burchgene - gen.ibu.edu.ba · bosnia and herzegowina, additionally intriguing reader to give...

BurchGeneDecember 2017 Volume 2 Issue 2

ISSN 2490-3515

Can we stop ageing?

B u r c h G e n e M a g a z i n e | D e c e m b e r 2 0 1 7

2

Executive editors: Ahmed Osmanović Adnan FojnicaFatima Mrkulić

Editorial board:Prof. Dr. Rifat HadžiselimovićProf. Dr. Dragan PrimoracProf. Dr. Damir MarjanovićProf. Dr. Mrsada HukićAssoc. Prof. Dr. Amina Kurtović KozarićAssoc. Prof. Dr. Enisa OmanovićAssist. Prof. Dr. Almir BadnjevićAssist. Prof. Dr. Serkan Dogan

Lectors:Monia Avdić Ibrišimović, PhDSabina Halilović, BSc

Graphic Design:Ahmed Osmanović

Publisher:International Burch University

Address: Francuske revolucije bb, Ilidža 71210

Telephone: 033 782-130

E-mail: [email protected]

Dear colleagues, students, respected professors, collaborators

and respected readers. We are happy to share with you, this very

special New Year’s third edition of the BurchGene magazine.

Special, as it is introduced, this number is full of enthusiasm,

very entertaining, completely informative, but above all enough

simple and eyes catching. Inside it you’ll find a mixture of

news, features, interviews and scientific reviews encompassing

wide range of genetics and engineering related topics.

Beginning with this issue, we will introduce you with famous

professor Le Duc, expert in virus diseases, biodefense and

global health giving his presentation on emerging disease such

as MERS, ZIKA virus outbreak and Ebola. Also, read about his

view regarding Burch University, our beloved country and posi-

tion of science it has.

Cancer disease, as probably hottest topic ever in a science

was explained and analysed thoroughly by our colleagues from

Faculty of Science. Interestingly you would be able to read

something more about most common cancer types presented in

Bosnia and Herzegowina, additionally intriguing reader to give

special attention to it.

In third part you will meet our beloved professor, incredible

person and her journey in science, Prof. Dr. Amina Kurtović-

Kozarić. Don’t miss this pathway full of passion, innovation,

desire, intelligence, hardwork and persistence.

For people having interest in engineering, especially inter-

esting would be section with “Top 8 Medical Technology

Innovations” were you will find out innovations that are going

to change our future.

If you have thought that you know everything about pathology,

that you are familiar with diseases existing all over the world,

then you will see you were wrong after reading sections: “Rare

hereditary diseases” and “Rare genetic disorders in man”.

Main focus in this number is going to be topic named “Can we

stop aging?”. Great effort was done in order to interview best of

best in this field Professor at University of California, Michael

R. Rose. For third issue of our magazine you would be able to

hear interesting theories and arguments on how we can postpone

or completely stop ageing.

As it was case in the past, third issue as well is free of charge.

At the end, we are going to express thankfulness to our sponsors:

International Burch University and BH Futures foundation,

whom we are sincerely grateful for supporting us every step of

the way.

Enjoy reading,

The Editors

FROM THE EDITORS


3

Executive editors: Ahmed Osmanović Adnan FojnicaFatima Mrkulić

Editorial board:Prof. Dr. Rifat HadžiselimovićProf. Dr. Dragan PrimoracProf. Dr. Damir MarjanovićProf. Dr. Mrsada HukićAssoc. Prof. Dr. Amina Kurtović KozarićAssoc. Prof. Dr. Enisa OmanovićAssist. Prof. Dr. Almir BadnjevićAssist. Prof. Dr. Serkan Dogan

Lectors:Monia Avdić Ibrišimović, PhDSabina Halilović, BSc

Graphic Design:Ahmed Osmanović

Publisher:International Burch University

Address: Francuske revolucije bb, Ilidža 71210

Telephone: 033 782-130

E-mail: [email protected]

C O N T E N T S

» p.7

4 PROFESSOR LE DUC: BURCH GIVES THE BEST TO ITS STUDENTS BUT ALSO TO B&H

Professor James Le Duc, head of Galvenston medical laboratory, held a lecture on our university on Emerging pathogens and diseases. In his lecture, professor Le Duc focused on the emerging disease such as MERS, ZIKA virus outbreak and Ebola.

6 INTERVIEW

Interview with Jim Le Duc, Ph.D., the director of the Galveston National Laboratory and a Professor in the Department of Microbiology and Immunology at the University of Texas Medical Branch in Galveston, Texas.

8 CANCER: A GROWING PROBLEM IN B&H

Cancer is genetic disease of somatic cells due to aberrant cell division or loss of normal programmed cell death. The development of a cancer is a multistage process of genetic errors accumulated in cells.

12 MY SCIENTIFIC JOURNEY

Amazing interview with Prof. Dr. Amina Kurtović-Kozarić. She is one of the leading experts in the field of Molecular Biology and Molecular diagnostics in the country. She has published in journals such as Nature, Leukemia and British Journal of Haematology.

14 BURCHGENE PUBLIC POSTS

BurchGene club is established last year in November. The club is composed of gifted and talented students that have aim to present newest scientific discoveries in the fields of genetics and bioengineering in an interesting way.

16 ARTIFICIAL INTELLIGENCE

“Everything we love about civilization is a product of intelligence, so amplifying our human intelligence with artificial intelligence has the potential of helping civilization flourish like never before – as long as we manage to keep the technology beneficial.“

18 TOP 8 MEDICAL TECHNOLOGY INNOVATIONS

In today’s world, technology plays an important role in every industry as well as in our personal lives. Today’s best medical technologies strike a balance between reducing the overall cost of medical care and increasing safety and survival rates.

20 CAN WE STOP AGING?

Researchers known as biomedical gerontologists are searching for ways to end aging. By understanding how we age, these researchers believe we can learn how to slow or stop the process, much like how we’d treat a disease.

24 RARE HEREDITARY DISEASES

A rare disease, also referred to as an orphan disease, is any disorder that affects a small percentage of the population. Although the disease may be rare, patients and families share a common struggle. Rare Disease Day is held on the last day of February every year to raise awareness of rare diseases.

» p.4

» p.24 » p.24

» p.20

» 16


4

Professor Le Duc: Burch Gives the Best to its

Students but also to B&H

SPECIAL VISIT Dženeta Šišić

Professor James Le Duc, head of the Galvenston medical laboratory, held a lecture on our university on Emerging pathogens and diseases. Professor began his lecture by de-scribing his workplace, Galvenston national laboratory, spe-cifically its facilities and type of research that is mainly being conducted there. It is one of the oldest labs in west USA, having been founded in 1891. The lab possesses facilities of all four safety levels, is built to withstand hurricanes and the air that exists within the laboratory is passed through HEPA filters. All this is done in an effort to prevent the “escape” of pathogens being researched and to prevent the cause of an outbreak. Further measures of security are the guards that are placed in front of the door 24/7 to prevent misuse of the pathogens held there. Other specialized areas include an insectary where ticks and mosquitoes are grown to observe replication of pathogens in vector species and their survival in nature, and aerobiology where aerosol is generated to ob-serve and study air transmitted pathogens. Studies in trans-mittance and drug tests are completed on animals such as ferrets, mice, rats, guinea pigs and monkeys- the latter being used for drug trials. The laboratory has strains of 700 named viruses and 7000 different strains. In the remaining part of his lecture, professor Le Duc focused on the emerging dis-ease such as MERS, ZIKA virus outbreak and Ebola. When it comes to the ZIKA virus, he highlighted the fact that it is asymptomatic in pregnant women but can cause devastating problems to the child, who is later born with microcephaly. He pointed that one of the challenges in vaccine production is to grow enough viruses and verocells being used to coun-ter this problem. So far the most effective vaccine is the live attenuated ZIKA vaccine. MERS like ZIKA has had global impact in economic sector due to treatment cost, and faces the problem of finding a good laboratory animal model. Re-cently, transgenic mice that were made susceptible to MERS were developed as a solution. VUSV vaccines are being used to treat Ebola and Marburg virus, with siRNA treatment as one of the possible treatments for Ebola. The rest of the lecture was left for answering student’s questions. The first one to be answered was how much freedom for academ-ic research does a laboratory have. The professor answered that this is regulated by scientific community, there are cer-tain studies that should not be done like making pathogens

more virulent and more resistant. All protocols are reviewed and work is funded by external partners. Next question was related to the recent Ebola outbreak- if the initial outbreak had been taken more seriously would the end result have been better. The answer was that while the outbreaks are usually isolated and left to burn themselves out, the transmit-tance was difficult to control in a hospital setting. One of the biggest problems was that due to poor conditions- transfer from rural to urban areas had been relatively easy. Regarding laboratory outbreaks, they had only exposures due to the fact that all staff goes trough rigorous training program for safe-ty procedures and mentorship program before being granted independent access. Final questions were related to bioter-rorism or as professor called it a poor man’s nuclear weapon, how to fight it and why we do not see more of it. The answer lies in the fact that the laboratory invests in security guards 24/7 for this very reason, labs are inspected and the number of vials are constantly checked to assure that nothing has been taken away. Students are educated on the potential mis-


5


6

Respected pro-fessor LeDuc, we are glad to have this opportunity to host one such promi-nent scientist at our University. You are an expert in virus diseases, biodefense and global health, therefore we would like to know why did you choose these areas, since the scope of microbiology and immunology is very wide.

