impact

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Famines in the world• 441 BC the first recorded famine of ancient Rome

• 26 BC Near East and Lavant: ~20000+ deaths

• 800-1000 AD Mayan Mesoamerica: 1 million+ deaths

• 1601-03 Russia: 2million+ deaths

• 1702-04 India (Deccan): 2 million

• 1763-73 Great Bengal Famine 1770: 10 million deaths (~1/3rd population)

• 1783-84 Chalisa famine: 11 million deaths

• 1810, 11, 46 and 49 Four famines of China: 45 million deaths

• 1837-38 Agra famine: 1 million deaths

• 1845-49 Great Famine in Ireland: 1.5 million deaths

• 1869-79 Famine in India (5.25 million deaths), China (13 million deaths), Brazil, Northern Africa

• 1907, 1911 Famines in east-central China: 25 million deaths

• 1921 Russia: 5 million deaths

• 1959-61 The Great Chinese Famine: 15-43 million deaths

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Agricultural Revolutions

• Three major evolutions– Neolithic

• Change from hunters-gatherers society to farming• ~12000 years ago• Domestication of plants and animals• Cereal grasses, flax, peas, chickpeas, lentils

– British• Related to industrial revolution• Crop yield increased 2.7 fold between 1700-1870

– Green• Third revolution• 1950s & 60s• Started in Mexico and used extensively in India,

Philippines

• Two minor– Arab

• 8th-13th Century• Details of plant parts and how to propagate them• Animal-powered irrigation wheel

– Scottish• 17th-19th Century• Modernisation of agriculture

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Green Revolution

• Norman Borlaug (Nobel Peace Prize 1970) was considered “Father of Green Revolution” [credited for saving over billion lives from starvation]

• Funded by Ford Foundation and Rockfeller Foundation• Term “Green Revolution” by William S. Gaud, administrator of USAID in 1968• Salient features

– High yielding varities (HYVs) of cereals– Chemical fertilizers– Controlled water supply– Modernization of cultivation techniques

• Mexico– Government started Mexican Agricultural Program (MAP)– New breeds of maize, beans and wheat– Chemical fertilizers and pesticides– Wheat production 1951 (70%), 1965 (80%) and 1968 (90%)

• Philippines– A new variety of rice IR8 was developed by crossing Dee-Geo-woo-gen and Peta– Required use of fertilizers and pesticides– Annual production increased from 3.7 million to 7.7 million in two decades– Philippines became rice exporter from a starving nation

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• In 1961 Norman Borlaug was invited by adviser to Indian Agriculture Minister, Dr. M. S. Swaminathan

• Imported wheat seeds from International Maize and Wheat Improvement Centre (CIMMYT)

• Punjab was chosen to try growing seeds– Guaranteed water supply– Strong agricultural heritage

• Indian efforts– Plant breeding– Irrigation development– Financing of agrochemicals– Tractors– Fertilizers and pesticides

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Green Revolution in India

0

20000

40000

60000

80000

100000

120000

1961 1971 1981 1991 2001 2011 2015 2018

Green Revolution (1000MT)

Wheat Rice

• IR8 rice variety from International Rice Research institute

• IR8 rice yielded 5 tonnes/hectrewithout fertilizers and 10 tonnes/hectre with pesticides and fertilizers: 10 times more than traditional

• India exports rice • Criticism faced

– Demand for high irrigation and fertilizer and pesticide

– Environmental issues• Polluted water bodies• Resulted in death of wild life and

beneficial insects• Overuse results in depletion of soil

nutrients

– Increase in disparity– Disappearance of diversity

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Green Revolution in India

Cancer Train , Punjab

• Punjab’s total area is just 1.5% of India but it contributes 19% of wheat and 12% of rice production in India.

• Malwa region of Punjab “the laboratory for Green Revolution in India” includes Barnala, Bathinda, Faridkot, Moga, Muktsar, Fazilka, Patiala, Ludhiana, Ferozepur, Ropar, Mohali, Sangrur, Fatehgarh sahib and Mansa.

