HUMAN

Studies of human populations, volunteers and patients

HUMAN BRAIN PROJECT An atlas of the human brain containing maps of brain areas previously unidentified has been developed. The atlas shows the brain’s cellular architecture in a three-dimensional space and reflects variability between individual brains. The massive amounts of data require supercomputers and AI. The atlas is openly available on EBRAINS, where new data is constantly integrated. This enables researchers to collaboratively decode the brain and clinicians to improve treatments of patients suffering from neurological disease. See e.g. Hashemi et al, Neuroimage 217, 116839, 2020. See also ‘Scientists build largest maps to date of cells in human brain’ National Institutes of Health, 31st October 2023.

Google maps of the whole human body are being developed. ‘Google maps for the human body - How spatial genomics is revolutionizing our understanding of disease’ Charlie Carter, Select Science 18th Feb. 2024.

SCANNING TECHNOLOGIES: Several scans have been developed to check on diverse health issues. MEG, MRI, PET and CT are the most common. For example, scans have isolated brain abnormalities in humans providing information about the causes of disease and disorder.

Laser Doppler perfusion imaging can be used to directly investigate the circulation of tiny blood vessels of diabetic human volunteers.

TRANSCRANIAL MAGNETIC STIMULATION (TMS) has been used to study the function of the human brain in healthy volunteers. For example, a study by Professor Walsh and colleagues aimed to learn more about neural processing by safely mimicking brain damage. The technique is now used in place of some experiments on non-human primates.

Research is currently being conducted into TMS as a possible treatment for psychiatric disorders. See Bersani, F.S. et al 2013 ‘Deep cranial magnetic stimulation as a treatment for psychiatric disorders’ Eur. Psychiatry 28 (1) pp. 30-9; Li, H et al 2014 ‘Repetitive transcranial magnetic stimulation for panic disorders in adults’. The Cochrane data base of systematic reviews. 9.

Repititive transcranial magnetic stimulation (rTMS) could be a treatment tool for various neurological conditions such as:

Stroke: Mansur, D et al 2005 ‘A sham-stimulation controlled trial of rTMS of the unaffected hemisphere in stroke patients’, Neurology, 64, pp.1802-1804.

Neuropathic pain: Lefaucheur, JP et al 2014, ‘Evidence based guidelines on the therapeutic use of repetitive transcranial magnet stimulation (fTMS)’, Clinical Neurophysiology, 126 (11), pp. 2150-2206.

Parkinson’s disease: Khedr. E et al 2006 ’Effects of daily repetitive transcranial magnetic stimulation on motor performance in Parkinson’s disease. Movement Disorders, pp. 2201-2205.

HUMAN CELLS AND TISSUE The use of human cells and tissue left over from surgical procedures, placentas or donated cadavers can be used to produce vaccines, develop drugs, detect toxicity and corrosiveness of chemicals etc. (See In Vitro for more details). Saliva may prove to be of use in cancer detection, NPJ Genomic Medicine, 2021)

CLINICAL PATCH TEST The use of clinical patch test in human volunteers can confirm that a chemical will not cause irritation or allergic skin reaction. The “human 4-hr patch test is a valid alternative to the equivalent rabbit test for the assessment of skin irritation hazard to humans”. Griffiths, HA et al, 1997, ’Interlaboratory evaluation of a human patch test for the identification of skin irritation potential/hazard", Food and Chemical Toxicology 35 (2), pp.259-260.

POST-MARKETING DRUG SURVEILLANCE A system hat allows consumers to report all effects of a medication after it has been released to the public. If alerts to negative side effects but could also increase the likelihood of finding new uses for existing drugs.

HUMAN MICRODOSING This technique involves giving minute doses of novel medicines to volunteers. A microdose is too small to be toxic but it allows the pharmakinetics of the active ingredient to be studied. Langley, G et al 2010 ‘Opinion: Microdosing: safer clinical trials and fewer animal tests’, Bioanalysis, (3) pp.393-395. Henderson, PT et al 2010 ‘Human microdosing for the prediction of patient response’ , Bioanalysis, (3) pp.373- 376.

Human Microdosing aims to reduce the resources spent on non-viable drugs and reduce the number of animal experiments.

