Gerhard Fasol: today’s agenda. Entropy, information and Ludwig Boltzmann – and Japan’s economic growth, 12th Ludwig Boltzmann Forum, 20 February 2020

Gerhard Fasol, CEO , Eurotechnology Japan KK. Guest Professor, Kyushu University, former faculty Cambridge University, and Trinity College, and Tokyo University

Purpose of the Ludwig Boltzmann Forum

• Leadership Forum based on logic, science and technology.
• Create impact and change
• Contribute to solutions of important issues which make a difference to our lives
• “Superstar leaders” as keynote speakers

Today’s program:

• Increased economic growth from increasing international cooperation between Japan and Europe, eg in the fields of railways, sleep, genetics, 5G and 6G communications, in research and business
• Governance and management of companies – growth of companies must improve for economic growth and to pay for the costs of an aging society
• Research, development, and Universities are key for economic growth – they must improve to recover economic growth. We can learn from Ludwig Boltzmann

Some of Japan’s top issues and opportunities

• Japan’s economy stopped growing in 2000. A new business model is needed for Japan. Japan has many fantastic technologies, products, business models with big opportunities for global value creation.
• Aging society.
• University reform is urgently necessary in order to restart growth.
• Company management and supervision reform is urgently necessary. About 1/2 of TOPIX companies have market capitalization lower than book value, and too many Japanese companies have no growth and no profits since 2000, and no growth of market capitalization/company value since 2000.

Some results which might areas from today’s conference

• Safety is top priority for JR-East and sleep of managers and driving staff is a primary factor for safety and accident prevention. Today we have the leader of JR-East, and a top global leader in sleep science, maybe today’s conference can lead to cooperation, joint research or development with JR-East on sleep and safety.
• 5G and 6G communications will impact all areas of society, how can society influence the development of 5G and 6G services and ecosystems. Society and 5G/6G ecosystems evolve in sync.
• We are at the start of a novel virus crisis, how will an epidemic affect mobility, communications, sleep, medicine.

Family background: Boltzmann & Chiari

Johann Baptist Chiari (1817-1854)

Gynecologist & Obstetrician 産婦人科医

Professor in Prag and Vienna

https://de.wikipedia.org/wiki/Johann_Baptist_Chiari

https://en.wikipedia.org/wiki/Johann_Baptist_Chiari

• Chiari-Frommel Syndrome (hyperprolactinaemia): a rare condition where galactorrhea and amenorrhea continues for an abnormal length of time after birth
• Teacher of Ignaz Semmelweis (discovered cause and cure for puerperal fever, “childbed fever”)
• “Klinik der Geburtshilfe und Gynäkologie” First text book to present Ignaz Semmelweis work on hygiene at birth

Johann Baptist Chiari in the Official History of Vienna:

https://www.geschichtewiki.wien.gv.at/Johann_Baptist_Chiari

Ottokar Chiari (1853-1918)

Ear Nose and Throat specialist, laryngologist, rhino laryngologist 耳鼻咽喉専門医

Professor and Director of the Ortorhinolaryngological University Clinic at Vienna University. Ottokar Chiari performed the first transbronchial operation, introducing minimal-invasive surgery.

In 1912 he introduced the transethmoid trans-sphenoid operation.

He founded the Ear-Nose-Throat Clinic (Ortorhinolaryngological University Clinic) at the University of Vienna, the first Ear-Nose-Throat (Ortorhinolaryngological University Clinic) worldwide, of which he was appointed Director (Leiter der Laryngoloischen Abteilung der Allgemeinen Krankenhauses) from 1900 and Chair Professor (ordentlicher Professor) from 1912.

Ottokar Chiari was appointed the personal medical doctor of Emperor Franz-Joseph, and was elevated to the status of “Freiherr” in 1917.

Ottokar Chiari (Ottokar Freiherr von Chiari) is the son of Johann Baptist Chiari. His daughter Paul Chiari married the son of Ludwig Boltzmann, and is my (Gerhard Fasol’s) grandmother.

Ottokar Chiari in the Official History of Vienna

https://www.geschichtewiki.wien.gv.at/Ottokar_Chiari

Since 23 March 1932, Chiarigasse in Wien-Favoriten is named after Ottokar Freiherr von Chiari, see Vienna’s official history: https://www.geschichtewiki.wien.gv.at/Chiarigasse

https://de.wikipedia.org/wiki/Ottokar_von_Chiari

https://en.wikipedia.org/wiki/Ottokar_Chiari

Hans Chiari (1851-1916)

Pathologist

Pathologist 病理医

University of Strasbourg: Professor and University President 

Hans Chiari in the official History of Vienna https://www.geschichtewiki.wien.gv.at/Hans_Chiari

https://de.wikipedia.org/wiki/Hans_Chiari

https://en.wikipedia.org/wiki/Hans_Chiari

• Budd-Chiari-Syndrom
• Chiari-Malformation.

Karl Chiari (1912-1982)

Karl Chiari is the son of Richard Chiari (1882-1929), Director of the Linz General Hospital (Allgemeines Krankenhaus Linz). Karl Chiari is the founder of orthopedics in Vienna, he was the first head of the new Department of Orthopaedics at the University Hospital Vienna.

Karl Chiari pioneered many new modern therapies and surgery methods in the field of Orthopaedics. He pioneered therapies and treatments in the fields of Scoliosis (a medical condition where a patient’s spine is curved sideways), bone tumors, orthopaedic rheumatology, knee entroprothetic, hip endoprotethic, and operations to correct hip dysplasia.

In 1967, Karl Chiari became Chair Professor (ordentlicher Professor), and since 1962 he was the first Director of the Orthopaedic Clinic at the Vienna University Hospital., which spun out from the 1. Surgical University Clinic at the University of Vienna. He was Director of the Orthopaedic Clinic for 20 years.

Today at the Medical University Vienna (MedUni Wien) the Laboratory for Orthopaedic Biology is named Karl Chiari Lab for Ortopaedic Bilogy in honor of Karl Chiari, https://www.meduniwien.ac.at/hp/orthopaedie/forschung/karl-chiari-lab-for-orthopaedic-biology/mission-statement/

As children we used to ski together with Karl Chiari’s family, and at the age of 6 years I (Gerhard Fasol) broke my leg while skiing together with Karl Chiari and his children. Back in the farm house pension where we all stayed, Karl Chiari adjusted my broken bones with his hands, and put my legs in plaster, which he always had with him. Later in his Clinic in Vienna, he x-rayed my broken leg, made more adjustments, put on a proper longer time plaster, and oversaw my leg until it was properly healed.

More about Karl Chiari:

official history of Vienna: https://www.geschichtewiki.wien.gv.at/Karl_Chiari_(Orthopäde)

https://www.oeaw.ac.at/fileadmin/Institute/INZ/Bio_Archiv/bio_2012_06.htm

https://www.meduniwien.ac.at/hp/orthopaedie/forschung/karl-chiari-lab-for-orthopaedic-biology/who-was-karl-chiari/

Ludwig Boltzmann 20 February 1844 – 5 September 1906

• Physicist
• Mathematician
• Philosopher
• Leader
• Venture investor (air planes)

The Ludwig Boltzmann Forum is a platform of leaders driving improvements based on logic and science

• inspire leaders by Ludwig Boltzmann’s example
• honesty, humility
• asking profound questions and working towards the answers using logic, mathematics, science
• understand nature and systems

Ludwig Boltzmann in the official history of Vienna https://www.geschichtewiki.wien.gv.at/Ludwig_Boltzmann

We use Ludwig Boltzmann’s results and tools every day

as examples

• S = k log W – linking macroscopic entropy to statistics of molecules > information theory: Shannon entropy
• Boltzmann transport equations > optimal transport
• Definition of Kelvin, Celsius directly linked to Boltzmann constant
• Stefan-Boltzmann radiation law
• statistical mechanics and Maxwell-Boltzmann statistics
• Philosophy of nature: is the space we live in curved? How can we determine the curvature of our space? Using philosophy – or using the tools of physics and mathematics?

Ludwig Boltzmann was several times proposed for the Nobel Prize 1903, 1905 and three times in 1906 – the year he passed away.

Ludwig Boltzmann started young

1865, at the of age of 21 years he published his first scientific work: “Über die Bewegung der Elektrizität in krummen Flächen” (Electricity on curved surfaces).

About 20% of Boltzmann’s publications were in the field of electro-magnetism. 1861-1862 James Clerk Maxwell had created the foundations of modern electro-magnetism with Maxwell’s equations.

Linking the initially macroscopic 2nd law of thermodynamics to the statistical mechanics of atoms and molecules governed by Newton’s laws

1866 at the age of 22 years Ludwig Boltzmann published one of his most important works in a field he created and worked on for all his life: “Über die mechanische Bedeutung des zweiten Hauptsatzes der Wärmetheorie” (About the mechanical meaning of the second law of thermodynamics).

https://reader.digitale-sammlungen.de//en/fs1/object/display/bsb10133426_00003.html

As a reminder: the 2nd law of thermodynamics says that an isolated system spontaneously evolves to the state of greatest entropy. The 2nd law of thermodynamics was first formulated by Sadi Carnot in 1824 as part of the efforts to optimize steam engines and is also known as Carnot’s theorem.

Boltzmann linked this initially macroscopic law to the statistical mechanics of atoms and molecules governed by Newton’s laws at a time when the existence of atoms was not yet generally accepted.

Boltzmann’s dilemma: how can time-reversible Newton’s laws at the microscale lead to the time-irreversible 2nd law of thermodynamics

Newton laws govern the microscopic collisions and motion of atoms and molecules in gases and are completely time reversible. Processes we observe macroscopically, e.g. a gas escaping from a pressure vessel, are time irreversible. This dilemma, how Newton’s reversible laws governing the microscopic motion can lead to irreversible processes on the macroscopic scale, occupied Boltzmann’s mind and work his whole life long. Boltzmann’s answers depend on the realization that the 2nd law of thermodynamics cannot be explained by Newton’s laws of mechanics alone, but the mathematical tools of statistical mechanics are required, many of which Boltzmann created.

Boltzmann’s path through life: starting young – and global

• 1865 (age 21) first publication “Electricity on curved surfaces”
• 1867-1869 (age 23-25) Privat-Dozent (Associate Professor)
• 1869-1873 (age 25) Full Professor, Mathematical Physics, University of Graz
• 1873-1876 (age 29) Full Professor, Mathematics, University of Vienna
• 1875 (age 31) declined offer of Professorship in Zürich and Freiburg (Germany)
• 1876-1890 (age 32) marriage, Full Professor for Experimental Physics and Head of the Institute of Physics, University of Graz
• 1887-1888 (age 43-44) Rector (President), University Graz
• 1888 (age 44) March: Professor in Berlin, June: resigned from Professor position
• 1890 (age 46) Professor in München (one of his students was Nagaoka Hantaro, who later became the first President of Osaka University, and created a model of the atom)
• 1892 attended 300 year celebrations of Trinity College Dublin
• 1894 visit to Oxford University
• 1894-1990 (age 50) Professor, University of Vienna
• 1895 attending Naturforscherversammlung in Lübeck
• 20 June – 2 August 1889 (age 55) first trip to the USA: Clark University, Worcester MA, Boston, Montreal
• 1900-1902 (age 56) Professor of Theoretical Physics in Leipzig
• 1902-1906 (age 58) Professor of Theoretical Physics at University Vienna
• Trips to Göttingen, Kassel, Southport Meeting of the British Association for the Advancement of Science and to Paris.
• 1903/1904 Vorlesungen über Naturphilosophie (Lectures on philosophy of nature)
• 21 August – 8 October 1904 second trip to the USA to attend St Louis World Fair and Congress “Physics for a new century”, Detroit, Chicago, Washington DC
• 11 June – 3 August 1905 third trip to the USA: Lectures at the University of California Berkeley and at Stanford University

What can we learn from Ludwig Boltzmann?

• Empower young people, recognize and support talent early
  • LB published first scientific work at age 21
  • Full Professor at 25
  • Head of Department at 32
  • President of University at 43
• Talent is not linear – talent is exponential
• Move around the world. Connect. Interact.
• Empower women (LB promoted many women)
• Don’t accept authority for authority’s sake
• Science/physics issues need to be treated with the methods of physics/science
• No dogmas
• Support entrepreneurs (LB supported airplane developers before airplanes existed)

Summary: understanding and learning from Ludwig Boltzmann

Boltzmann’s results are a big part of our understanding of the world and the universe

His mathematical tools are used every day by today’s engineers, bankers, IT people, physicists…

LB stood up for his ideas and conclusions and did not accept scientific authorities for authorities’ sake

contact

Copyright (c) 2020 Eurotechnology Japan KK All Rights Reserved

Masaki Ogata: Open Innovation and MaaS of JR East

12th Ludwig Boltzmann Forum, 20 February 2020

Summary by Gerhard Fasol

Masaki Ogata

• East Japan Railway Company, Board Director and Vice-Chairman, Executive Vice President of Technology & Overseas Related Affairs
• Honorary President, UITP (International Association of Public Transport)
• Member of Council for Science and Technology, Chairperson of Subdivision on Professional Engineers, Ministry of Education, Culture, Sports, Science and Technology Japan
• Chairman & CEO, Japan Institute of IT
• Chairman Tohoku Tourism Promotion Organization
• Director Tohoku Electric Power Company Inc.

