COVID-19: WHAT IS IN THE BOX OF ALTERNATIVE METHODS? - CONFLICT OF INTEREST: AXOSIM, ASTRAZENEKA, ATCC, APPLE, MERCK/MILLIPORE, UL, TOXTRACK ...
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COVID-19: What is in the Box of Alternative Methods? Conflict of Interest: AxoSim, AstraZeneka, ATCC, Apple, Merck/Millipore, UL, ToxTrack
COVID-19 - so far a medical success story!
• Dec’19 First cases recognized
• 31 Dec’19 WHO informed
• 10 Jan’20 First PCR (UK)
• 11 Jan’20 Genome revealed Photo of cheering physicians
(China) (deleted for lack of copyright)
• 17 Jan’20 WHO PCR diagnostic
published (Germany)
• Mar’20 several antibody tests https://www.dreamstime.com/
HIV 2018: 38 million infected,
(EU) +1.7 million per year, 770,000 deaths
• 1 May’20 FDA Emergency Use Jun’81 First cases; May’83 Virus identified
Authorization (not full Nov’83 1st WHO meeting Mar’85 1st blood test
approval) for drug Remdesivir Mar’87 1st treatment Aug’87 1st vaccine trial
1996 1st home test kit 1997 HAART therapy
??? 1st vaccine
Content page
Accuracy examplediagnostics
of COVID-19 1
Photo of taking swab
(deleted for lack
of copyright)
PCR: Sensitivity 90+ % & Specificity 95+ %
= BAC
Serologic: Sensitivity 88+ % & Specificity 96+ % ~93%
Accuracy applied to testing
US: 40 cases per 10,000 citizens
Photo of taking swab The result of a 93% accurate test is positive
(deleted for lack
of copyright) Testing 10.000 people with this test will result
in 37 real-positive but 700 false-positive:
Probability of COVID-19: 37/734 = 5%
Of value only with clinical symptoms
Negative Case: Testing 10.000 will result in
I WANT YOU 9,300 real-negative but 3 false-negative:
Probability of no COVID-19: 99.9%
TO GET A COVID-19 TEST
Content page example 1 Are these 95% false-positives our “asymptomatic carriers”?
The medical challenge
Content page example 1
Photo of stethoscope under stress
(deleted for lack of copyright)
Drugs Vaccines Fast,
Please!
Photo of tablet in front of virus
(deleted for lack of copyright) Fast pre-clinical models
needed for fast-track
clinical testing if not just
repurposing
The Cochrane study register for COVID-19 listed (on 19 August
2020) more than 10,000 studies launched, with 2630 of them
Photo of COVID-19
being interventional (https://covid-19.cochrane.org). vaccine
(deleted for lack
Already more than 160 vaccines for COVID-19 are under
of copyright)
development (115 in April, Thanh et al. 2020).
Arch. Toxicol. 2020, 94:2263–2272
Content page example 1
• Drug repurposing
• Target discovery
• Drug Efficacy
• Vaccine development
• Combination therapies
Photo of SARS-CoV-2 • Drug Safety
(deleted for lack
of copyright) • Quality
Need for
models
Evolution of Cell Culture
- high-tech & business opportunity -
Marx et al., Biology-
inspired micro-
physiological system
approaches to solve the
prediction dilemma of
substance testing using
animals. ALTEX 2016,
33:272-321.
Marx et al., Biology-
inspired
microphysiological
systems to advance
medicines for patient
benefit and animal
welfare. ALTEX 2020,
• Marx et al. 2016
37:364-394 .
