THREE MAJOR RESAERCH PROJECTS
by Miroslav Radman and colleagues:
This three tier project offers, at itsR & D stage,original science-based solutions to three major problems of humanity: healthy longevity, local food supplyand local energy supply.
Mission and purpose of the first two projects is to profoundly change the public health by combining an original molecular diagnostics with a new treatment employing natural compounds, ofnutriceutical kind, that is both preventive and therapeutic. The diagnostics is expected to provide personal disease-predisposition profiles (“biological destiny”). The conceived treatment is expected to:(i) delay the emergence of disease (prevention) and (ii) slow down, or reverse, the development of the ongoing disease (unlike thesymptom-suppressing therapies). Thus, an extension of healthy life can be expected. The third company offers a new strategy for bioconversion of sunlight energy, simplest food supply, and health improvement methods, all by the engineering of new symbioses.
(1) Potential Diagnostic Company:BIOPROFILER or DESTINION or GERONTOMETRICS
Scientists: Professor Miroslav Radman and Dr. Anita Krisko
Potential investors: Truffle Capital, Cellectis, Mérieux, La Roche, etc.
This company’s business is to establish a molecular diagnostic system for personalized medicine at two levels:
(a) Determination of the real biological age of each individual by the measurement of the global level of protein oxidation.Protein oxidation (carbonylation) shows exponential relationship with age - like the morbidity and mortality in human population.The product is a kit for use by all health centers and biomedical test laboratories.
(b) Determination of the predisposition to specific diseases, i.e., the predictive diagnostic, at young age, of specific disease expected to emerge at advanced age. The product: hi-tech proteome carbonylation equipment for all clinical health centers.
In a nutshell, the ambition of this project/company is to provide methods to establish a health-related biomedical profile of each person at any time in the individual life history, i.e., to determine and follow the biology ofindividual health destinies and their polymorphism at the population level.
The technology is based on the protected improved methods for quantification of protein oxidation (carbonylation) and on a protected discovery that single amino acid substitutions (part of natural polymorphism) can increase the susceptibility of that protein morph to oxidative damage by at least ten-fold. This susceptibility to oxidation of a single relevant protein correlates with the onset of specific disease in the patient. In other words, the protein polymorphism determines the oxidative age-related “burn-out” rate of individual proteins with specific health-related consequences (viz. telomerase, sirtuins, PGC, p53, oncogenes, etc…).
(2) Potential Therapeutic Company: PROTECTON or PERPETUON or PERRENION
Scientists: Professor Miroslav Radman and Dr. Anita Krisko
Potential investors: Truffle Capital, Naos group, Nestle, Novartis, etc.
This company’s business is to isolate, from diverse robust organisms, a plethora of the most effective substances that neutralize reactive oxygen species (ROS) and thereby protect the cellular proteome of resilient species. The biological robustness of special bacteria (Deinococcusradiodurans) and animals (Bdelloid rotifers) was shown by us to result from proteome defense systems against the oxidation. No other known anti-oxidant shows comparable protective effect on the proteome. The protective substances are small molecular weight compounds (metabolites) that protect equally efficiently the proteome of sensitive and robust species and are non-toxic to mice. Isolated proteins from robust and sensitive species are equally sensitive to oxidation and inactivation by ROS; thus, the proteome robustness is not intrinsic to protein structure but results from the protection against ROS-induced damage that we wish to apply to humans.
The chemistry of cellular functional degeneracy and death was shown to occur at the level of oxidative damage to proteins (Krisko& Radman, PNAS, 2010) that alters their properties and inactivates their function. Therefore, the protection against protein oxidation and the protein turnover (selective degradation and neosynthesis) are expected to prevent accumulation and aggregation of oxidized proteins and even reverse the noxious effects of previously accumulated oxidized proteins (functional “rejuvenation”). This is the basis of the expected preventive and therapeutic effects of an active prevention of protein oxidation.
Note: the DNA integrity is important to life only to the extent of its effect on phenotype, i.e., function (proteins, and perhaps small RNAs).DNA repair proteins maintain the genetic integrity;therefore protection of DNA repair proteins assures genome integrity by preserving their repair activity, as shown by us for D. radiodurans.This aspect is relevant more specifically to the prevention of carcinogenesis.
(3) A Potential Company Based on “Symbiosis Engineering”:
Company’s name: PANSYMBION
Scientists: Dr. ZoranDermanovic and Professor Miroslav Radman
Potential investors: Cellectis, Truffle Capital, Total, CDC, etc
Mission of this project/company is to develop new biotechnologies in the areas of energy, food, health, bioremediation and bioproduction using a novel approach of mixing genetic resources of different species through experimental creation of new endo- and exo-symbioses.