Traditional preclinical studies take up to 18 months and cost US$3-$5 million. “Human Microdosing proves its value in drug R & D” , 2005. Drug Researcher.com

Microdosing can cut the time spent in early testing down to 4 months and cut costs by 10 times. European Union Microdose AMS Partnership Programme (EUMAPP) - Background Paper, 2006. Microdosing identifies which drugs are unlikely to be successful pre-Phase 1 of the testing process. Combes, RD et al 2003, ‘Early microdose drug studies in human volunteers can minimise animal testing: Proceedings of a workshop organised by Volunteers in Research and Testing’, European Journal of Pharmaceutical Sciences, 19 (1) pp. 1- l1.

Arora, T et al 2011, ‘Substitute of animal in drug research’, Indian J. Pharm Sci’, 73 (1) pp. 1-6.

EVOLUTIONARY GAME THEORY Evolutionary game theory is used to improve our understanding of cancer dynamics. It draws on mathematics to work out a drug regime that will ‘fool’ the cancer cells and reverse the processes that made the cancer in the first place. Ss McEvoy, JW 2009 ‘Evolutionary game theory: lessons and limitations, a cancer perspective’, British Journal of Cancer, 101, pp.2060 - 2061; Dingli, D. et al 2009 ‘Cancer phenotype as the outcome of an evolutionary game between normal and malignant cells’, British Journal of Cancer, 101 (7): 1130 - 1136.

TISSUE ENGINEERING Tissue engineering has led to the first successfully grown replacement organ. A bladder made from the patient’s own cells. (Atala, A et al 2006 ‘Tissue-engineered autologous bladders for patients needing cystoplasty’, The Lancet, 367 (9518), pp. 1241-1246). Atala adds that they are also working on growing bio-engineered hearts and pancreases. newscientist.com/article/dn8939-bioengineered-bladders-successful-in-patients.html; Also see P. Ball 2023 ‘Robots made from human cells can move on their own and heal wounds’ Scientific American, 1 December.

For an overview see Fodor, W 2003 ‘Tissue engineering and cell based therapies, from the bench to the clinic": The potential to replace, repair and regenerate’, Reprod. Biol. Endocrinol. (1), p.102).

Some fields of possible application are bone, cartilage, heart, pancreas, vascular and cancer: Castells-Sala, C et al 2013 ‘Current applications of Tissue Engineering in Biomedicine’, J. Biochip Tissue chip, S2:004.doi10.4172/2133-0777.S2.004.

3D PRINTING TECHNOLOGY FOR MEDICAL APPLICATIONS Lesions and defects that require tissue or organ transplantation remain urgent problems in clinical medicine and problems still exist regarding the use of current approaches, which include auto-transplantation, xeno-transplantation and the implantation of artificial mechanical organs. Auto-transplantation (transplanting tissue from one part of the body to another) may lead to complications and secondary injuries. Risks associated with xeno-transplantation include immunological rejection and viral transmission (as well as moral objection!). Three-dimensional (3D) printing technology is expected to solve limitations that are encountered when using traditional methods by incorporating the personalized construction of human bionic tissue or organs. See Yan, Q et al, 2018 ‘A Review of 3D Printing Technology for Medical Applications’, Engineering 4 (5), pp. 729-742; ‘How India is building its 3D bioprinting industry’, Nature India, 25th Jan. 2024; Mullard, Asher ‘These 3D model brains with cells from several people are first of their kind’, Nature, 26 June, 2024; S. Lorenzetti et al ‘#d bioprinting of human skin and squarmois cell tumors as advanced models for precision medicine’, Altex, 41 (3) 2024

CLINICAL TRIALS Clinical trials are research studies performed in people that are aimed at evaluating a medical, surgical, or behavioural intervention. They are the primary way that researchers find out if a new treatment, like a new drug or diet or medical device (for example, a pacemaker) is safe and effective in people. Other clinical trials test ways to find a disease early, sometimes before there are symptoms. Still others test ways to prevent a health problem. A clinical trial may also look at how to make life better for people living with a life-threatening disease or a chronic health problem See Australian Clinical Trials Handbook 2018 www.tga.gov.au/book-page/clinical-trials-involving-therapeutic goods. 3D printing is also being investigated for use in making precise implants in the Faculty of Medicine and Health and the Faculty of Engineering at the University of Sydney.