• Bathinda has reported fast growth of number of cancer patients: Cancer capital of the state

• Excessive use of pesticide, insecticides etc. is thought to be the reason for cancer cases

• Punjab farmers' use of pesticides is 923 g/ha, vs. national average of 570 g/ha (grams per hectare).

• Fertilizer use is at 380 kg/ha (kilo per hectare), three times the national average of 131 kg/ ha, as per the National Centre for Agricultural Economics and Policy Research.

• "20 different types of pesticides are used in our village, every year. They cost us more than Rs two crore“- a farmer

• Every village with a population of 3,000-5,000 has at least 30 cancer cases in a period of 8 to 10 years and atleast 18 deaths due to cancer in Punjab everyday

• Women are more prone to death due to cancer

• Farmers in this region use 15 different pesticide sprays

• Of the 15 pesticides used, at least 7 are considered cancer causing by the US environment protection agency because it affects the drinking water.

• Abohar-Jodhpur passenger train travels from Bhatinda in Punjab to Bikaner in Rajasthan

• The ticket is priced at Rs 210, but for cancer patients the eight hour journey to Bikaner is free, while one accompanying attendant gets a concession of 75 percent.

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INSECTICIDES

1. Monocrotophos: 17 firms

2. Chlorpyriphos: 13 firms

3. Diazinon: 2 firms

4. Quinalphos (RRL-J): 2 firms

5. DDVP (RRL-J): 3 firms

6. Trimethyl Phosphite:3 firms

7. Profenofos: 1 firm

HERBICIDE

8. Glyphosate: 1 firm

INSECTICIDES

1. Lambda Cyhalothrin: 1 firm

2. Esfenvalerate: 3 firms

3. Cypermethrin : 1 firm

4. γ-BHC : 2 firms

5. Indoxacarb : 1 Firm

FUNGICIDES

6. MBC : 2 firms

7. Thiophanate methyl: 1 firm

8. Dodine : 2 firms

HERBICIDE

9. Butachlor : 4 firms

10. Isoproturon : 2 firms

Over all 42 firms availed knowhow from CSIR-IICT

Enquiries from industries for process/ yield improvements

CSIR-IICT Interventions for comprehensive crop care

Revisiting process routes for improvements

Phosphorous based Agrochemicals

PHEROMONE APPLICATION TECHNOLOGY (PAT)1. Controlling major pests

on vegetable and fruit crops

2. Cotton Bollworms Industries : 14Networking with ICAR institutes/ Agri Univ. : 19

BIOPESTICIDESExtracts of 1. Azadirachta indica (Neem)2. Annona squamosa 3. Pongamia glabra

(KARANJA seeds) ‘7’ Indian Industries

Process technologies released to industry

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Non-Phosphorous Agrochemicals

Integrated Pest Management

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Agro mission @ CSIR‘12’ Agromolecules were identified for process development

Metofluthrin FlubendiamideSpirotetramat Pymetrozine

Epoxiconazole

GlufosinatePenoxasulam

Picoxystrobin Penflufen

PyroxasulfoneTembotrione

Prothioconazole

Insecticides

Fungicides

Herbicides

Tomato Leaf Miner50 Ha

Spotted Bollworm Pest of cotton

100 Ha

Diamond Back Moth 100 Ha

Melon Fly50Ha

Pink Bollworm 500Ha

Rice Yellow stem borer1000 Ha

Sugarcane Inter node Borer5000 Ha

Cotton Leaf Worm50 Ha

Brinjal Shoot & Fruit Borer1100 Ha

Groundnut Leaf miner 10,000 Ha

Sugarcane Early Shoot Borer200Ha

American Bollworm1000 Ha

Citrus leaf minerNursery NRCC Nagpur

Pheromone Application Technology – Insect Pest Management

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➢ Rice Yellow Stem Borer ; YSB

