BIOINFORMATICS –APPROACHING THE BIG CHALLENGES IN LIFE SCIENCES

IN 5130 – Oct 7 2019

Ragnhild Halvorsrud, SINTEF Digital

If you were biologists

What is ..• .. a PC?

• .. a keyboard and mouse?

• .. operating system?

• .. algorithm?

• .. name of a search engine?

• .. name of a programming language?

• .. artificial intelligence?

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Quiz

• If you know what a cell is, remain standing

• If you know the shape of the DNA molecule, remain standing

• If you know what DNA is coding for, remain standing

• If you know the four letters of the DNA alphabet, remain standing

• If you can name a protein, remain standing

• If you know the building blocks of a protein, remain standing

• If you know the name of the method for editing DNA, remain standing

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PhilosophyCogito ergo sum

Brain and perception

DNA basics

Neurons

User experience

Brain revisited

E = MC2

What are these?

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ArginineHistidineLysineAspartic acidGlutamic acidSerineThreonineAsparagineGlutamineCysteineSelenocysteine

GlycineProlineAlanineValineIsoleucineLeucineMethioninePhenylalanineTyrosineTryptophan

The DNA code

AAA ATG TCT TGA GTG GAG ATC TTG TAA CCA TGA CTG CAC AAA ATG TCT TGA GTG GAG ATC TTG TAA GGA GAT CTT GTA ATG ATG GAG ATC TTG TAA TGA AAA ATG TCT TGA GTG

GAG CTC CTG ATG TTT GTG AAC CAA CAC CTG TGC GGC TCA CAC CTG GTG GAA GCT CTC TAC CTA GTG TGC GGG GAA CGA GGC TTC TTC TAC ACA CCC AAG ACC GGC ATT GTG

GAA CAA TGC TGT ACC AGC ATC TGC TCC CTC TAC CAG CTG GAG AAC TAC TGC AAC TGA TGG AGA TCT TGT AAT GGA GAT CTT GTA ATG ATG GAG ATC TTG TAA TGA AAA ATG TCT TGA GTG GAG ATC TTG TAA TGA CTC TTG TCA CTG CTG

Bla bla bla bla bla bla START aminoacid1 aminoacid2 …. aminoacid53 STOP bla blabla bla

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DNA is the code. What is the product?

• DNA is a code for proteins (=chains of amino acids)

• Every cell carries identical DNA. Every cell encapsulates information about the entire organism

• One cell contains 2 meters of DNA

• DNA has 4 "letters": A, T, C, G• Three letters form a "word" codon (for example "ACC")

• There are 4 x 4 x 4 = 64 possible codons• But we only have ca. 20 amino acids

• => the code is degenerate

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As if every brick of a building stored an architectural plan of the entire building

Amino acids

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ArginineHistidineLysineAspartic acidGlutamic acidSerineThreonineAsparagineGlutamineCysteineSelenocysteine

GlycineProlineAlanineValineIsoleucineLeucineMethioninePhenylalanineTyrosineTryptophan

A recipe and a product

AAA ATG TCT TGA GTG GAG ATC TTG TAA CCA TGA CTG CAC AAA ATG TCT TGA GTG GAG ATC TTG TAA GGA GAT CTT GTA ATG ATG GAG ATC TTG TAA TGA AAA ATG TCT TGA GTG GAG ATC TTG TAA TGA

CTC TTG TCA CTG CTG ATG TTT GTG AAC CAA CAC CTG TGC GGC TCA CAC CTG GTG GAA GCT CTC TAC CTA GTG TGC GGG GAA CGA GGC TTC TTC TAC ACA CCC AAG ACC GGC ATT GTG GAA CAA TGC

TGT ACC AGC ATC TGC TCC CTC TAC CAG CTG GAG AAC TAC TGC AAC TGA TGG AGA TCT TGT AAT GGA GAT CTT GTA ATG ATG GAG ATC TTG TAA TGA AAA ATG TCT TGA GTG GAG ATC TTG TAA TGA CTC The recipe for TTG TCA CTG CTG

Bla bla bla bla bla bla START Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Thr Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gln Leu Glu Asn Tyr Cys Asn STOP bla bla bla bla

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The genetic code

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The central dogma

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Source: Yourgenome.org

The central dogma of molecular biology explains the flow of genetic information, from DNA to RNA, to make a functional product, a protein.

