BIOPHYSICAL CANCER RESEARCH FOUNDATION
By trust deed dated 23 February 1982 Dr Brian Hagan founded a trust ‘for the promotion of scientific knowledge…to solve the cause of cancer and to develop new methods of treatment through research’ by the formation of the Biophysical Cancer Research Foundation. The trust was established pending incorporation of a company limited by guarantee to be called the ‘Biophysical Cancer Research Foundation Limited’. Despite a panel of world class medical scientists the Federal Government withheld tax deductible status in 1982-83 by requiring proof of the panel’s cancer research grant approval expertise. This misunderstood the purpose of the foundation which was for the foundation to conduct the research itself and not to assess applications for others. So, the foundation was not able to pursue its objectives at that time and Dr Hagan’s passing intervened in the interim period. Therefore, this trust is now being fulfilled 39 years later! Dr Hagan went on to spend many years on cancer research projects both in collaboration with other scientists and on his own. It was not until 2017 that Dr Hagan’s daughter found the missing cancer research files before she and her brother Christopher Hagan recommenced the valuable work started by Dr Hagan which has now culminated in the formation of the foundation this year.
These files included key material on Dr Hagan’s cancer research including GGF and a radiology project which Dr Hagan published with a past colleague in the journal Medical Hypothesis. This project had attracted the attention of the media with full scale feature articles published in the Australian in 1982. The concept behind the project was that the Fourier Transform governed biological systems – to take one example of the use of the Fourier Transform in medicine the Fast Fourier Transform has been used to analyse the ECG signal’s P, Q, R, S and T waves representing functions of the heart. Also, it was reported in May 2021 that 19 patients in South Australia and New South Wales suffering Parkinson’s disease had benefited from infra-red light therapy causing changes in their gut microbiome. Continuing Dr Hagan’s basic research would involve use of a Fourier Transform technology at the cellular level. This might take the form of testing the impact of waveforms upon cell growth and cancer from the viewpoint of determining what type of waveforms inhibit or activate normal and abnormal cell growth. Such research would aim to develop new radiological techniques for both testing and therapeutic use.
Reflecting the 1982 trust deed the aims of the Biophysical Cancer Research Foundation Limited are:
The research, development and promotion of medical science, knowledge and methodologies utilizing biology, physics and mathematics with the objective of solving the cause or causes of cancer to enable effective treatments or cures for patients suffering from cancer.
Dr Brian Hagan and the Foundation
Dr Hagan’s areas of research included cancer, genomics, bio mathematics and physics with a special interest in the DNA code and bio mathematics. He was a researcher with the Queen Elizabeth II Research Institute associated with Sydney University and former Chairman medical staff Prince of Wales hospital , Sydney. He was published in The Lancet, Medical Hypothesis, Medical Journal of Australia and Applied Physics Communications. He had published 7 medical science papers with many more unpublished. Dr Hagan had sought to form the Biophysical Cancer Research foundation as an organization by harnessing a formidable scientific network that he had assembled including two members of Jet Propulsion laboratory- Caltech in the United States (Professor Hank Keyser had won the NASA achievement award and the other professor , Professor Felix Gutman, had also received the NASA achievement award, authored 115 papers , written 6 books and had invented the solid state device used in 80% of cardiac pacemakers in the United States.) Yet when applying for a mere approval for research tax deductible status in Australia the Director General of the Department of Health advised “…the publications cited by each member…are not in the nature of research publications normally associated with members of Scientific Advisory Committees”. Despite this they had already identified one member- Dr Bransgrove who “held a post in the Research School of Surgery at Sydney University”. (He also conducted his own research laboratory). Another was a Dean of Faculty of Mathematical & Computing Sciences at The NSW Institute of Technology. Another , Dr Graham Grant had not only made a career from research and development but his inventions had become working medical devices used in clinical practice. The failure to approve granting of tax deductible status by the Director General stymied any chance of utilizing the world class cancer research team that Dr Hagan had assembled.
CANCER RESEARCH AND ALLIED PROJECTS
Selected cancer research and allied projects appear below where the GGF technology could contribute to increase the prospects for success in cancer therapies or other therapies.