Well, that’s a good question. As I look at my life, in retrospect, it looks like a lot of excellent decisions, in fact going forward, it was a lot of opportu-nities that I just said yes to and said that sounds like fun. The most sig-nificant one was saying yes to going to West Africa, to work for the Smithsonian Institute of the United States and living in a tent, col-lecting rats and mice for two years. This did a number of things. Number one: I was just out of undergraduate studies the same age as your students, basically, and it broadened my perspective of the world , how the rest of the world lived and how fortunate I was to be born in the United States, something that none of us can control, where we’re born. It gave me a global perspective. The next saying yes was to join the army, this was just during the Vietnam era and I say join in quotation marks, because

I was drafted basically or encouraged to participate. But I was able to come in as an officer and at that time I met some of the most brilliant scientists I’ve ever known. I was able to work in world class facilities conducting research on infectious diseases. I think those two things fed a career that just developed as opportunities arose. I think the fact that I had a lot of experience in wild-life and zoonoses, seeing the interface between animals and pathogens that existed there and diseases that resulted in man was the trigger that helped me guide my career.

You already mentioned your work as the field biologist for the

Smithsonian. Do you have any special events at the beginning of your career that you would like to add?

Well, I was fortunate to have had a very good education and to be exposed to professionals from number of dif-ferent fields that prepared me well for the work. By education I mean well, certainly a large part of it was in the University system, but also in the work-place where people mentored me, took me under their wing and taught me how to do things. I think that’s an important part of education today having a senior person mentor you, guide you through

An expert in virus diseases, biodefense and

global health

INTERVIEW Dženeta Šišić


7

the process, encourage you, correct you when you’re wrong and help you develop your own career.

My next question is what do you think of the state of biology and bio-logical sciences here in Bosnia and Herzegovina?

I’m very impressed with what I have seen and I’ve enjoyed visiting your university, seeing the facilities and

meeting some of the students. I’m very sorry that I didn’t more of a chance to talk to them individually but as you know, I’ve been working in former Yugoslavia and now in the independent countries that evolved and I’ve always been impressed with quality of educa-tion both before the war and after the war. You have some brilliant scientists, some very talented individuals doing very important work. Obviously you’re

somewhat economically limited but nonetheless through collaboration and efficiency, I think you’re making excellent progress, so I commend you all.

Thank you. My final question is do you have a final message to send to the readers of our magazine?

I think the message would be to be open t o o p p o r t u n i t i e s . Sometimes the oppor-tunities are presented to you and you think “Why would I ever do that?” but sometimes you need to think carefully. By that I mean, it might mean taking a sabbatical or postdoc overseas, outside of the are you’re living

in, your home and the comforts of the stability of your environment and new opportunities. That being said, I think it’s also important to remember your roots and to develop your country, to give back to the nation and people that help you develop yourself. It’s good to be a global citizen but it’s also good to be a good neighbor at home. Use your expertise where it is needed the most.


8

Cancer: a growing problem in Bosnia and Herzegovina

GENETIC DISEASE

Hana KomićSelma DizdarevićDženana HercegErna Islamagić

There are six main hallmarks of cancer acquired during the multistep development of human tumors (Figure 1.):1. Sustaining proliferative signaling While normal tissues carefully control the production and release of growth-promoting signals ensuring a homeostasis of cell number, and regulation of normal tissue architecture and function, cancer cells deregulate these signals which de-fines their destiny. Cancer cells display somatic mutations which activate additional downstream pathways and disrup-tions of negative-feedback mechanisms that attenuate pro-liferative signaling (Hanahan & Weinberg, 2011). 2. Evading growth suppressorsThe two prototypical tumor suppressors are RB (retino-blastoma-associated) and TP53 proteins that govern the decisions of cells to proliferate or, alternatively, activate senescence and apoptotic programs. Tumor cells develop a variety of strategies to limit or avoid apoptosis, and the most common is the loss of TP53 tumor suppressor func-tion enabling the proliferation of damaged cells (Hanahan & Weinberg, 2011).3. Resisting cell deathMany cancer cells fail to undergo programmed cell death (apoptosis), a differentiation program of many cell types, which leads to increased life span compared to their normal counterparts and tumor development. Tumor cells are usu-ally growth-factors independent (Cooper, 2000).4. Enabling replicative immortalityCancer cells require unlimited replicative potential in or-der to generate macroscopic tumors, which is in contrast to the behavior of normal cells (only a limited number of successive cell growth-and-division cycles). This limitation

has been associated with senescence (irreversible entrance into a nonproliferative but viable state) and crisis (apopo-sis). The presence of telomerase activity is associated with senescence and crisis/apoptosis induction resistance, thus enabling the replication of tumor cells (Hanahan & Wein-berg, 2011). 5. Inducing angiogenesisAngiogenesis helps the growth of a tumor when new blood vessels are required for nutrients and oxygen supply to the proliferating tumor cell. New vessels formation is a re-sponse to growth factors, secreted by the tumor cells that stimulate proliferation of endothelial cells in the walls of capillaries in surrounding tissue, resulting in the outgrowth of new capillaries into the tumor. Cancer cells easily pene-trate new capillaries, enter the circulatory system and begin the metastatic process (Cooper, 2000).6. Activating invasion and metastasisThis is a process represented by a sequence of discrete steps, often termed the invasion-metastasis cascade. It con-sists of the following: epithelial cells in primary tumors invade locally (1) through surrounding extracellular matrix and stromal cell layers, (2) they enter the lumina of blood vessels, (3) survive the rigors of transport through the vas-culature, (4) arrest at distant organ sites, (5) exit into the pa-renchyma of distant tissues, (6) initially survive in these for-eign microenvironments in order to form micrometastases, and (7) re-initiate their proliferative programs at metastatic sites, thereby generating macroscopic, clinically detectable neoplastic growths (the step often referred to as “metastatic colonization”) (Fidler, 2003)Cancers can be classified according to the following param-

Cancer is genetic disease of somatic cells due to aberrant cell division or loss of normal programmed cell death. However, a small proportion is strongly predisposed by inherited germline mutations, transmitted according to Mendel’s laws. This does not contradict traditional understanding that some environmental factors are etiologically more important, than genetic factors (e.g. industrial cancers). Cancer cells typically display abnormalities in the mechanisms that regulate normal cell proliferation, differentiation, and survival. It is usually hard to distinguish between genetic and environmental factors, and evidence to help came from a combination of epidemiology, family and twin studies, disease associations, and viral factors, and in the modern era, molecular analysis and/or DNA tumor profiling (Turnpenny & Ellard, 2017).


9

eters: by primary site of origin (breast cancer, lung cancer, prostate cancer etc), by tissue types (carcinoma, sarcoma, myeloma, leukemia, lymphoma, mixed types), by grade (1,2,3 or 4) and by stage (TNM; T-tumor size, N- the degree of regional spread or node involvement, M-distant metastasis). Among many different cancer types the most common in Bosnia and Herzegovina are breast, colorectal and lung can-cer.

A) Breast cancerBreast cancer is the most common form of cancer world-wide and the second most common cause of death from a neoplastic disease affecting both genders. The disease is rep-resented by abnormal breast cell multiplication which lead to formation of a malignant tumor (Figure 2) (Ferlay et al., 2008; Lalloo et al., 2012). Breast cancer is a multifactorial disease that can be caused by a variety of factors, including: Age, alcohol use, benign breast conditions, ethnicity, family history, genetic predis-position, gender, geographic region, hormones, obesity and sedentary lifestyle, personal history of breast cancer and ra-diation exposure (Schneider, 2011). However, the key fac-tor for development of this cancer type is the early onset of disease, and individual risk increases proportionally with affected relatives with breast cancer and early age of onset (Lalloo et al.,2012).

Multistage Process of CarcinogenesisIt represents a transformation of normal cells via the steps of hyperplasia, premalignant change and in situ carcino-ma. Different cytogenetic and molecular genetic analysis of breast cancer samples shows that tumor development in-volves the accumulation of various genetic alterations, such as mutation or loss of tumor suppressor genes and onco-genes amplification. Loss of normal tumor suppressor pro-tein function can occur through sequential gene mutation events (somatic alteration) or through a single mutational event of a remaining normal copy, when a germline muta-tion is present. The second event is usually mitotic recombi-nation, chromosome loss, or partial chromosome deletion. BRCA1 and BRCA2 genes are the most commonly mutated genes, but additional genes associated with hereditary breast cancer are emerging. Some of these genes have also been associated with increased risk of other cancers, such as ovar-ian, pancreatic, and colorectal cancer. BRCA1- encodes a nuclear phosphoprotein, which acts

as a tumour suppressor gene in terms of maintaining the genomic stability. The encoded protein combines with other DNA damage sensors, and signal transducers to form a large multisubunit protein complex, known as the BRCA1-associ-ated genome surveillance complex (Wang et al.,2000).BRCA2- involved in the maintenance of genomic stability and more specifically, the homologous recombination (HR) pathway which repairs double-strand DNA breaks.TP53- a tumor suppressor gene, causes Li-Fraumeni syn-drome and affects adults and children. This gene predisposes for a wide spectrum of tumors, including sarcomas, adreno-cortical carcinomas, brain cancer, and very early onset breast cancer (Weitzel et al.,2009; Chompret et al., 2000).