A T C G

A U C G

Met His Ser Val Iso

DNA

RNA

protein

Proteins – what we are made of

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https://www.thoughtco.com/protein-structure-373563Illustration by Nusha Ashjaee. ThoughtCo.

The Book of You

3 billion "letters" (A, T, C, G)

1 billion "words" (AAG, CCT)

Same amount as 1300 bibles

.. or 200.000 scientific papers

Source: D. McCandless "Information is Beautiful"

The Book of You

Only 2% are genes (coding DNA)

The remaining 98% is non-coding DNA (earlier called "junk-DNA")

Source: D. McCandless "Information is Beautiful"

The quest for the human genome (2001)

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274 authors, 15.000 citations

J. Craig Venter1,*, Mark D. Adams1, Eugene W. Myers1, Peter W. Li1, Richard J. Mural1, Granger G. Sutton1, Hamilton O. Smith1, Mark Yandell1, Cheryl A. Evans1, Robert A. Holt1, Jeannine D. Gocayne1, Peter Amanatides1, Richard M. Ballew1, Daniel H. Huson1, Jennifer Russo Wortman1, Qing Zhang1, Chinnappa D. Kodira1, Xiangqun H. Zheng1, Lin Chen1, Marian Skupski1, Gangadharan Subramanian1, Paul D. Thomas1, Jinghui Zhang1, George L. Gabor Miklos2, Catherine Nelson3, Samuel Broder1, Andrew G. Clark4, Joe Nadeau5, Victor A. McKusick6, Norton Zinder7, Arnold J. Levine7, Richard J. Roberts8, Mel Simon9, Carolyn Slayman10, Michael Hunkapiller11, Randall Bolanos1, Arthur Delcher1, Ian Dew1, Daniel Fasulo1, Michael Flanigan1, Liliana Florea1, Aaron Halpern1, Sridhar Hannenhalli1, Saul Kravitz1, Samuel Levy1, Clark Mobarry1, Knut Reinert1, Karin Remington1, Jane Abu-Threideh1, Ellen Beasley1, Kendra Biddick1, Vivien Bonazzi1, Rhonda Brandon1, Michele Cargill1, Ishwar Chandramouliswaran1, Rosane Charlab1, Kabir Chaturvedi1, Zuoming Deng1, Valentina Di Francesco1, Patrick Dunn1, Karen Eilbeck1, Carlos Evangelista1, Andrei E. Gabrielian1, Weiniu Gan1, Wangmao Ge1, Fangcheng Gong1, Zhiping Gu1, Ping Guan1, Thomas J. Heiman1, Maureen E. Higgins1, Rui-Ru Ji1, Zhaoxi Ke1, Karen A. Ketchum1, Zhongwu Lai1, Yiding Lei1, Zhenya Li1, Jiayin Li1, Yong Liang1, Xiaoying Lin1, Fu Lu1, Gennady V. Merkulov1, Natalia Milshina1, Helen M. Moore1, Ashwinikumar K Naik1, Vaibhav A. Narayan1, Beena Neelam1, Deborah Nusskern1, Douglas B. Rusch1, Steven Salzberg12, Wei Shao1, Bixiong Shue1, Jingtao Sun1, Zhen Yuan Wang1, Aihui Wang1, Xin Wang1, Jian Wang1, Ming-Hui Wei1, Ron Wides13, Chunlin Xiao1, Chunhua Yan1, Alison Yao1, Jane Ye1, Ming Zhan1, Weiqing Zhang1, Hongyu Zhang1, Qi Zhao1, Liansheng Zheng1, Fei Zhong1, Wenyan Zhong1, Shiaoping C. Zhu1, Shaying