OVERVIEW
Cancer is bound to the essential processes of life – cell cycles, tissue generation and the key sub units of life – proteins in their many forms and functions. Viruses, bacteria and archaea are thought to be symbiotic processes at the cutting edge of origin of life and are highly relevant to cancer research. Cancer vaccines were preceded by virus vaccines. Indeed some viruses cause cancer and yet some viruses are rendered benign to be used as vector carriers of cancer medication. The promise of immunotherapy where the body’s immune system is recruited to fight cancer just like it fights viruses and bacteria is offset by the specialized ‘patient centric’ nature of clinical immunotherapy. For example, researchers have lamented the lack of automated manufacturing processes for CarT therapies amongst others as opposed to the present process of taking samples from the patient to develop a cancer vaccine for reinjection with a vector carrying the medicine into the patient. A universal cancer medicine rather than specialized treatment is sought which requires a generic cancer vaccine as opposed to this customized approach. So, a universal cancer medicine is paramount just as a universal flu vaccine has been the holy grail for flu vaccines. Even when a cancer vaccine is found then as with any drug- biologic, biosimilar or conventional – the toxicity, side effects or even rejection by the body for whatever reason is a key factor. Success rates for drugs quoted at 1 in every 100 developed is often explained by toxicity. Some of the most advanced biologic drugs that hold promise for cancer are the aptamer ligands that can be highly specific yet well tolerated by the patient. They are an emerging field with many aptamer based cancer drugs under development or undergoing clinical trials. Aptamers with such new techniques as CRISPR hold much promise for great advances in cancer therapy in the future. We believe that the GGF technology has much to contribute to the use of aptamers for both cancer therapeutics and diagnostics. Aptamers are also being used as carrier vectors to deliver cancer drugs to patients as they are so targeted in homing into the right receptor.
Thus, widening the scope and range of candidate drugs with ‘smart methods’ such as the GGF Geneseeker or GGF Codeweaver should be valuable tools for medical science. In particular, the Codeweaver technology could be a ‘game changer’ for many cancer and allied projects due to its ability to aid modelling of candidate molecules for any given cancer or part thereof, sub unit protein molecule or other antigens. How?
The GGF Codeweaver method involves these key steps:
- A medical scientist submits the formatted profiles of a cancer protein’s receptor site;
- The codeweaver algorithm is then applied to that profile or profiles;
- This outputs selected candidate DNA sequences that encode proteins that are designed to be ligands docking to the target molecule on a ‘lock and key’ basis or to be candidate aptamers such as a DNA or RNA molecule folding to become the ligand;
- The selected candidate molecules can then be virtually screened or synthesized before being placed in microarrays of target molecules for efficacy testing or rounds of directed evolution (such as occurs with aptamers).
- More candidate molecule designs can be produced in great variety and numbers if required depending on the settings of the algorithm;
Thus it is hoped that workable ligands docking with the target molecule can be identified as a prelude to producing biologic or biosimilar cancer drugs or indeed for other diseases.
The search for a universal cancer vaccine across different cancers has become a possibility with the discovery of certain features common to many cancers. Mentioned below is one instance of childhood cancer, Neuroblastoma where researchers have discovered a process where two proteins bind to drive cancer growth in that disease. Researchers believe the same process could be common to 6 other major cancers. Thus, a ‘generic’ ligand across different cancers that docks or reacts to inhibit such binding might become a semi universal cancer drug.
SELECTED CANCER & ALLIED PROJECTS WHERE GGF CAN CONTRIBUTE
Research Project: Childhood cancer : Neuroblastoma
Neuroblastoma is a cancer forming in certain types of nerve tissue caused by a genetic mutation causing tumours with histology showing tumour cells as small,round and blue, with rosette patterns. The GGF technology has its core concepts founded in geometrical principles of cell growth and in particular on theory involving chromatin and nuclesomes – the winding of DNA around histones which mediate access to genes in DNA which is relevant to apoptosis and abnormal cell growth such as cancer. Epigenetic histone modifications have functional consequences in cellular processes where transcription factors/enzymes play key roles. It is hoped that underlying GGF theory may further contribute to the understanding of the genetic processes driving cancer.
Apart from theory, the GGF Technology may facilitate more practical uses. As background, in early 2021 Medical scientists at the Children’s Cancer Institute in Sydney announced their discovery of an ‘Achilles Heel’ with respect to a driver of Neuroblastoma cancer. They found that a process where two proteins bind to drive the cancer presents a possible target for drug design. Then in May 2021 the Children’s Cancer Institute further announced promising results for a combination of two compounds – curaxin (similar to an anti malarial drug) and panobinostat ( a histone deacetylase inhibitor).
How could the Biophysical Cancer Research Foundation contribute to these valuable advances? The GGF technology to be used by the Foundation might generate candidate analogues of such compounds which might be needed for toxicity testing or aptamer carrier candidates depending on the receptors which need targeting. The fact that this work could lead to cures for the other cancers mentioned underscores the importance of this work.
Importantly, this same binding process is apparent in a number of other major cancers namely breast, prostate, blood, ovarian, brain and kidney cancers and so this project could be a lightning rod for many lines of cancer research.
