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One Problem
(c) Gerck Research
It can be proven that most claimed
research findings in Biology,
Neuroscience, Genetics and
Biomedicine are false.
Ed Gerck, Ph.D.
UCSanDiego|Extension|OSHER
Winter 2017 Program
February 16, 2017
Science and the Search for Truth:
How a Big Idea in Physics will spread to
Biology, Economics and even Politics
Ed Gerck
ed@gerck.com
Ph.D., Physics
Max Planck Institute for Quantum Optics
Ludwig-Maximilians-Universitaet, Muenchen
© Gerck Research, 2013-17
+ The Bouncing Ball Experiment
Biology: Brownian Motion (1827)
Robert Brown
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Brown’s experiment:
Pollen grains in water,
particles (organelles)
come out and move.
Brown observed:
Two types of movement:
global flow and localized
jittery (independent).
Questions:
How are the particles
moving independently?
Are they alive?
No. What does it mean
to be alive?
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From Earth to the Bubble Nebula (8000 light-years away)
Move mouse over picture for movie. If watching PDF, go later to skysurvey.org
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Molecular cloud: dipeptide (*) creation, possible Origin of
Life (OoL) on Earth and in the Universe.
(*) Dipeptides are a vital link in the formation of proteins on early
Earth. See Ralf. I Kaiser et. al., “On the formation of dipeptides in
interstellar model ices”, The Astrophysical Journal 765(2):111 ·
February 2013.
Bubble Nebula (NGC 7635):
Observed by Hubble Telescope
(2016), ten light-years across,
8000 light-years away from Earth.
Borg cube?
Physics, Chemistry, Biology
Science is unitary (one thing)
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Biology Physics
Chemistry Mathematics
•1827 Biology observation:
Brownian motion
•80 years later: Physics (Einstein)
explained it.
•It was fundamental to all
Science: existence of molecules
(DNA), atoms and particles.
Scientists
Open questions from Biology:
•Life
•Origin of Life (OoL)
•Mind
•Consciousness
Review: How Scientists Work
© Gerck Research
To be a scientist is a way of thinking!
1. Use the Scientific Method to find or break rules
2. Accept rule as “not yet false” instead of “true”
3. Keep asking… keep testing…
Ref.: E. Gerck, UCSD/OSHER Seminar, January 19, 2017.
.
- Science runs on Hypothesis
not on observation alone!
- Running > 2,300 years!
- Keeps Evolving
- Open and Fair
- Self-Correcting
- Full Recycling
-Open-ended …
(testable relationship)
true
Scientific Method correct mistakes
accept
rule
break
Hypothesis
false
not yet false
Why Biology?
There is a big problem:
“It can be proven that most claimed research
findings [in Biology, Neuroscience, Genetics
and Biomedicine] are false.”
Ioannidis, John P. A. “Why Most Published Research Findings
Are False.” PLoS Medicine 2.8 (2005): e124. PMC.
US National Institutes Of Health (NIH): Hard to
reproduce at least 3/4 of published biomedical
findings.
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The Devil
Prof. Ioannidis (Stanford)
•Powerful new experimental methods and techniques
•Becoming less authority-based, more evidence-based
•More dialogue between theory and experiment
•Going from ‘soft science’ to ‘hard science’ in Biology,
Neuroscience, Genetics, Biomedicine, etc.
Systemic failure: published research is provably false
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Theory is thin and scientists want surprising results (ego, marketing,
financing) hypotheses are pretty unlikely and often very unlikely.
Consider 1,000 hypotheses being tested of which just 100 are true (green,
albeit unknown, see chart).
With a high Sensitivity (avoiding false negatives) of 80% and a high
Specificity (avoiding false positives) of 95% 1/3 of “true” results are
false, 1/5 of true results were missed. Actual Sensitivity and Specificity are
much lower.
The Irreproducibility Crisis
The best that can be done today in biological sciences?