Summary: Open Innovation and MaaS of JR East

With 17.9 million passengers/day, 12,209 trains/day on a network of 7402 km, JR-East is one of the largest railway companies in the world. JR-East is a fully integrated group including ownership, manufacture and maintenance of rolling stock, infrastructure including track, stations and real-estate, trains and buses, and life-style business, and one of the first and most advanced fin-tech systems globally: electronic payment systems and electronic money.

JR-East receives no government subsidies, and had no fare or charge increases for 33 years (except for increases in the consumption tax).

JR-East is constantly innovating, developing MaaS, deepening fin-tech and mobile payments, and increasing Shinkansen speeds to 360 km/h.

Mr Ogata sees the MaaS revolution as a revolutionary economic wave occurring once in 100 years, and works for JR-East to drive this Maas wave.

7 Features of JR East Management

Vertical structure

• (1) non-rail business: life-style business, IC card
• (2) operation: trains and busses
• (3) maintenance: rolling stock and infrastructure
• (4) ownership: rolling stock and infrastructure

Horizontal structure

Passengers: 17.9 million/day – largest number of passengers globally

Network: 7402 km

Trains: 12,209 trains/day

• (5) Shinkansen
• (6) Tokyo region
• (7) regional lines in North-Eastern Japan

Business Structure

17.9 million customers / day (largest in the world)

FY2018 Revenues: € 24.6 billion

• Transportation business: € 16.7 billion (68%)
  • Tokyo metropolitan 58%
  • Shinkansen 29%
  • Regional 3%
  • other transportation (bus, monorail etc) 9%
• Life service business: €7.9 billion (32%)

Safety is always the top priority of JR East management

Multiple business models

a mobility company, covering 24 hours and all the life of people. Synergetic growth with railways as the base and towards Mobility as a Service (MaaS)

1. Railway
2. Life style (shops, buildings…)
3. Micropayment
4. Rolling stock manufacture
5. Overseas business

Public Transport (PT) in Japan and in the world

• railway companies – Japan: 200, globally: 3000
• bus companies – Japan: 7000, globally: 80,000
• taxi companies – Japan: 16,000, globally: 200,000
• (taxi cars in Japan: approx. 260,000)

Public Transport (PT) leads Mobility as a Service (MaaS)

• PT innovation
• improvement by intermodal cooperation (e.g. JR-East through trains to other railways companies and Tokyo subways)
• integration with new mobility solutions

STTT Model (Shortening Total Trip Time = STTT)

Customers are mainly interested in the total trip time. Shorten total trip time by reducing the time of each component of the trip, and in particular access to public transport at both ends (e.g. by bicycle, moped or “new personal mobility” e.g. shared electro-scooters etc), and shorten transitions between different means of transport.

Maximum transport capacity per direction per hour:

• automobile: 1000
• bus: 2500
• LRT: 11,000
• monorail: 21,000
• mini-metro: 35,000
• heavy rail, incl. metro: 64,000
• heavy rail (e.g. JR East Chuo Line): 100,000

Mobility as a Service (MaaS): a once-in-a-century wave of change including the public transport (PT) industry

We see the development of Mobility as a Service (MaaS) as a massive once-in-a-century change of paradigm which includes the public transport (PT) industry

We see an evolution from privately owned, manually operated automobiles to sharing, on-demand, autonomous operation integrated with public transport. Current public transport + new concepts such as UBER, Lyft, in Japan “Times Car Plus” integrating with innovations in public transport.

Once in 100 years wave of change in transportation (MaaS) is a threat to the automobile industry

the new paradigm CASE was always the case for the railway industry:

• Connected
• Autonomous
• Shared
• Electric

Many industries aim at becoming the dominating MaaS platform

We see a big threat to the automobile industry from several directions:

• data businesses may overwhelm automobile companies
• automobile companies may decline into commodity manufacturing
• customer needs (and value to the customer) will shift from the product (car) itself to mobility service

Mobility wave as economic cycle

• Kitchin cycles (inventory): 3.3 years (3-5 years, e.g. pork cycle)
• Juglar cycles (investment): 10 years (7-11 years, see e.g. Korotayev, Andrey V; Tsirel, Sergey V., “A Spectral Analysis of World GDP Dynamics: Kondratieff Waves, Kuznets Swings, Juglar and Kitchin Cycles in Global Economic Development, and the 2008–2009 Economic Crisis”)
• Kuznetsk cycles (demand of buildings, infrastructure investments): 20 years
• Kondratieff cycles (innovation): 50 years (naming suggested by Joseph Schumpeter)
• “Mobility wave”: 100 years

Open Innovation of JR East

(1) innovation of operations

• Speed-up of Shinkansen
  • 1987 operation speed = 240 km/h
  • 2019 operation speed = 320 km/h
  • 2019 test speed = 400 km/h
  • aiming at operation speed of 360 km/h
• Number of trains
  • 1987: 11,175 trains/day
  • 2019: 12,209 trains/day (+ 9.3%)
• Enhancement of sustainability
  • average CO2 emission per railway passenger
    • 1/7 of automobiles
    • 1/5 of airplanes
    • JR East: 1/2 of global rail average
• Enhanced efficiency of train operations
  • 1987: 71,000 staff in JR East’s Railway Operation Division
  • 2019: 39,000 staff

(2) IT innovation

• Number of IT systems
  • 1987: 3 IT systems
  • 2019: 1224 IT systems
• Big Data and Condition Based Maintenance (CBM)
  • CBM is now being introduced for track, rolling stock, electric facilities…
• IT for customer service: “JR East App”
  • Japanese version: 4.8 downloads
  • Multi-lingual version (English/Chinese/Korean): 500,000 downloads (as of January 2020)

No government subsidies and no fare/charge increases for 33 years

For the past 33 years (since 1987):

• no subsidies from central or local governments
• no increased fares or charges (except for consumption tax increases)

Examples of innovation: SUICA and fintech since November 2001

Evolution from analog paper tickets to fintech

• paper tickets (analog)
• magnetic ticketing cards stage 1: NRZ1 (non-return-to-zero) (these tickets have a brown backside)
• magnetic ticketing cards stage 2: FM (F2F) (Frequency modulation) (these tickets have a black backside)
• magnetic cards for stored fares (SF)
• SUICA IC Chip memory since 18 November 2001
• Authentication, micropayments > fintech from March 2004
• Mobile SUICA integration with mobile phones, start: January 2006
• development of new business

SUICA started on 18 November 2001: an example of open innovation

SUICA: cooperation between JR East and SONY

• transactions in 200 milli-seconds
• ticketing
• commuter passes
• micropayments
• mobile SUICA

Open strategy

• technical disclosure to industry peers: disclosure to more than 200 railway companies in Japan
• standardization of the technology – de-facto standards:
  • better customer service
  • big impact on society and the nation
  • scale merit: scaling!
• 23 March 2013: completion of nationwide platform
  • complete mutual usage
  • coverage: 12% of the population
  • 5000 railroad stations
  • 50,000 buses

Development of SUICA

• 18 Nov 2001: implemented IC ticketing SUICA in Tokyo
• 22 March 2004: launched micropayment service (e-money) based on SUICA IC card ticketing system
• 28 January 2006: launched “mobile SUICA” for feature phones
• 18 March 2007: interoperable service with PASMO
• 23 July 2011: launch of Mobile SUICA services for smart phones
• 23 March 2013: launched interoperable service with 10 regional transport cards for 142 operations, later expanded to currently 258 operating companies
  • interoperable transport IC card systems: total 160 million cards
  • mobile SUICA: 9.0 million members
  • micropayments:
    • maximum transactions/day: 9.58 million
    • transactions per month: 253 million
    • member stores: 850,000 (as of December 2019)

Micropayment fintech in Japan is driven by SUICA and railroad payment cards:

3 tsu (通）

• Tsushin (通信) = communications
• Kotsu (交通）= transport
• Ryotsu (流通) = logistics

It took almost 20 years to move from the initial introduction of IC card based SUICA micropayments for transport on 18 November 2001 to the cashless society policy movement in Japan from 2018.

MaaS of JR East

The MaaS platform of JR East aims to include a wide range of business areas:

• single mode type: automated driving and car sharing
• integrated type of multi PT modes: bus, railways, Shinkansen
• integrated type of mobility: bike sharing, rent-a-car, taxi
• MaaS of JR East platform further includes: restaurants, shopping, hotels, tourism, inns, kiosks, luggage lockers etc
• telecommunication carriers
• local government and other services

MaaS aims for all integrated services = all mobility + any added values with lean start-up and agile development philosophies

Proof of concept for JRE MaaS

• Niigata, Shonai area: Niigata MaaS Trial since October 2019
• Tohoku area: under consideration, PoC from 2012
• Sendai area: PoC since February 2020
• Tokyo Metropolitan area: PoC since August 2018, public release from January 2020
• Izu (Shizuoka Prefecture), PoC in cooperation with local operator Izukyu Corporation.
  • Phase 1: April 2019 – June 2019
  • Phase 2: December 2019 – March 2020

Future customer journey will provide “24 hours, one-stop” services from wake-up, digital time management to transportation with flexible schedule change, meeting management, and one-stop reservations for transport, restaurants, hotels etc including easy and automatic check-in

“3D smooth trip”

• horizontal: through operations
• vertical: barrier free equipment
• psychological: smart card in stations and trains with 0.2 second transactions

4 service levels – MaaS app under PoC

• Level 1: integration of information: information app and route search engine
• Level 2: integration of booking and payment, SUICA micropayments
• Level 3: integration of service offer, bundling, subscriptions, contract, commuter pass and through operations
• Level 4: integration of national policy, government

Moving Further Forward

MTOMI model = Management + Technology + Operation + Maintenance + Infrastructure

Integrating technology and service industry provides value and service to customers, community, society and the nation.

The moment of truth is hospitality.

The Triangle:

• customers and the moment of truth: hospitality
• management policy
• MTOMI model + well-disciplined employees

Genuine infrastructure = MTOMI Model optimizes multiple resources and services and offers multiple options to consumers

Integration of the MTOMI Model + sophisticated service provides value to customers, communities, societies, nation and the world > MaaS of JR East

Public Transport (PT) will lead MaaS

In the ICT field GAFA (Google, Apple, Facebook, Amazon) and other Silicon Valley and Chinese companies are far ahead, however Japan has unique infrastructure, especially railway infrastructure as unique fields of application for ICT.

Just Shinjuku station alone is a unique application field.

Scale and speed are the keys to success.

ICT and Public Transport (PT) are an excellent match for each other.

Ultimate mobility means: everyone can move freely at anytime to anywhere with comfort by mobility of high quality

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Copyright (c) 2020 Eurotechnology Japan KK All Rights Reserved

Masashi Yanagisawa: Solving the Mysteries of Sleep: Toward the Real-World Implementation of Sleep Science, 12th Ludwig Boltzmann Forum, 20 February 2020

Masashi Yanagisawa, International Institute for Integrative Sleep Medicine (WPI-IIIS), Director, University of Tsukuba, Professor

Professor Yanagisawa is founder and Director of the International Institute for Integrative Sleep Medicine (IIIS), which he founded and is leading to study sleep – one of the most important puzzles of nature. He build the IIIS based on his long work at the University of Texas Southwestern Medical Center, and learning from the principles guiding departments at major US Universities.

Summary by Gerhard Fasol

Solving the mysteries of sleep: what physically is “sleepiness”?

Tokyo is the world’s most sleep-insufficient city with 5 h 28 mins/night

The world’s most sleep-insufficient city is Tokyo – actigraphy shows that the average sleep time in Tokyo is 5 hours 28 minutes – and this is unsustainable. (GF: see notes towards the end of this page)

A study by the sleep app company SleepCycle and mentioned in The Economist/1843 magazine shows average time in bed per day based on 1 million users of the SleepCycle app vs GDP/person for 55 countries (see notes below for sources). While New Zealand, Finland and Netherlands show similar GDP/person, their time in bed is longest 0n the order of 7 h 45 mins/night, while South Korea and Japan are at the bottom of the figure with time in bed around 6 h 15 mins to 6 h 30 mins.

Lack of sleep is estimated to cost Japan about US$ 138 billion (3% of GDP) annually

The study “Why Sleep Matters: Quantifying the Economic Costs of Insufficient Sleep” by RAND Europe

https://www.rand.org/randeurope/research/projects/the-value-of-the-sleep-economy.html

estimates that insufficient sleep costs Japan about US$ 138 billion (about 3% of GDP) annually. While less dramatic, sleep in other major industrial countries is also insufficient, and ist estimated to cost Germany about 1.6%, UK 1.9%, the USA 2.3%, and Canada 1.3% of GDP.