EPIDEMIOLOGY Epidemiology is the study of how often diseases occur in different groups of people and why. Epidemiological information is used to plan and evaluate strategies to prevent illness and as a guide to the management of patients in whom disease has already developed.

Epidemiological studies have led to the discoveries of the relationshp between smoking and cancer, the identification of heart disease risk factors, the isolation of the mechanism of the transmission of AIDS and other infectious diseases and preventative programs.

Some Australian research centres: Australian National University, National Centre for Epidemiology and Population Health Cancer Council NSW, The Cancer Epidemiology Research Unit (CERU) Cancer Council Victoria, Cancer Epidemiology Centre Curtin University of Technology, School of Pulbic Health: Epidemiology and Biostatistics Monash University, Department of Epidemiology and Preventative Medicine Occupational Respiratory Epidemiology Queensland Institute of Medical Research, Genetic Epidemiology University of Newcastle, Centre for Clinical Epidemiology and Biostatistics University of NSW, National Centre in HIV Epidemiology and Clinical Research University of Queensland, Health Studies: Clinical Epidemiology University of Tasmania, Menzies Research Institute

GENOMIC Pharmoene Laboratories in Royston, England uses only human tissues and computer echnologies in the process of drug development and testing. (‘Pioneers Cut Out Animal Experiments’, New Scientist, 31 August, 1996.

UK Biobank is making available the whole genomes of 500,000 people to probe genetic codes for links to disease.

Australian genomics research into Parkinson’s Disease was given a boost by the Federal Government in 2019. $30 million is set aside for this research at the Garvan Institute of Medical Research.

Genomics Resources in Australia AUSTRALIAN GENOME RESEARCH FACILITY www.agrf.org.au Australia’s largest genomic services provider with state-of-the-art facilities in Brisbane, Melbourne and Adelaide. Servicing the academic and commercial markets, AGRF provides genomic solutions across the entire biological spectrum from microbes to plants, animals and humnans.

GENETIC REPOSITORIES AUSTRALIA https://www.neura.edu.au/scientific-facility/gra/ GRA has been supported by an NHMRC Enabling Facility Grant to establish a central national facility for establishiing, distributing and maintaining the long-term secure storage of human genetic samples from a variety of sources. This includes the production and provision of immortalised lymphoblast cell lines and DNA samples. GRA is based at the Prince of Wales Medical Research Institute in Sydney.

GENOMICS AUSTRALIA www.bioplatforms.com.au/platforms/genomics Consortium of genomics service providers from around Australia. Builds on AGRF. Includes a regional network and a development team focussing on new research tools.

AUSTRALIAN GENOMICS Australian Genomics is an independent research collaboration launched in 2016 to build the evidence and inform policy for the integration of genomics into mainstream healthcare. It represent 80 organisations including hospitals, research institutes, universities, sequencing laboratories and community groups across Australia. It is funded by the NHMRC and Medical Research Future Fund. (australiangenomics.org.au)

see Hansen, D et al 2019 ‘Preparing Australia for genomic medicine: data, computing and digital health’,* Medical Journal of Australia*, 210 (6) pp. 530-532.

IN VITRO

In vitro (Latin for within the glass) refers to the technique of performing a given procedure in a controlled environment outside a living organism.

TOXICOLOGY In vitro methods can be used to identify potential toxic hazards in the following areas:

• Biological products and vaccines
• Cardiac toxicity
• Embryotoxicity
• Endocrine disruptor
• Eye and Skin irritancy
• Genotoxicity
• Liver and intestine toxicity
• Pyrogenicity (fever producing)

DRUG SCREENING Synthetic and natural products are evaluated in vitro as potential anticancer agents and to combat the AIDS virus. In particular, the U.S. National Cancer Institute (NCI) has developed a Human Tumor Cell Line Screen and an AIDS Antiviral Screen. http://nci.chemfinder.com/

BIOLOGICAL PRODUCTS AND VACCINES Cell and tissue cultures are used to test a number of pharmaceutical products, including vaccines, antibiotics, therapeutic proteins, toxins and antitoxins (e.g. SNAP-25/Endopeptidase assay for Botulinum Toxin Potency Testing).