•As an enterprise dedicated to discovering the truth;
•Where investors fund researchers to find out what works in the real-
world, not just in the lab;
•As an expounder to governments and society of facts that should be
trustworthy, including on disease control and health care;
•To scientists, who would like to trust their work and references; and
•To society, who think of science as self-correcting.
Keeping this outlook is a shaky foundation for biology.
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Strategies to address the
irreproducibility of biomedical research
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Trouble at the Bio Lab (The Economist, 2013)
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Biology is not Physics: Bio
research cannot achieve
Physics 5-sigma error (1: 4
million) due to low number of
samples, random mutations.
Claims of fundamental
fuzziness: No two organisms,
organs or cells are exactly
equal.
Subjectivity, Statistics: Thin
theory, models can be ‘tuned’
and ‘detuned’ in many ways,
showing a pattern where
none exists, even if double-
blinded.
Hard-to-spot Fraud: Very
likely a second factor in
erroneous results.
Current Approach:
There is no real trouble.
Biology is not Physics. Just keep improving research, collaboration, and
publication practices.
Examples
Irreproducibility is a feature not a bug: (The American Society for Cell Biology, 2014) No
experiment is ever exactly the same as a prior experiment [it’s a feature]. Focus on resolution
success, not reproducibility failure; the most common (60%) resolution is via amicable
communication between the parties. Support existing methods and new initiatives of
community-based standards. http://www.ascb.org/wp-content/uploads/2015/11/How-can-
scientist-enhance-rigor.pdf
Denial and Faith: (The Academy of Medical Sciences, UK, 2015) There is no single cause of
irreproducibility. Overarching will drive the implementation of specific measures and ultimately
[by faith?] enhance reproducibility. http://www.acmedsci.ac.uk/viewFile/56314e40aac61.pdf
The old More Details, More Funding: (Biofisica Editorial, blog, 2016) A major source of
irreproducibility is lack of detail in the experimental methods and conditions described in
publications. Appropriate incentives by funding and regulatory agencies, and with a minimum
consensus within the scientific community.
http://www.uv.es/biophys/sbe/4/PDFsite/IrreproducibilityInResearch.pdf
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New strategy: qualitative change
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What it is and what could be?
•Non-reproducible research is an error (not to live with).
•Desired: reduce errors.
•2005: error rate was worse than a coin toss.
Error rate: 75% (NIH) or > 50% (Ioannidis).
•2013: Same situation (The Economist)
•Error plateau: Eight years of work and still stuck below coin toss level.
•Hypothesis: After a large and long effort, the scientific method in Biology has
reached the diminishing returns phase.
More published details, more community-consensus, more peer-
review, more funding, and more time have not brought a
qualitative change.
What is missing?
Can errors be starkly reduced?
(c) Gerck Research
?
errors
Revisiting Biology
Q: What are the elements of which a cell is composed, from which it is
built up?
A: It consists of a cell membrane, a liquid cytoplasm, maybe organelles
and, possibly, a nucleus.
Q: We need more details. What are the elements of which a cell
membrane is composed, from which it is built up?
A: It consists of a phospholipid bilayer with embedded proteins.
… we need more details…
Q: We reached the atomic level. What else is needed?
A: We also need knowledge of the relationships of objects to one
another. As we get more objects in, research needs grow exponentially.
…
And, with more details, biomedical research
seems to be even more irreproducible!
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What we can measure
Q: What is the distance of my hand?
A: Not possible to define without a reference. Distance is relative.
Q: What is the time of my hand?
A: Not possible to define without a reference. Time is relative.
Q: What is the angle of my hand?
A: Not possible to define without a reference. Angle is relative.
Q: Speed is the ratio of two relationships, distance and time. What is the
speed of my hand?
A: Still not possible to define without a reference. Speed is relative.
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Is everything indeed relative?
Is everything possible?
Physics once thought that
everything is relative…
"If then only pointer readings [relative data] or their
equivalents are put into the machine of scientific
calculation, how can we grind out anything but pointer
readings? But that is just what we do grind out.“
Sir A. S. Eddington (1882-1944, physicist) in The Nature of the Physical World
If everything is relative… then
everything could be possible.