PTEN- tumor suppressor gene, mutations are the cause of autosomal-dominant disorder called Cowden syndrome. The disorder is characterized by multiple hamartomas with a high risk of benign and malignant tumors of the thyroid, breast, and endometrium (Apostolou & Fostira, 2013).

Changes in other genes are also associated with breast can-cer, and they include ATM, BRIP1, CDH1, CHEK2, MRE11A, NBN, PALB2, PTEN, RAD50, RAD51C, STK11.

Figure 1. The most important hallmarks of cancer (retrieved from: Hanahan & Weinberg, 2011)

Figure 2. Breast cancer tumorigenesis A) schematic diagram of tumor development B) schematic representation of breast tissue

(retrieved from: www.researchgate.net)

B) Colorectal Cancer (CRC)

An inherited cancer susceptibility gene is the main cause of approximately 5% of colorectal and breast cancers. About 1 in 40 people in the developed countries of West-ern Europe and North America will develop cancer of the bowel or colon, and an understanding of the development of colorectal tumorigenesis has helped understand car-cinogenesis more generally (Turnpenny & Ellard, 2017). Most colorectal cancers occur due to an old age and life-style factors. Some risk factors include smoking, diet, obe-sity and lack of physical activity. Dietary factors that in-crease the risk include red and processed meat as well as alcohol (“Colorectal Cancer Prevention”, 2014).


10

Multistage Process of CarcinogenesisThe majority of colorectal cancers are supposed to devel-op from benign adenomas, though only a small proportion of adenomas proceed to invasive cancer. Adenomatous pol-yps smaller than 1 cm in diameter rarely contain areas of carcinomatous change, whereas the risk of carcinomatous change increases to 5% to 10% as adenoma grows bigger and reaches 2 cm in diameter. It takes between 5 to 10 years to complete the transition from a small adenomatous polyp to an invasive cancer. RAS gene mutations occur in less than 10% of cases with adenomatous polyps which are smaller than 1 cm in diameter. As the size of the polyp increases to between 1 and 2 cm, the prevalence of RAS gene mutations may reach 40%, rising to approximately 50% in full-blown CRCs (Turnpenny & Ellard, 2017).In approximately 40% of adenomatous polyps and 70% of colorectal carcinomas occurs allele loss of chromosome 5 markers. Also, deletions on chromosome 17p in the region containing the TP53 gene occur in more than 75% of car-cinomas. A region on 18q is deleted in approximately 10% of small adenomas, rising to almost 50% when the adenoma shows foci of invasive carcinoma, and in more than 70% of colorectal carcinomas (Figure 3) (Turnpenny & Ellard, 2017). Other genes such are SMAD2, BMPR1A, LOH, MLH1, MSH2, and MSH6 are also believed to be involved with CRCs. SMAD4 is part of the transforming growth factor- β (TGF- β) pathway. In some CRCs mutations in the TGF- β receptor gene have been identified (Brosens, 2011). The DCC gene shows homology with the family of genes

encoding cell adhesion molecules—and cell-cell and cell–basement membrane interactions are lost in overt malignan-cy (Shussman & Wexner, 2014).It appears that mutations of the RAS and TP53 genes and LOH on 5q and 18q accumulate during the transition from a small ‘benign’ adenoma to carcinoma (Figure 3). It seems that the accumulation of alterations is more important than sequence. More than 90% of carcinomas show two or more alterations, and approximately 40% show three (Turnpenny & Ellard, 2017). Several genes have been recognized as playing a role in the development of colorectal cancer via the adenoma-to-carci-noma sequence. These genes include the tumor suppressor genes APC, DCC, and p53; the proto-oncogenes K-RAS and MYC; and the DNA mismatch repair genes MLH1, MSH2, and MSH6. Each of these genes is believed to have a specific stage of tumor formation in which its de-activation (tumor suppressor gene) or activation (proto-oncogene) is critical (Shussman & Wexner, 2014).

C) Lung cancerLung cancer is the leading cause of cancer deaths worldwide. The 2 major forms of lung cancer are non-small cell lung cancer and small cell lung cancer, which account for 85% and 15% of all lung cancers, respectively. Non-small cell lung cancer can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. Cigarette smoking causes all types of lung can-cer, but it is most strongly linked with small cell lung cancer and squamous cell carcinoma. Adenocarcinoma is the most common type in patients who have never smoked (Figure

2). Non-small cell lung cancer is often diagnosed at an ad-vanced stage and has a poor prognosis (Herbst, Heymach & Lippman, 2008).

More than half of people with lung cancer are diag-nosed with metastatic dis-ease, in which the cancer has spread to distant organs or lymph nodes. Symptoms can be mistaken for other health conditions and they often do not appear until the disease is advanced (National Acad-emies of Sciences, Engineer-ing, and Medicine, 2017).

Process of Carcinogenesis

and Affected GenesGerm-line mutations in p53, retinoblastoma, and other genes, as well as a germ-line

Figure 3. The development of colorectal cancer is a multistage process of genetic errors accu-mulated in cells. The red arrows represent a new critical mutation event, followed by clonal expansion. At the stage of carcinoma, the proliferating cells contain all the genetic errors that

have accumulated (Turnpenny & Ellard, 2017).


11

mutation in the epidermal growth factor receptor (EGFR) gene are the causes of inherited cancer syndromes that can increase lung cancer susceptibility. More recently, three large genomewide association studies identified an association between single-nucleotide polymorphism (SNP) variation at 15q24–15q25.1 and susceptibility to lung cancer. The region of the SNP variation was recently linked to lung carcino-genesis and includes two genes encoding subunits of the nicotinic acetylcholine receptor alpha, which is regulated by nicotine exposure (Herbst, Heymach & Lippman, 2008).

Promoter methylation of the CDKN2A, CDH13, RASS-F1A and APC genes in tumors and in histologically tu-mor-negative lymph nodes was associated with tumor re-currence, independently of NSCLC stage, age, sex, race, smoking history, and histologic characteristics of the tumor (Brock et al., 2008).

Other researches have shown that point mutations in KRAS and inactivation of the p53 pathway can also be one of many causes of lung cancer. Cross-species analysis identi-fied the NK2-related homeobox transcription factor Nkx2-1 as a candidate suppressor of malignant progression. It is found that Nkx2-1 downregulation is specifically linked to loss of differentiation, enhanced tumor seeding ability, and increased metastatic proclivity (Winslow et al., 2011).Another studies sequenced 623 genes with known or po-tential relationship to cancer in 188 human lung adeno-carcinomas. They identified 26 genes that are mutated at significantly high frequencies and are probably involved in carcinogenesis. The frequently mutated genes include ty-rosine kinases, among them the EGFR homolog ERBB4; then receptor genes EPHA3; KDR; and NTRK. Suppressor genes involved in other cancers are: NF1, APC, RB1, and ATM, and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status, and DNA repair defects. In general, genetic alterations in lung adenocarcinoma frequently occur in genes of the MAPK, p53, WNT, cell cycle, and mTOR signaling pathways (Ding et al., 2008).

ConclusionThe most common cancer types worldwide are breast, colorectal and lung cancer. Due to the poor lifestyle, unfa-

vorable environmental conditions like pollution as well as irregular physician office visits, these cancer types are in-creasingly occurring in Bosnia and Herzegovina. As already mentioned, tumor cells are primarily characterized by spe-cific changes in gene sequence or gene expression, mainly resulting in uncontrollable cell growth, ability to avoid cell death and to invade other tissues (metastasis). Healthy hab-its, lower stress exposure and making regular visits to the doctor would greatly reduce risk of developing cancer and would contribute to the decrease in cancer incidence.

References:1. Apostolou, P, & Fostira, F. Hereditary Breast Cancer: The Era of New Suscep-tibility Genes. BioMed Research International, 2013, 747318. 2. Brock, M, Hooker, C, Ota-Machida, E, et al. DNA Methylation Markers and Early Recurrence in Stage I Lung Cancer. New England Journal of Medicine. 2008;358(11), 1118-1128. 3. Brosens, L. Juvenile polyposis syndrome. World Journal of Gastroenterology. 2011;17(44), 4839.4. Chompret A, Brugières L, Ronsin M, et al. P53 germline mutations in child-hood cancers and cancer risk for carrier individuals. British Journal of Cancer. 2000;82(12):1932–1937.5. Colorectal Cancer Prevention. (2014). National Cancer Institute. Retrieved 17 November 2017, from https://www.cancer.gov/types/colorectal/hp/colorec-tal-prevention-pdq#link/_1014_toc6. Cooper GM. The Cell: A Molecular Approach.2nd edition. Sunderland (MA): Sinauer Associates: 2000.7. Ding, L, Getz, G, Wheeler, D, et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature. 2008; 455(7216), 1069-1075.8. Ferlay J, Parkin DM, & Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. European Journal of Cancer. 2010;46(4):765–781.9. Fidler, IJ. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat. Rev. Cancer 2003;3, 453–458. 10. Hanahan D & Weinberg RA. Hallmarks of cancer: the next generation. cell. 2011;144(5):646-74.11. Herbst, R, Heymach, J, & Lippman, S. Lung Cancer. New England Journal of Medicine. 2008;359(13), 1367-1380. 12. Lalloo F, Varley J, Ellis D, et al. Prediction of pathogenic mutations in patients with early-onset breast cancer by family history. The Lancet. 2003;361(9363):1101–1102.13. National Academies of Sciences, Engineering, and Medicine. (2017). Imple-mentation of lung cancer screening: Proceedings of a Workshop. Washington (DC): National Academies Press (US)14. Schneider KA. Counseling about cancer: Strategies for genetic counseling. John Wiley & Sons; 2011.15. Shussman, N, & Wexner, S. Colorectal polyps and polyposis syndromes. Gas-troenterology Report. 2014; 2(1), 1-15. 16. Turnpenny, P., & Ellard, S. Emery’s elements of medical genetics (15th ed) Philadelphia: Elsevier. 201717. Wang Y, Cortez D, Yazdi P, et al. BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes and Development. 2000;14(8):927–939.18. Weitzel JN, Gonzalez KD, Noltner KA, et al. Beyond Li Fraumeni syndrome: clinical characteristics of families with p53 germline mutations. Journal of Clinical Oncology. 2009;27(8):1250–1256. 19. Winslow, M, Dayton, T, Verhaak, R, et al. Suppression of lung adenocarcinoma progression by Nkx2-1. Nature. 2011;473(7345), 101-104.


