Chemistry-biology interface: a historical perspective
Federico Cisnetti
ICCF/SEESIB
Formation Initiation scientifique en Anglais Outline
• 1. Contemporary view • 2. Historical perspective of “organic” chemistry • 3. Four Nobel prizes: evolution of chemistry applied to biology during the 20th century. • Conclusion and outlook
2 1. Contemporary view
• … Physics
• Matter is constitued of atoms. Chemistry • Atoms form molecules • Molecules interact to form complex structures • These assemble themselves to form cells. • Cells forms tissues. Biology • Organs are made from tissues • …
3 What we know today
O,C,H,N: bulk elements K,P,Ca,S,Na,Cl: Macro-elements Oligo-elements All or most compounds toxic
Dose-effect curve
Deficiency of essential metals is lethal … but these are toxic at high dose
4 4 What we know today Chemical composition of the human body
Organic Matter CHNOPS
Water H2O
Inorganic compounds: Ca5(PO4)3(OH) (hydroxyapatite): bones 5 What we know today
Mitochondria Nucleus Typical Cell
Mass: 1 ng 5 1013 carbon atoms 1014 cells by human being
A cell is simultaneously:
Very large compared to molecules ~200.000 C-C bonds Very small compared to the body 6 The place of chemistry in contemporary science
Chemistry: science studying matter, its structure and properties above the atomic level and its modifications in chemical reactions.
Contemporary chemistry relies on the principles of quantum physics (first half of the XXth century)
Biology: is a natural science concerned with the study of life and living organisms
Biochemistry: study of chemical processes in living beings. Organic chemistry: chemistry based on the molecular compounds of carbon.
7 T. Balaban and Douglas J. Klein, Scientometrics, 2006 Historical perspective of ‘organic’ chemistry
Chemists were interested in living matter:
• before the rise of the modern concepts of atoms and molecules (XXth century) • before the understanding of what defines a chemical compound (XVIIIth-XIXth centuries) • before… chemistry if one considers alchemy as precursor of chemical practice.
Key historical questions:
• which substances are necessary for life? • could man-made substances be used in medicine? • is living matter obeying the same laws as mineral, inert substances?
8 The beginnings of « chemistry » applied to living beings: Alchemy
Antiquity middle ages renaissance Egypt, Greece Arab world Europe & rest of the world
Antiquity • Origin: Alexandria, Egypt, intellectual centre of egypto-greco-roman civilisation (Great Library) • Technical recipes focused on manufactory of gold: alloys of golds superficial gilding. • Mercury was recognised as able to dissolve gold, and, simultaneously as a poison
Most primary sources lost during the dark ages Experimental setup by Zosimus 4th century CE 9 Alchemy
Arab alchemists → Arab translation of greek sources Jābir ibn Hayyān (721-815), Al-Razi (865-925)...
Several important "pre-chemical" developments • Techniques: crystallisation, distillation. • Sophisticated laboratory apparatus : e.g. ovens athanor • First intuition about the fact that definite quantities of each substance are needed for alchemic processes • Discovery of important substances: alcohol, acetic acid, nitric and sulfuric acids • Elixir to transmute a metal in another one.
European Alchemists → latin translation of arab texts Metals form deep inside Earth under the influence of celestial bodies. Corrosion of metals Illness Analogy between alchemy and medecine Gold is the most perfect metal. Purify a metal and transmute it into gold a cure for the sick patient
Elixir, panacea: universal remedy The alchemist, Joseph Wright, 1771
10 From alchemy to chemistry
Paracelsus (1494-1541, Switzerland), focused on the concept of chemical pharmacopeia. He is considered as the founder of iatrochemistry (medical chemistry)
Attemps of therapies with metal-based preparations Correspondances Sun Gold Heart Dosis facit venenum. The dose makes the poisson Moon Silver Brain Very modern idea! Jupiter Tin Liver Venus Copper Kidneys ….
Jean-Baptiste Van Helmont (Flanders, 1627-1691)
Precursor of pneumatic chemistry.
Van Helmont applied the experimental method to verify alchemical assumptions
Experiment that allowed Van Helmont to conclude that water is the primordial element - 11 - Discovery of gases: biological properties
• Jean-Baptiste van Helmont discovered that "gas sylvestre" originated from the combustion of charcoal. Later on, he recognised that this gas was unbreathable and was the same that originated from fermentation.
