by cofounders Miroslav Radman and Ivan Matic  
March 2015


The intention of the initial founders of MedILS (Marija Alacevic and M. Radman) was to select primarily exceptional scientists rather than promising projects in belief that creative well-trained scientist will eventually come up with original projects whereas untalented scientist will ruin even a good project. Starting an institute from the scratch, in a scientifically isolated area of Europe, the aim was to gain rapidly visibility and significance by taking certain advantage of such isolation by using unusual biological systems (we chose robust death-resistant organisms) and testing ideas that are not yet on the repertoire of the international 'mainstream' science. Furthermore, the founders wanted MedILS to become a hub for attracting young talents from South-East European countries and adventurous senior scientists from abroad for spending a sabbatical year, or longer for post-retirement scientists.

Over 60 theoretical and practical scientific workshops and summer schools, including "MedILS science factory" for children (that received a Google award for science education) took place in first 6 years.  With the planned research and education activities, MedILS is expected to spread seed for biotech start-ups in the area of Split, mostly from IP derived from its free academic research. Indeed, the first and principal MedILS research team "Biology of robust organisms" led by M. Radman and Anita Krisko came up with original results leading to a new concept about the cause of aging and associated diseases and a large repertoire of interconnected projects for exploring the fundamental chemistry of aging and death (below). It turned out that the emerged project entitled "Biology of aging and age-related diseases" has huge potential scientific, medical and societal impacts and no obvious research limits (see below). Therefore, this vast project imposed itself as the current scientific trademark of MedILS.



Scientific Essentials: We studied molecular repair mechanisms operating in rare robust "death-resistant" bacterial and animal species (review1). Exponential survival curves with "shoulders" suggest that, like radiation-resistance, longevity can be considered as chrono-resistance. We found that the lethal damage inflicted by radiation and time (aging) is the same1-3. The three papers below present the incentives for proposing a hypothesis to interpret the emergence of endless number of complex phenotypes such as functional deficiencies and disorders with increasing intensity and complexity seen as person-specific phenotypic patterns of aging and age-related diseases. The basic concept is that complex phenotypic changes can emerge and develop solely because of protein deficiency and damage, without the necessity of change in DNA1,2. However, protein damage can cause massive genomic change2 (genetic and epigenetic) as the consequence of functional defects in proteins dedicated to replication, repair and modification of DNA.

Our concept of the aging process is that age-related diseases and aging itself are snowballing phenotypes of oxidative protein damage accumulating exponentially in the course of individual life time3.The latter relationship, shown initially in 1980-ies by Earl Stadtman & coworkers, was interpreted to mean that protein oxidation is just a consequence, or biomarker, of aging. The concept that proteome damage is the fundamental cause of aging is compatible with everything we know about aging and is derived from our observations that oxidative damage (carbonylation) exclusively to the proteome generates in bacteria2 and yeast (A. Krisko and coll., unpublished) phenotypic changes akin to aging. Since most proteins possess an evolved resistance to oxidation that can be lost by single mutations3, the pattern of proteome oxidation is expected be specific for each person, with likely exception of monozygotic twins. Thus, protein sequence polymorphism underlies polymorphism of protein oxidation3.

Apparently, protein structures have evolved towards optimized compromises between protein activity and stability, i.e., to an optimized functional lifespan of each protein molecule3. Since (i) irreversible protein oxidation (e.g., carbonylation) destroys their activity1,2 and/or precision2 and (ii) some polymorphic mutations affect protein resistance to oxidation3, we expect that many of initially "silent" polymorphisms will alter the stability of protein function (by changing the susceptibility to oxidation) and become progressively phenotypic with age as damaged proteins accumulate due to decrease in protein turnover. Our concept posits that aging and all age-related diseases have a simple cause (proteome damage) and a common underlying mechanism (progressive proteome dysfunction) while readily providing an implicit explanation for high complexity of the consequences of such aging process.

Expected practical health span and life span consequences: Obviously, huge amounts of data, involving large numbers of cell samples taken at different age and health status (including lifestyle and family history data), are now needed to provide (i) the proof of principle for each age-related disease and (ii) the adequate knowledge of the molecular nature of each disease-associated polymorphism, e.g., the intrinsic oxidability of the incriminated protein morphs.

The perspectives for public health are stunning. For instance, if radiation1 or another oxidative treatment of cell biopsies reveals even approximately what will happen to that person's proteome at advanced age, then we can expect the following: (1) Each individual could be diagnosed, at any stage of life, as to his/her innate predisposition to age-related disease, (2) Preventative strategy acting on the cause of disease may involve consumption of "generic" antioxidants lowering cellular ROS/RNS levels (but see J.D. Watson, 2013, 2014)* or application of designed or screened for molecules stabilizing protein's structures vulnerable to oxidation - sort of protective protein "band aids", (3) monitoring the effect of such treatments on oxidative damage to the whole proteome, and specifically to the incriminated proteins (2D OxyDIGE method), (4) Treatment of the cause of already manifested disease by the application of specific protein protector (perhaps in addition to an antioxidant cocktail isolated from robust species1, see Krisko and Radman, PNAS, 2010).

Monitoring of carbonylation and other protein damage as the identified causes of disease (e.g., oxidative damage to disease-associated protein morphs) gives huge advantage and credibility to testing the efficacy of preventative and therapeutic treatments against aging and age-related diseases. Since about 90% mortality in developed countries is age related, obviously, preventing and curing age-related diseases should extend productive healthy lifespan.


* James D Watson, Lancet 2014; 383: 841–43. Counter the first impression, Watson's hypothesis is not in collision with ours because of our findings that (i) S-S bond breakage by reduction increases greatly the susceptibility of lysozyme to the irreversible oxidative damage (carbonylation) and (ii) there is a correlation between the age of emergence of Parkinson's disease in patiens carrying a predisposing alpha-synuclein polymorphism and the susceptibility of the respective alpha-synuclein morph to spontaneous and radiation-induced carbonylation 3. Disulfide bonds are "chaperoning" the relevant protein's structure/stability and classical chaperne activities (improving accurate folding of the synthesized proteins) show impressive reduction in proteome carbonylation in proportion to beneficial phenotypic consequences2. Hormesis is induced adaptative response to low level stress that may play a dominant role in exercise-induced beneficial clean-up and protection effects (like the benefits of starvation via autophagy).


Key publications:

(1) Anita Krisko and Miroslav Radman (2013) Biology of Extreme Radiation Resistance: The Way of Deinococcus radiodurans, Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a012765

(2) Krisko A, Radman M (2013) Phenotypic and Genetic Consequences of Protein Damage. PLoS Genet 9(9): e1003810. doi:10.1371/journal.pgen.1003810

(3) Miroslav Radman and Anita Krisko "Protein damage in aging and age-related diseases". U.S. Provisional Application Serial No. 61/765,370, filed February 15, 2013.

 Related to our concept of the MedILS institute in Split, see Brenner interview:


Related to the timeliness of our Aging/Disease/Longevity project, see:,9171,2152422,00.html

The List of Current Projects (when required)