Lack of sleep causes a decrease of performance similar to alcohol intoxication

Dawson and Reid in study compared the decrease of performance caused by extended wakefulness with that caused by alcohol intoxication, and found that 17 hours of sustained wakefulness (e.g. from 7am to midnight) causes a drop in performance similar that caused by a blood alcohol concentration of 0.05%.

Wakefulness of 24 hours (e.g. from 7am until 7am the next day) leads to performance reduction corresponding to a blood alcohol concentration of 0.1%.

reference: Dawson, D., Reid, K. Fatigue, alcohol and performance impairment. Nature 388, 235 (1997)

https://doi.org/10.1038/40775

https://www.nature.com/articles/40775

The neurobiological “cost” of sleep reduction accumulates, and sleep deprived individuals underestimate this cost

Van Dongen et al show that the “cost” of short sleep, “sleep debt” accumulates, and is systematically underestimated by individuals as a consequence of insufficient sleep.

reference: Van Dongen HP, Maislin G, Mullington JM, Dinges DF. The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation. Sleep, Volume 26, Issue 2, March 2003, Pages 117–126,

https://doi.org/10.1093/sleep/26.2.117

https://academic.oup.com/sleep/article/26/2/117/2709164

Healthy young individuals are at risk of accumulating “sleep debt”, from which it is hard to recover

Laboratory experiments show that healthy young individuals are at risk of sleeping one hour/day less than optimal, and a 1 hour “sleep debt” takes 4 days of optimum sleep to recover to full performance.

reference: Shingo Kitamura, Yasuko Katayose, Kyoko Nakazaki, Yuki Motomura, Kentaro Oba, Ruri Katsunuma, Yuri Terasawa, Minori Enomoto, Yoshiya Moriguchi, Akiko Hida & Kazuo Mishima, Estimating individual optimal sleep duration and potential sleep debt, Sci Rep 6, 35812 (2016).

https://doi.org/10.1038/srep35812

https://www.nature.com/articles/srep35812

Short sleep duration is independently associated with prevalent and incident atrial fibrillation

Lack of sleep is associated with atrial fibrillation. Atrial fibrillation is associated with increased risk of heart failure, dementia, and stroke.

reference: Michael V. Genuardi MD, Rachel P. Ogilvie, PhD, MPHb,Aisha Rasool Saand, MD, Rebecca S. DeSensi, BA, Melissa I. Saul, MS, Jared W. Magnani, MD, Sanjay R. Patel, MD, Association of Short Sleep Duration and Atrial Fibrillation, Chest, (September 2019) Volume 156, Issue 3, Pages 544–552

https://doi.org/10.1016/j.chest.2019.01.033

https://journal.chestnet.org/article/S0012-3692(19)30196-5/

Do all animals sleep? When in evolution did sleep develop? Do animals without a centralized nervous system sleep?

How far back in Darwin’s evolution did sleep develop? Sleep has been observed in a wide range of animals, in worms, flies, zebrafish and mice. Although it’s hard to prove scientifically, its likely that all animals with a central nervous system sleep, however sleep patterns differ.

Do animals without a centralized nervous system sleep?

Three characteristics define sleep:

1. a period of decreased activity
2. reduced responsiveness to stimuli
3. homeostatic regulation

Ravi et al demonstrated sleep in “upside down jellyfish”, Cassiopea jellyfish, which belong to the Cnidaria evolutional lineage. These have a non-centralized nerve net, but no centralized nervous system or brain.

Cassiopea pulse by relaxing and contracting their bell about 1 pulse per second. Nath et al observed this pulse for a large number of Cassiopea jellyfish with an imaging system, and found that Cassiopea pulse less during night than during day, this sleep state is rapidly reversible, and shows all other characteristics of sleep.

Thus it seems that sleep arose before the evolution of a centralized nervous system.

see: Ravi D. Nath, Claire N. Bedbrook, Michael J. Abrams, Ty Basinger, Justin S. Bois, David A. Prober, Paul W. Sternberg, Viviana Gradinaru, and Lea Goentoro, The Jellyfish Cassiopea Exhibits a Sleep-like State, Current Biology 27, 2984–2990, (October 9, 2017)

http://dx.doi.org/10.1016/j.cub.2017.08.014

https://www.cell.com/current-biology/fulltext/S0960-9822(17)31023-0

Motivation and sleep

Lazarus/Oishi Laboratory (International Institute for Integrative Sleep Medicine WPI-IIIS)

https://www.wpiiiislazaruslab.org

Sleep is understood to be driven by two factors:

• homeostatic drive, and
• circadian rhythm. The 2017 Nobel Prize in Physiology or Medicine was awarded for the discoveries of molecular mechanisms controlling the circadian rhythm
  • https://www.nobelprize.org/prizes/medicine/2017/advanced-information/

However, we all know that motivation, emotion also influence sleep.

Why are we sleepy when we are bored?

The Nucleus Accumbens (NAc) is located close to the hypothalamus (which links the nervous system to the endocrine system and regulates processes in the autonomous nervous system) in our brains, and contributes to processing motivation, aversion, reward, and is also involved in inducing slow-wave sleep.

The Nucleus Accumbens (NAc) links motivation and sleep.

Adenosine A2A acting on the NAc via A2A-Receptors (A2AR) induces slow-wave sleep. Chemogenetic inhibition of NAc neurons suppresses sleep. A2A receptors allow sleep gating.

Motivational stimuli act on the NAc via Dopamine as a neurotransmitter.

References

• Yo Oishi, Qi Xu, Lu Wang, Bin-Jia Zhang, Koji Takahashi, Yohko Takata, Yan-Jia Luo,Yoan Cherasse, Serge N. Schiffmann, Alban de Kerchove d’Exaerde, Yoshihiro Urade, Wei-Min Qu, Zhi-Li Huang & Michael Lazarus, Slow-wave sleep is controlled by a subset of nucleus accumbens core neurons in mice, Nat Commun 8, 734 (2017)
  • https://doi.org/10.1038/s41467-017-00781-4
  • https://www.nature.com/articles/s41467-017-00781-4
• Ray Luo, Akira Uematsu, Adam Weitemier, Luca Aquili, Jenny Koivumaa, Thomas J. McHugh & Joshua P. Johansen, A dopaminergic switch for fear to safety transitions. Nat Commun 9, 2483 (2018).
  • https://doi.org/10.1038/s41467-018-04784-7
  • https://www.nature.com/articles/s41467-018-04784-7
• Michael Lazarus, Yo Oishi, Theresa E. Bjorness and Robert W. Greene, Gating and the Need for Sleep: Dissociable Effects of Adenosine A1 and A2A Receptors, (2019) Gating and the Need for Sleep: Dissociable Effects of Adenosine A1 and A2A Receptors. Front. Neurosci. 13:740
  • https://doi.org/10.3389/fnins.2019.00740
  • https://www.frontiersin.org/articles/10.3389/fnins.2019.00740/

Orexin (= hyprocretin) controls arousal, sleep and appetite – discovered by Masashi Yanagisawa’s and Lecea and Kilduff et al. groups

Orexin is a neuropeptide controlling arousal, sleep and appetite and was discovered in 1998 simultaneously by two independent groups of researchers: Masashi Yanagisawa’s group named this newly discovered neuropeptide “orexin”, while Lecea and Kilduff et al’s group named it “hypocretin”.

• Masashi Yanagisawa’s lab at the University of Texas Southwestern Medical Center at Dallas: Takeshi Sakurai, Akira Amemiya, Makoto Ishii, Ichiyo Matsuzaki, Richard M Chemelli, Hirokazu Tanaka, S. Clay Williams, James A Richardson, Gerald P Kozlowski, Shelagh Wilson, Jonathan R.S Arch, Robin E Buckingham, Andrea C Haynes, Steven A Carr, Roland S Annan, Dean E McNulty, Wu-Schyong Liu, Jonathan A Terrett, Nabil A Elshourbagy, Derk J Bergsma, Masashi Yanagisawa, Orexins and Orexin Receptors: A Family of Hypothalamic Neuropeptides and G Protein-Coupled Receptors that Regulate Feeding Behavior, Cell, 92, 573-585 (Feb 20, 1998)
  • https://doi.org/10.1016/S0092-8674(00)80949-6
  • https://www.cell.com/cell/fulltext/S0092-8674(00)80949-6
• L. de Lecea, T. S. Kilduff, C. Peyron X.-B. Gao, P. E. Foye, P. E. Danielson, C. Fukuhara, E. L. F. Battenberg, V. T. Gautvik, F. S. Bartlett, II, W. N. Frankel, A. N. van den Pol, F. E. Bloom, K. M. Gautvik, and J. G. Sutcliffe, The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity, Proc Natl Acad Sci USA. (1998) Jan 6; 95(1): 322–327.
  • https://doi.org/10.1073/pnas.95.1.322
  • https://www.pnas.org/content/95/1/322

Source of this picture: Wikipedia. This work has been released into the public domain by its author, Boghog2 at the Wikipedia project. This applies worldwide. In case this is not legally possible: Boghog2 grants anyone the right to use this work for any purpose, without any conditions, unless such conditions are required by law.

Narcolepsy: “sleep attacks”

Narcolepsy is a sleep disorder, where wake-sleep cycle control is defective. Narcolepsy is a serious disorder, where patients can be affected by “sleep attacks”, sudden sleep during daytime, a pathological intrusion of REM sleep into wakefulness.

Sarah Elizabeth very generously published to following video on YouTube for educational purposes, to show us a narcolepsy “sleep attack”: (source: (c) Sarah Elizabeth on YouTube)

Peyron et al showed that there is a loss of orexin (hypocretin) in narcolepsy patients.

references:

• Christelle Peyron, Juliette Faraco, William Rogers, Beth Ripley, Sebastiaan Overeem, Yves Charnay, Sona Nevsimalova, Michael Aldrich, David Reynolds, Roger Albin, Robin Li, Marcel Hungs, Mario Pedrazzoli, Muralidhara Padigaru, Melanie Kucherlapati, Jun Fan, Richard Maki, Gert Jan Lammers, Constantin Bouras, Raju Kucherlapati, Seiji Nishino & Emmanuel Mignot, A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains, Nat Med 6, 991–997 (2000)
  • https://doi.org/10.1038/79690
  • https://www.nature.com/articles/nm0900_991

Sleep/wake switching circuitry

Scammell et al review the major components of the wake-promoting circuitry (neurons) and the sleep-promoting neurons.

references

• Thomas E. Scammell, Elda Arrigoni, and Jonathan O. Lipton, Neural Circuitry of Wakefulness and Sleep, Neuron 93(4), 747-765 (Feb 22, 2017)
  • http://dx.doi.org/10.1016/j.neuron.2017.01.014
  • https://www.cell.com/neuron/fulltext/S0896-6273(17)30038-7

Orexin agonists and antagonists as potential therapeutics

Orexins are produced by there hypothalamus and are involved in wakefulness and arousal. Blocking the signaling by Orexins is promising as therapy for insomnia. Orexin receptors as drug targets: towards a therapy for narcolepsy.

Orexin antagonists for treatment of insomnia.

• Takashi Nagahara, Tsuyoshi Saitoh, Noriki Kutsumura, Yoko Irukayama-Tomobe, Yasuhiro Ogawa, Daisuke Kuroda, Hiroaki Gouda, Hidetoshi Kumagai, Hideaki Fujii, Masashi Yanagisawa, Hiroshi Nagase, Design and Synthesis of Non-Peptide, Selective Orexin Receptor 2 Agonists, J. Med. Chem. (2015), 58, 20, 7931-7937
  • https://doi.org/10.1021/acs.jmedchem.5b00988

Sleep regulation: sleep need (hours) vs sleep/wake switching (seconds)

Sleep regulation can be symbolized by a Shishi-odoshi (鹿威し), a bamboo device often found in Japanese gardens. The bamboo is mounted off midway on a pivot, and slowly fills with water. The shorter part of the bamboo tube fills with water from a well, and as it fills, the point is reached where the bamboo tips over suddenly and releases the water. Sleep need similarly build up over time, until the sleep center tips over and we fall asleep suddenly. Assisted by orexin, the arousal center inhibits the sleep center in the brain while we are awake. When we are asleep, the sleep center inhibits the arousal center, and the sleep need decreases while we are sleeping.

references

• Clifford B. Saper, Thomas E. Scammell & Jun Lu, Hypothalamic regulation of sleep and circadian rhythms, Nature 437, 1257–1263 (2005)
  • https://doi.org/10.1038/nature04284
  • https://www.nature.com/articles/nature04284
• Vosko AM, Colwell C, Avidan A, Jet lag syndrome: circadian organization, pathophysiology, and management strategies. Nature and Science of Sleep, Volume 2010:2 Pages 187—198 (Aug 19, 2010)
  • https://doi.org/10.2147/NSS.S6683
  • https://www.dovepress.com/jet-lag-syndrome-circadian-organization-pathophysiology-and-management-peer-reviewed-article-NSS

Breading “Sleepy” mice mutants to study the genetics of sleep regulation

To study the switching mechanisms between wakefulness, REM-sleep and NREM-sleep (REM = Rapid Eye Movement), “sleepy” mice genetic mutants were studied and compared with normal non-sleepy mice.

references

• Funato H, Miyoshi C, Fujiyama T, Kanda T, Sato M, Wang Z, Ma J, Nakane S, Tomita J, Ikkyu A, Kakizaki M, Hotta-Hirashima N, Kanno S, Komiya H, Asano F, Honda T, Kim SJ, Harano K, Muramoto H, Yonezawa T, Mizuno S, Miyazaki S, Connor L, Kumar V, Miura I, Suzuki T, Watanabe A, Abe M, Sugiyama F, Takahashi S, Sakimura K, Hayashi Y, Liu Q, Kume K, Wakana S, Takahashi JS, Yanagisawa M. Forward-genetics analysis of sleep in randomly mutagenized mice. Nature 539, 378–383 (2016)
  • https://doi.org/10.1038/nature20142
  • https://www.nature.com/articles/nature20142

Solving the mysteries of sleep: International Institute for Integrative Sleep Medicine (IIIS)

https://wpi-iiis.tsukuba.ac.jp

Director: Masashi Yanagisawa

https://wpi-iiis.tsukuba.ac.jp/research/member/detail/masashiyanagisawa/

Basic concept of IIIS: learning from “departments” in major US Universities.