Some of the components of Insects Pheromones

➢ Sugarcane inter node borer

Japanese blendZ-11-Octadecenal , Z-13-Octadecenal Z-11-Octadecenol, Z-13 –OctadecenolIndian blend Z)-11-hexa-decenyl acetate (Z)-13-octadecenyl acetate

➢ Rice Leaf Folder

➢ Sugarcane Top shoot borer

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➢ Pheromone system of Red

palm weevil (RPW) -

aggregation pheromone

➢ Groundnut Leaf Miner; GLM

➢ Brinjal shoot and fruit borer; BSFB

➢ Pink Boll Warm (PBW) - Cotton

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Significant Observations

Socio- economic Benefits Derived by the Farming Community:The benefits are innumerable as PAT is eco-friendly and

environmentally safe .The application has greater impact on developing healthy agro produce and there by improving health of farming community, live stalk & society.

CSIR-IICT under farmers' participatory approach successfully demonstrated PAT & controlled the devastating pests:

❖Groundnut leaf miner (350 acres)❖ Rice Yellow stem borer (300 acres) and❖Brinjal shoot & fruit borer (50 acres)

Reduction in pesticide sprayings due to implementation of PAT

➢ Groundnut crop 80% .➢ Rice crop by 70%➢ Brinjal crop by 50 %

Additional income derived by PAT farmer to non PAT farmer(after substracting expenditure incurred towards PAT inputs)

❖Groundnut farmer Rs.2996 / per acre❖Rice farmer by Rs. 4696/ per acre❖Brinjal farmer by Rs. 13,640/-per acre

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Plant Based Crop Protection Products in Development at CSIR-IICT

❖ Development of optimal extraction protocols

❖ HPLC analysis / method development

❖ Quantification of the active ingredient in various extracts

❖ Extracts of AZADIRACTHA indica(NEEM seed/ Kernel)

❖ Extracts of ANNONA squamosa(CUSTARD APPLE seeds)

❖ Extracts of PONGAMIA glabra(KARANJA seeds)

NATURAL appeals more in commercial aspects

Botanical Active Ingredient

Chrysanthemum Pyrethrins

Garlic Allicin

Millettia Rotenone

Wild Asparagus StemonineStemonone

Indian Lilac Toosendanin

Sophora Matrines

Tulsi Ocimene, Eugenoletc

Cnidium monnieri Osthol

Plant Based Products in exploration

Delivered to ‘7’ Indian Industries

Neem Seed/ Kernel

Extract of A IAzadirachtin

Neem oil Left over Cake

BiopesticideCoating UreaSoap Industry

Used in fieldsas soil nutrients 31

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GM Crops: Boon or Bane?• Genetically modified crops

– Resistance to pests, diseases and environmental conditions

– Reduction of spoilage– Resistance to chemical treatment– Improving nutrient profile

• 1996- 1.7 million hectres to 2016- 185.1 million hectres

• Major crops– Soyabean– Maize– Canola– Cotton

• Reduced pesticide use by 37%• Increased crop yield by 22%• Increased farmer profit by 68%• Centre for Food Safety and other

organizations caution that risks related to GM foods are not adequately studied

• Concerns over damage to bio-diversity

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Late 20th Century

First generation cell phones

First generation laptops New laptops

First generation computerNew computer

New cell phones

Ancient healthcare

Modern healthcare

Good health

Good Health

Prevention

Diagnosis

Cure

Personalised Medicine

By 2030, one should expect more targeted therapies, practitioners will also be able to predict the likelihood of a patient being diagnosed with a disease or health condition, and shift from treatment of symptoms to prevention measures and complete cures, rather than providing temporary respite.Pharma 2030: From evolution to revolution

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Antibacterial Chemotherapy

• Paul Ehrich (Nobel Prize 1908) proposed ‘certain dyes could selectively stain bacterial cells’

• Prontosil the first azo dye drug to treat streptococci infection invented by Bayer Laboratories

• Gerhard Domagk (Nobel 1939) administered prontosil to his daughter who had streptococci infection