12

My scientific journey

INTERVIEW Lemana Spahić

One of the interviews in this issue of BurchGene Magazine is with our Prof. Dr. Amina Kurtović-Kozarić. She is one of the leading experts in the field of Molecular Biology and Molecular diagnostics in the country. Prof. Amina was born in 1980 in Tuzla. She lived in the United States of America for seven years during high school (Friends’ Central School) and undergraduate studies (Cornell University). Afterwards, she decided to obtain her Phd in Vienna in the field of neu-robiology and genetics. Her thesis was titled “Characteri-zation of putative odorant receptors in D. melanogaster”. She was also Fulbright Scholar during 2012-2013 in Taussig Cancer Center at Cleveland Clinic, Cleveland, USA. She was a visiting scholar at many institutions including Brigham and Women’s Hospital, Boston, and Johns’ Hopkins University School of Medicine. Prof. Amina attended numerous semi-nars, workshops, courses etc. Special scientific contributions are as follows: establishment of diagnostic and translational cancer research laboratory in Bosnia and Herzegovina, es-tablishment of tumor bank, establishment of molecular di-agnostics for hematology and oncology, and others. She has published in journals such as Nature, Leukemia and British Journal of Haematology.

So in the following few questions, Prof. Amina explained to us how did she become what she is today.

Do you remember how did your scientific journey be-gin?

My interest in science started in middle school, but devel-oped towards biology in high school, when we did cloning of carrots with my high school teacher Mr. Gruber. At the same time, I was making weekly visits to a biophysics lab run by late Prof. Britton Chance at the University of Penn-sylvania. Starting from the very first day in college, I worked in a microbiology lab. I stayed in this lab for the entirety of college under the mentorship of late Prof. Jim Russell who was also my thesis advisor. I spent very long working hours there and I remember doing my first PCRs in December of 1998. Prof. Russell gave me incredible opportunities to develop scientifically and I will always remember his stories about being a scientist.

Why did you decide to go study abroad?

I studied abroad mainly because of war circumstances. My twin sister and I went to USA in the summer of 1995 and we were both so excited to go there. We went to a family that already had three daughters, and my sister and I look at them as our own sisters, and so we have maintained contact up till now and regularly visit each other.

Professor, could you please tell our read-ers something about your experience in studying in the US and Cornell Univer-sity as an Ivy League and one of the top world universities?

Well, good high school grades are mandatory for enrollment, good recommendation let-ters, as well as extracur-ricular activities. And I was lucky to have a full scholarship. I lived in an international house there and met a lot of friends from different cultures. Scientifically, it was incredible because you could choose your classes, so I chose a lot of biology, physics and chemistry along with graduate courses in bi-ochemistry and molec-ular biology. You could challenge yourself as much as you want to. First, second and


13

fourth year I worked in microbiology lab and third year I worked in immunology lab, so I got a lot of laboratory research experience.

So how did cancer become your field of expertise and not microbiology?

I would say it was all by chance. Firstly I worked on Drosophila genetics during my graduate studies in Vienna. But when I came back here I was given the opportunity to start a new lab for cancer diagnostics. I loved the oppor-tunity and decided to take up the challenge of starting the first

molecular diagnostics laboratory that does karyotyping, FISH, PCR and other molecular techniques that are need-ed for diagnosis, prognosis, and targeted therapy for cancer patients.

Why did you come back to B&H?

You could say destiny. I thought that a challenge of opening a lab here was a challenge good enough to keep me here, at least for the beginning. I loved that I had to start from scratch, from the beginning to set up something completely

new that never existed before. So, I like that challenge, be-cause when you finish your PhD, you do not often have the opportunity to start something new. After 10 years, it is a diagnostics and research laboratory that has >1600 samples and >2500 analyses annually.

What is your everyday motivation?

This is a very good question. I like the challenge of learning new things and the challenge of doing something new and exciting and by my opinion, science is very exciting and every day you can learn something new. That is what motivates me every day.

Do you have a message for our readers?

Be productive and multiply your knowledge in a sense that you should try to learn something new every day. You have to be very adaptable and let the scientific curiosity drive you forward.

We are very grateful to our Professor Amina Kurtović-Ko-zarić who gave us this beautiful insight in her scientific life and inspiring us to strive for knowledge and have a passion for science.


14


15

THANKS TO OUR SPONSORS

“Supporting the next generation of engineers, scientists and entrepreneurs of Bosnia & Herzegovina”

Bosnia & Herzegovina Futures Foundation believes that no student should miss out on a quality education due to disadvantaged circum-stances. There are many students who need your support to access education and technology in Bosnia & Herzegovina.” Their vision is to trans-form young talents into future leaders and break down ethnic barriers in Bosnia & Herzegovina through access to technology and education. More info on www.bhfuturesfoundation.org


16

Artificial Intelligence

PROGRESS OR DOWNFALL OF MANKIND

Dalibor ĐumićJasmin Kevrić

Do you like to remember the scenes from Sci-Fi movies where robots are assisting the military, robots that solve ultra-tough mathematical tasks, robots that gather people, IronMan’s Jarvis and his incredible assistive abilities? Well, we live in a time where all these unimaginable things are slowly becoming possible. For instance, Boston Dynamics based in the USA is developing a great robot whose design is reminiscent of a man called Atlas and until now they suc-ceded to give Atlas many abilities similar to a human. For instance, Atlas now can easily take simple boxes and bring them to any place without issues. It can run, which is really impressive. But the most impressive of all abilities Atlas have is jumping and doing aback-flip. Yeah, you’ve read it well! In November 2017, the Boston Dynamics has published a recorded video of Atlas jumping and back-flipping on You-Tube and the video is still viral. With that progress, Boston Dynamics is able to make a very acrobative-skilled robot in a bright future for military purposes. By the end of October

2017, something amazing was revealed: the first robot de-clared as a citizen in Saudi Arabia and its name is „Sophia“. „Sophia“ was created by Hanson Robotics and was the main attraction at a UN-hosted conference in Geneva. What’s so special about Sophia? She is a humanoid robot which means „she“ can talk, make different facial expressions and share some good jokes. „AI is good for the world, helping people in various ways.“ says Sophia and tilting her head and fur-rowing her brow convicingly. It’s kind of creepy from her, but this really can be true. However, there are some negative comments about AI from important people such as Prof. Stephen Hawking and Elon Musk, CEO of Tesla. Let’s go back in December 2014, when esteemed Profesor. Stephen Hawking gave his comment about AI: „The devel-opment of full artificial intelligence could spell the end of the human race.“ His warning came in response to a ques-tion about a revamp of the technology he uses to communi-cate, which involves a basic form of AI. Prof Hawking said

the primitive forms of artificial intelligence developed so far have already proved very useful, but he fears the consequences of creating something that can match or sur-pass humans. “It would take off on its own, and re-design itself at an ever increasing rate,” he said. “Humans, who are limited by slow biological evolution, couldn’t com-pete, and would be superseded.”He was right, because in February 2017 there were some signs of agression, but not too serious, of AI. Google’s Deep-Mind is an AI program which is capable for self-learning and it is often used in playing the games. DeepMind uses his agression very often for winning the games. In the last tests, two DeepMind agents played a game called „Gathering“, in which the win-ner is who has the most collected apples. The agents were behaving normally when there were enough apples, but afterwards

Figure 1. Meet Sophia the Robot: The first robot in history to be granted a full citizenship


17

they changed themselves and became more aggressive by us-ing guns against other players. Well, it might not be a big sign of aggression. But we know for one wise sentence: „Better prevent it than treat it.“ so engineers should be careful in making positive AIs.As Prof. Stephen Hawking has negative (or it could be pos-itive) opinion about AI, so Elon Musk shares similar opin-ion with him. He has said that artificial intelligence could be humanity’s greatest existential threat, this time by starting a third world war. “AI is a fundamental risk to the existence of human civilization in a way that car accidents, airplane crash-es, faulty drugs or bad food were not — they were harmful to a set of individuals within society, of course, but they were not harmful to society as a whole.” said Musk. His fears were prompted by a statement from Vladimir Putin that „AI is the future, not only for Russia, but for all humankind. It comes with colossal opportunities, but also threats that are difficult to predict. Whoever becomes the leader in this sphere will become the ruler of the world.”