Zhao12, Dennis Gilbert1, Suzanna Baumhueter1, Gene Spier1, Christine Carter1, Anibal Cravchik1, Trevor Woodage1, Feroze Ali1, Huijin An1, Aderonke Awe1, Danita Baldwin1, Holly Baden1, Mary Barnstead1, Ian Barrow1, Karen Beeson1, Dana Busam1, Amy Carver1, Angela Center1, Ming Lai Cheng1, Liz Curry1, Steve Danaher1, Lionel Davenport1, Raymond Desilets1, Susanne Dietz1, Kristina Dodson1, Lisa Doup1, Steven Ferriera1, Neha Garg1, Andres Gluecksmann1, Brit Hart1, Jason Haynes1, Charles Haynes1, Cheryl Heiner1, Suzanne Hladun1, Damon Hostin1, Jarrett Houck1, Timothy Howland1, Chinyere Ibegwam1, Jeffery Johnson1, Francis Kalush1, Lesley Kline1, Shashi Koduru1, Amy Love1, Felecia Mann1, David May1, Steven McCawley1, Tina McIntosh1, Ivy McMullen1, Mee Moy1, Linda Moy1, Brian Murphy1, Keith Nelson1, Cynthia Pfannkoch1, Eric Pratts1, Vinita Puri1, Hina Qureshi1, Matthew Reardon1, Robert Rodriguez1, Yu-Hui Rogers1, Deanna Romblad1, Bob Ruhfel1, Richard Scott1, Cynthia Sitter1, Michelle Smallwood1, Erin Stewart1, Renee Strong1, Ellen Suh1, Reginald Thomas1, Ni Ni Tint1, Sukyee Tse1, Claire Vech1, Gary Wang1, Jeremy Wetter1, Sherita Williams1, Monica Williams1, Sandra Windsor1, Emily Winn-Deen1, Keriellen Wolfe1, Jayshree Zaveri1, Karena Zaveri1, Josep F. Abril14, Roderic Guigó14, Michael J. Campbell1, Kimmen V. Sjolander1, Brian Karlak1, Anish Kejariwal1, Huaiyu Mi1, Betty Lazareva1, Thomas Hatton1, Apurva Narechania1, Karen Diemer1, Anushya Muruganujan1, Nan Guo1, Shinji Sato1, Vineet Bafna1, Sorin Istrail1, Ross Lippert1, Russell Schwartz1, Brian Walenz1, Shibu Yooseph1, David Allen1, Anand Basu1, James Baxendale1, Louis Blick1, Marcelo Caminha1, John Carnes-Stine1, Parris Caulk1, Yen-Hui Chiang1, My Coyne1, Carl Dahlke1, Anne Deslattes Mays1, Maria Dombroski1, Michael Donnelly1, Dale Ely1, Shiva Esparham1, Carl Fosler1, Harold Gire1, Stephen Glanowski1, Kenneth Glasser1, Anna Glodek1, Mark Gorokhov1, Ken Graham1, Barry Gropman1, Michael Harris1, Jeremy Heil1, Scott Henderson1, Jeffrey Hoover1, Donald Jennings1, Catherine Jordan1, James Jordan1, John Kasha1, Leonid Kagan1, Cheryl Kraft1, Alexander Levitsky1, Mark Lewis1, Xiangjun Liu1, John Lopez1, Daniel Ma1, William Majoros1, Joe McDaniel1, Sean Murphy1, Matthew Newman1, Trung Nguyen1, Ngoc Nguyen1, Marc Nodell1, Sue Pan1, Jim Peck1, Marshall Peterson1, William Rowe1, Robert Sanders1, John Scott1, Michael Simpson1, Thomas Smith1, Arlan Sprague1, Timothy Stockwell1, Russell Turner1, Eli Venter1, Mei Wang1, Meiyuan Wen1, David Wu1, Mitchell Wu1, Ashley Xia1, Ali Zandieh1, Xiaohong Zhu1