CARDIAC TOXICITY Early assessment of the cardiac safety of compounds can be done using the in vitro hERG electrophysiology assay http://avivabio.com/ InVitroHeart is a project using human embryonic stem cells. The aim is to create pre-validation in vitro models and reduce the use of animal experimentation for cardiotoxicity testing.

EMBRYOTOXICITY ECVAM Scientific Advisory Committee (ESAC) has endorsed the following methods: - Embryonic stem cell test for embryotoxicity - Micromass embryotixicity assay

RHEUMATIC AND MUSCULOSKELETAL DISEASES In vitro studies have been shown to be better alternatives than animal models for drug testing Broeren, M. et al ‘A three-dimensional model to study human synovial pathology’, ALTEX : Alternatives to animal experimentation, 36 (1), pp 18 - 28.

ENDOCRINE DISRUPTOR In vitro tests can detect for chemicals that act as oestrogen agonists or antagonists e.g. Certi-Chem ER Assay, LUMI-CELLER Assay.

EYE AND SKIN IRRITANCY Agarose Diffusion Method tests for toxicity of plastic and synthetic devices used in medical devices such as heart valves, artificial joints and intravenous lines, using human cells.

Agarose Diffusion Method can also be used to test for eye irritancy. See Cottine, M et al 1993 ‘Critical evaluation of an agorose diffusion method for the assessment of eye irritancy’ ATLA 21, pp.427-440.

Synthetic tissues and human skin recombinants provide a non-animal alternative for testing skin corrosion and toxicology.

See also Vindardell, MP et al 2008 ’ Alternative methods for eye and skin irritation tests: an overview’ J. Pharm Sci, 97 (1), pp. 46-59

GENOTOXICITY The Ames test (a bacterial test for mutagenic properties of chemicals) is the most widely used. (Manahan, SE 2002, ‘Toxicological chemistry and biochemistry’, *CRC Press, p.175. )

There are a number of in vitro tests modelled on the Ames test which use eukaryotic cells and human cells and are thus more accurate e.g. GreenScreen.

Olaharski, A et al 2009 ‘Evaluation of the GreenScreen GADD45a-GFP indicator assay with non-proprietary and proprietary compounds’, Mutation Research/genetic Toxicology and Environmental Mutagenesis, 672 (1), pp.10-16.

The in vitro micronucleus test could be used as an alternative to the chromosome aberration test or the mouse lymphoma assay in the regulatory genotoxicity battery. Lorge, et al 2007, ‘Genetic toxicity assessment employing the best science for human safety evaluation, Part !!: Performances of the in vitro micronucleus test compared to the mouse lymphoma assay and the in vitro chromosome aberration assay’, Toxicol Sci, 96 (2). pp 214-17.

LIVER AND INTESTINE TOXICITY lintop (Liver/Intestine Optimisation) is a project that aims to evaluate and improve in vitro models for pharmacokinetics and pharmacodynamics.

VitroCellomics is another project which uses human embryonic stem cells. The aim is to develop in vitro models that reliably reflect human hepatic properties, thus reducing the use of animal experiments for predicting drug metabolism and toxicity.

PYROGENICITY Interagency Coordinating Committee on the Validation of Alternative Methods (*ICCVAM) reviewed five in vitro tests for detecting the progenicity of pharmaceutical and other products. http://iccvam.niehs.nih.gov/methods/pyrogen/pyr_brd.htm

REPROGRAMMING SKIN CELLS Donated human cells are converted back to their original plurpotent stem cell state so that they can be used in disease modelling and drug discovery. See lhmri.uow.edu.au

ALTERNATIVE TO FETAL CALF SERUM (FCS) VitroGro (animal product free, growth enhancing factor technology) can use used instead of FCS. It enhances cell replication, protein synthesis and migration. See tissuetherapies.com/

Zet (Centre for Alternative and Complementary Methods to Animal Testing) have compiled a catalogue of commercially avail formulations, structured for their specified fields of application ie. cells/tissues/cell lines and manufacturers. Serum Free Cell Culture Media - Updated Product Guids provide an overview of the range of commercially available serum-free media for cell culture.