• Joseph Priestley isolated pure oxygen in 1774 but did not recognise it as an element. Instead he believed that his sample contained "dephlogisticated air". He noticed that "five or six times better than common air for the purpose of respiration, inflammation, and, I believe, every other use of common atmospherical air “.
•Lavoisier discovered that air was consituted of two gases "vital air " (later renamed to oxygen) and azote (greek etymology: lifeless). It was recognised that « vital air » allowed both combustion and respiration.
The parallel between combustion (or corrosion) and respiration was understood since the very first modern chemical experiments.
- 12 - Beginnings of ‘organic’ chemistry
Nicolas Lémery (France, XVIIth century) suggested the extension to chemistry of the division of the world into vegetal, animal and mineral. Organic chemistry was founded as the chemistry of organised substances (vegetal and animal)
1780-1820: foundation of modern chemistry (Lavoisier) Chemical analysis of living matter. Decomposition in species that chemists could analyse and quantify.
Justus Liebig (Germany, 1803-1873) used CuO to analyse organic matter. Elemental analysis chemical formula
Liebig’s laboratory in Giessen
13 Composition of (living) matter
Today, chemistry is based on the descption of matter as molecules as assemblies of atoms. John Dalton introduced the first modern atomic theory. He established the law of multiple proportions ("New System of Chemical Philosophy“, 1808)
“If two elements form more than one compound between them, then the ratios of the masses of the second element which combine with a fixed mass of the first element will be ratios of small whole numbers”
John Dalton, the first modern atomist
14 Hot debate between atomists and anti- atomists (equivalentists) throughout the XIXth century
15 Vital force theory (vis vitalis)
Jöns Jacob Berzelius (Sweden, first half of the XIXth century ): Study of mineral compounds, discovery of several elements.
Chemists cannot prepare by synthesis compounds found in living beings Need of a « vital spark » (transcendent/religious explanation)
Chemists could decompose or modify an organic sample but not reconstitute it.
First counter-evidence: Friedrich Wöhler (1828)
Pb(CNO)2 + 2NH3 + 2 H2O → Pb(OH)2 + 2NH4(CNO)
The vitalist theory, was not completely overturned…
- 16 - The action of living beings on chemical compounds revived the vitalist theory
i.e. in modern terms: enantiopure compounds are accessible only from living sources
The vitalist theory was definitively overturned by the proof enzymes (ferments) as isolated chemical compounds could allow chemical transformations.
Although the vitalist theory is obsolete, « organic chemistry » remains.
17 Four Nobel Prizes: 1907-1964
The history of the Nobel Prize in chemistry throughout the XXth century allows to understand the greatest achievements of this science and the topics that attracted and continue to attract the attention of scientists.
More than 30 of the Nobel Prizes in chemistry awarded (each year between1901- 2013 with very few exceptions) correspond to topics belonging chemistry-biology interface
Eduard Buchner (Germany) Norman Haworth (USA) 1907 1937
Vincent du Vigneaud (USA) Dorothy Hodgkin(UK) 1955 1964
1907 for his biochemical researches and his discovery of cell-free fermentation
“The work on which I have to report lies on the boundary between animate and inanimate nature. I therefore have reason to hope that I can interest not only the chemists but also the wide circles of all those who follow the advance of biological science with close attention.”
• 1680: microscopic observation of yeast. (van Leeuwenhoek). Not recognised as a living organism
•Last part of XIXth century: biologists established « yeast as live cells of a plants » Fermentation as a result of life
Mixed receptions among chemists: Some of them were vitalists, others opposed the Microscopic Image of yeast theory 19 Before Eduard Buchner
Jöns Jacob Berzelius (1779-1848) assumed that yeast caused the decomposition of sugar catalytically, simply by its presence as a contact substance or catalyst.
Justus Liebig (1803-1873) opinion was that yeast caused fermentation "in consequence of a progressive disintegration which it suffers in the presence of air in contact with water”
Louis Pasteur (1822-1895), finally recognised that in Nature without living organisms, no fermentation exists.
