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Isotopic Resonance –the first 10 years
Xueshu Xie, Alexander R. Zubarev, Sergei Rodin, Xupei Zhang and Roman A. Zubarev
Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles väg 2, S-171 77 Stockholm, Sweden
able Isotopes affect Kinet
ofopic composition of Eart is beneficial for Life
Life on Mars is unlikely
Isotope Mass Abundance
1H 1.007825102H (D) 2.01410222 0.0148%
12C 12.0(0)13C 13.0033544 1.108%
14N 14.0030743915N 15.0001077 0.365%
16O 15.9949150217O 16.9991329 0.037%18O 17.99916002 0.204%
Masses and abundances of stable isotopes
Πυθαγόρας
c. 570 – c. 495 BC
• “All things are numbers”
• “Harmony of the spheres” (Musica universalis)
π = 3.1415926…
Is π a random number?Or is there hidden harmon
there?
Finding π from Pythagoras's Theoremhttp://www.physicsinsights.org/pi_from_pythagoras-1.html
Proper mapping revealsorder (symmetry) hidden in number π
Puent C.E., DNA, π and the Bell, Complexity, 2001, 6, 16-22
Randomization of every 10,000th bit destroys this picture
π = 3.1415926…
Isotope Mass Abundance1H 1.007825102H (D) 2.01410222 0.0148%
12C 12.0(0)13C 13.0033544 1.108%
14N 14.0030743915N 15.0001077 0.365%
16O 15.9949150217O 16.9991329 0.037%18O 17.99916002 0.204%
Masses and abundances of stable isotopes
Lots of numbers…
Where is the music?
Frog skin peptides
Peptide cocktail
Electric stimulation
Rana ridibundaRana arvalis
Rana temporaria
De novo MS sequencing
Hundreds of peptides5-6 families of peptides
with A. Lebedev and T. Samgina, Moscow State University
3 4903 4853 480
100
90
80
70
60
50
40
30
20
10
0
average massC=12.011N=14.03
…
monoisotopic mass
C=12.000(0)N=14.00307439
…
nominal massC=12N=14
…
C153H224N42O50
Molecular mass is the isotopic distribution!
3450 3455 3460
Massdefect
Isotopicshift
Molecular mass, Da
Introducing two mass parameters:
Normalized mass defect, NMD = 1000*(Mmono - Mnominal)/Mnominal
Normalized isotopic shift, NIS = 1000*(Maverage - Mmono)/Mnominal
Mnominal
MaverageMmono
2D mass mapping
NMD - refers to binding energy of the nucleusNMD = 1000*(Mmono - Mnominal)/Mnominal
14N = 14.00307439 Da
NIS - refers to abundances of other isotopesNIS = 1000*(Maverage - Mnmono)/Mnominal
A(14N) = 99.625%
Mnominal
MaverageMmono
2D mass mapping
R. arvalis 2D mass map
FVPLLVSKLVC*VVTKKC*PLLVSKLVC*VVTKKC*
Artemenko et al. Anal. Chem. 2009, 81, 3738–3745
R. temporaria 2D mass map
Artemenko et al. Anal. Chem. 2009, 81, 3738–3745
Masses and abundances of stable isotopes
What is this?...
August 2008
Central line
Molecules satisfying:
S = 0H = 2C - N;
O - any
z = C - (N + H)/2z = 0 - on-Line
On-Line as residues On-Line in free form
Basic
Aromatic
z = C - (N + H)/2
√√√√
√√√√√
√ -√ -√ -√ -
---
√√
√
√√√
√√√
√√√
NANA
Not all amino acids are equally abundant on-Line
Alanine, C3H5NO
0
Asparagine, C4H6N2O2
0
Glutamine, C5H8N2O2
0
Glycine, C2H3NO
0
Isoleucine C6H11NO
0
Leucine C6H11NO
0
Serine, C3H5NO2
0
Threonine, C4H7NO2
0
Valine, C5H9NO
0
Aspartic Acid, C4H5NO3
1
Glutamic Acid, C5H7NO3
1
Histidine, C6H7N3O
1
Proline, C5H7NO
1
Arginine, C6H12N4O
-2
Lysine, C6H12N2O
-1
Phenylalanine, C9H9NO
4
Tryptophan, C11H10N2O
5
Tyrosine, C9H9NO
4
19
Reducing/Oxidizing Environment
Conditions: Electric spark
13 amino acids essential for life were produced
Most of them have Z = 0
Stanley Miller ( 1930 - 2007)
Raw materials: CH4, NH3, H2O, H2
The Miller-Urey Experiment (1953)