Some Australian suppliers of In vitro products

Auspep Pty Lty 1800 805 393 http://www.auspep.com.au/ auspep@auspep.com.au

Agenix Ltd 08 9478 4753 www.agenix.com

BioCore Pty Ltd 1800 003 991 www.biocore.com.au sales@biocore.com.au

Bioscientific Pty Ltd 1300 246 724 www.biosci.com.au

CSL Ltd (which has incorporated Zenyth Therapeutics) 1800 063 892 www.csi.com.au customerservice@csi.com.au

Dermatest Pty Ltd 02 0597 7115 www.dermatest.com.au

John Morris Scientific www.johnmorris.com.au

In Vitro Technologies Pty Ltd 1300 552 003 www.invitro.com.au care@invitro.com.au IVD Australia 1300483237 www.lvd.org.au

Invirtogen Australia Pty Ltd 1800 331 627 www.invitrogen.com mail.australasia@invitrogen.com

Millenium Science 1800 678 242 www.mscience.com.au customerservice@ mscience.com.au

Australian human tissue banks

FOR BRAIN RESEARCH The Prince of Wales Medical Research Institute. Tissue Resource Centre (TRC) - https//www.neura.edu.au/scientific-facility/sydneybrainbank/ - QIMR Berghofer/RBWH Brain Cancer and Cell Culture Bank Translational Brain Cancer Research Laboratory, Herston, Qld. Queensland Brain Tumour Bank, Wesley Hospital, Qld. - Steve and Lynette Waugh Brain Tumour Bank Lowy Cancer Research Centre, University of NSW. - Telethon Kid’s Institute Brain Tumour Research Program Biobank Telethon Kids Institute, Subiaco, Perth.

FOR CANCER RESEARCH - Breast Cancer Tissue Bank - abctb.org.au/abctbNew2/aboutUs.aspx - The Human Colorectal Tumour Bank, Cancer Research Laboratories, Sydney South West Area Health Service, Liverpool Hospital. - St Vincent’s Hospital Prostate Cancer Tissue Bank - Victorian Cancer Biobank, a consortium of tissue banks - University of N.S.W. Lowy Cancer Research Centre. - Brisbane Breast Bank, University of Queensland Centre for Clinical Research. - Children’s Cancer Centre Tissue Bank, Royal Children’s Hospital, Victoria - Hunter Cancer Biobank, Newcastle, NSW. - Kolling Institute Tumour Bank, Royal North Shore Hospital, Sydney - Monash Children’s Cancer Biobank, Monash Children’s Hospital, Melbourne. - Queensland Children’s Tumour Bank, The University of Queensland, Brisbane. - The Children’s Hospital at Westmead, Sydney. - Victorian Cancer Biobank Melbourne - Melanoma Institute, Sydney - largest melanoma biobank in the world, 628,000 blood, tissue researcher sand stool sample. - Sydney Brain Tumour Bank. Royal Prince Alfred Hospital.

• Biochain - US based but exports total protein human tissue for a wide range of organs www.biochain.com

See 2001 ‘Tumour banks: providing human tissue for cancer research’ The Medical Journal of Australia, 175, pp.293-294.

FOR HEART RESEARCH - St Vincent’s Institute of Medical Research and the Victor Change Cardiac Research Institute Myocardial Tissue Bank. Sydney Heart Valve Bank produces homograftcardiovascular tissues including aortic and pulmonary valves, thoracic and abdominal vessels, pericardium patches, email: SVHS.SHVB@syha.org.au The Heart Bank at Sydney University is one of the largest human heart tissue banks in existence. It provides high quality human heart tissue for research. Sydney.edu.au/medicine/people/academics/profiles/sean.lai.php The Sydney Heart Bank, University of Sydney, shares frozen tissue with heart researchers in the world. It has led to major improvements in knowledge about heart functioning

FOR LEUKAEMIA AND LYMPHOMA - The PricewaterhouseCoopers (PwC) Foundation Leukaemia and Lymphona Tissue Bank - leukaemia.org.au/web/research/tissuebank.php

FOR MULTIPLE SCLEROSIS (MS) - University of Sydney, Multiple Sclerosis Brain Bank - msbrainbank.org.au/

FOR BONE AND TISSUE GRAFTS - Australian Biotechnologies - Perth Bone and Tissue Bank Inc.