1. Strong leadership of “department head”
2. Appointment of early career PI
3. Flat personnel hierarchy
4. Open and mixed research environment
5. Flexible and dynamic allocation of research resources including floor space
6. Sharing of large facilities and equipment
7. Streamlined administrative services

Notes by Gerhard Fasol

Japan is the most sleep deprived country of a very long list of major countries

The American Academy of Sleep Medicine (AASM) and the Sleep Research Society (SRS) in a joint consensus statement say:

“Adults should sleep 7 or more hours per night on a regular basis to promote optimal health”.

see: Watson NF, Badr MS, Belenky G, Bliwise DL, Buxton OM, Buysse D, Dinges DF, Gangwisch J, Grandner MA, Kushida C, Malhotra RK, Martin JL, Patel SR, Quan SF, Tasali E. Recommended amount of sleep for a healthy adult: a joint consensus statement of the American Academy of Sleep Medicine and Sleep Research Society. SLEEP 2015;38(6):843–844.

https://www.st-va.ncbi.nlm.nih.gov/pmc/articles/PMC4434546/

https://dx.doi.org/10.5665%2Fsleep.4716

https://academic.oup.com/sleep/article/38/6/843/2416939

sleepcycle.com, which markets the SleepCycle app has been downloaded by 37.4 million people and has tracked 4.38 billion hours of sleep, and publishes statistics on sleep in different countries based on sleep statistics shared by their users/customers.

In a short report dated December 5, 2014, SleepCycle lists Japan as the No. 1 sleep-deprived country in a list of 20 countries and including the analysis of 351,044 users during 1-30 November 2014. All countries have a minimum of 2000 registered users.

Average time in bed, 1-30 November 2014, SleepCycle study of Dec 5, 2014:

1. Japan 5 h 56mins
2. South Korea 8 h 03mins
3. Brazil 6 h 37 mins
4. Mexico 6 h 40 mins
5. China 6 h 42 mins
6. Italy 6 h 58 mins
7. Spain 6 h 58 mins
8. Germany 7 h 09 mins
9. Norway 7 h 10 mins
10. Switzerland 7 h 11 mins
11. US 7 h 11 mins
12. Canada 7 h 15 mins
13. Denmark 7 h 16 mins
14. Sweden 7 h 16 mins
15. France 7 h 16 mins
16. Australia 7 h 20 mins
17. UK 7 h 22 mins
18. Belgium 7 h 23 mins
19. Netherlands 7 h 26 mins
20. New Zealand 7 h 27 mins

More detailed data based on 1 million users of SleepCycle were published by The Economist/1843 magazine in the April/May 2018 issue: “Which countries get the most sleep?” The data in this article also show Japan with the shortest length of sleep, about 6 h 20 mins/night at the bottom of a list of 55 major countries. The same SleepCycle data are also shown in a blog article by the World Economic Forum: “Which countries get the most sleep – and how much do we really need?”

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Hiromitsu Nakauchi: Stem cell technology and its potential for future medicine, Ludwig Boltzmann Forum, 20 February 2020

Hiromitsu Nakauchi, Stanford University School of Medicine, Professor, and University of Tokyo, Project Professor, Divn. of Stem Cell Therapy, Institute of Medical Science

Summary by Gerhard Fasol

Summary: solving the shortage of organ donors and immune rejection with stem cells

There are far more patients requiring organ transplants than organ donations. Transplanted organs are rejected by the recipient’s immune system requiring life-long immune suppression. Professor Nakauchi explains his path towards growing organs based on a patient’s stem cells injected into an animal’s embryo, which then is implanted into a host animal, and when fully grown this organ is transplanted back into the patient. While this long term target is still very difficult and far in the future, Professor Nakauchi and his teams at Tokyo University and Stanford University have solved several of the intermediary steps, bringing this final target closer.

What are stem cells?

Stem cells are undifferentiated or partly differentiated cells at the origin of cell lineages, can develop into different types of cells, and can divide to create more of the same stem cells. Stem cells were found in the 1960s by Ernest McCulloch and James Till’s group at the University of Toronto/Canada.

see: A. J. Becker, E. A . McCulloch, J. E. Till, Cytological Demonstration of the Clonal Nature of Spleen Colonies Derived from Transplanted Mouse Marrow Cells, Nature 197, 452-454 (1963)

• https://www.nature.com/articles/197452a0
• https://doi.org/10.1038/197452a0

Stem cells are important for development, maintenance and tissue recovery in our bodies.

Hierarchy of stem cells

• Totipotent stem cells differentiate into all cells > fertilized egg
  • https://www.nature.com/subjects/totipotent-stem-cells
  • https://www.gurdon.cam.ac.uk/research/gurdon
  • https://en.wikipedia.org/wiki/John_Gurdon
• Multipotent stem cells differentiate into all cells except placenta
  • two types
    • embryonic stem (ES) cells,
    • induced pluripotent stem (iPS) cells, the 2012 Nobel Prize in Physiology or Medicine was jointly awarded to Sir John B Gurdon and Shinya Yamanaka for “for the discovery that mature cells can be reprogrammed to become pluripotent.”. see: https://www.nobelprize.org/prizes/medicine/2012/summary/ and https://www.gurdon.cam.ac.uk/research/gurdon
  • differentiate into
    • muscle stem cells
    • nerve stem cells
    • bone stem cells
    • other tissue stem cells
• adult stem cells
  • blood stem cells, hematopoietic stem cells (HSCs)
    • red blood cells
    • white blood cells

Embryonic stem (ES) cells

Embryonic stem cells can be cultured indefinitely, have high differentiation potential (e.g into neurons, muscle cells, blood cells, liver cells etc), and gene manipulation is possible.

However, ES cells cannot be established from patients and may not represent a healthy individual. In addition there are ethical difficulties regarding the manipulation of human embryos.

Because ES cells cannot be established from the patient, ES cell based therapy requires Human leukocyte antigen (HLA) matching, and may lead to immune rejection and / or infections.

Cell therapy using a patient’s own cells is desired, by generating pluripotent stem cells from patients.

Induced pluripotent stem (iPS) cells

Patient-derived pluripotent stem cells can be generated from somatic cells (skin fibroblasts, blood cells, epithelial cells, …) by introduction using Sendai virus as vectors of four genes that are expressed in ES cells. These four genes are:

• Oct3/4
• Sox2
• c-Myc
• Klf4

Patient derived iPSCs are useful as an unlimited source of human material:

• studies of pathogenesis
• development of therapies
• drug screening
• gene/cell therapy
• toxicology studies
• …

see:

• Kazutoshi Takahashi, Shinya Yamanaka, Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors, Cell 126, 663-676, (August 25, 2006)
  • https://www.cell.com/cell/fulltext/S0092-8674(06)00976-7
  • https://doi.org/10.1016/j.cell.2006.07.024
• Kazutoshi Takahashi, Koji Tanabe, Mari Ohnuki, Megumi Narita, Tomoko Ichisaka, Kiichiro Tomoda, Shinya Yamanaka, Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors, Cell 131, 861-872 (November 30, 2007)
  • https://www.cell.com/cell/fulltext/S0092-8674(07)01471-7
  • https://doi.org/10.1016/j.cell.2007.11.019

• Noemi Fusaki, Hiroshi Ban, Akiyo Nishiyama, Koichi Saeki, and Mamoru Hasegawa, Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome, Proc Jpn Acad Ser B Phys Biol Sci v.85(8); 348-362 (2009)
  • https://doi.org/10.2183/pjab.85.348
• Hiroshi Ban, Naoki Nishishita, Noemi Fusaki, Toshiaki Tabata, Koichi Saeki, Masayuki Shikamura, Nozomi Takada, Makoto Inoue, Mamoru Hasegawa, Shin Kawamata, and Shin-Ichi Nishikawa, Proc Natl Acad Sci U S A. (2011 Aug 23); 108(34): 14234–14239.
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3161531/
  • https://dx.doi.org/10.1073%2Fpnas.1103509108

From basic research to clinical translation

Professor Nakauchi’s research focus was always riding basic research and clinical applications.

From basic research to clinical translation:

• generation of organs from iPS cells
  • next generation regenerative medicine
• ex vivo expansion of hematopoietic stem cells
  • non-myeloablative HSC transplantation using autologous HSCs
• novel adoptive T cell therapy using iPSC technology
  • co-founded Century Therapeutics in 2019
  • pre-clinical stage
• generation of platelet from iPS cells
  • transfusion using iPSC-derived platelets
  • co-founded Megakaryon in 2011
  • going into clinical trials

Generation of organs from iPSCs

Interspecies organogenesis for generation of functional organs from iPSCs

There is a lack of donor organs:

• 116,000 men, women and children are on the US national transplant waiting list as of August 2017,
• every 10 minutes another person is added to the waiting list for transplants
• 33,611 transplants were performed in 2016
• 20 people die each day waiting for a transplant
• source:
  • US Government Information on Organ Donation and Transplantation
  • https://www.organdonor.gov
• illegal organ trafficking: more than 10,000 organs were sold in 2010, about 10% of transplantations performed world wide
  • see: Karen Honey, Putting a stop to organ trafficking and tourism, J Clinical Investigation 119(3), (March 2, 2009), 425
    • https://dx.doi.org/10.1172%2FJCI38814

transplant requires life-long immunosuppression

Issues in transplantation medicine

• shortage of donor organs
• immunological rejection
• side effects and high medical cost due to lifetime immunesuppression
• ethical issues (brain death, living donor, definition of death)

Generation of functional organs from the patient’s own stem cell has the potential for a solution

Future goal: generation of human organs in livestock animals

concept:

• iPS cells are generated from the patient
• iPS cells are implanted in an organogenesis-disabled animal: interspecies organ complementation
• generation of a human organ in a livestock animal
• organ transplant from animal to patient

Development complementation via an “organ niche” by blastocyst complementation (kidneys)

Pluripotent stem cells from (ESCs, iPSCs) are introduced into SALL1-/- mouse blastocyst to generate organs derived from pluripotent stem cells.

see:

• Jo-ichi Usui, Toshihiro Kobayashi, Tomoyuki Yamaguchi, A.S. Knisely, Ryuichi Nishinakamura, and Hiromitsu Nakauchi, Generation of Kidney from Pluripotent Stem Cells via Blastocyst Complementation, American Journal of Pathology, Vol. 180, No. 6, (June 2012) 2417-2426
  • http://dx.doi.org/10.1016/j.ajpath.2012.03.007
  • https://ajp.amjpathol.org/article/S0002-9440(12)00238-6/fulltext
• Kobayashi T, Yamaguchi T, Hamanaka S, Kato-Itoh M, Yamazaki Y, Ibata M, Sato H, Lee YS, Usui J, Knisely AS, Hirabayashi M, Nakauchi H: Generation of rat pancreas in mouse by interspecific blastocyst injection of pluripotent stem cells. Cell (2010), 142:787–799
  • https://www.cell.com/cell/fulltext/S0092-8674(10)00843-3
  • https://doi.org/10.1016/j.cell.2010.07.039

Proof of concept data were obtained in mouse-mouse chimeras for

• pancreas (Pdx1 KO),
• thymus (nude mouse),
• kidney (Sall1 KO),
• liver (Sek1 KO),
• vessels and blood (Flk1 KO)

Generation of interspecies chimeras: mouse <> rat

Generation of chimeras across “Xeno-barrier”

see:

• Masumi Hirabayashi, Megumi Kato, Toshihiro Kobayashi, Makoto Sanbo, Takeshi Yagi, Shinichi Hochi, Hiromitsu Nakauchi, Establishment of rat embryonic stem cell lines that can participate in germline chimerae at high efficiency, Mol. Reprod. Dev. 77: 94, (2010)
  • https://doi.org/10.1002/mrd.21123
  • https://onlinelibrary.wiley.com/doi/abs/10.1002/mrd.21123
• Sanae Hamanaka, Tomoyuki Yamaguchi, Toshihiro Kobayashi, Megumi Kato-Itoh, Satoshi Yamazaki, Hideyuki Sato, Ayumi Umino, Yukiko Wakiyama, Mami Arai, Makoto Sanbo, Masumi Hirabayashi, Hiromitsu Nakauchi, Generation of Germline-Competent Rat Induced Pluripotent Stem Cells, PLoS ONE 6(7) (2011): e22008.
  • https://doi.org/10.1371/journal.pone.0022008
  • https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0022008

Interspecies organ complementation – blastocyst complementation across xenogenic barrier

• generation of (Pdx1 KO) mouse with rat pancreas > mouse with rat PSC derived pancreas > mouse-sized rat pancreas in mouse
  • Toshihiro Kobayashi, Tomoyuki Yamaguchi,Sanae Hamanaka, Megumi Kato-Itoh,Yuji Yamazaki,Makoto Ibata,Hideyuki Sato,Youn-Su Lee,Jo-ichi Usui,A.S. Knisely,Masumi Hirabayashi,Hiromitsu Nakauchi, Cell 142(5) 787-799 (Sept 3 2010)
    • https://www.cell.com/fulltext/S0092-8674(10)00843-3
    • https://doi.org/10.1016/j.cell.2010.07.039

• generation of (Pdx1 KO) rat with mouse pancreas > rat with mouse PSC derived pancreas > rat-sized mouse pancreas in rat
  • Yamaguchi T, Sato H, Kato-Itoh M, Goto T, Hara H, Sanbo M, Mizuno N, Kobayashi T, Yanagida A, Umino A, Ota Y, Hamanaka S, Masaki H, Rashid ST, Hirabayashi M, Nakauchi H. Interspecies organogenesis generates autologous functional islets. Nature 542, 191–196 (2017)
    • https://www.nature.com/articles/nature21070
    • https://doi.org/10.1038/nature21070

Transplantation of mouse islets generated in rats

Rat pancreata can be created from rat PSCs in mice trough interspecies blastocyst complementation, however the resulting pancreata were of mouse size, creating insufficient number of islets to treat diabetes in the rat.

To solve this issue, the reverse experiments were performed:

Mouse PSCs were injected into Pdx-1 deficient rat blastocysts, and rat sized pancreata composed of mouse-PSC derived cells were grown. Islets prepared from these mouse-PSC derived pancreata grown in rats were then transplanted into mice with streptozotocin-induced diabetes. The transplanted islets maintained mouse-host blood glucose levels for over 370 in the absence of immunosuppression.

These experiments show that in principle organs can be grown based on PSCs across animal barriers and used for therapy.

• Yamaguchi T, Sato H, Kato-Itoh M, Goto T, Hara H, Sanbo M, Mizuno N, Kobayashi T, Yanagida A, Umino A, Ota Y, Hamanaka S, Masaki H, Rashid ST, Hirabayashi M, Nakauchi H. Interspecies organogenesis generates autologous functional islets. Nature 542, 191–196 (2017)
  • https://www.nature.com/articles/nature21070
  • https://doi.org/10.1038/nature21070

Pigs and sheep have similar organ size and anatomy to human and grow to adult human size in a short time

pigs grow to adult human size in 9 months, sheep in 10 months, but monkeys in 4 years.

Blastocyst complementation in pigs

• Ryo Sumazaki, Nobuyoshi Shiojiri, Shigemi Isoyama, Masayuki Masu, Kazuko Keino-Masu, Mitsujiro Osawa, Hiromitsu Nakauchi, Ryoichiro Kageyama & Akira Matsui. Conversion of biliary system to pancreatic tissue in Hes1-deficient mice. Nature Genetics, 36(1), 83 (2004)
  • https://www.nature.com/articles/ng1273
  • https://doi.org/10.1038/ng1273
• Hitomi Matsunari, Hiroshi Nagashima, Masahito Watanabe, Kazuhiro Umeyama, Kazuaki Nakano, Masaki Nagaya, Toshihiro Kobayashi, Tomoyuki Yamaguchi, Ryo Sumazaki, Leonard A. Herzenberg, and Hiromitsu Nakauchi. Blastocyst complementation generates exogenic pancreas in vivo in apancreatic cloned pigs. PNAS (March 19, 2013) 110 (12) 4557-4562,
  • https://doi.org/10.1073/pnas.1222902110
  • https://www.pnas.org/content/110/12/4557
• Hitomi Matsunari, Masahito Watanabe, Kazuaki Nakano, Shin Enosawa, Kazuhiro Umeyama, Ayuko Uchikura, Sayaka Yashima, Toru Fukuda, Nikolai Klymiuk, Mayuko Kurome, Barbara Kessler, Annegret Wuensch, Valeri Zakhartchenko, Eckhard Wolf, Yutaka Hanazono, Masaki Nagaya, Akihiro Umezawa, Hiromitsu Nakauchi, and Hiroshi Nagashima. Modeling lethal X-linked genetic disorders in pigs with ensured fertility. PNAS (January 23, 2018) 115 (4) 708-713
  • https://doi.org/10.1073/pnas.1715940115
  • https://www.pnas.org/content/115/4/708

Implantation of human/animal admixed embryos was prohibited by guidelines in Japan, therefore:

Move from the University of Tokyo to Stanford University, Institute for Stem Cell Biology and Regenerative Medicine

Achieving apancreatic sheep is the first step towards growing human iPSC derived pancreas in sheep for implantation back into humans: generation of apancreatic sheep by CRISPR/Cas9 microinjection into sheep oocytes.

• Marcela Vilarino, Sheikh Tamir Rashid, Fabian Patrik Suchy, Bret Roberts McNabb, Talitha van der Meulen, Eli J. Fine, Syed Daniyal Ahsan, Nurlybek Mursaliyev, Vittorio Sebastiano, Santiago Sain Diab, Mark O. Huising, Hiromitsu Nakauchi & Pablo J. Ross, CRISPR/Cas9 microinjection in oocytes disables pancreas development in sheep. Sci Rep 7, 17472 (2017)
  • https://www.nature.com/articles/s41598-017-17805-0
  • https://doi.org/10.1038/s41598-017-17805-0
• Fabian Suchy, Tomoyuki Yamaguchi, Hiromitsu Nakauchi, iPSC-Derived Organs In Vivo: Challenges and Promise, Cell Stem Cell 22(1) 21-24 (4 January 2018)
  • https://www.sciencedirect.com/science/article/pii/S1934590917305039
  • https://doi.org/10.1016/j.stem.2017.12.003

Human iPSC in mouse and sheep embryos

The next step in the quest for developing iPCS based human organs in animals for transplant back into human patients is to investigate human iPCS in mouse and sheep.

Human iPSC cells injected into mouse or sheep embryos normally to not migrate into the inner cell mass (ICM), however migration and proliferation can be achieved by injecting primed human iPSCs with Bcl2 expression.

A major difficulty is caused by evolutionary divergence rats and mice diverged less than 30 million years ago, while humans and pigs or sheep diverged over 60 million years ago.

The Japanese Government finally lifted the ban on human-animal chimera research

• Kelly Servick, Taking ‘baby steps’ to human organs in livestock, Science, 364, 1217-1218 (28 June 2019)
  • https://science.sciencemag.org/content/364/6447/1217.full
  • DOI: 10.1126/science.364.6447.1217
• David Cyranoski, Japan approves first human-animal embryo experiments Nature (news 26 July 2019)
  • doi: 10.1038/d41586-019-02275-3
  • https://www.nature.com/articles/d41586-019-02275-3

contact

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Energy. Entropy. Leadership.

Gerhard Fasol, Chair

11th Ludwig Boltzmann Forum 2019, Wednesday 20 February 2019 at the Embassy of Austria, Tokyo.

Program

• Welcome by the Ambassador of Austria, Hubert Heiss.
• Gerhard Fasol, CEO and Founder Eurotechnology Japan K, Guest-Professor Kyushu University, former faculty Cambridge University and Tokyo University, Past-Fellow Trinity College Cambridge “Today’s agenda. Entropy, information and Ludwig Boltzmann“
• Noriko Osumi, Tohoku University, Vice-President. Professor of Neuro-Science. Executive Director, United Centers for Advanced Research and Translational Medicine (ART). Director of the Center for Neuroscience. “Towards understanding the mystery for neuroscience-developmental disorders: lessons from animal models“
• Takaaki Kajita, University of Tokyo, Professor and Director of the Institute for Cosmic Ray Research. Nobel Prize in Physics 2015 for the discovery of neutrino oscillations. “Neutrino research in Kamioka and the status of Japanese basic science with large research infrastructures“.
• Hiroshi Nakamura, NTT DOCOMO INC. Executive Vice-President, Member of the Board of Directors. Executive General Manager of R&D Innovation Division. “NTT DOCOMO Driving digital transformation in 5G era – co-create new values with partners“
• Peter Zoller, University of Innsbruck, Professor of Physics, Director at the Institute for Quantum Optics and Quantum Information. “Quantum computing and quantum simulation with cold atoms“

The Ludwig Boltzmann Forum is invitation only. Contact us here for enquiries and cooperation

Copyright (c) 2019 Eurotechnology Japan KK All Rights Reserved

Entropy, information and Ludwig Boltzmann. 11th Ludwig Boltzmann Forum 20 February 2019

Gerhard Fasol, Eurotechnology Japan KK, Founder and CEO. Guest Professor, Kyushu University. Former tenured faculty at Cambridge University and Tokyo University, Past Fellow Trinity College Cambridge.

Agenda of the 11th Ludwig Boltzmann Forum

Purpose of the Ludwig Boltzmann Forum is to bring outstanding leaders in different areas, technology, science, medicine, business, finance together to create new ideas, new research, new business, new initiatives. Over the last 10 Ludwig Boltzmann Forum conferences we have created many new partnerships in this way.

Some participants – also here today – have told me that they know of no better forum in Japan to freely discuss ideas and exchange views.

Today Noriko Osumi (Vice-President of Tohoku University) will show us results of her genetic research concerning autism. Neurological disorders are sometime coupled with fantastic creativity in the same person, and Ludwig Boltzmann may be an example. Takaaki Kajita (Nobel Prize in Physics 2015) will explain his discovery of neutrino oscillations and how it is linked to our understanding of the origin of our universe. Hiroshi Nakamura (Board Director and General Manager for R&D Innovation at NTT DOCOMO) will show us what 5G mobile communications mean for us users, and how important partners are to bring 5G to market. Peter Zoller (Director at the Institute for Quantum Optics and Quantum Information at the University of Innsbruck) will explain his work on optical quantum computing and how quantum computing can create new levels of computation and secure data transmission. Gerhard Fasol (Eurotechnology Japan KK and Guest Professor at Kyushu University) will explain some of Ludwig Boltzmann’s work, and why we use his results and tools every day in our lives and work, and what we can learn from Ludwig Boltzmann today.

Physicist. Mathematician. Philosopher. Leader. Venture investor (in aircraft research)

I am creating and developing the Ludwig Boltzmann Forum as a platform for leaders, driving improvements based on logic and science and mathematics – inspired by Ludwig Boltzmann: physicist, mathematician, philosopher, leader and venture investor – Ludwig Boltzmann was a venture investor in aircraft research and experimentation at a time when it was not yet clear whether air travel will be with balloons, zeppelins, bird like flapping wings, air-screws or other devices.

Inspire leaders by Ludwig Boltzmann’s example. Honesty, humility, asking profound questions and working towards answers using logic, mathematics, science – understanding nature and systems, and creating new tools to solve practical problems.

We use Ludwig Boltzmann’s results every day

S = k log W – Ludwig Boltzmann linked the macroscopically defined Entropy, which was introduced from work to optimize steam engines for the first industrial revolution, to the statistical mechanics of molecules and thus also to information theory. Boltzmann’s statistically defined Entropy was rediscovered independently by Shannon, and is fundamental to understand information moving through “channels” including the internet.

For his work, Ludwig Boltzmann was proposed many times (1903, 1905, three times in 1906) for the Nobel Prize, but died in 1906 before any potential Nobel Prize could have been decided for him.

Ludwig Boltzmann started early: published his first work in 1865 at the age of 21

Boltzmann’s first published work is entitled “Über die Bewegung der Elektrizität in krummen Flächen” (Electricity on curved surfaces), published in 1865 at the age of 21. About 20% of Boltzmann’s work is about electro-magnetism. It was the time when Maxwell created Maxwell’s equations in 1861-1862. It is also the time when electricity started to replace gas and steam engines. Tokyo Dentou KK received the license to produce and sell electricity in Tokyo on 15 February 1883.

