Nefrologie 2.0

An De VrieseNierziekten en Infectieziekten

AZ Sint-Jan Brugge

Nefrologie 2.0

• Biotechnology revolution: CRISPR-Cas9

• Information revolution: • Biometric signals

• Natural language processing

• Artificial Intelligence: Deep learning

CRISPR=Clustered Regularly Interspaced Short Palindromic Repeats

Cas9=CRISPR associated protein 9=DNA endonuclease

CRISPR Cas9

TARGET MALARIA

Morphological appearance of genetic males and females heterozygous (dsxF+/−) or homozygous (dsxF−/−) for theexon 5 null allele.

CRISPR Cas9

• Malaria muggen die uitsterven

• Tomaten die maanden bewaard kunnen worden zonder te rotten

• Planten die de opwarming van het klimaat doorstaan

• Ultragespierde politiehonden

• Koeien zonder hoornen

=//= GGO’s!

If a defect is genetic, it is druggable.

Fyodor Urnov

CRISPR Cas9in Medicine

Nefrologie 2.0

• Biotechnology revolution: CRISPR-Cas9

• Information revolution: • Biometric signals – wearable sensors

• Natural language processing

• Artificial Intelligence: Deep learning

Attia et al. J Am Heart Assoc 2016; 5: e002746

Novel Bloodless Potassium Determination Using a Signal-Processed Single-Lead ECG

Natural Language Processing=a way for computers to analyze human language and derive useful meaning from it.

a. Phonologyb. Morphologyc. Syntaxd. Semanticse. Pragmaticsf. Discourseg. World Knowledge

Chatbot

= computer program or smart algorithm conducting conversation via auditory or textual methods.

• Multiple healthcare applications –virtual medical coaches

• Bingli: best start-up of 2018

Amazon Comprehend Medical

Amazon Comprehend Medical

Nefrologie 2.0

• Biotechnology revolution: CRISPR-Cas9

• Information revolution: • Biometric signals

• Natural language processing

• Artificial Intelligence: Deep learning

Artificial IntelligenceIntelligence = Ability to accomplish complex goals

• Memory = Storage of encoded information until it’s needed

• Computation = Transformation of one memory state into another

Computation = Transformation of one memory state into another

Artificial IntelligenceIntelligence = Ability to accomplish complex goals

• Memory = Storage of encoded information until it’s needed

• Computation = Transformation of one memory state into another

• Learning = Rearrangement to get better at computing the desired function

SUBSTRATE INDEPENDENCE!

The "deep" refers to the number of layers through which the data is transformed.

Artificial Neural Network

Deep Mind AI learns to play Atari Breakout

The game of Go• The rules of Go are so elegant, organic

and rigorously logic, that if intelligent life exists elsewhere in the Universe, it almost certainly plays Go.

• Possible Go positions:

2.0811681994 x 10170 =

Two hundred quinquinquagintillion

AlphaGo

Move defying millennia of human wisdom

Alpha Go vs. Lee Sedol

AlphaGo Zero

Poker• Human psychology

• Hidden information

no-limit Texas Hold’em poker

Soulful human compositions versus the lifeless artefact of the machine: the Bach story

• EMI (Experiments in Musical Intelligence) created by David Cope, professor of musicology at University of California

• Steve Larson, professor of musicology at University of Oregon, pioneer of music cognitive study

• Johann Sebastian Bach, German composer

EMI

Larson

Bach

EMI

Larson

Bach

Soulful human compositions versus the lifeless artefact of the machine: the Bach story

Why is Medicine Behind?

Medical Applications in which Deep Learning

achieved State-of-the-art Results

Nature Medicine | VOL 44 25 | JANUARY 2019 | 44–56

HALICIN = potent bactericidal activity against wide spectum of pathogens

➢Training of deep neural network to predict growth inhibition of E.Coli, using library of 2.335 molecules

➢Application to library of >107 million compounds

➢Selection of a list of candidates

➢Halicin is structurally divergent from conventional antibiotics

➢Elucidation of mechanism of action = dissipates the cytoplasmictransmembrane potential