FOR DISEASE PATHOGENESIS - Fetal tissues from Diabetes Transplant Unit, Prince of Wales Hospital, Sydney

FOR ALCOHOL RESEARCH - Human ‘Brain Bank’, Tissue Resource Centre, Neuropathology Unit of the Department of Pathology, University of Sydney - Australian Bioengineering of Tissues - Perth Bone and Tissue Bank Inc.

FOR NEUROPATHOLOGY - Brain and Mind Centre, University of Sydney; RPA Hospital together with the Brain and Mind Centre are using post-mortem tissue to study the impact of sports related concussion on the human nervous system.

• South Australian Neurological Tumour Bank Human Physiology, Flinders Medical Centre, South Australia

Also see the following articles:

For liver transplants: - Chihara, Y et al, 2011 ‘Primary human hepatocyles on biodegradable poly (l-lactic acid) matrices: A promising model for improving transplantation of tissue engineering’, Liver Transplantation, 17 (2), pp.104-114.

For kidney diseases: - Song B et al, 2011 ’Generation of induced pluripotent stem cells from human kidney mesangial cells, Journal of the American Society of Sephrology*, 22 (7), pp.1213-20.

For disorders of the Endometrium: - Ye, L et al, 2011 ‘Generation of human female reproductive tract epithelium from human embryonic stem cells, Plos one 6 (6) e21136.
- Also see 3-D bio-printing: the human tissue printer by Invetech; http://www.invetech.com.au and ’The world’s first commercial 3D human tissues bioprinter’ Australian Government website for Innovation, Industry, Science and Research, 2011.

Useful Links

ESTV European Society of Toxicology in Vitro promotes in vitro toxicology in scientific studies and education in Europe.

IIVS Institute for in vitro sciences is dedicated to the advancement of alternative methods worldwide - iivs.org.

IVTS in Vitro Toxicology Society is a discussion forum for scientists on in vitro toxicology - estiv.org

Sens-it-iv provide in vitro alternatives to animal tests currently used for the risk assessment of potential skin or lung sensitisers.

IN SILICO RESEARCH, MULTIMEDIA CD-ROMS AND MODELS

Research teams around the world are working on biosimulation and virtual humans. These models are designed to predict drug metabolosm and metabolite interaction with any given organ.

BioSim Biosim is a European Union sponsored Network of Excellence on biosimulation. It aims to improve drug development and provide alternatives to animal testing.

A 3-D virtual human heart model developed by Leeds University, UK will be distributed through BioSim. Currently, it is being used to simulate the effects of a commonly used heart drug (lidocaine).

Pharmaceutical companies such as Roche have already used biosimulation to approve heart drugs and find new uses for existing drugs (eg Pegasys). http://www.pharsight.com/library/MODELS_THAT_TAKE_DRUGS.pdg).

Biographics Laboatory 3R http://www.biograf.ch The Biographics Laboratory 3R is a non-profit research organisation. It develops computational technologies with the aim of reducing and replacing animal tests in the biomedical sciences.

Their research is currently focused on the prediction of adverse effects triggered by drugs and chemicals. They have developed VirtualToxLab an in silico tool for predicting the toxic (endocrine-disrupting) potential of existing and hypothetical compounds (drugs, chemicals, natural products) by stimulating and quantifying their interactions towards a series of proteins known to trigger adverse effects using automated, flexible docking combined with multi-dimensional QSAR.

Center for Cardiovascular Bioinformatics and Modeling (CCBM)

The Centre aims to develop new methods for the representation, storage, analysis and modeling of biological data, and to use these quantitative approaches to better understand cardiovascular function in both health and disease.

Entelos http://www.entelos.com/

A commercial company that provides computer models of virtual patients for drug research. The system improves the success rates of clinical trials, and helps bring therapeutics to market faster

Fetal Charlotte

http://www.aspects.net/~fetchar/Index.html

Computer modelling of the physiology of human foetuses.