Researchers noticed that the Artificial Intelligence they had created has started to make up their own code words, initially it looks like absolute gibberish, but it became clear that the machines – nicknamed Bob and Alice – were actually com-municating with one another. The robot abruptly stopped using English and could only be understood by other AI. This creates a friendly little argument about the fate of hu-manity. Elon Musk, the chief of Tesla and SpaceX, has long-standing worries about the potentially apocalyptic future of AI. “I keep sounding the alarm bell,” he told attendees at a National Governors Association meeting this month. “But until people see robots going down the street killing people, they don’t know how to react” in a Facebook Live broadcast, Zuckerberg, Facebook’s CEO, offered riposte. He called Musk a “naysayer” and accused his fears of unnecessary neg-ativity. “In some ways, I actually think it is pretty irrespon-sible,” Zuck scolded. Musk then reported on Twitter: “I’ve talked to Mark about this. His understanding of the subject is limited.” Elon Musk is increasingly out on his own with his doomsday predictions of a future where artificial intelligence threatens human existence. “This is a case where Elon and I disagree. “The so-called control problem that Elon is wor-ried about isn’t something that people should feel is immi-nent,” says Microsoft co-founder Bill Gates. “There’s a lot I think we can do to shape our own future instead of thinking, this is just going to happen to us. Control is a choice. We should try to keep that control.”

Well, there are two-sided opinions about AI from very im-portant scientists, leaders and engineers. The most common negative opinion is related to the possibility of agression from AI which would dangerously affect on human man-kind, while the most common positive opinion is that AI can improve the human lifestyle, save lives and assist to mankind. In the end, the choice is on us. If we want AI to control our life, then we have to be ready to take a responsibility for possible unpredictable behaviours from AI or we can still choose to live „old-fashioned“ style of life.

Figure 3. Future Intelligence

Figure 2. Elon Musk, the chief of Tesla and SpaceX


18

Top 8 Medical Technology Innovations

HEALTHCARE & MEDICAL TECHNOLOGY

Melanoma is the most serious and deadly

type of skin cancer, devel-ops in the cells (melanocytes) that produce melanin. A huge number of moles are actually harmless, but it is impossible to know for sure without an invasive surgical biopsy. Today, we have a new technology to help us making the right call — a handheld tool approved by the FDA for multispectral analysis of tissue morphology. This MelaFind scanner is important to provide additional information a doctor can use to

determine if a biopsy is must or not. This will help in reduc-ing the number of patients left with unnecessary biopsy scars, and reducing the cost of unnecessary procedures. The MelaFind technology uses missile navigation technologies to scan the surface of a suspicious lesion at 10 electromag-netic wavelengths. Signals are processed using heavy-duty algorithms and matched against a registry of 10,000 digital images of melanoma.

W e all know that aspirin is used to relieve pain. It is used also to treat mild pain and fever, to pre-

vent and to treat heart attacks, to prevent strokes, and to treat arthritis or inflammation. A technology under clini-cal investigation called Electronic Aspirin at Autonomic Technologies, is a patient-powered tool for blocking SPG signals (facial nerve bundle) at the first sign of a headache. The system involves the permanent implant of a small nerve stimulating device in the upper gum on the side of the head normally affected by headache. The lead tip of the implant connects with the SPG bundle, and once you sense the onset of a headache, you need only to place a handheld remote controller on the cheek nearest the implant. SPG nerves will be stimulated to block the pain-causing neurotransmitters.

Layla Abdel Ilah

In today’s world, technology plays an important role in every industry as well as in our personal lives. Out of all those industries, healthcare is definitely one of the most important. Today’s best medical technologies strike a balance between reducing the overall cost of medical care and in-creasing safety and survival rates. Medical technology companies are focusing more than ever on

products that deliver cheaper, faster, and more efficient patient care. Medical technology is a field where innovation plays an important role in maintaining health. Areas like biotechnol-ogy, pharmaceuticals, information technology, the development of medical devices and equipment, and more have all made significant assessments to improve the health of people all around the world. In the healthcare industry, the independence on medical technology is impossible, and as a result of the development of these brilliant innovations, healthcare practitioners can continue to find ways to improve and develop their prac-tice – from better diagnosis, more accurate devices, safer surgical procedures, and improved patient care. You have here the top 8 medical technology innovations that will advance the medical technologies significantly, and you can visit AABME.org for up-to-the-minute developments on this field.


19

D iabetic patients need needles to draw blood for glucose testing,

and for daily insulin shots, which means a high risk of infection. Nowadays, glu-cose monitors and insulin pumps are very useful for reducing the needles amount but they cannot totally replace them. Echo Therapeutics (Philadelphia, PA) is developing a needle-free solu-tion for diabetic patients. This technology depends on a transder-mal biosensor that reads blood ana-lytes through the skin without drawing blood. The technology involves a hand-held electric-toothbrush-like device that removes just enough top-layer skin cells to put the patient’s blood chemistry within signal range of a patch-borne biosensor. Then data will be sent wire-lessly to a remote monitor, triggering audible alarms when levels exceed the patient’s optimal range.

M ore and more sophisticated technology is implemented

every day to provide a cost-effec-tive means of patient care in hospi-tals and health centers. Medical robots are the next step forward. Produced by InTouch Health and iRobot Corp, RP-VITA Remote Presence Robot is equipped with a two-way video screen and medical monitoring equipment that is programmed to maneuver itself across the busy hallways of a hospital, they can periodically prowl hospital hall-ways on more routine rounds, checking on patients in room and managing their individual charts and vital signs.

T he first fully absorbable stent was approved by the U.S. Food

and Drug Administration to treat cor-onary artery disease. The stent was named the Absorb GT1 (BVS), and was created to release different drugs while also being naturally absorbed by the body in three years. This procedure eliminates the need of using metallic substances in the body, which often cause infections and irritation.

F irst free lead pacemakers were approved to be sell this year. This

will be the first pacemaker approved for placement by the U.S. Food and Drug Administration that does not have any lead. The product is only an inch long and does not have any wire connections. This wireless device helps eliminating the risk of infections and is easier to be used. This technology could help keep patients healthier and extend the lives of devices.

T hese smart sensors are devel-oped by Briteseed medical com-

pany and can help surgeons in reducing mistakes in operations rooms. Surgeons can prevent unintentional bleeding during procedures. These sensors can easily also detect bile ducts, blood ves-sels and other vulnerable sites that can easily get punctured during surgery because of their tiny size and placement.

T he Sapien transcatheter aortic valve is an alternate to an open-

heart surgery designed for people who need a replacement valve, but cannot endure the severity of the open-heart surgery procedure. This procedure is very efficient in reducing the health care costs incurred as a result of pro-longed hospitalization. This valve is guided through the femoral artery by catheter from a small incision near the rib cage. Its material is made of bovine tissue attached to a stainless-steel stent, which is expanded by inflating a small balloon when correctly placed in the valve space.


20

Can we stop aging?

MATH SAYS ‘NO’, GENETICISTS SAY ‘YES’

Adnan FojnicaFatima Mrkulić

Ahmed Osmanović

Researchers known as biomedical gerontologists are search-ing for ways to end aging. By understanding how we age, these researchers believe we can learn how to slow or stop the process, much like how we’d treat a disease. This en-deavor is particularly impressive if you consider how new a phenomenon old age is. At the turn of the 20th century, people living in the United States could expect to live ap-proximately 45 years; just 100 years later, the life expectancy in the U.S. had risen to about 78 years.Much of the leap in this statistic is due to better sanitation practices and medical advances like vaccinations and antibi-otics that improved the infant mortality rate. With a greater likelihood that children would make it through their first years, the average life expectancy skyrocketed. But as more people lived longer, they didn’t like what they saw. Aging-re-lated conditions such as dementia, stroke and heart disease became more common. And while some scientists have dedicated themselves to curing those ills, others see those individual problems as part of a bigger picture. If they treat-ing aging like a disease that can be cured, the thinking goes, then the troubles that go along with it will also disappear.By curing aging, scientists believe we can create another huge increase in the average life expectancy. Some believe that we’ll eventually reach a maximum life expectancy of about 120 years, while others believe that there’s no limit on how many years a person can age, leaving the possibility of immortality on the table.

BIOGRAPHY OF MICHAEL R. ROSE

Michael R. Rose is a Professor in the Department of Ecolo-gy and Evolutionary Biology at the University of California, Irvine. His Ph.D. advisor was Brian Charlesworth. His main area of work has been the evolution of aging, approached both theoretically and empirically via the technique of ex-perimental evolution. In 1991, he published Evolutionary Biology of Aging ex-ploring a view of the subject based on antagonistic pleiot-ropy, the hypothesis that aging is caused by genes that have two effects, one acting early in life and the other much later. The genes are favored by natural selection as a result of

their early-life benefits, and the costs that occur much later appear as incidental side-effects that we identify as aging. For us important point here to stress is that Dr. Rose sug-gests that aging can stop in a latter stage of life.

ROSE’S VIEW ON AGING

“Humans eventually achieve a period of non-aging, Rose suggests, just as several other multicellular living forms do, such as a creosote bush growing in the Mojave desert that has lived for longer than 10,000 years and the Galapagos tortise.”