The novelty of Symbiosis Engineering. Bioengineering based biotechnology produces either new goods (not known to be produced by existing species) or known goods that are produced more efficiently, at a lower cost. In the classical approaches, one generates either mutants, or DNA rearrangements, or else one generates a combination of desired properties present in different species integrated into one targeted industrial process. The latter can be achieved by three approaches:
(i) Mixing genomes by cloning DNA fragments of one or more foreign species into an industrial “recipient” strain by standard genetic engineering methods. The bottleneck of this approach is in the expression and regulation/control of the foreign genes that are not in homeostasis with the recipient (host) genome. The engineered strains lack Drawinian selection and are typically fragile. This problem has killed many promising projects and start-up biotech companies.
(ii) Establishment of new endosymbioses, or “Symbiosis Engineering” (S.E.). This approach was conceived and protected by Z. Dermanovic and M. Radman. Symbiosis is a natural process, therefore the proof of principle for S.E. can be found in nature; endosymbioses occur on a daily basis; yet most have no durable selective advantage (e.g., the photosynthesizing animal – the sea slug Elysiachlorotica), given the availability of the natural food supply. The two endosymbionts that led to the explosion of life on Earth, about 1.5 billion years ago, are: the mitochondrion (ex-proteobacterium) and chloroplast (ex-cyanobacterium) in eukaryotic cells. The challenge of turning endo-symbiosis into biotechnology is in achieving fusion between a large (host, recipient) cell and a small (future organelle) cell and apply appropriate selection for establishment of a stable heritable endosymbiotic relationship. There are means to achieve this (Z. Dermanovic and M. Radman, patent pending).
The advantages of S.E. are that different biosynthetic machineries are (initially) maintained in separate compartments of a cell, but the desired metabolites can mix; the newly created “mutual survival advantage” promotes adaptation and allows an easy reversibility of the change (e.g., removal of the symbiont by appropriate antibiotics).
(iii) Establishment of new exosymbioses, or “mixed cultures”, by mixing two or more cell populations (species) endowed with different desired properties that are stably associated in a fermentor or a chemostat. This approach is “politically correct” – no GMOs! But, the fundamental research on cooperation is scarce: we have little idea how hundreds, or thousands, of microbial species form very stable robust “mixed cultures” in our intestine, in the soil and in the sea. Metabolic cooperation - by deleting different single specific essential biosynthetic pathways in each of cooperating species (e.g., amino acid auxotrophy) - is one way to achieve this in the laboratory. This can be considered as artificial creation of new exosymbioses.
The pending patent (Dermanovic-Radman, WO2011007110) protects the change in the host phenotype by introducing new endo- or exo-symbiont, or by changing only the genotype of a resident symbiont, in the following areas of exploration and application:
(1) Bioconversion of energy: production of bioethanol directly from water, sunlight and CO2 by a symbiotic fusion between a large sugar-fermenting host cell (e.g., yeast) and a small efficient photosynthetic bacterium (e.g., cyanobacterium). In such symbiotic yeast, sugar is produced during daylight by photosynthesis, and is fermented into bioethanol during the night.
(2) Food: a photosynthesizing autotrophic yeast is potentially the most efficient (simplest and fastest) way of producing a high quality nutrient directly from water and sunlight. Yeast extract is among the richest sources of proteins and vitamins, and hunger is prevalent in the sunniest parts of the world.
(3) Health:(3.1) healing the metabolic deficits by the introduction of an exo- or endo-symbiont, (3.2) provision of therapeutic proteins, hormones, neurotransmitters, vitamins, antioxydants, or any drug produced by a genetically modified natural intestinal bacterial symbiont (e.g., E. coli Nissle 1917). This renders the patients independent of daily therapeutic provision, especially in times of crises. (3.3) Also: immunomodulation of the host to prevent or cure autoimmune diseases, as well as direct life-extension of the host (e.g., four-fold byM. margaritifera inSalmosalar)
(4) Bioremediation: ameliorating environmental parameters by detoxification and biological recycling using robust engineered symbionts.
(5) Terraformation: generation of autonomous autotrophic “mosaic” organisms highly resistant to desiccation and radiation to seed life on other planets.
(6) Engineering of host behavior change/control (host behavior modification) in xeno-(non-native) hosts, by modifying, attenuating and manipulating the symbionts (e.g pest control, etc.).