Hurel Corporation http://www.hurelcorp.com

Hurel is a microfluidic ‘biochip’ with separate, yet connected compartments. The compartments contain a sample of tissue from different parts of the body. They compartments are linked by microchannels through which a blood substitute flows. The test drug is added to the blood substitute and circulates around the device; thus mimicking what does on in the body on a micro scale. Sensors in the chip feed back information for computer analysis.

Hurel is compatible with virtually any type of traditional in vitro assay modality (mass spectroscopic, immunohistochemical, immunofluorescent, gene expression and others.

Lhasa Limited http: http://www.lhasalimited.org/

Lhasa Limited is a not-for-profit company and educational charity. They develop expert computer systems for predicting whether a chemical is toxic. They have also developed software which predicts the metabolic fate of chemicals.

NETWORK Engineering virtual tissues and organs

Leeds University integrated biology project is involved in developing human virtual tissues: heart, uterus and spinal cord.

Physiome Project http://www.physiome.org/

The National Simulation Resource (NSR) Physiome Project is the worldwide effort to collect information on physiology, pharmacology and pathology of humans and to present this information via computer modeling.

SIMCYP http://www.simcyp.com/

Simcyp’s pharmacokinetic software provides a modeling tool for drug absorption, distribution, metabolism and excretions (ADME) in virtual populations. The software even allows simulation of patient variability. ‘Simcyp Paediatric’ allows predictions of pharmacokinetics in neonates, infants and children.

Simulab Corporation http://www.simulab.com/

Producers of medical and surgical simulators. For example, the TraumaMan System Is an anatomical human body form, designed for students to practice several surgical procedures. This simulator is approved by the leading Surgical Education Society as an alternative to live, non-human models or cadavers for their Surgical Practicum of their leading Trauma Training Course. The TraumaChild is a high fidelity soft tissue simulator designed to train advanced trauma surgical skills. This simulated five year old human breathes, bleeds, and has replaceable tissues for the first cut experience. It is also approved by leading surgical societies for the medical curriculum.

Solidus Biosciences http://www.solidubiosciences.com/

Solidus have developed Datachip (Data Analysis Toxicology Assay Chip) and MetaChip (Metabolizing Enzyme Toxicology Assay Chip). These are ‘in vitro’ tests using glass slides with DNA chips designed to mimic human reactions to potentially toxic chemical compounds. Computer analysis is used to evaluate the metabolic reactions which yield rapid identification of both harmful and useful substances and allows individualized patient therapy.

topkat

Toxicology Prediction by Komputer-Assisted Technology (TOP-KAT) was originally developed by Health Design Inc. Topkat is a computer software program that measures toxicity, mutagenicity, carcinogenicity and teratonogenicy.

Here is a partial list of Topkat users: Amgen; Buckman Labs International; US Centres for Disease Control and Prevention (CDC); Health and Welfare Canada; US National Cancer Institute; US National Institute for Occupational Safety; Pfizer; National Institute for Public Health and Environment, Netherlands; Us Environmental Protection Agency, Vertex Pharmaceuticals; Walter Reed Army Institute of Research; Wyeth Pharmaceuticals

http://accelrys.com/products/datasheets/ds_topkat.pdf

Microchips lined with human cells awarded Design of the Year 2015

Human Organs-on-Chips, designed by Donald Ingber and Dan Dongeun Huh at Harvard University’s Wyss Institute, won the Design Museum Design of the Year Award for 2015. The chip replaces animal subjects with a complex package of human cells.

Multimedia

NORINA: Norwegian Inventory of Audiovisualss http://norecopa.no/norina-database An English-language data base with approximately 3,800 visual aids on alternatives. Also includes dissection alternatives - at all levels from junior school to university.