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Physics once also faced a complexity barrier...
1. 19th century Physics: knowing the objects and their relationships to
one another is not enough to understand or solve completely the
dynamics of a group of such bodies put together.
2. Complexity barrier: Newton’s laws are not enough to describe the
motion of more than two bodies.
3. With more objects, Physics became more irreproducible…
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Sun
Newton’s laws
cannot describe
the Earth-Moon-
Sun system.
Sounds familiar?
Revisiting Physics
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1. Physics is no longer what people have learned or even learn today in High
School, AP Physics, College Science, Chemistry, and Biology.
2. In the last hundred and fifty years, an entirely different framework has
been developed for Physics, based on conservation laws, invariants, least
action, and symmetry. Just not yet in the media news cycle! Ref.: “Light
and Matter”, by Benjamin Crowell, Chapter 14 [PDF]
3. The new approach applies inside an atom or near a black hole, where
Newton's laws do not.
4. Even in everyday situations the new approach can be vastly superior.
Some phenomena or machines are also too complex to be easily
understood otherwise.
5. Conservation laws , least action, and symmetry tell us that
something must remain the same, invariant, regardless of the
complexity of the process, and regardless of path.
The Big Idea in Physics
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•The existence of conservation laws, invariants and symmetry lead Max Planck
to go beyond objects, relationships and the relative measurements that
seemed to limit physics and the complexity of systems that could be
investigated.
•In 1899, Max Planck calculated five universal constants, based only on the
properties of free space. Called natural units (now Planck units), all are
invariants and normalized to 1. For example, the speed of light is 1.
•In 1905, Max Planck made the first statement of The Big Idea in Physics:
“Our task is to find in all these [relative] factors and data, the absolute, the
universally valid, the invariant, that is hidden in them.“
Ref.: Max Planck, Scientific Autobiography: and Other Papers, first published 1949,
ISBN 0806530758.
The absolute, the universally valid, the invariant, exists,
can be stated, and can be tested in a much larger scope.
Let’s use The Big Idea!
•The Big Idea in Physics is to go from
testable relationships to the absolute.
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The Bouncing Ball Experiment
For the skeptical: Some things do work the same way, anywhere,
anytime. Here and in the Bubble Nebula. See by yourself that not
everything is possible, not everything is relative.
I will show the experiment first and then anyone can try. If you are not in the Seminar,
you can view the experiment in the next slides.
You can also try at home! (carefully)
The Bouncing Ball
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It is a simple problem that is complex to calculate
using forces. Many wrong answers in the Internet,
and correct answers are often voted down.
V
V
V
?3v
V
V
123
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We already saw it: The smaller ball can go up at 3x the
end speed (and reach up to 9x the drop height).
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Many other systems are complex.
Could we apply
The Big Idea in Physics
to other systems?
To Biology?
Scale invariance:
the power-law footprint
of a universal mechanism
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Physical systems can exhibit spatial and temporal scale
invariance. These scale-free phenomena can also show
criticality, where systems spontaneously arrange themselves.
Understanding the scale
invariance of earthquakes is
important for the development of
building codes and insurance
tables, and in day-to-day living.
Scale invariance in Biology: coincidence or
footprint of a universal mechanism?
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Biological systems can also exhibit spatial and temporal scale
invariance. Can these scale-free phenomena exibit criticality?
Firing response of a neuron from
the visual cortex of a cat when
exposed five separate times to
the same stimulus.
T. Gisiger, Biol Rev Camb Philos Soc.
2001 May;76(2):161-209.
Scale invariance in Economics
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Plot of the upper-tail
of cumulative size-
distribution incomes of
largest paid CEOs of US
companies. Abscissa in
$million.
Scale invariant distributions have been known to Economics
under another name: Pareto, since the end of the XIXth
century.