Isotopic Resonance Now and Then
Early Life
Probably,
70-80% of all AAs (by abundance) had Z = 0
Modern LifeRelict Line
57% of all AAs (by abundance) have Z = 0
Z-value
Z = 0
Data of Norbert Hertkorn
CHN molecules in meteorites
Z=0 is a singular valuefor small organic molecules
z = C - (N + H)/2z = 0 - on-Line
1. An isotopic resonance reduces the complexityof a molecular system with Z=0.
2. Complexity reduction leads to faster kinetics.
3. Z=0 represents the simplest and the most abundant class of molecules formed spontaneously.
4. If so, early Life could have been helped bythe terrestrial isotopic resonance to emerge
or take root on Earth.Zubarev R. et al. Cent. Eur. J. Biol. 2010, 190-196
Isotopic resonance hypothesis
Less complex systems are in general faster
Simpler = Faster
At the core of the Isotopic Resonance hypothesis:
Symmetry reduces complexity
System A System B
The same number of Parts and Links
What is symmetry?
Nobel laureate PW Anderson wrote in his 1972 article More is Different:
"it is only slightly overstating the case to say that Physics is the study of symmetry."
In Quantum Mechanics:symmetry leads to degeneracy of QM states.
Symmetry = Reduction of complexity
W – number of QM states
Symmetry leads to instability: Jahn-Teller effect
• Symmetry-> degeneracy of energy levels
• Degenerate systems -> instability (higher in energy than the corresponding asymmetric system)
• Symmetric systems -> undergo distortions (“Jahn-Teller distortions”) tobecome lower-energy asymmetric systems
16O17O16O -> 676
Mass independent isotope fractionation:effect of compositional symmetry
O2 + O2* -> O3* + O
Symmetry & Kinetics
A more complex system(less symmetric)
A less complex system(more symmetric)
Otherwiseidentical
Hotter molecules –Faster chemistry
No isotopic resonance Isotopic resonance
Isotope Mass Abundance
1H 1.007825102H (D) 2.01410222 0.0148%
12C 12.0(0)13C 13.0033544 1.108%
14N 14.0030743915N 15.0001077 0.365%
16O 15.9949150217O 16.9991329 0.037%18O 17.99916002 0.204%
14 parameters
Without a linear dependence
Average molecular mass
3 4903 4853 480
100
90
80
70
60
50
40
30
20
10
0
Isotope Mass
1H 1.00782510
12C 12.0(0)
14N 14.00307439
16O 15.99491502
a
b
6 parameters (if a ≠ 0, b ≠ 0)
y = 0.3613x + 0.3978R² = 0.99989
0,56
0,57
0,58
0,59
0,6
0,61
0,62
0,63
0,64
0,4 0,45 0,5 0,55 0,6 0,65 0,7
Maverage = a • Mmono + b
32
13C, %
Reac
tion
rate
Re
acti
onra
te
Conventional theory
Isotopic resonance hypothesis
Isotopic resonance hypothesis: predictions
13C, %
BioScreen
Isotopic resonance hypothesis: testing
E. coli stock in glycerol (-700C)
Agar plate
Media for 3-4 h
Measure the growth curve
E. coli growth curve
34
E. Coli growth parameters
Effect of 15N content on E. Coli growth
3.5% 15N
Normal 0.37% 15N
“Flat line” resonance for z=0
Effect of 13C content on E. Coli growth
Effect of 15N content on E. Coli growthRe
lati
ve m
axim
um d
ensi
ty
% 15N
Effect of 15N content on E. Coli growth
Higgs boson evidence from Atlas experiment
0.35% 13C
Normal 1.1% 13C
“Flat line” resonance for all molecules
Effect of 13C content on E. Coli growth
Effect of 13C content on E. Coli growth
Normal 1.1% 13C
“Thin line” resonance for all moleculesAverage mass ≈ to nominal mass
2H – Normal; 13C, 15N and 18O ≤ 13%
Effect of “Super resonance” on E. Coli growth
Effect of “Super resonance” on E. Coli growth
Deuterium content effect - predictions
D content, %
Com
plex
ity re
duct
ion,
arb
. uni
ts
Z=0 Resonance
Earth, 0.015%
Abundances of C, N, O isotopes –normal
Deuterium content – 150 ppm
1/6000
≈300-400 ppm
0.1% 1% 10% 100%
Normal concentration, 150 ppm
Fast water
Slow water
Rela
tive
grow
th ra
te
Deuterium concentration, parts per million (ppm)
Natural range, 90-160 ppm
Deuterium content effect - predictions
150 ppm
200 ppm
300 ppm
400 ppm
Lobyshev V.I. et al., Biophysics, 1978, N2, 390-391.
ValentinLobyshev
Deuterium content effect - experimentsN
a, K
-ATP
ase
activ
ity, a
rb. u
nits
Deuterium concentration in water, %
Deuterium content effect on luciferase activity
≈30%
Rodin, S.; Rebellato, P.; Lundin, A. Isotopic resonance at 370 ppm deuterium negatively affects kinetics of luciferin oxidation by luciferase, Sci. Rep. 2018, art. 16249.