ARTIFICIAL INTELLIGENCE

Many studies are coming out on the use of artificial intelligence for investigations that once used animals e.g. ‘A guide to artificial intelligence for cancer researchers’ Perez-Lopez, R et al, Nature Reviews, Vol 24, June, 2024, 427-441; ‘Large-scale pancreatic cancer detection via non-contrast CT and deep learning’ Cao, K et al. Nature Medicine, 20 Nov, 2023; ‘How AlphaFold and other AI tools could help us prepare for the next pandemic’, Callaway, E. Nature News, October, 2023; Zhou, Y et al, ‘A foundation model for generalizable disease detection from retinal images’, Nature, 13 Sept, 2023; Castelvecci, D. ‘Mind blowing IBM chip speeds up AI’ Nature, 19 October, 2023; Mallopaty, A. ‘AI traces mysterious metastatic cancers to their source’ Nature* 17 April, 2024; Lenharo, M. ‘AI detects eye disease and risk of Parkinson’s from retinal images’, Nature, 13 September, 2023. `.

** Australian Initiatives**

RealBrain Drug Screening Platform as the future of neuroscience drug discovery

Tessara Therapeutics is breaking barriers in neurology by enabling the pharmaceutical and CRO industries to discover and develop safer and more effective drugs to treat debilitating neurological diseases. As mentioned in the news above, regulatory agencies worldwide recognise that the current drug development model is broken with its reliance on non-predictive animal tests to determine the safety and efficacy of new drug candidates, leading to a 95% failure rate in human clinical trials. Regulators in major markets worldwide are driving the paradigm shift away from traditional animal-based drug testing methods. Examples are given in the News above. These directives accelerate the shift towards accurate, high-throughput in vitro test systems based on human cell-based tissue constructs. Tessara’s RealBrain Drug Screening Platform is exactly such a system. It is based on human 3-D brain micro-tissues, featuring fully functional neural networks embedded in their own, cell-secreted support matrix. The platform is highly reflective of human neurophysiology, and reproducible at scale for use in the pharmaceutical industry.

Tessara’s Early Access Program

While building a network of Contract Research Organisations to scale up and expand access to the RealBrain Platform worldwide, Tessara offers an Early Access Program (EAP) and works directly with selected collaborators interested to gain early human insights and explore the pharmacology of their compounds in ReadBrain Micro-Tissues. Tessara runs the EAP on a pre-commercial basis. Collaborators can express their interest to participate in Tessara’s EAP to test their experimental compounds on the RealBrain drug screening platform by completing the contact form on the website: www.tessaratherapeutics.com.

On-line Respiratory Control Practical

Dr Laura C. Minasian-Balmanian and Gautham Jayachandran have designed a novel interactive practical, which allows students to question and understand the roles of various chemical, mechanical and nervous factors important in the regulation of ventilation.

Batmanian, L 2005 ‘An innovative, interactive, self-instructional, online alternative to replace face-to-face respiratory control practical’, British Journal of Educational Technology, 36, pp. 335 - 337.

On-line Cardiovascular Control Practical

This online interactive practical was also developed by Dr Laura C Minasian-Batmanian. It will replace the use of approximately 250 rabbits per year at the University of Sydney. The practical will reduce animal-based learning and thus promote alternatives to animal experimentation in teaching in universities.

MICROORGANISMS

Yeasts have been used as model organisms. They grow rapidly in large numbers and are easily manipulated.

See Castrillo, J & Oliver, S. 2004 ‘Yeast as a touchstone in post-genomic research’ J. Biochem. Mol. Biol. 37 (1), pp. 93 -106.

Abdulkhair, W.M.H. (ed.) 2018 The yeast role in medical applications, Intech Open.

Microorganisms can be harnessed for uses such as creating steroids and treating skin diseases.

ENVIRONMENTAL SCIENCE

Environmental science can give for example, analyses of environmental risks relating to asbestos contamination, meth.amphetamine contamination in houses, leaky buildings and mold and effects of both on health. Occupational hygenisists may be involved in such studies. The field is promising but needs more regulation.

BIOELECTRONIC MEDICINE

A new field exploring bioelectronic approaches to monitoring and controlling biological processes. For example, implants for rheumhatoid arthritis involving nerve stimulation. See bioelecmed.biomedcentral.com

Pavlov, V and Tracey, K. 2019 Bioelectronic Medicine.

Lorach, H. et al 2023 ‘Walking naturally after spinal cord injury using a brain-spine interface’ (about building a digital bridge between the brain and the spinal cord enabling volitional control over the timing and amplitude of muscle activity, restoring more natural control of standing and walking in people with paralysis due to spinal cord injury’.) Nature 618 126-133.