The fact that such a diversity of eukaryotic organisms -all life forms except bacteria- can have indefinite lifespan shows you that there is precisely nothing about eukaryotic cell or molecular biology that requires an aging process,” Rose said, countering the view that aging is an inevitability, caused primarily by an accumulation of molecular damage and decline in physical function.

The term “biologically immortality” in gerontology is the point in which the exponential increase in mortality rates of a species population appears to level off, producing a sud-den late-life plateau, which happens when a species reaches a state where it ceases to age, or no longer experiences a further loss of physiological function, Rose said. Rose sug-gests humans also experience a biological immortality phase if they are able to live long enough. “You can die, but the idea here is that you are non-aging,” Rose said, “versus ag-ing with a decline of survival likelihood under good condi-tions.”Rose argues that an organism ages because the process is a byproduct forced upon us by evolution by natural selection, because across evolutionary species in eukaryotes, the genes selected generally favor survival of the young in a popula-tion, and then mortality rates begin to rise exponentially.

“This is why you are all aging,” Rose said. The forces of natural selection, in other words, allow an “aging phase” be-cause they fade out.


21

He began his work on fruit flies by tricking natural selection to produce what eventually became “Methuselah flies,” by taking the eggs from fruit flies that have maintained enough of their physiological function to reproduce in old age, and repeating the process, producing selection for late-life repro-duction. This delayed-reproduction lineage, Rose showed, lives up to five times longer than average.

The aging phase eventually passes, Rose explained, and sur-vival reaches a plateau, which is when the biological immor-tality phase starts. The chances of dying become constant, neither increasing or decreasing, a period of no more aging.

Rose has created what he calls his “natural immortality plan” for humans that he hypothesizes can keep us living far be-yond the old-age record of Jeanne Calment, who lived un-til age 122 and inspired his new plan—because before the immortality phase theory, there was no reason for why she or other supercentenarians could survive so long. Rose ex-plained that Calment may have reached a phase where phys-ical decline stabilized.

The unfortunate problem for humans vs fruit flies, Rose expalined, is that they have a rough and long aging phase. “We hit late-life immortality plateaus very late in life, in our nineties—in your eighties you’re still aging—and we do so in terrible condition,” he said. “But,” he added, “there are good reasons theoretically that hunter-gatherer populations are more like fruit flies which hit immortality plateaus quite early. That, in fact, they might hit their transition from aging to late-life immortality perhaps in their fifties or sixties and do so in better shape.

“When you have an earlier likelihood of death from some-body’s spear in the back or because you can’t cope with in-fection,” Rose added, “immortal phases should start earlier. The key is not to slow the rate of aging, but go directly to the immortal phase at a lower rate of mortality, which is exactly what the fruit flies do,” he said.

Rose’s prescription for humans is to adhere to a regiment of what is natural for humans, what is our best environment, which excludes an industrial lifestyle and a Western-style diet that involves sitting several hours in front of a TV or com-puter and munching on junk food. Instead, adopt an ances-tral hunter-gatherer lifestyle and a “paleo” diet that includes only foods available before the agricultural revolution of the Neolithic, which includes lean meats, shore-based foods, fruits and vegetables. Foods types that became available after the Neolithic such as grains, dairy, and processed foods are all avoided.

But, interestingly, Rose told me, for people of Eurasian an-cestry, he disagrees with the age a paleo diet should be adopt-ed as advised by main proponents of the paleo diet, such as evolutionary nutrition researchers Loren Cordain and S. Boyd Eaton. He said that young people of Eurasian ancestry have actually adapted well to new environments brought on by the agricultural revolution.

“But at later ages,” he added, “you will lose that adaptation to a novel environment and you will revert back to a condi-tion to which you are better conditioned to a long ancestral environment.”

He explained that after age 40, the physiology of people of Eurasian ancestry appears to return to a pre-adapted state with age to one that is better off with the same foods our pre-Neolithic ancestors ate: meat, seafood, nuts, fruits and vegetables.

“Don’t eat anything derived from a grain or grass of any type—that includes rice and corn—and don’t eat anything from the udder of a cow if you are over 35 or 40,” Rose warns. “If you are under 30 you should probably eat an An-drew Weil-style organic, agricultural diet.”Let’s better introduce him to you, trough out this special in-terview.


22

14

Aging stops on its own in species like ours ”


23

1. Could you please tell us why exactly did you choose human evolution and ag-ing for your research field?

I was persuaded to work on aging by my doctoral advisors, Brian Charlesworth and John Maynard Smith, from 1975 to 1976. I describe their efforts of persuasion in my memoir, “The Long Tomorrow.”

2. Could aging be stopped in multicel-lular organisms and how? Are there any used methods for anti-aging and could they be applied on humans?

Aging stops on its own in species like ours, as we (L. Mueller, C. Rauser, and myself) explain in our recent book, “Does Aging Stop?” I discuss the possibilities for inter-vening in human aging at the website, 55the-ses.org. Specifically, the 55 theses themselves explain my thinking and research findings step by step, one sentence at a time.

3. What are the main challenges in using these methods on humans?

There are four steps that people need to embrace. ONE. Accepting that only the evolutionary theory of aging based on the forces of natural selection is valid. All other theories of aging are fundamentally wrong. TWO. Altering human lifestyles to match the focus of natural selection at each age. More specifically, the best human lifestyle depends on a person’s ancestry as well as each per-son’s chronological age. THREE. We need benign pharmaceuticals that disrupt our age-specific adaptation as little as possible. I have started a company with my former graduate student, Dr. Larry G. Cabral, to try to achieve this goal. The company is called Lyceum Pharmaceuticals. FOUR. We need decades of genomic, transcriptomic, and metabolomic research dedicated to unravel-ling the profound physiological complexity of human aging. That research will provide more detailed knowledge than we have now, knowledge comparable to our present un-derstanding of the microbial foundations of infectious diseases.

4. What is the difference between stopped and reversed aging on cellular level? Which of these two processes are more likely to be used in everyday life?

I don’t think anyone knows enough to an-swer this question at the moment.

5. What are the latest research results on topic “biological immortality”?

I have a Google Scholar page that lists our latest publications. My lab and that of my colleague Professor Laurence D. Mueller publish a lot on biological immortality. Pro-fessor Caleb E. Finch of the University of Southern California also publishes on the related topic of negligible senescence. The recent result that I find most interesting is the demonstration of a long non-aging phase after the onset of reproduction in a number of our labora-tory Drosophila popula-tions. (Burke et al. 2016. “Evolution” journal).

6.Could you please send a final message to young researchers, students and readers of BurchGene Magazine?

The scientific problems of aging and biological immortality have seen great progress recently. The most important chal-lenge of our time, this 21st Century, is applying those results to the problems of human aging. I believe that people who are now under thirty years of age will live to see aging brought under ef-fective control during their lifetimes. As a result, I expect many of them to live with good health past 100 years of age, if not longer. But only if we act based on the evolutionary analysis of aging. Not if we continue to pursue the failed cell-molecular reductionist theories of ag-ing that have been popular over the last fifty years.

“Does Aging Stop?“

Michael R. Rose is a Professor in the Depart-ment of Ecology and Evolutionary Biology at the University of Cali-fornia, Irvine. Michael is the leading scientist in the field of Aging.


24

Rare hereditary diseases

MOLECULAR GENETICS

Denis SmajićEna Kučuković

Emina BojićLada Lukić Bilela

“Rare diseases are rare, but rare disease pa-tients are numerous” Orpahnet

Summary

A rare disease, also referred to as orphan disease, is any dis-order that affects a small percentage of the population. Al-though the disease may be rare, patients and families share a common struggle. Most rare diseases are life-threatening and chronically debilitating conditions and the vast majority of them are genetically determined. Rare Disease Day is held on the last day of February every year to raise awareness of rare diseases. IntroductionGenerally, a rare disease is any disease that affects a small per-centage of the population. Rare diseases represent a group of various conditions/diseases with a low prevalence as a common characteristic, regarding to the affected individuals number of a given population. The prevalence of a disease in an area may be expressed as the number, percentage, or proportion of people found to have diagnosed the particular disease with a total num-ber of people included in study (Field and Boat, 2010). Due to definitions that include reference to treatment availability, a lack of resources, and severity of the disease, the term orphan disease is used as a synonym for rare disease. Rare Disease Day is held on the last day of February every year to raise awareness of rare diseases.Orphan medicines are those intended to diagnose, prevent or treat rare diseases, in the European Union (EU) further specified as life-threatening or chronically debilitating conditions. According to the Orphan Drug Act (1983), a rare disease or condition is defined as one that either affects fewer than 200,000 people in the United States (US). To qualify as an orphan indication, the prevalence of the condition must be fewer than 5 in 10,000 indi-viduals in the EU, fewer than 50,000 affected in Japan, or fewer than 200,000 affected in the US. In 1993, the National Institutes of Health (NIH) created the Office of Rare Diseases (ORDR) to promote research on rare conditions and help develop a more systematic strategy for such research. The ORDR includes more than 6,800 conditions in its list of rare diseases, which is available online (http://rarediseases.info.nih.gov/RareDiseaseList.aspx?PageID=1). The RARE List™ is comprised of approximately 7,000 different