One of the researchers at the Children’s Cancer Institute referred to the importance of identifying specific drivers of the disease and the TERT oncogene rearrangement to enable design of drugs to combat these drivers. ( The TERT oncogene is the telomerase reverse transcriptase (TERT) gene that drives malignant cell growth by shortening/stabilizing telomere length- this has been shown in up to 90% of major human cancers.)
GGF potential contribution
Utilizing the GGF Codeweaver algorithm ligands can be designed to dock or react with these 2 proteins to inhibit the binding. This would be achieved by taking the profiles of the 2 proteins and give collections of candidate molecules for microarray testing utilizing the Codeweaver procedure (see (i) to (v) above ), In addition GGF research has disclosed meaningful GGF motifs in intergenic regions with implications for genetic theory. Thus it may be GGF could add insights to the long intergenic noncoding RNA MALAT1 in Neuroblastoma that might be targeted for future therapies.
Research Project: Biomimicry to design pharmaceuticals
* J.M. Benyus, Biomimicry – Innovation Inspired By Nature (1997) William Morrow-Harper Collins pp102-103
GGF potential contribution
Here the GGF Codeweaver presents good synergy with these projects. These venoms are ‘black boxes’ in that researchers really do not know how they fully work but realize they contain a cocktail of proteins (peptides/enzymes) such as Australia’s own Funnel Web spider with 3000 compounds. Now the holy grail for anti venom researchers is a polyvalent anti venom to help the over 5 million people who are bitten by all creatures on this earth each year (80,000 to 130,000 deaths pa) and already they do have some polyvalent anti venoms. CSL subsidiary Seqiris, a flu vaccine producer, already produces polyvalent anti venoms at its facility in Queensland harvesting them from horse plasma.
The GGF Codeweaver could be set to work to take moulds of the profiles of these mysterious proteins in venoms and reverse engineer the DNA sequence that encodes aptamers mimicking the shapes of these proteins and in the process target universal ‘swiss army knife’ polyvalent compound medicines to improve health outcomes and even save lives. The Codeweaver algorithm can provide arrays of candidate molecules widening the possibilities for anti venom medical researchers and drug developers.
Another example of biomimicry involves a protein from a fish
The Victor Chang institute has made a major discovery concerning Zebra fish and its ability to repair its heart , kidneys and spine using a protein KLF1. If KLF1 can be put into a drug form it could repair damage to the heart after heart attacks.
The GGF Codeweaver may be able to mimic or model the protein. Utilizing the GGF Codeweaver algorithm the profile of KLF1 can be processed to produce alternative biologic molecules to mimic KLF1 to replace , supplement it or act as a complementary filler to enhance efficacy or sustain less side effects by reducing toxicity or to even design an aptamer carrier to deliver the protein.
Research Project: Pancreatic Cancer
A number of cancer research organisations target pancreatic cancer as it is one of the most difficult cancers to treat. No simple early detection method, multiple genetic alterations in tumour cells and limited ability for drugs to reach the tumour provide serious obstacles to viable therapeutic solutions and diagnostics. The Biophysical Cancer Research Foundation hopes that its GGF technology might provide new insights to this intractable problem as explained below. An example of how one leading research institute is tackling Pancreatic cancer involves a new clinical trial.
Project leader, the Garvan Institute stated in their media release (26.2.2021) : “A national clinical trial program will test promising new targeted therapy for pancreatic cancer, one of the deadliest forms of cancers of which more than 3000 cases are diagnosed annually in Australia alone.
The clinical trial program (MoST–P), led by researchers and clinicians at UNSW Sydney and the Garvan Institute of Medical Research, will provide patients with access to either targeted therapies matched to the genomic signature of their individual tumour, or targeted to the tumour environment.”
GGF potential contribution
The public statements included reference to scar tissue changing its behaviour in the presence of the pancreatic tumour. If the scar tissue changes are caused by genomic changes in the scar tissue cells genomic analysis such as NGS sequencing may provide insights to formulate typical genomic sequences encoding the etiology of the scar tissue. However, statistical analysis may be challenging to identify typical patterns across the genome due to the expected ‘noise’ across intergenic regions etc. GGF Geneseeker software suite developed in conjunction with Mathematica consultants in 2020 can provide advanced analysis of genomes especially across intergenic regions with minimal ‘noise’ due to the meaningful results to date from many genomes. Each ‘run’ of the Geneseeker software produces up to 15 frameshift images for comparison, both 2D superimposition and 3D mesh modelling and other modelling. These may assist in developing generic motifs of cells in tissue surrounding tumours. Moreover , if it appears that the tumour is spreading its own ‘antigens’ (such as aberrant proteins leaking from tumours) which reach the surrounding tissues the GGF Codeweaver algorithm could also be enlisted to develop DNA sequences encoding potential candidate ligands to inhibit such ‘antigens’ and packaged in delivery vectors as medication for scar tissue to limit spread of the tumour or metastases . Already companies are developing small molecule drugs to recruit ubiquitin ligases to dock onto and inhibit ‘antigens’ such as these aberrant proteins leaking from tumours.