150 authors, 23.000 citations

Lander ES1, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W, Funke R, Gage D, Harris K, Heaford A, Howland J, Kann L, Lehoczky J, LeVine R, McEwan P, McKernan K, Meldrim J, Mesirov JP, Miranda C, Morris W, Naylor J, Raymond C, Rosetti M, Santos R, Sheridan A, Sougnez C, Stange-Thomann Y, Stojanovic N, Subramanian A, Wyman D, Rogers J, Sulston J, Ainscough R, Beck S, Bentley D, Burton J, Clee C, Carter N, Coulson A, Deadman R, Deloukas P, Dunham A, Dunham I, Durbin R, French L, Grafham D, Gregory S, Hubbard T, Humphray S, Hunt A, Jones M, Lloyd C, McMurray A, Matthews L, Mercer S, Milne S, Mullikin JC, Mungall A, Plumb R, Ross M, Shownkeen R, Sims S, Waterston RH, Wilson RK, Hillier LW, McPherson JD, Marra MA, Mardis ER, Fulton LA, Chinwalla AT, Pepin KH, Gish WR, Chissoe SL, Wendl MC, Delehaunty KD, Miner TL, Delehaunty A, Kramer JB, Cook LL, Fulton RS, Johnson DL, Minx PJ, Clifton SW, Hawkins T, Branscomb E, Predki P, Richardson P, Wenning S, Slezak T, Doggett N, Cheng JF, Olsen A, Lucas S, Elkin C, Uberbacher E, Frazier M, Gibbs RA, Muzny DM, Scherer SE, Bouck JB, Sodergren EJ, Worley KC, Rives CM, Gorrell JH, Metzker ML, Naylor SL, Kucherlapati RS, Nelson DL, Weinstock GM, Sakaki Y, Fujiyama A, Hattori M, Yada T, Toyoda A, Itoh T, Kawagoe C, Watanabe H, Totoki Y, Taylor T, Weissenbach J, Heilig R, Saurin W, Artiguenave F, Brottier P, Bruls T, Pelletier E, Robert C, Wincker P, Smith DR, Doucette-Stamm L, Rubenfield M, Weinstock K, Lee HM, Dubois J, Rosenthal A, Platzer M, Nyakatura G, Taudien S, Rump A, Yang H, Yu J, Wang J, Huang G, Gu J, Hood L, Rowen L, Madan A, Qin S, Davis RW, Federspiel NA, Abola AP, Proctor MJ, Myers RM, Schmutz J, Dickson M, Grimwood J, Cox DR, Olson MV, Kaul R, Raymond C, Shimizu N, Kawasaki K, Minoshima S, Evans GA, Athanasiou M, Schultz R, Roe BA, Chen F, Pan H, Ramser J, Lehrach H, Reinhardt R, McCombie WR, de la Bastide M, Dedhia N, Blöcker H, Hornischer K, Nordsiek G, Agarwala R, Aravind L, Bailey JA, Bateman A, Batzoglou S, Birney E, Bork P, Brown DG, Burge CB, Cerutti L, Chen HC, Church D, Clamp M, Copley RR, Doerks T, Eddy SR, Eichler EE, Furey TS, Galagan J, Gilbert JG, Harmon C, Hayashizaki Y, Haussler D, Hermjakob H, Hokamp K, Jang W, Johnson LS, Jones TA, Kasif S, Kaspryzk A, Kennedy S, Kent WJ, Kitts P, Koonin EV, Korf I, Kulp D, Lancet D, Lowe TM, McLysaght A, Mikkelsen T, Moran JV, Mulder N, Pollara VJ, Ponting CP, Schuler G, Schultz J, Slater G, Smit AF, Stupka E, Szustakowki J, Thierry-Mieg D, Thierry-Mieg J, Wagner L, Wallis J, Wheeler R, Williams A, Wolf YI, Wolfe KH, Yang SP, Yeh RF, Collins F, Guyer MS, Peterson J, Felsenfeld A, Wetterstrand KA, Patrinos A, Morgan MJ, de Jong P, Catanese JJ, Osoegawa K, Shizuya H, Choi S, Chen YJ, Szustakowki J; International Human Genome Sequencing Consortium.