• Prontosil is a prodrug that releases sulphanilamide

• Sulpha drug based chemotherapy started from there

• Sulfamethaxozole is the one of the most celebrated sulfa drugs

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Sulfamethoxazole

Prontosil

Story of Vaccines

Small Pox Vaccine by

Edward Jenner 1796

BCG Vaccine

1924

Tetanus vaccine

1927

Diphtheria, Tetanus, Pertussis

(DTP Vaccine)

1930

Polio injectable

vaccine 1955

Polio Oral Vaccine

1960

Measles, Mumps, Rubella (MMR

Vaccine) 1960-69

Hepatitis B vaccine

1981

Human papilloma

virus licensed

2006

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• Vaccine is derived from “Variole vaccinae” (smallpox of cow)• Smallpox vaccine was developed by Jenner after observation that people had cowpox did

not catch smallpox• Jenner isolated smallpox pus and injected into 8 year boy, smallpox infection did not occur

By 2030, one should expect more targeted therapies, practitioners will also be able to predict the likelihood of a patient being diagnosed with a disease or health condition, and shift from treatment of symptoms to prevention measures and complete cures, rather than providing temporary respite.Pharma 2030: From evolution to revolution

Penicillin

• Discovered by Sir Alexander Fleming, from Penicillium notatum in 1928, awarded Nobel Prize in 1945.

• Presence of β-lactam confirmed by X-Ray crystallography by Dorothy Crowfoot Hodgkin.

• Large scale bio-transformation process was from P. chysogenum.

• During World War II, penicillin was in short supply and had to be isolated from urine of patients.

• First total synthesis achieved by J. C. Sheehan after 10 years of campaign.

Famous Molecules

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Salicylic acid

Penicillins

Lovastatin AzithromycinPaclitaxel

Cyclosporin

Rapamycin and analogues

Rapamycin = Amrut?????

• Sirolimus (rapamycin) produced by bacterium Streptomyceshygroscopicus

• Is immuno-suppressant and used to prevent rejection in organ transplant

• Analogue temsirolimus is approved for renal cell carcinoma• Everolimus has application as immunosuppressant• Sirolimus increases lifespan in mice but has not shown any

effect on aging process• Sirolimus has shown to play role in cancer as antiproliferative

agent; treating tuberous sclerosis complex; reduced brain lesions for Alzheimer’s treatment; may work in muscular dystrophy; decreases disease activity in systemic lupus erythematosus patients; inhibit HIV replication; may become a therapeutic option for autosomal-dominant polycystic kidney disease and finally, may combat progeria.

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History of Rapamycin

• Isolated from soil bacterium Streptomyces hygroscopicus from Easter island and found effective as an antifungal agent

• Named Rapamycin from Rapa Nui for Easter Island, Sample with Ayerst Laboratories in Montreal

• Dr Suren Sehgal did not destroy the sample going against the diktat of his company supervisors

• Wyeth Pharmaceuticals bought Ayerst and allowed Sehgal to continue work on rapamycin

• FDA approved rapamycin as immunosuppressant in 1999• Sample sent to National Cancer Institute and found effective against breast, kidney and

lung cancers [Novartis earnings more than 1 billion USD (2013)]• Scientists at Sandoz independently identified the target protein called mammalian Target

of Rapamycin (mTOR) in 1990s40

• Cardio-Vascular Disease 31.5%– Heart diseases– Brain stroke

• Infectious and Parasitic Disease 16.7%– Bacterial (Tuberculosis 2.7%)– Viral– Fungal

• Cancer 13.4%– Prostrate– Breast– Lung– Leukemia

• AIDS/HIV 3.5%• Neuro-psychiatric Disorders 2.2%

– Alzheimer’s Disease and other Dementia– Parkinson’s Disease– Depression and Schizophrenia

• Road accidents Unaccountable

Major Causes of Mortality Worldwide (2012 WHO report)

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Role of Scientists

Problem identification

Solution to the identified

problem

Development from the solutions

Side-effects arising

Solutions to side-effects

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Scientists

Challenges

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