rare diseases and disorders affecting more than 300 million people worldwide (www.globalgene.org). According to the definition adopted by the EU, rare hereditary diseases are those who are involved in less than 5 per 10,000 thou-sand people or 1:2,000 (Regulation (EC) No. 141/2000). Accord-ing to European Organization for Rare Diseases (EURORDIS), 27-36 million people in Europe suffer from rare hereditary dis-eases. EURORDIS also includes both rare diseases and neglected diseases into a larger category of orphan diseases (EURORDIS, 2005a). Rare diseases are characterized by a wide diversity of symptoms and signs that vary not only from disease to disease but also from patient to patient suffering from the same disease (eurordis.net). In addition to low prevalence, they are heterogeneous in terms of etiology, time of occurrence, flow of disease as well as the engage-ment of individual organs or organic systems. Delayed diagnoses are a common and major stressor for the affected people and their families. There are many factors of late diagnosis as insufficient knowledge of physicians, lack of data as well as expensive diag-nostic methods and techniques, especially for the Least Devel-oped Countries (LDCs) (Field and Boat, 2010). The vast majority of the rare diseases are genetically determined (Ségolène, & Schmidtke, 2007). EURORDIS estimates that at least 80% of them have identified genetic origins, while other rare diseases are the result of infections and allergies. Many of them appear early in life, at birth or in childhood, and about 30% of children with rare diseases unfortunately die before reaching their fifth birthday. Molecular basis of rare diseases often includes different genetic or epigenetic abnormalities of nuclear (nDNA) and/or mitochondrial (mtDNA). The abnormality can range from minuscule to major - from a point mutation in a single base in DNA of a single gene (e.g. Cystic Fibrosis – CF and Alpha-1 anti-trypsin Deficiency – AATD) to a gross chromosome abnormality involving the addition/subtraction of an entire chromosome or set of chromosomes (Stöppler, 2016). There are many types of chromosome anomalies, organized into two basic groups: numer-ical and structural aberrations. Aneuploidy (an abnormal number of chromosomes) occurs when an individual either is missing a chromosome from a pair (monosomy; e.g. Turner syndrome) or has more than two chromosomes of a pair (Trisomy 21 or Down syndrome; Chromosome 18p tetrasomy, etc.) Structural abnormalities mostly involve: deletions (Wolf-Hirch-horm syndrome – WHS; Jacobsen syndrome; Cri-du-Chat syn-drome; Williams syndrome), duplications (Charcot-Marie-Tooth disease – CMT), translocations, inversions, insertions and rings


25

forming. A particular group includes inherited conditions asso-ciated with chromosomal instability and breakage, chromosome instability syndromes, as Ataxia telangiectasia and Ataxia telangiec-tasia-like disorder, Bloom syndrome and Nijmegen breakage syn-drome (Taylor, 2001).Genomic imprinting is an epigenetic phenomenon that leads to parent-specific differential expression of a subset of genes. As im-printed genes have an important role in growth and development, aberrant expression of imprinted genes due to genetic or epige-netic abnormalities is involved in the pathogenesis of human dis-orders, or imprinting disorders. Beckwith-Wiedemann syndrome – BWS is a representative imprinting disorder with a five known causative epigenetic and genetic alterations: loss of methylation (LOM) at KvDMR1, gain of methylation (GOM) at H19DMR, pa-ternal uniparental disomy, CDKN1C mutations and chromosomal rearrangements. Opposite methylation defects, GOM and LOM, at H19DMR are known to cause clinically opposite disorders: BWS and Silver-Russell syndrome, respectively (Soejima & Higashimoto, 2013).Although most DNA is packaged in chromosomes within the nu-cleus, mitochondria also have a small amount of their own DNA. Some of the rare hereditary diseases are caused by mutations in mitochondrial DNA. Examples of rare mitochondrial hereditary diseases are Leber’s hereditary optic atrophy (LHON), Myoclonic epilepsy with ragged red fibers (MERRF) and Mitochondrial en-cephalomyopathy, lactic acidosis and stroke-like episodes (MEL-AS) (Stöppler, 2016) Interestingly, mitochondrial myopathies are regulated by two ge-nomes: the nDNA, and mtDNA. While, so far, most studies have dealt with mitochondrial myopathies due to deletions or point mutations in the mtDNA, a new field of investigation is that of syndromes due to mutations in the nDNA (Angelini et al, 2009).MITOMAP database for the human mitochondrial genome in-volve overview of polymorphisms and mutations in human mtD-NA with reports published data on human mtDNA variation. The data presents detailed information about the molecular basis of this diseases with links to other databases and links with even more important information like coding and control region mutations, major and minor rearrangements (Brandon et al, 2005; www.mi-tomap.org). The other useful databases are MITOP (Scharfe, 2000) and MITONUC (Attimonelli et al, 2002). MITOP is a compre-hensive database for genetic and functional information on both nuclear- and mitochondrial-encoded proteins and their genes. It contains a Human disease catalogue with a total of 110 human

diseases related to mitochondrial protein abnormalities, sorted by clinical criteria and age of onset, links to relevant MITOP proteins entries and hyperlinks to Online Mendelian Inheritance in Man (OMIM) (Hamosh et al, 2002). DistributionRare diseases can vary in prevalence between populations, so a dis-ease that is rare in some populations may be common in others. In smaller communities, the founder effect can result in a disease that is very rare worldwide being prevalent within the smaller commu-nity. Other diseases, such as many rare forms of cancer, have no apparent pattern of distribution but are simply rare. The classifica-tion of other conditions depends in part on the population being studied. All forms of cancer in childhood are generally considered rare, because so few children develop cancer, but the same cancer in adults may be more common (Eurordis, 2005b).Cystic fibrosis or mucoviscidosis, is an autosomal-recessive disease, caused by mutations in the CF transmembrane conductance reg-ulator (CFTR) protein at the chromosome 7q31.2 (CFTRΔF508). It is rare in most parts of Asia but relatively common in Europe and in populations of European descent. In the US approximately 30, 000 individuals have CF and in Canada 4,000 (Marshal, 2014). In the EU it is considered that this disease affects one child in 2000-3000 newborns (Farell, 2008). Cystic fibrosis most common-ly occurs in the white population of infants (1:3200), then African Americans (1:15,000), while the most common occurs in Asian Americans (1:30,000). In Federation of Bosnia and Herzegovina, between March 2003 and December 2014, were registered 40 cas-es of cystic fibrosis. Advanced diagnostics led to the diagnosis in the early stages of the disease which greatly facilitates the further treatment of patients and thus prolongs the life span. Survival of patients with CF has dramatically improved since the disease was discovered. Seventy years ago patients died in the first year of life, while today the average life expectancy of CF patients is 37.4 years (Selimovic et al., 2015). Classification of rare hereditary diseasesMostly, rare diseases are absent in the International Classification of Diseases (ICD10) and those with a specific code are often mis-classified. As a consequence, morbidity and mortality of rare dis-eases is invisible only in health information systems. To overcome this difficulty, Orphanet – The portal for rare diseases and orphan drugs has established a partnership with World Health Organiza-tion (WHO) to ensure a fair representation of rare diseases in gen-eral. Orphanet is working systematically to identify and classify rare


26

conditions along several dimensions which includes prevalence, age at onset, pattern of inheritance, prevalence, clinical category and identifier in the OMIM database. Orphanet has collected all published expert classifications and established a database of phe-notypes indexed with ICD10 codes, MIM codes, genes, mode of inheritance, age of onset and class of prevalence. Phenotypes are assigned to as many classification systems as necessary to repre-sent them. The Orphanet nomenclature of rare diseases is a sta-ble one, directly exploitable by information systems and available on request (Rath et al. 2010; Rath et al, 2012). Rare disorders in Orphanet, depending on their clinical presentation, are included in as many classifications as needed. Classifications are based on published scientific articles and reviewed by experts (http://www.orpha.net). Also, NORD Guide to Rare Disorders summarize information (e.g., differential diagnosis, signs and symptoms, eti-ology/epidemiology, and treatment) of over than 800 conditions (Field and Boat, 2010).Challenges and opportunities in diagnostics and treat-ment of rare hereditary diseasesEURORDIS as a non-governmental patient-driven alliance of pa-tient organizations represents a 765 rare disease patient organiza-tions in 69 countries. Thereby, EurordisCare represents a series of case and research studies aiming to compare access to care for rare disease patients in Europe. EurordisCare 2 survey from 2007, that focused on eight rare diseases: Crohn’s disease, Cystic fibrosis, Duchenne muscular dystrophy, Ehlers-Danlos syndrome, Marfan syndrome, Prader Willi syndrome, Tuberous sclerosis and Fragile X syndrome, was launched to provide evidence on the delay to di-agnosis and identify its main causes. According to this survey, late diagnoses delay the beginning of adapted treatments and can lead to irreversible consequences. Delay in diagnosis can vary greatly depending on the disease and on the country, as well as on indi-vidual factors. Unfortunately, 25% of patients had to wait between 5 and 30 years from early symptoms to confirmatory diagnosis of their disease, 40% of patients first received an erroneous diagnosis, others received none. This led to many unnecessary medical inter-ventions, even surgery and psychiatric treatments. Mostly, patients had to travel to a different region or different countries to obtain the confirmatory diagnosis. Paradoxically, given the genetic origin of rare diseases, the genetic nature of the disease was not commu-nicated to the patient or family in 25% of cases. Also, the genet-ic counseling is included in only 50% of cases (Faurisson, 2004; Survey “EurordisCare 2”, 2007). Relatively common symptoms can hide underlying rare diseases, leading to misdiagnosis. Usually, physicians consider common conditions that are consistent with the available information before considering rare conditions (Field & Boat, 2010).Many organizations that educate, assist, and advocate for patients with rare conditions seek to educate physicians about the diseases. For example, the Cystic Fibrosis Foundation developed criteria to help standardize approaches to diagnosis (Rosenstein & Cutting, 1998).A number of unique clinical, regulatory and commercial challeng-es are associated with the development of therapies for the treat-ment of rare diseases. ‘Orphan drugs’ are the medical products developed for the treatments of rare diseases. The orphan drugs are intended to treat diseases so rare that sponsors are reluctant to develop them under usual marketing conditions. The process from the discovery of a new molecule to its marketing is very long (10 years in average), extremely expensive and very uncertain. Orphan drugs may be defined as the drugs that are not developed by the pharmaceutical industry for economic reasons, but which respond to public health need (www.orpha.net).In recognition of these challenges, there has been legislation in