9
Commercial human lung models
http://www.epithelix.com/products/smallair-hf
http://www.epithelix.com/products/mucilair https://www.mattek.com/products/epiairway/
10Organ-on-chip: LUNG
11Good Cell
Content page
Culture Practice
example 1
GCCP 2.0
Draft published
• Stakeholder
discussion
• Editor workshop
ALTEX 2020, 37: 490-492
• Funding bodies
Register at:
At ESTIV 2018 CAAT@jhu.edu
CAAT/ESTIV pre-symposiumDr Francis Collins, NIH Director
2011 - “With earlier and more rigorous target validation in
human tissues, it may be justifiable to skip the animal model
assessment of efficacy altogether.” FS Collins, 2011,
www.ScienceTranslationalMedicine.org 6 July 2011 Vol 3 Issue 90
2016 - Testimony by Francis S Collins to Senate Labor, Health & Human Services
Subcommittee, April 7, 2016
“I predict that, ten years from now, safety testing for newly developed drugs as well
as assessment of the potential toxicity of numerous environmental exposures, will
be largely carried out using human biochips … [and] will mostly replace animal
testing for drug toxicity and environmental sensing giving results that are more
accurate, at lower cost, and with higher throughput.”
https://www.appropriations.senate.gov/hearings/hearing-on-fy2017-
national-institutes-of-health-budget-requestIn preparation
New Orleans, 13-17 Dec 2021
Hosts:
Suzie Fitzpatrick, FDA
M P S Thomas Hartung, Hopkins
Don Ingber, Harvard
Microphysiological Systems ~30 organizations
Scientific Advisory Board
World Summit
Stay tuned!Content page example 1
OUR MINI-BRAIN
PROJECT
▪ FROM SKIN OF DONORS,
INDIVIDUAL STEM CELLS
▪ IN 3 MONTHS THOUSANDS
OF IDENTICAL ORGANOIDS
▪ NEURONS = BAC
COMMUNICATING
▪ SOME BRAIN ~93%
FUNCTIONALITYBrainSpheres
Content page example 1
iPSCs NPCs BrainSpheres
NANOG/OCT4/DAPI NESTIN/FOXG1/DAPI
NPC NPC single cell plating for 3D Gyratory shaking
expansion differentiation 8 weeks
Pamies et al. ALTEX 2017, TAP 2018Content page example 1
Photo of SARS-CoV-2
Virus and human brain
(deleted for lack
of copyright)
Altered mental status Stroke Encephalopathy
Neurocognitive (dementia-like) syndrome
Guillain-Barré syndrome Encephalitis
Acute cerebrovascular disease Psychosis
Seen in 30-60% of patientsVirus page example 1SARS-2-CoV
infection
Content
• Earlier neurotropic infection
with Zika, Dengue, HIV and JC virus
• COVID-19 in Wuhan: 36% neurological
symptoms, cases of virus encephalitis
• Other coronaviruses are neurotropic
Addition William Bishai Cynthia Korin Bullen
of micro-glia
Our partners
Also:
HIV & JC virus
…. Abreu et al. Frontiers Microbiology, 2018; 9: 2766.Content page example 1
A SARS-2-CoV-
= BAC
infected
~93%
human brain
cellContent page example 1 Our DNT & DIT team Helena Hogberg, Fenna Sillé & Lena Smirnova Carolina Romero William Bishai Cynthia Korin Bullen Andrew Pekosz
Content page example 1
SARS-CoV-2
infected
brain cellsContent page example 1
Transfer of
organoids for
more stringent
washing
Virus
PCRPresence of ACE2 receptor
at all stages of mini-brain
development
Some neural cells infected
https://covid19.tabipacademy.c Replication shown by PCR
om/2020/06/17/corona-virus-
beyin-ve-sinirlerde-kalici-hasar-
yaratiyor/Content page example 1
Which cells?
Pathology?
Role of blood-brain-barrier?
Disrupted neurodevelopment?
Latent infection – neurodegeneration?
= BAC
Just a
first
~93%step….Medline and “covid-19 or sars-cov-2”
19 August 2020:
41,926 articles published
+ self-published archives
Photo of person
Some people will have Overwhelmed by articles
to read and condense (deleted for lack
them for us! of copyright)
Peer-review!!!
Evidence-based approaches:
Systematic review, QA scoring$$$$page
Content NIH, EU, 1
example
…. • Anybody who can spell
COVID-19 writes a grant or
paper
• Most are ill-equipped
• Few get rich
and these are mostly those
selling the shuffles and
sieves
A scientific
Gold Rush
at KlondykeAlternative methods are
enabling technologies
Photo of SARS-CoV-2
(deleted for lack
of copyright)You can also read