Moritz Traube (1826-1894), assumed that there was in micro-organisms a certain chemical body which caused fermentation.
How to study fermentation chemically?
20 Eduard Buchner
1000 g yeast + hard, fine-divided (quartz, etc) 500 g liquid extract
Carbon dioxide bubbles and formation of ethanol if added to a solution of sugar. First experimental setup, fermentation then sophisticated hydraulic presses.
21 Norman Haworth
1937 for his investigations on carbohydrates and vitamin C
Haworth introduced the representation that bears his name nowadays.
Simple sugars had already been explored decades before by Emil Fischer (Nobel Prize 1902)
“Twenty years ago it could have been said that the wealth of natural products which comprise the carbohydrate group was bewildering in its complexity. Such materials as cellulose, glycogen, and starch seemed almost beyond the range of structural investigation” (N. Haworth Nobel lecture)
Haworth and others established the structures of natural carbohydrate polymers by chemical means. These works contributed greatly to the understanding of the general properties of life’s macromolecules. 22 Haworth’s legacy: carbohydrate polymers
Monosaccharides = carbohydrates
(CH2O)n where n ≤ 7(most often)
Disaccharides: 2 monosaccharides. Oligosaccharides > 3 monosaccharides. Giant polysaccharides: up to several thousand units Potato amyloplasts with starch colored by iodine Example : D-glucose polymers (glu)n • Starch (plants, energy storage) • Glycogen (animals, energy storage) • Cellulose (plants, structure) 23 Structure of starch
1) Amylose
Linear, water-soluble polymer (14) bond
2) Amylopectin
Ramified polymer, 1 ramification each 24-30 glu units Sparingly soluble in water Ramification : (16) bond
24 Structure of cellulose
= linear glu chains with (14) bonds (instead of (14) in starch)
Forms fiber in plants wood, cotton, paper.
Animals cannot break (14) bonds
Overall: glucids as pioneered by Haworth illustrate that function is aquired by polymerization, 3D structure and interactions with other molecules
25 Haworth’s legacy: synthesis of vitamin C
Haworth correctly determined, by chemical means, the structure of vitamin C (ascorbic acid)
Acidic compound without carboxylic group, strong reductant, derived from sugars.
Tadeusz Reichstein (1933) developed this process for synthesis of vitamin C
ascorbic acid
1955 "for his work on biochemically important sulphur compounds, especially for the first synthesis of a polypeptide hormone“
Peptides have been investigated since the beginning of the XXth century
Theodor Curtius
1902
O H NH N COOH Emil Fischer H N COOEt H N 2 HN 2 O O Diketopiperazin
O CH3 H2, [Pd] O NH-peptide CO2 H2N-peptide Introduction of protective groups Max Bergmann, Leonidas Zerwas, 1932 27 Vincent du Vigneaud
Disulphide bridge
Synthetic oxytocin did possess the same physical and chemical characteristics than natural peptides and displayed its activity
Very important hormone in human behaviour 28 J. Am. Chem. Soc. 1954
After du Vigneaud’s works…
The synthesis of peptides is now mostly performed using solid phase chemistry.
This technique relies on sophisticated protection/deprotection schemes.
29 Dorothy Hodgkin
1964 "for her determinations by X-ray techniques of the structures of important biochemical substances “
“…. [The] great advantage of X-ray analysis as a method of chemical structure analysis is its power to show some totally unexpected and surprising structure with, at the same time, complete certainty...“ (D. Hodgkin Nobel lecture)
Contemporary apparatus
30 Dorothy Hodgkin Cholesterol: steroid Pepsin Penicillin: demonstration of the structure contrary to scientific opinion at the time
Vitamin B12 31 Conclusion and outlook
• The chemistry/biology interface has always been actively considered by chemists
• Contemporary research:
- Macromolecular structure is accessible by physico-chemical techniques necessary for understanding the mechanism of action of drugs
- Biological polymers may be synthesized chemically but macromolecular synthesis remains a challenge
- Macromolecules such as enzymes may be used in new chemical processes ‘greener’ chemistry?
- The molecular complexity of life is now understood it is still a challenge to apply analytical methods to detect a species of interest in a living system.
Thank you for your attention! 32