the US and EU. In addition, the FDA has created the Office of Orphan Products Development and, in 2010 the FDA created the Rare Disease Program within the Office of New Drugs with the specific focus of developing the policies and procedures for the review of new drug applications for orphan drug products and to ensure the appropriate training for FDA reviewers. In both the US and the EU, orphan drug designation can be applied for at any stage of the development process. (Vickers, 2013).ReferencesAngelini, C., Bello, L., Spinazzi, M., & Ferrati, C. (2009). Mitochondrial disorders of the nuclear genome. Acta Myologica, 28(1), 16-23.Attimonelli, M., Catalano, D., Gissi, C., Grillo, G., Licciulli, F., Liuni, S., Santamaria, M., Pesole, G., & Saccone, C. (2002). MitoNuc: a database of nuclear genes coding for mitochondrial proteins. Nucleic Acids Research, 30, 172-173.Brandon, M.C., Lott, M.T., Nguyen, K.C., Spolim, S., Navathe, S.B., Baldi, P., & Wallace, D.C. (2005). MITOMAP: a human mitochondrial genome database - 2004 update. Nucleic Acids Research, 33: D611-613;URL: http://www.mitomap.org.EURORDIS (2005a). Rare diseases: Understanding this public health priority. Eu-ropean Organisation for Rare Diseases (EURORDIS). EURORDIS (2005b). Rare diseases in numbers. European Conference on Rare Diseases, Luxembourg, June 21-22, 2005.Farell, P.W. (2008). The prevalence of cystic fibrosis in the European Union. Jour-nal of Cystic Fibrosis, 7(5), 450-453.Faurisson, F. (2004). EurordisCare2: Survey of Diagnostic Delays, 8 Diseases, Eu-rope. http:// archive.eurordis.org/imprimer.php3?id_article=454.Field, J.M. & Boat, T.F. (Eds). (2010). Rare Diseases and Orphan Products: Ac-celerating Research and Development. Washington, DC: The National Academies Press. 47-51.Field, J.M., & Boat, F.T. (2010). Rare diseases and orphan products: Accelerating research and development. Committee on accelerating rare disease research and orphan product development, Institute of Medicine of the National Academies, USA.Hamosh, A., Scott, A.F., Amberger, J., Bocchini, C., Valle, D., & McKusick, V. (2002). Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders. Nucleic Acids Research, 30(1), 52-55.Marshal, C.B. (2014). Cystic Fibrosis Foundation Patient Registry: Annual data report to the center directors. Maryland: Cystic Fibrosis Foundation. Available from: http://www.cff.org/UploadedFiles/aboutCFFoundation/AnnualReport/ 2013-nnual-Report.pdfOfficial Journal of the European Communities L 18/1 I: Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on Orphan Medicinal Products. “Orphan Drug Act of 1983”. US Food and Drug Administration. 4 January 1983. Retrieved 27 October 2015.Rath, A., Ségolène, A. & Bertrand B. (2012). Classification of rare diseases: a world-wide effort to contribute to the International Classification of Diseases. Orphanet Journal of Rare Diseases, 5(1), Q21.Rath A., Olry A., Dhombres F., Brandt, M.M., Urbero, B., Ayme, S. (2012). Rep-resentation of rare diseases in health information systems: the Orphanet approach to serve a wide range of end users. Human Mutation. 33(5), 803–808.Rosenstein, B. J. & Cutting, G. R.. (1998). The diagnosis of cystic fibrosis: a consen-sus statement. Cystic Fibrosis Foundation Consensus Panel. Journal of Pediatrics, 132(4), 589-595.Scharfe C., Zaccaria, P., Hoertnagel, K., Jaksch, M., Klopstock, T., Lill, R., Prokisch, H., Gerbitz, K.D., Mewes, H.W. & Meitinger, T. (2000). MITOP, the mitochondrial proteome database: 2000 update. Nucleic Acids Research., 28, 155–158.Ségolène, A. & Schmidtke J. (2007). Networking for rare diseases: a necessity for Europe. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz, 50(12), 1477-1483.Selimovic, A., Mujicic, E., Milisic, S., Mesihovic-Dinarevic, S., Dzinovic, A., Cengic, S., Bakalovic G., Moro, M., Djozic M., & Lukic-Bilela L. (2015). Analysis of Cystic Fibrosis in Federation of Bosnia and Herzegovina. Medical Archives. 69(4), 222-225. Soejima, H., & Higashimoto, K. (2013). Epigenetic and genetic alterations of the imprinting disorder Beckwith-Wiedemann syndrome and related disorders. Journal of Human Genetics, 58(7), 402-409.Stöppler, M.C. (2016). Genetic Diseases Overview. Medicine.net, 23.11.2017Survey “Eurordis 2” (2007). https://www.eurordis.org/IMG/pdf/FactSheet_Eu-rordiscare2.pdfTaylor, A.M. (2001). Chromosome instability syndromes. Best Practice & Research Clinical Haematology, 14(3), 631–44. Vickers, P.J. (2013). Challenges and opportunities in the treatment of rare diseases. http://www.ddw-online.com/therapeutics/p211490-challenges-and-opportuni-ties-in-the-treatment-of-rare-diseases-spring-13.htmlZuarynski, Y., Deverell, M., Dalkeith, T., et al. (2017). Australian children living with rare diseases: experiences of diagnosis and perceived consequences of diagnostic delays. Orphanet Journal of Rare Diseases, 12, 68. DOI: 10.1186/s13023-017-0622-4.


27

Down Syndrome Albinism

Down syndrome is a chromosomal condition that is associated with intellectual disability, a characteristic facial appearance, and weak muscle tone (hypotonia) in infancy. About half of all affected chil-dren are born with a heart defect and aproximately half of adults with Down syndrome develop Alzheimer disease. Although wom-en of any age can have a child with Down syndrome, the chance of having a child with this condition increases as a woman gets older.

RaRe Genetic DisoRDeRs in Humans

Cystic Fibrosis Fragile X syndrome

Hemophilia Angelman syndrome

Albinism is a disorder that causes lack of pigmentation in skin, hair, and eyes. It is caused by mutations in genes involved in produc-tion of melanin (the substance that gives skin, hair, and eyes their color). Due to lack of melanin in the retina people with albinism have vision problems such as reduced sharpness; rapid, involun-tary eye movements (nystagmus); and increased sensitivity to light. Around the world, between one in 17,000 and one in 20,000 people are albinos.

Mucus is a slippery substance that lubricates and protects the lin-ings of many tissues. In people with cystic fibrosis, cells produce mucus that is abnormally thick and sticky. This leads to severe problems with breathing and bacterial infections in the lungs. Over time, mucus buildup and infections result in permanent lung dam-age, including the formation of scar tissue (fibrosis) and cysts in the lungs. The incidence of cystic fibrosis in the European Union one in 2000-3000 newborns.

Individuals affected by the Fragile X Syndrome usually have delayed development of speech and language and intellectual disabilities. Many people with fragile X syndrome have characteristic physical features, including long and narrow face, large ears, a prominent jaw and forehead, unusually flexible fingers, flat feet, and in males, enlarged testicles (macroorchidism) after puberty. Fragile X syn-drome affects approximately 1 in 2500-4000 males and 1 in 7000-8000 females.

Hemophilia is a bleeding disorder that slows the blood clotting process. In severe cases, continuous bleeding occurs after minor trauma or even in the absence of injury (spontaneous bleeding). Two major types of this condition are hemophilia A (classic hemo-philia) and hemophilia B. Although similar in signs and symptoms, they are caused by mutations in different genes. Hemophilia affects 1 in 5,000 male births in the U.S. The most famous family with hemophilia B was that of Queen Victoria of England.

Children with Angelman syndrome typically have a happy, excitable demeanor with frequent smiling, laughter, and hand-flapping move-ments. Characteristic features of this condition include intellectual disability, severe speech impairment, and problems with movement and balance (ataxia). Most affected children also have epilepsy and microcephaly. Very specific and commonly occuring trait of this condition, is fascination with water and shiny objects. Angelman syndrome affects an estimated 1 in 12,000 to 20,000 people.

Kenan Kraković

Genetics plays a

huge part in who we are.

But we also have free will.

Genetics plays a

huge part in who we are.

But we also have free will.

burchgene - gen.ibu.edu.ba · bosnia and herzegowina, additionally intriguing reader to give...

Documents