IsoRes confirmation by other groups
3.5% 15N
What is the strongest resonance?
A more complex system(less symmetric)
A less complex system(more symmetric)
Otherwiseidentical
Faster chemistry
Natural isotopic abundance
Monoisotopic: all carbons – 12C, all hydrogens – 1H, etc.
Monoisotopic
Predictions of the isotopic resonancehypothesis
• Monoisotopic molecules will possess beneficial properties, such as:
- Faster kinetics (enzymes) (?)
- Stronger binding (antibodies) (??)
- Better protein crystals for X-ray structures (?)
- Higher resolution in neutron spectroscopy (?)
16O17O16O -> 676
Mass independent isotope fractionation:effect of compositional symmetry
O2 + O2* -> O3* + O
Example:Silicon: 28Si – 92%, 29Si – 5%, 30Si – 3%Monoisotopic silicon 28Si has 60% higher thermal conductivity than silicon with natural isotopic composition.
Same with GaAs
69Ga≈60%71Ga≈40%
Example:
Monoisotopic diamond 12C (99.98 %):The thermal conductivity exceeds that of natural diamond (12C = 98.9%)by 1.5 times at 300 K.
T.R. Anthony, W.R. Banholzer, J.F. Fleischer, L. Wei, P.K. Kuo, R.L. Thomas, and R.W. Prior, Phys. Rev. B 42, 1104 (1990)
Nature Materials 11, 203–207 (2012)
Thermal conductivity of isotopically modified graphene
Monoisotopic proteins do not exist in nature.E. Coli bacteria can be grown in monoisotopic media.
Monoisotopic: all carbons – 12C, all hydrogens – 1H, etc.
Cytochrome c – 12.4 kDa
Average mass
E. Coli growth in minimal media
0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0 500 1000 1500 2000 2500 3000
OD,
AU
Time (min)
Monoisotopic
Normal
Monoisotopic E. Coli and their proteins are less stable thermally
-0.3 -0.2 -0.1 0.0 0.1 0.2 0.3 0.40
2
4
6
p
Mono
Poly
Towards monoisotopic biology
• Grow E. coli in monoisotopic media
• Extract proteins, hydrolyze them into free amino acids
• Formulate mammalian cell monoisotopic growth media
• Grow hybridoma cells in it, extract monoclonal antibodies
• Test the prediction of faster binding kinetics compared topoly-isotopic antibodies
There is no monoisotopic media for mammalian cells, so…
W o r k i n p r o g r e s s …
D/H on other planets
∂13C: 46±4‰ ∂18O: 48±5‰
Curiosity Rover
Mars
∂D = 5880±80 ‰ from evolved water∂15N: 680 ‰
Resonance 1: C + 2(N - H) + 5O = 0
Resonance 2: 2N - H + 4O = 0
Earth Mars
Mars does not contain stroisotopic resonances
Life on Mars is unlikely
Will Martian soil be good for growing
human food?
BYOES – a semi-closed ecosystem
BYOES Experiment:November 2014-February 2016
Earth
Mars
IsoRes predicts life on other planets?
Harmony of the worldFrom Sibly, Ebenezer: “Astrology” (1806).
Conclusions• CHON isotopic compositions on Earth are close to the resonance values for z = 0; z = C -( N + H)/2
• z=0 is a singularly important value for simple organic molecules.
• Isotopic resonances alter (often, increase) the speed of biological and biochemical processes.
• Terrestrial isotopic resonance has likely facilitated Lifeemergence/taking root on our planet.
• Other planets are less lucky. Martian isotopic compositions may not be optimal for humans. IsoRes can evaluate the likelihood
of life on other planets.
• Isotopic resonances affect chemistry and biology, whichcan be used in science, medicine and technology.
• Monoisotopic resonance is the strongest isotopic resonance.
IsoRes in Sci Art
Science and Art - SciArt
AcknowledgementsKim HaselmannBogdan BudnikFrank Kjeldsen
Michael Lund NielsenJesper OlsenIgor IvoninOleg Silivra
Christopher AdamsAlexander Misharin
Mikhail SavitskiThomas Köcher
Corina MayrhoferY.M. Eva Fung
Konstantin ArtemenkoTherése Hemström
Pierre Le GrevèsAtim EnyenihiDavid Good
Ernesto GonzalesConsuelo Marin VicenteMarta Guerrero Valero
Constantin ChinginYaroslav LyutvinskiyAleksandr Manoilov
Hongqian YangPiliang Hao
Mohammad PirmoradianNataliya Tarasova
Alexandra BernadotteBo Zhang
Luciano di Stefano
ThermoFisher ScientificBiomotif AB
Swedish Research CouncilKAW foundation, VINNOVA
European UnionCancerfonden
Alexander MakarovYury Tsybin
Dimitris PapanastasiuThorleif LavoldJuan Astorga-Wells
Molecules
Isotopes
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