The Big Idea in Physics
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•Uses symmetry and invariants to go from testable relationships to
the absolute.
•Finds patterns, reduces errors.
•Improves descriptive power.
•Advantageously uses complexity.
•Goes beyond objects, relationships and relative measurements.
•Breaks science free from limitations of sensorial phenomena and
the complexity of systems that can be investigated.
“Our task is to find in all these relative factors and data, the
absolute, the universally valid, the invariant, that is hidden in
them.“ Max Planck, 1901.
The Big Problem in Biology
•The level of non-reproducible research in biology, aka “the
trouble at the bio lab“, has reached the unbearable level of 3/4
(NIH) or > 50% (Ioannidis). A coin toss is better than research!
•Considering how long “the trouble at the bio lab" has been going
on at this level, it's likely that the process for improving research
reproducibility in biology has reached the diminishing returns
phase, even after a large effort.
•After so many years, it also seems unlikely that adding a second
layer of referees or creating a result moratorium for open
consultation before publication, or other ideas that we see
suggested, will be enough.
Real change cannot just be quantitative in this case, we need to
seek qualitative change.
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Using The Big Idea From Physics
•Look for biologically-relevant absolutes / invariants, as used in
Physics for 150 years, to help peg theories and results to a
large reference frame that is "universally" valid in forecasting
and validating results.
•Still, scientific results are not the “truth” and need to be
considered as NOT YET false (the scientific method).
•Using a large reference frame can greatly improve the
trustworthiness of published results.
This approach should allow outliers and fraud to be more easily
spotted, and can help develop new theory also when invariants
are not observed -- breaking symmetry, for example.
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Next
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•The Big Idea can help in research and in citizen understanding of
complex systems, and in Medicine in particular.
•Science is not what we do in the lab, science is a way of thinking!
Anyone can think like a scientist.
•Copy: Go to http://gerck.com and tap link in item “Profile and
Publications” to retrieve this and other presentations at
ResearchGate.
The Big Merit of Science
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A merit of physics and natural science is being a
science of testable relationships.
Science establishes, and possibly conveys in a
mathematically exact form, relationships between
phenomena. Action, reaction, force, osmosis,
Newton’s laws.
We can multiply the power of our means of
observation and reasoning, while our starting and
ending points remain firm in Nature, the phenomena
and relationships.
Let’s flip the coin…
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1. A fault of physics and natural science is exactly that of
being a science of testable relationships.
2. Science seems bound to establish, although possibly
conveyed in a mathematically exact form, only
relationships between phenomena. Action, reaction,
force, osmosis, Newton’s laws.
3. Max Planck and others understood that we can multiply
the power of our means of observation and reasoning…
but our starting and ending points still remain on the
sensorial, the phenomena and relationships.
APPENDIX I: The Polymerization Problem
Early Earth Origin of Life (OoL) hypothesis: organic molecules came together
and reacted spontaneously, forming longer chains (polymerization).
amino-acid-1 + amino-acid-2 <----> dipeptide (aa1-aa2) + H2O proteins
This is considered a problem because:
1. reaction produces water.
2. reactions must occur in the presence of water
3. water drives the chemical equilibrium in the wrong direction!
DNA codes for proteins. Many proteins are just assemblies of several
polypeptides.
Polypeptides are a chain of amino acids linked together by a CO-NH
bond, beginning with dipeptides such as the Gly–Gly and Leu–Ala.
Dipeptides are a vital link in the formation of proteins on early Earth.
APPENDIX II: Exogenous Origin Of Life?
Dipeptides (a vital link in the formation of proteins):
•Can be formed in radiation-induced, non-enzymatic processes in
molecular clouds in space (e.g., near the Bubble Nebula).
•Were detected in the Murchison meteorite and cosmic dust near
Earth.
•Their space origin and delivery to early Earth presents an
alternative route to their terrestrial formation.
•They could have been delivered to habitable planets such as early
Earth by meteorites and comets, thus seeding the beginning of
life as we know it.
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