Research Project: Molecular Testing Database
Prominent cancer research/treatment network organization Omico has called for the Australian government to provide $280 million in funding for ‘molecular testing’ to avoid unnecessary radiation and chemo therapy. This would be achieved by a patient database linking their data to relevant genes and proteins which in turn can indicate the right treatment options for patients.
Dr Michael Mina, epidemiologist and Assistant Professor at Harvard T.H. Chan School of Public Health has outlined a proposal in a June 8, 2020 article in eLife for a Global Immunological Observatory which would establish a database storing antibodies test results (for infectious agents) from the public – eg blood donors or anyone willing to participate in such a program. He referred to such a system serving as a ‘weather vane’ for the ‘weather system’ of viruses at any point in time.
Such an idea might also extend to cancer indicator molecules such as aberrant proteins leaking from cancers to provide a control data set against which more routine testing could take place to detect elevated risks of cancer in a person such as the PSA test does with prostate cancer.
GGF potential contribution
The GGF Geneseeker software suite provides the tools to create a genetic library/database of cross links between oncogenes and unique protein expression signatures shown as GGF motif images. This library might be a suitable adjunct to the Molecular Testing database proposed by Omico as it has overlapping aims. GGF Global Genomics Pty Ltd has already created a cloud database which could be shared with this library or vice a versa in the hope that populating such database- library will help develop cancer therapies. A strategic alliance to build an ontology for the GGF algorithm leading to a database to service users of the GGF for research and development (eg a ‘code library’ or ‘atlas’ of images linked to their DNA sequences) would be a valuable resource for researchers.
There is potential for a further use of the GGF Geneseeker software in relation to genetic testing of individual patients and this relates to oncogenes. Control data could be collected via a blood sample from patients of their ‘normal’ oncogenes ie normal genes that when mutated present a cancer risk. The DNA sample taken from each patient could then be processed by the GGF Geneseeker algorithm to capture 15 key GGF motifs related to the reading frame or frames relevant to that oncogene. Then the patient might be tested annually (such as occurs with a PSA test for prostate cancer) for any change in the GGF motif as an early warning indicator. The Geneseeker software can take 15 frameshifts per execution of the algorithm which is designed to capture the correct reading frame for the oncogene. Simulations of such testing by GGF Global Genomics Pty Ltd show promise that such a test can be developed.
Research Project: Etiology of Alzheimer’s Disease
Causes for Alzheimer’s disease have ranged from beta -amyloid clumps forming in the gut before migrating to the brain (New Scientist, Alice Klein, 25 July 2020-p14) to neuronal tangles caused by the tau protein/exosomes leaking from the lysosomes of neurons. In an article, “Toxic Protein Discovery in Alzheimer’s Research”, (The Australian, 2.2.2021) , University of Queensland dementia expert, Professor Jurgen Gotz referred to the toxic accumulation of the neuronal tangles inside of neurons leading to memory loss and further impairments. Queensland Brain Institute research fellow Dr Juan Polanco also referred to the relevance of this research to cancer research: “…there was emerging evidence that exosomes could enable cancerous tumours to metastasize more quickly…Improving our understanding of how Alzheimer’s and other diseases spread through exosomes will allow us to create new ways to treat and intervene in [the cellular processes by which Alzheimer’s and other diseases spread]”. He also said that the ‘more that is discovered about these mechanisms the greater the chance of ultimately devising ways of interfering with the process”.
GGF potential contribution
The GGF Geneseeker software suite can create GGF motifs for DNA sequences encoding all proteins of interest for comparison, reference and further analysis. The GGF is thought to produce profiles of key protein sub units from the relevant genes and their alleles and so due to the uniqueness of GGF motifs these GGF profiles may disclose abnormalities not apparent from other forms of testing.
In terms of clinical research, GGF Codeweaver can also take profiles of toxic proteins and process them to produce DNA sequences encoding potential ligands to target these proteins with a view to making candidate pharmacophores leading to a drug to treat Alzheimer’s. These drug candidates could then be tested using virtual screening microarray or other lab techniques.