Cell 180, 688–702, February 20, 2020

Cell 180, 688–702, February 20, 2020

HALICIN

➢Murine model

➢Inhibits pan-resistantAcinetobacter baumannii

➢Clears Clostridium difficilebetter than vehicle andmetronidazole

Male, 55 year

• No relevant medical history

• Family history negative

• No medication use

• Seeks care for headache

• BP 195/110, bisoprolol

• Screat 3.5, K+ 5.9, Uprotein 3.5

• Biopsy: end-stage kidney

• Diagnosis: “nephrangiosclerosis”

• Info on diet/dialysis/transplantation, AV-fistula

• 1 year later: start hemodialysis

2000 2020

Male, 55 year

• Alexa natural language processing symptoms: “head is bursting, …”

• Alexa biometrical data: BP, bioimpedance, ECG (K+=5.9)

• Alexa: facebook post of a cousin living in Canada with a kidney transplant

• Human Dx (DL + physician crowdsourcing): renal failure, DD genetic, primary GN

• NGS: hemizygous c.215T>G (p.Leu72Arg) substitution in Cd2ap (never described)

• DeepVariant (open source DL): variant is pathogenic

• Semantic Scholar DL: Mutations in CD2AP (important component of the slitdiaphragm) in childhood onset FSGS (Takano et al. Kidney Int 2019; 95, 57–61). Diagnosis: genetic FSGS

• Inscripta Therapeutics: design CRISPR-Cas9 gene editing probes: correctionmutation + reduction renal fibrosis

• After 1 year: Screat 1.8

• Genetic screening children: 23-year-old son affected, creat 1.15

2030

Data AcquisitionData Analysis

Produce Diagnosis Initiate Treatment

Information Revolution Deep Learning Biotechnology Revolution

CoordinationCare

Creativity

Tempora mutantur, nos et mutamur in illis

Coordination• Absence of routine• Simultaneous use of wide range of skills• Unforeseen scenarios

Care• Empathy• Charisma• Sonzai-kan

Creativity• Groundbreaking research• Development of new

medicines/techniques/algorithms

Tempora mutantur, nos et mutamur in illis

Coordination• Absence of routine• Simultaneous use of wide range of skills• Unforeseen scenarios

Care• Empathy• Charisma• Sonzai-kan

Creativity• Groundbreaking research• Development of new

medicines/techniques/algorithms

Human

AI

Anyhuman

Any AI

Complex critical thinkingSocial intelligenceCreative problem solving

Processing vast amounts of data“Non-human” behavior

Male, 55 year

• Alexa natural language processing symptoms: “head is bursting, …”

• Alexa biometrical data: BP, bioimpedance, ECG (K+=5.9)

• Alexa: facebook post of a cousin living in Canada with a kidney transplant

• Human Dx (DL + physician crowdsourcing): renal failure, DD genetic, primary GN

• NGS: hemizygous c.215T>G (p.Leu72Arg) substitution in Cd2ap (never described)

• DeepVariant (open source DL): variant is pathogenic

• Semantic Scholar DL: Mutations in CD2AP (important component of the slitdiaphragm) in childhood onset FSGS (Takano et al. Kidney Int 2019; 95, 57–61). Diagnosis: genetic FSGS

• Inscripta Therapeutics: design CRISPR-Cas9 gene editing probes: correctionmutation + reduction renal fibrosis

• After 1 year: Screat 1.8

• Genetic screening children: 23-year-old son affected, creat 1.15

2030

2030Male, 55 year

CARE

CARE

CREATIVITY

COORDINATION

Nephrologist interprets data and discusses diagnostic plan

Nephrologist discusses diagnosis and treatment plan

Scientist Inscripta Therapeutics designs CRISPR Cas9 gene editing probe

Nep

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logi

st s

up

ervi

ses

enti

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roce

ss

Alexa

Biometric dataSocial MediaNLP symptoms

NGS and DL: pathogenic mutation Cd2ap

DL: search medical literature

23-y old son treated: Screat 1.15

Family screened

Patient treated: Screat 1.8

Nefrologie 2.0

Make Healthcare Human Again

By these means we may hope to achieve not indeed a brave new world, no sort of perfectionist Utopia, but the more modest and much more desirable objective –

a genuinely human society

- Aldous Huxley