Ludwig Boltzmann’s teachers and the “reversibility paradox”

Ludwig Boltzmann studied in the midst of a very active physics school in Vienna. Among his teachers where Josef Loschmidt, who proposed structures for 300 chemical compounds including benzene, who determined the number of gas molecules in a unit volume, today called the Loschmidt constant, and Jozef Stefan, who was the first to determine the temperature of the sun, and created what is known today as the Stefan -Boltzmann Law together with his student Ludwig Boltzmann. Josef Loschmidt conflicted with Ludwig Boltzmann and challenged him with the “reversibility paradox”: how can completely reversible microscopic laws, based on Newton’s laws, cause irreversible macroscopic phenomena as expressed by the Second Law of Thermodynamics, which says that an isolated system spontaneously evolves to the state of greatest entropy – but never reverses to lower entropy, (at least not within finite time).

The mechanical meaning of the Second Law of Thermodynamics

Important research starts by asking the right questions. Ludwig Boltzmann asked how the Second Law of Thermodynamics is linked to mechanics of particles. He published one of his most important publications at the age of 22 in 1866 “Über die mechanische Bedeutung des zweiten Hauptsatzes der Wärmetheorie” (About the mechanical meaning of the second law of thermodynamics), linking the macroscopically defined Entropy – a quantity created to improve the design of steam engines – to the microscopic statistical mechanics of molecules. Thus Ludwig Boltzmann created some of his most important work at the age of 22.

Boltzmann’s transport equations and optimal transport

The French mathematician Gaspard Monge started the field of optimal transport in the year 1781.

Monge worked for the French military on a very important problem: given a number of quarries at different locations, and the need to build a number of fortifications at other locations, what is the optimal way to transport sand and rocks from the quarries to the building sites for these fortifications.

Boltzmann created what is today called “Boltzmann’s transport equations” to calculate how particles (molecules or atoms) forming a gas move from one particular state to another. Taking into account the statistical nature of this problem, Boltzmann” transport equations are partial differential equations for the density in location and momentum space.

Boltzmann’s transport equations today are used in a wide are of applications from electrons in semiconductor electronic devices to the design of aircraft wings and racing cars.

Optimal transport results are used for many modern big data applications, image processing and many more, and two Fields Medals have been awarded:

• Cédric Villani, Fields Medal 2010 “for his proofs of nonlinear Landau damping and convergence to equilibrium for the Boltzmann equation”
• Alessio Fialli, Fields medal 2018 “for his contributions to the theory of optimal transport, and its application to partial differential equations, metric geometry, and probability”

What can we learn from Ludwig Boltzmann?

There is much to learn from Ludwig Boltzmann far beyond the enormous impact his scientific work has on our daily lives and on the daily work of every engineer, physicist, scientist.

• empower young people, recognize and support talent early:
  • LB published his first scientific work at age 21 – I am sure that should be possible today also (also I am ashamed to say my own first scientific publication was published when I was 24 years old)
  • LB became Full Professor at 25
  • Head of Department at 32
  • President of University at 43
• talent is not linear, its exponential
• move around the world. Connect. Interact.
• Empower women
• Don’t accept authority for authority’s sake
• science/physics problems need to be treated with the methods of physics/science
• no dogmas
• support entrepreneurs (LB supported aircraft developers before it was clear which technology will win: flapping wings? balloons? Zeppelins?)

Summary

Boltzmann’s thoughts and ideas are a big part of our understanding of the world and our universe.

His results and mathematical tools are used every day by today’s engineers, bankers, IT people, physicists. The definition of 1 degree Kelvin/Celsius/Fahrenheit with which we measure temperature since 2018 is directly via Boltzmann’s constant k.

Ludwig Boltzmann stood up for his ideas and conclusions and did not give in to authority.

Copyright (c) 2019 Eurotechnology Japan KK All Rights Reserved

Energy. Entropy. Leadership.

Gerhard Fasol, Chair

10th Ludwig Boltzmann Forum 2018, Tuesday 20 February 2018 at the Embassy of Austria in Tokyo

Program

• Welcome by the Ambassador of Austria, represented by Magister Konstantin Saupe (Embassy of Austria)
• Gerhard Fasol CEO Eurotechnology Japan KK, Board Director GMO Cloud KK, Guest-Professor Kyushu University, former faculty Cambridge University and Tokyo University, past Fellow, Trinity College Cambridge “Entropy, Information and Ludwig Boltzmann“
• Tomoko Nakanishi Commissioner, Japan Atomic Energy Commission, President, Japan Society for Nuclear and Radiochemical Sciences, Tokyo University Professor “What is revealed by radiation in living plants“
• Hiroyuki Sasaki Vice-President Kyushu University, Director of the Epigenome Network Research Center, Professor, Medical Institute of Bioregulation “Strategy and Serendipity in Science“
• Wolfgang Kautek Professor for Physical Chemistry at University of Vienna, Member of Scientific Board of Austrian Research Associations, President of the Erwin Schrödinger Society for Nanosciences (ESG), Chairman of the Research Group “Physical Chemistry” of the Austrian Chemical Society (GÖCh) “Nanotechnology and Critical Raw Materials“

Copyright (c) 2018 Eurotechnology Japan KK All Rights Reserved

Energy. Entropy. Leadership.

Gerhard Fasol, Chair

9th Ludwig Boltzmann Forum 2017, Thursday 16 February 2017, at the Embassy of Austria in Tokyo

Program

• Welcome by the Ambassador of Austria
• Gerhard Fasol CEO, Eurotechnology Japan KK, Board Director, GMO Cloud KK. former faculty Cambridge University and past Fellow, Trinity College Cambridge
  “Entropy, information and Ludwig Boltzmann”
• Masato Wakayama Executive Vice-President & Trustee, Kyushu University, Distinguished Professor of Mathematics
  “Endeavors for Mathematics for Industry in Japan”
• Chuck Casto Licensed Nuclear Power Station Operator. Was NRC regulator responsible for 23 nuclear power stations. Leader of the US Integrated Government and NRC efforts in Japan during the Fukushima nuclear accident in 2011.
  “Balance of Nuclear Power Policy in Post-Fukushima Japan”
• Yayoi Kamimura INTEL, Global Account Executive, previously: NTT Docomo, Director and Head of Business Development & Investment
  “Innovation – A style in Japan”
• Minoru Koshibe Mitsui Chemicals, Executive Vice-President, health care business sector and other business sectors
  “Growth and innovation at Mitsui Chemicals”
• Makoto Suematsu President, Japan Agency for Medical Research and Development
  “AMED challenges for global data sharing”

The Ludwig Boltzmann Forum is invitation only. Contact us here if you are interested to discuss current or future events and cooperations:

Copyright (c) 2017 Eurotechnology Japan KK All Rights Reserved

AMED challenges for global data sharing

Makoto Suematsu

keynote talk given at 9th Ludwig Boltzmann Forum, Embassy of Austria in Tokyo, 16 March 2017

by Makoto Suematsu, President, Japan Agency for Medical Research and Development (AMED)

Summary written by Gerhard Fasol

We share data in space science, why don’t we share data and expensive equipment in medicine?

AMED. Our Vision: to fast-track medical R&D. Create catalytic systems to fast-track medical R&D for human’s quality of life (QOL)

AMED is financed by three Japanese Government Ministries with a total budget of US$ 1.4 billion in FY2015.

• METI
• MEXT
• MHLW

AMED not only offers budgets, but also officers and scientists with new mindsets.

In a way AMED corresponds to the tricarboxylic acid (TCA) cycle:

Amino acids / glucose / lipids correspond to the METI / MEXT / MHLW Ministries.

AMED catalyzes these 3 different substrates to galvanize medical R&D processes.

Brain/MINDS (Brain Mapping by Integrated Neurotechnologies for Disease Studies) project

Purpose of the Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) project is to map a primate brain to help understand brain diseases such as Alzheimer’s disease and schizophrenia. For an overview see:

• Marmosets are stars of Japan’s ambitious brain project by David Cyranoski, Nature 514, 151–152 (09 October 2014) doi:10.1038/514151a
• home page of the Brain/MINDS program http://brainminds.jp/

Overcoming balkanization: patients’ needs vs physicians’ desire (e.g. to publish papers)

We need to overcome balkanization, and share ideas and data, e.g. we need to overcome the conflicts of interests between patients’ needs and the desire of physicians for example to publish scientific papers. We need to overcome balkanization of sequencers vs physicians, scientists vs bureaucrats, universities vs industry, and especially bureaucrats vs. bureaucrats (e.g. from a different Ministry) etc.

AMED: How to reform medical R&D systems?

• make “inflexible and balkanized funding” flexible and unified
• promote global alliances to facilitate data sharing
• support ARO network in University Hospitals for activating clinical research
• optimize peer-review in pilot projects: online in English (partly from FY2016), 5 all-English programs, database of all accepted proposals
• overcome “ECG budgets” and promote PPP
• social implementation of genomic medicine

Initiative on Rare and Undiagnosed Diseases (IRUD)

Homepage of AMED’s Initiative on Rare and Undiagnosed Diseases (IRUD):

• English: http://www.amed.go.jp/en/program/IRUD/
• Japanese: http://www.amed.go.jp/program/IRUD/

see also:

• “Orphan: The Quest to Save Children with Rare Genetic Disorders” by Philip R. Reilly, see: http://www.orphanthebook.org
• “The Emperor of All Maladies. A biography of cancer.” by Siddhartha Mukherjee (The Emperor of All Maladies: A Biography of Cancer is a book written by Siddhartha Mukherjee, an Indian-born American physician and oncologist. Published on 16 November 2010 by Scribner, it won the 2011 Pulitzer Prize for General Non-Fiction: the jury called it “an elegant inquiry, at once clinical and personal”). https://en.wikipedia.org/wiki/The_Emperor_of_All_Maladies, https://openlibrary.org/works/OL15686144W/Emperor_of_All_Maladies

Our aim is to overcome the “N-of-1 problem” by data sharing, i.e. we work to find patients with similar rare and undiagnosed diseases.

Why did we start from IRUD?

We want to improve 3 different types of life: life science, diary life and quality of life of patients and family.

We want to stop “research for budgets”, and empower “budgets for research”.

We want to encourage global data sharing, and overcome researcher’s inner biological behavior.

We want to overcome fragmentization of budgets and of expensive machines.

We want to overcome the phenomenon of “Darth Vader-type Professors”.

Data sharing not only for diagnosis, but also for drug discovery.

We respect front-line physicians who help patents who suffer from “diagnostic odyssey”, who are sent from test to test without hearing a valid diagnosis or treatment.

Our IRUD Regional Alliance includes 200 hospitals in Japan. We have more than 2000 registered families, and our program is showing first results with case matches of patients with similar rare diseases with foreign countries.

Tohoku Medical Megabank Organization (ToMMO)

Tohoku Medical Megabank Organization (ToMMO) at Tohoku University provides high quality genome variant data as an open resource: http://www.megabank.tohoku.ac.jp/

On 11 January 2016 we concluded a Memorandum of Cooperation between NIH and AMED.

SCRUM-Japan

SCRUM-Japan is a nation-wide, multi-centric cancer genome screening program with headquarters at the National Cancer Center in Kashiwa: http://epoc.ncc.go.jp/scrum/.
SCRUM-Japan is a successful academia-industry cooperation program encouraging data sharing among pharmaceutical sectors. Many major pharmaceutical companies cooperate.

National Clinical Database

The National Clinical Database includes more than 95% of operation data of general surgery in Japan: http://www.ncd.or.jp/

AMED supports the application of the National Clinical Database (NCD) to post-market surveillance of medical devices.

Real World Data (SSMIX 1+2) – Science Information NETwork 5 (SINET5)

Science Information NETwork5 (SINET5)

AMED will start investments from April FY2017

Data sharing in AMED: no trust – no sharing: no man is an island.

• IRUD & SCRUM-J, using ToMMo with more than 4000 Japanese variants
• NCD extension to clinical research
• Clinical genomics data base (from FY2016): rare diseases, cancer, infectious diseases, dementia
• Central IRB projects

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Growth and innovation at Mitsui Chemicals

Minoru Koshibe

keynote talk given at 9th Ludwig Boltzmann Forum, Embassy of Austria in Tokyo, 16 March 2017

Minoru Koshibe, Mitsui Chemicals, Executive Vice-President, health care business sector and other business sectors

Summary written by Gerhard Fasol

Minoru Koshibe – Profile

Minoru Koshibe majored in protein crystallography with a Master’s Degree. He started work at a predecessor company in 1978, worked in processor engineering, and later in head quarters in corporate planning.
Mitsui Chemicals was established by merger in 1997. Minoru Koshibe in 2003 joined the fine chemicals division, was involved in the Sankyo Agro acquisition, in the establishment of subsidiaries/affiliates (JPS, HMCI, OPC, YK, JC and others), and in M&A (Acumen, KOC, Hereaus Kulzer)
Minoru Koshibe worked 17 years in manufacturing, basic chemicals, R&D, construction and production,
9 years in the function chemicals business sector, and
12 years in corporate planning, and business planning.