How do you compare?

You

You vs Einstein

You vs a chimpanzee

You vs a worm

You versus a banana

100.0%

99.94%

≈ 96%

≈ 70%

≈ 60%

Genetic manipulation - CRISPR

• DNA editing: CRISPR method

• Changing human appearance, intelligence and physical performance.

• Most human characteristics are scattered throughout the genome in a complicated fashion

• Status of today: • We cannot design humans

• But many other advanced things (e.g. detect and repair faulty genes)

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Reality check

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We understand the world through terminology and senses.

Reality

The brain use the information from your senses to create a representation of the world.

"Reality" is electrical signals interpreted by the brain.

Perception

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http://morgana249.blogspot.com/2014/07/10-examples-of-how-animals-see-images.html

What is "real"?

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Human eye Snake eye The dress

The human brain

Neurons are connected in a

COMPLEX NETWORK

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86 000 000 000 neurons86 x 109

Each unit is complex!

• Dendrites are the input devices

• Thousands of synapses

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Spikes – action potentials

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http://bodell.mtchs.org/OnlineBio/BIOCD/text/chapter28/concept28.2.html

Resting state: cell builds up an electric potential= energy demanding

Upon stimulation: => cell "fires"Spike(s) generatedSignal transmission possible

Specific blocking of ion channels

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http://bodell.mtchs.org/OnlineBio/BIOCD/text/chapter28/concept28.2.html

TTX - Tetrodotoxin • Blocks Na+ channels• Found in puffer fish – a Japanese delicacy• About five diners die every year • Choose your Japanese chef with care

The "message" – and what about memory?

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Spike widthSpike broadeningSpike frequencyLTP Long-term potentiation

Spike trainsSimplified spike

Patch-clamping

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For studying neural signalling

Patch-clamp techniqueIntracellular recordings

Pyramidal cell in rat hippocampus

Frog egg

Experiment and simulation

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experiment simulation

experiment simulation

Simulation model

6-compartmental cell modelled with 9 ion currents:

• 1 Na+ current• 3 Ca2+ currents• 5 Ka+ currents

Hodgkin-Huxley formalism + 4-state Markov model

Cogito ergo sum

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I think, therefore I am

Cogito ergo sum

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I have an experience therefore I am

Measuring the user experience

"An incredible tribute to humanity"

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"Naked adults playing with naked children, rolling over each other, makes me sick"

User experience and emotions

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• The phenomenon "experience" is complex

• How we understand "experience" varies greatly across and within academic disciplines

• Human-computer interaction says:• UX is subjective

• UX changes over time

• UX depends on the context

• What can be measured through sensors and trackers?

• What can be inferred from the data concerning UX?

vital signs skin conductancepupillometrytone of voicevideoEEG, fMRI, TCSobservationinterviewquestionnaire

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Measuring the user experience

"Qi"Subjective energy level

When researching human experiences…

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.. we definitely "disturb the system"

Consciousness

• Understanding consciousness is referred to as "the ultimate challenge of our millennium" • Microcosm – nanophysics and quantum mechanics

• Macrocosm – astrophysics

• Neuroscience and consciousness research

• Integrated information theory (IIT)• A systems consciousness can be calculated

• A system's consciousness is determined by its causal properties and is therefore an intrinsic, fundamental property of any physical system

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"Man is a slow, sloppy and brilliant thinker;the machine is fast, accurate and stupid.”

William M. Kelly

Teknologi for et bedre samfunn