About the Mitsui Chemicals Group

Our corporate mission is:

Contribute broadly to society by providing high-quality products and services to customers through innovation and the creation of materials, while keeping in harmony with the global environment

And our corporate target is:

Constantly pursuing innovation and growth to become a chemical group with an undisputed global presence

• Founded: 01 October 1997 by merger, however Omuta Works started operation in 1912, so including predecessor companies Mitsui Chemicals has over 100 years history
• Paid in capital: YEN 125 billion
• Subsidiaries and affiliates: 133 (55 in Japan, 17 in the Americas, 20 in Europe, 16 in China, 7 in Singapore, and 18 elsewhere
• Employees: 13,600 (9,300 in Japan, 1,350 in the Americas, 1,100 in Europe, 800 in China, and 1,050 elsewhere

Business Segments

• Mobility (26%): PP compounds, elastomers, performance polymers, electrolytes
• Healthcare (13%): vision care, nonwovens, dental, amino acids
• Food and Packaging (16%): packaging films, protection films, agrochemicals, hybrid rice
• Basic materials (45%): gas pipes, bi-phenol, methyl methacrylate, PET resins, polyurethane

Origins and history of the Mitsui Chemicals Group:

• 1912. Contribute to solving food shortages caused by rapid population growth: manufacture raw materials for fertilizers from exhaust gas, a byproduct of coal business
• 1932. Contribute to preserve our indigo culture: achieve Japan’s first successful production of indigo dye by using chemical technology
• 1958. Contribute to industrial modernization. Construct Japan’s first petrochemical complex.

MCI 2025 Basic Strategies

• Pursue innovation
• Accelerate global expansion
• Strengthen competitiveness of existing businesses

Strategy for our Healthcare Domain

FY2016: Operating income = YEN 15 billion
FY2025: Operating income = YEN 45 billion + new business

Creation of new products

• vision: functional ophthalmic lens line-up
• hygiene: new functional nonwovens
• personal: new products for detergent and cosmetics
• oral: 3D printers and laser milling machines

Strengthen existing businesses

• vision: sales activities in North America, China and India
• hygiene: high functional nonwovens
• personal: licensing business
• oral: periodontal disease treatment drugs, IoT and network solution business, denture and OSA mouthpiece business in North America

New business

• vision: electronic glasses (see in the photographs below: Mr Minoru Koshibe was wearing prototype electronic glasses during the keynote lecture)
• personal: surgical materials, physical mobility
• oral: new domains of dental materials

Globalization

• hygiene: specialized products
• oral: dental business in India, ASEAN, Middle East and Eastern-Europe, dentures and OSA mouthpieces in Europe and Asia

Strategy for our healthcare domain: fusion of materials and IT, realization of personalized healthcare, open innovation

Super Aging Society is coming soon

As regenerative medicine technology advances, life expectancy might increase to 100 years age by the year 2050

Japan’s population has peaked around 125 million around 2010, and may decrease to around 50 million by 2100

When asked for their biggest regret in life, 70% of old people answer: Not to have taken on challenges:
Lets live to accomplish your purpose!
Lets make a meaningful life!

Lets change our thinking about aging: instead of seeing old age as a decrease in value, lets see old age as seniority, as increasing value through knowledge, challenges and experience!

Concern about Japanese Conglomerates

Over the last 20 years the “earning power” of Japanese companies decreased compared with other major countries.

Market capitalization (corporate value) of Japanese corporations is falling behind compared to both Western countries and emerging countries:

The stock index FY2016 / FY1990:

• Japan = 0.7
• USA = 7
• Germany = 7
• India = 24
• China = 24
• Indonesia = 12

thus while the stock index has grown 7 times both in Germany and USA, and grown 24 times in India and China, it has actually fallen by 30% in Japan.

Market capitalization FY2015 / FY1990:

• Japan = 1.7
• USA = 8.1
• Germany = 4.8
• India = 5.4
• China = 16
• Indonesia = 5.3

while the market capitalization has grown 8.1 times in USA, 4.8 times in Germany, and grown 5.4 times in India and 16 times in China, it has only grown 1.7 times in Japan.

Capital markets are actually highly complex systems including the markets (stock exchanges) investors, intermediaries, are influenced by disclosures and governance rules. We need to improve the system as a whole, as well as its parts, to improve the performance of Japanese corporations.

Epilogue

In the past technology was made for people, e.g. airplanes and jets. In future more and more products will be made for robots, drones and other machines. Where is the place for people in such a world?

Lets build a society where technology (robots) and people can coexist!

Copyright (c) 2017 Eurotechnology Japan KK All Rights Reserved

Innovation – A style in Japan

Yayoi Kamimura

keynote talk given at 9th Ludwig Boltzmann Forum, Embassy of Austria in Tokyo, 16 March 2017

by Yayoi Kamimura INTEL, Global Account Executive, previously: NTT Docomo, Director and Head of Business Development & Investment

Summary written by Gerhard Fasol

Yayoi Kamimura – self introduction

• 20 years experience in open innovation, services alliance and JV with foreign companies
• originally investment banker
• promote innovation to customers with cutting edge Silicon Valley technology
• Joint ventures and investments: PLDT, Sri Lanka Telecom, StarHub, Codelco, TT&T
• Service alliances and collaborations: runtastic for docomo, Toyota, M-TV, SEGA
• Anti-Fraud App: “hi its me” fraud crime exceeds US$ 400 million/year in Japan. Recently launched anti-mobile fraud app to protect the elderly population from these types of crime. The system monitors suspicious in-coming calls to the elderly, then sends alerts to their family

Snap shots: Macro view on Japan’s innovation landscape

R&D and patent applications

2016 R&D expenditure vs GDP

1. USA: GDP (PPP) = US$ 18,559 Bill, R&D 2.77% of GDP
2. China: GDP (PPP) = US$ 20,015 Bill, R&D 1.98% of GDP
3. Japan: GDP (PPP) = US$ 4,913 Bill, R&D 3.39% of GDP
4. Germany: GDP (PPP) = US$ 3,741 Bill, R&D 2.92% of GDP

Patent applications by Chinese companies have been sky-rocketing since 2000, while patent applications by US, Korean and European companies are steadily increasing, patent applications by Japanese corporations have peaked around 2000, and have been decreasing ever since 2000.

Japan is trailing in R&D efficiency, defined as total value add in the last 4 years / total $ spent for R&D between 8-6 years ago:

While R&D efficiency in USA and Germany is similar between 80-90 times during the last 10 years, R&D efficiency in Japan has dropped from 80 times in the 1990s to near 60 times currently.

Venture Capital and start-ups

With only 3.7% of the population, Japan has one of the lowest ratios of entrepreneurs in the world.

In countries like Zambia, Nigeria or Ethiopia the entrepreneur population is on the order of 40% of the population.

In China, USA, Canada, the entrepreneur population is on the order of 12-14%.

In Japan the entrepreneur population is only 3.7% – similar to France, Belgium, Germany.

Venture Capital Funding is shockingly low in Japan

VC Funding 2016:

• USA: VC Funding US$ 60 billion
• China: VC Funding US$ 20 billion
• Japan: VC Funding US$ 2 billion

Start-up ecosystem

Japan does not appear in rankings of the “hottest start-up ecosystems” (source: Spark Labs Global Venture):

1. Silicon Valley
2. Stockholm
3. Tel Aviv
4. New York
5. Seoul
6. Boston
7. Los Angeles
8. Beijing
9. London
10. Berlin

Start-up ecosystems require:

1. startup culture
2. engineering talent
3. technology infrastructure
4. economic foundation
5. funding and exits
6. active monitoring
7. legal and policy infrastructure
8. government policy and programs

As a result of “Digital-Capital” mobile internet unicorns in Q1 2015, which include Facebook at the top, only three Japanese “unicorns” appear in the ranking: DeNA, GREE, and Cookpad.

USA has a large number of young companies, established since the 1970s with high market caps, e.g. Apple, Google, Microsoft, Facebook, Amazon etc.

Japan has only one single such company: SoftBank.

What can we change today?

In the public domain we need changes:

• Education system, STEM: coding population, diversity, gender gap bridges
• Public sector R&D: DARPA like organization, TAX breaks
• Policy change: deregulation, promotion or open innovation, funds flow, capital markets
• Universities and research agencies: more funds, clear goal set and PDCA

In the private domain we need changes:

• Organization: double decker structure, CVC
• Management: vision and target setting, acquisition & development rather than R&D / not NIH, start-up inclusion
• Process: PDCA, SPEED, ROI monitoring
• People: talent, skilled labor, IP and Legal, Standardization
• Funds

We need entrepreneurs, especially those who can compete globally

We need many more coding population in face of the software defined economy, we need to rewrite our DNA

We need to expand the funds flow to startups, from public sector and from private capital markets

Conclusions

1. Japan is now facing big challenges and global competition to even keep the status quo in innovation
2. Both public and private level, we should rewrite our DNA and accelerate the rejuvenation our economy
3. Innovation happens where money is. We should be ready to invest in more riskier assets of start-ups, both on private and public level. And the money does flow where returns are sound
4. Build our ecosystems and gain the momentum to maximize innovation, producing next generations of Sony, Honda, Toyota… they were all ventures at their start
5. Large enterprises transform themselves and/or we welcome the rise of new generation entrepreneur players

Copyright (c) 2017 Eurotechnology Japan KK All Rights Reserved

Endeavors for Mathematics for Industry in Japan

Masato Wakayama

keynote talk given at 9th Ludwig Boltzmann Forum, Embassy of Austria in Tokyo, 16 March 2017

by Masato Wakayama Executive Vice-President & Trustee, Kyushu University, Distinguished Professor of Mathematics

(Summary of Professor Masato Wakayama’s talk written by Gerhard Fasol)

Two important energies: hydrogen energy and prime number energy

• Hydrogen drives the hydrogen economy
• Prime numbers are at the core of encryption, the RSA Cryptosystem

Prime number were discovered almost 2500 years ago by the Pythagorean school in ancient Greece: the infinitude of primes, and the unique prime decomposition of integers.

2017 and Ludwig Eduard Boltzmann (LEB)

2017 is prime in Z (the set of all integers), i.e. indecomposable.

However, Theorem:
2017 = |LEB|^2 in Z[i] where i = sqrt(-1), i.e. Gaussian integers

Proof of the Theorem:

2017 is a Pythagorean prime, 2017 = 9^2 + 44^2

LEB = 1844 = 18 + 44 = 9 x 2 + 44 = (twice 9) + 44 (mod 99)

twice 8 equals 9i. It follows that LEB = 9i + 44

Corollary:
LEB’s birth year decomposes the prime 2017, that is, LEB Symposium 2017 opens New Thoughts.

9i + 44, in Japanese can be pronounced as:

(44 + 9i) よし！行く！　which means: “Let’s go!”
(i9 + 44) 行くと良し　 which means: “Best to go.”

Manyo-Shuu Anthology （万葉集）

During Japan’s Manyo era, poets made puns based on multiplication tables.

Examples:
二二 = 2 x 2 = 4 = し
十六 = 16 = 4 x 4 = しし
八十一 = 81 = 9 x 9 = 九九
二五 = 2 x 5 = 10 = とを
etc

An example is:

『万葉集』巻十一（2542）
若草乃 新手枕乎 巻始而 夜哉将間 二八十一不在国
（若草の、新手枕を、巻き初めて、夜をや隔てむ、憎くあらなくに）
訳：若草のような妻とはじめて手枕をかわしそめて
どうして一夜でも間を置くことができようか
可愛くてしかたがないのに

“Manyo-shuu” Voll.11 (2542)
Ever since I started to sleep on the hand of
my new wife as a pillow, soft as young grass/
It is no longer possible to be separated from
her over night/ How could I, when there is not
a speck of hate in my heart

Historical background in Japan

1603 – 1868, Edo period, Samurai era

We had a peaceful period in Japan, and Japan was a closed country.

Takakazu Seki 関孝和 (1642 – 1708)

In 1674 discovered the determinant, earlier than the discovery by Leibniz in 1683.
He discovered Bernoulli numbers independently around the same time as Jacobi Bernoulli.

He discovered:
derivatives and integrals (in the West: Newton, Leibniz)
but, there was no discovery of the fundamental theorem of Calculus.
Mathematics votive tablets (san-gaku) featuring mathematical puzzles, mainly Euclidean Geometry.

1868 – 1912, Meiji Period, opening of Japan

Social system, law were imported from Britain
Science, technology were imported from Germany
Culture and arts were imported from France

In pure Mathematics, Göttingen in Germany was the leading center, and pure mathematics was imported from Göttingen to Japan

Applied mathematics was much harder to import to Japan.

1926 – 1989: Showa period, from 1989: Heisei period

Japan’s period of fast growth.

Japan had many strong applied mathematicians before high performance computers were developed in the mid-1990s, but they were not regarded or valued as mathematicians.

After the introduction of high performance computers, applied mathematics decreased in emphasis in Japan.

The Policy Study No. 12 of 2006 by NISTEP (of MEXT) created a shock for Japan’s mathematics community: the report wrote “Japanese mathematics is not as strong as we had expected”:

“Mathematics as deserted science in Japanese S&T policy” ― Current situation on mathematical sciences research in major countries and need for mathematical sciences from the science in Japan ―
May 2006
by: Moritaka Hosotsubo, Yuko Ito, Terutaka Kuwahara

The main reason for this weakness was found to be the weakness and decreasing numbers of applied mathematics, and applied mathematicians.

The report stated: “It is desirable to have the same percentage of workers in the private sector of research and development as the West, which is 65%. However, in Japan the percentage in the private sector is only 26%. This shortage and nearly 40% gap relative to the West must be overcome”

At the same time, there was a world-wide trend in favor of mathematics for industrial technologies:

• Institute for Math. Its Appl., Univ. of Minnesota (USA, 1982 – )
• Oxford Centre for Indust. Appl. Math. (OCIAM), (UK, 1989 – ), OCCAM (2008-)
• Fraunhofer Institute for Industrial Mathematics ITWM (Germany, 2000- )
• European Consortium for Mathematics in Industry (ECMI) (1986 – )
• OECD/Global Science Forum “Reports on Mathematics in Industry” (2008,2009)
• MATHEON (Germany)
• MITACS (MPRIM, Canada)

As a consequence, MEXT commissioned an investigation project “Investigation and estimation of promotion of cooperation of mathematics and mathematical science with other fields – Toward a proposal for the 4th governmental science & technology master plan”
(October 2009 – March 2010)
Implementing organizations were:
Kyushu University (Main),
University of Tokyo,
Mathematical Society of Japan,
Nippon Steel Company.
And the representative was: Masato Wakayama (Kyushu University)

We investigated and estimated the activities of mathematics and mathematical science, and those of their cooperation with the other fields that have been implemented in Japan, and thereby gained ideas for making a proposal to the Japanese government for promoting mathematics and for strengthening cooperation with various fields surrounding mathematics.

As a consequence of this investigation project:

1. The 4th Governmental Science & Technology Basic Plan (2011) of the Prime Minister’s Council of Science and Technology Policy (CSTP) for the first time ever stated that Mathematical Sciences are important and should be promoted.
2. The Mathematics Innovation Unit was established in MEXT
3. The Committee of Innovation by and for Mathematics was established by the Committee of Science and Technology (2011)
4. MEXT organized 22 workshops in mathematics and 36 workshops in mathematical sciences and math-for-industry
5. Cooperations with Mathematics programs and several leading schools of mathematics

2016: The 5th Governmental Science and Technology master plan again emphasizes mathematical science

Some resulting research programs:

• Alliance for breakthrough between mathematics and sciences (ABMS), leader: Yasumasa Nishiura (WPI Advanced Institute for Materials Research, Tohoku University) JST CREST/PREST 2007-2016
• Modeling methods allied with modern mathematics, leader: Takashi Tsuboi (Graduate School of Mathematical Sciences, University of Tokyo) JST CREST 2014-
• Collaborative mathematics for real world issues, leader: Hiroshi Kobuku (Dept of Mathematics, Graduate School of Science, Kyoto Univ) JST PREST 2014-
• Meiji Institute for Advanced Study of Mathematical Sciences (MIMS), leader: Ichiro Hagiwara (Director Meiji University) 2007 –

The Institute of Mathematics for Industry (IMI) of Kyushu University

• April 1911: Kyushu University was founded as the 4th of 7 Imperial Universities
• June 1939: Dept of Mathematics founded
• June 1994: Graduate School of Mathematics and Faculty of Mathematics founded
• April 2007: Mathematical Research Center for Industrial Technology (MRIT) founded
• April 2008: Global COE Program “Education & Research Hub for Mathematics-for-Industry”
• April 2011: Institute of Mathematics for Industry (IMI) founded
• September 2014: IMI Australia Branch at La Trobe Univ. (Melbourne) founded

Some achievements of Kyushu University’s Institute of Mathematics for Industry (IMI) include:

• Long term internships from industrial partners
• Joint projects with industry: 29 projects with 22 companies
• Study groups at IMI, Study Group Workshops
• Forum Math-For-Industry: 2014, 2015, 2016
• Pacific Journal of Mathematics for Industry
• Mathematics for Industry

Study of Casimir effects

The Casimir effect (https://en.wikipedia.org/wiki/Casimir_effect) leads to attraction between opposite mirrors in a vacuum, which are spaced a short distance apart, due to electro-magnetic wave fluctuations in the vacuum. The Casimir effect was first predicted in 1948 by Hendrick Casimir (1909-2000), and first measured by Steve K. Lamoreaux 1996.

An equivalent effect exists between ships which are spaced close to each other, see: SL Boersma, “A maritime analogy of the Casimir effect,” Am. J. Phys. 64, 539–541 (1996), http://dx.doi.org/10.1119/1.18150.

Derivation of the Casimir effect shows that the force between the two plates is directly related to Riemann’s zeta function, which again is directly connected with prime numbers.

Copyright (c) 2017 Eurotechnology Japan KK All Rights Reserved

Advancing women in healthcare

Dame Carol Black DBE FRCP FMedSci

keynote given at the Ludwig Boltzmann Forum on women’s development and leadership, Tokyo, Monday 16 May 2016

by Dame Carol Black DBE FRCP FMedSci, Principal of Newnham College, Cambridge University, and Expert Adviser on Health and Work, Department of Health and Public Health England

(Summary of Dame Carol Black’s keynote written by Gerhard Fasol)

Dame Carol Black DBE FRCP FMedSci
Principal of Newnham College, Cambridge University.
Dame Carol Black has held top positions in medicine and now holds high-level policy advisory positions on health and work in the United Kingdom.

• Dame Carol Black: Profile on the website of Cambridge University
• Dame Carol Black, Principal of Newnham College, Cambridge
• Wikipedia: https://en.wikipedia.org/wiki/Carol_M._Black

Women in healthcare – Women in the British National Health Service

The gender imbalance in the National Health Service is reflected by the facts that 77% of the total workforce is female, while only 7% of female staff are doctors or dentists, ie only 5.4% of total workforce are female doctors or dentists.

41% of Chief Executives are women.

81% of non-medical staff are women.

Alison Wolf and the XX Factor

Alison Margaret Wolf, Baroness Wolf of Dulwich CBE, is a British economist, and the Sir Roy Griffiths Professor of Public Sector Management at King’s College London, see:

• King’s College, London: Alison Wolf, Baroness Wolf of Dulwich, Sir Roy Griffiths Professor of Public Sector Management
• Alison Wolf, Baroness Wolf of Dulwich: https://en.wikipedia.org/wiki/Alison_Wolf,_Baroness_Wolf_of_Dulwich

In her book “The XX Factor: How Working Women Are Creating A New Society” (Profile Books 2013), Alison Wolf writes that women are split into two groups: one group sacrificing family for rapid professional advancements, while the other group of women opts for having children at a young age, and remain in low level positions. As a result, inequality is growing faster among women than among men, and low status and low paid jobs are predominantly done by women:

• 97% of secretaries are female
• 92% of registered nurses are female
• 89% of nursing, psychiatric and home health aides are female
• 90% of maids and housekeeping cleaners are female

The fundamentals: what are the essential characteristics of “good employment”?

• Good work: is stable and safe, allows individual control, is flexible, gives opportunities, promotes wellbeing, reintegrates sick or disabled people if possible.
• Good workplaces: have visible senior leadership and well trained managers, enable staff engagement, empower employees to care for their own health

Good news for medicine, less good news for academic medicine

Generally we have achieved a good situation regarding gender equality in medicine. We have achieved meritocracy, and their are no reports providing evidence for systematic barriers against women’s professional advancement. Both intake and retention for women in medicine is high, and the pay scales are the same.

A study (Royal College of Physicians (RCP) Working Party 2009), investigated the female share of Consultants (= established Senior Medical Professionals in the UK), and showed the ratio of women is highest (38% – 49%) in “more plan-able” and “more people oriented” specializations such as general practice or paediatrics, while women’s share is lowest (8% – 23%) in “more technology oriented” and “more unpredictable” specializations such as anaesthetics or surgical specializations.

There is far less progress in academic medicine, and cultural stereotypes and bias remain, see:

• Carol A. Isaac, Anna Kaatz, Molly Carnes: Deconstructing the Glass Ceiling
• Molly Carnes, MD, MS, Christie M. Bartels, MD, MS, CAROL ISAAC, PhD, Anna Kaatz, MPH, PhD, and Christine Kolehmainen, MD, MS: Why is John More Likely to Become Department Chair Than Jennifer?

Women’s advance into top leadership positions suffers from “cultural” prejudices, e.g. prejudices that women too kind, too caring, not logical or strong enough, or otherwise unsuited to lead.

Prominent leadership roles for women, Prominent medical leadership

Prominent leadership roles need investment in the “extras”, leads leadership dimension in each speciality, and requires career single-mindedness.

Prominent medical leadership requires investment of time “over and above” the ordinary duties, requires professional “stewardship contributions”.

The top 200 leadership positions will naturally go to those who pursue their career goals with a high degree of single-mindedness.

Women choosing the route towards prominent leadership roles need encouragement and support, they need:

• role models
• mentors, and
• sponsors

Role models: Prominent women leaders in UK medicine

• Una O’Brien, Permanent Secretary, Department of Health
• Professor Dame Sally Davies, Chief Medical Officer
• Dame Julie Moore, CEO, University Hospitals Birmingham, NHS FT
• Claire Murdoch, CEO, Central and NW London NHS Foundation Trust
• Professor Jane Dacre, PRC Physicans
• Clare Marx CBE, PRC Surgeons
• Dr Suzy Lishman, PRC Pathologists
• Dr Maureen Baker, Chair, RC General Practitioners

Need to debunk leadership myths

Its important not to fall into the traps of common leadership myths, e.g. that leadership is inborn, that leadership is that of a lone genius, that they must inspire others to follow their vision, the leadership requires formal authority, or that all leaders have common personality features.

We need to avoid similar leadership myths in medicine, e.g. that men naturally make better leaders.

Dame Carol Black: From a shoe-making village in decline to Government Advisor

Dame Carol Black is born in the shoe-making village of Barwell, Leicestershire, went to Grammar School in Market Bosworth, were she became Head Girl, despite her working class background.

Dame Carol Black studied first History, then Medical Social Work and finally Medicine at the University of Bristol, specialized in Rheumatology research, focusing on Scleroderma. Later advanced to Medical Director, Royal Free Hospital, President of the Royal College of Physicians, Chairman of the Academy of Medical Royal Colleges, Chair of the Nuffield Trust on Health Policy, then advising Government as National Director for Health and Work, and now Principal of Newnham College, Cambridge.

A major step was Dame Carol Black’s advancement to Medical Director of the Royal Free Hospital, since this meant not just responsibility for an institution or a group or a department, but also responsibility for the health of a population.

Leading the Royal College of Physicians

The Royal College of Physicians was founded by Royal Charter by Henry VIII on 23 September 1518 with the aim to promote the highest standards in medicine.

The skills required were: understanding a wide landscape, consensual leadership, standing ground when necessary, negotiating with Whitehall (= British Government) and building trust.

Chairing all the Medical Royal Colleges – The Academy, 2006-2009

Dame Carol Black from 2006-2009 chaired this group of 21 independent organizations. As Chair, Dame Carol Black had no executive powers, needed to lead by persuasion and with consensus.

Advising Government

Dame Carol Black shared several of her experiences advising Government and highest ranking Government officials and Ministers.

Key was to become valuable in the eyes of Government officials by giving independent advice based on scientific evidence, in combination with remaining totally unpolitical.

Dame Carol Black became a champion for the “cause” of health and work, and kept totally out of politics, never revealing any political views or opinion, and wrote three major reports.

The Confidence Code – forget perfection…Striving for perfection can waste women’s time, and hold back the best from reaching the top

Perfectionism and lack of confidence is large a female issue, see Katty Kay and Claire Shipman: The Confidence Code – the science and art of self-assurance, and what women should know.

Women tend to be held back by striving for perfection, while men tend to take more risks. Striving for perfection can waste women’s time, and hold back the best from reaching the top.

Women in healthcare, Women and careers, women in scientific careers

The issue of Women in Scientific Careers was examined in the “Science and Technology Committee – Sixth Report – Women in scientific careers” by the British House of Commons Science and Technology Committee in February 2014, which can be downloaded here as a pdf file:
http://www.publications.parliament.uk/pa/cm201314/cmselect/cmsctech/701/701.pdf

This UK House of Commons report finds some common traits which hold women back from reaching top leadership positions, including that women may perceive promotions as undesirable, wait until they meet all perceived criteria for promotion while men often take higher risks and may behave more speculatively, and women may think that “political” skills are required to reach the top.

Finally, to reach top leadership positions, we need:

• self confidence
• aspiration
• risk taking
• resilience
• speaking out
• staying motivated after failure
• mentors, sponsors, role models
• networks
• personal values aligned to organisational values

Notes

Summary of Dame Carol Black’s keynote written by Gerhard Fasol

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