Presented by The Qatar Foundation
Biomedical Research: Qatar Foundation Annual Research Forum 2011
Posted February 15, 2012
The Qatar Foundation Annual Research Forum convened for the second time from November 20 – 22, 2011, in Doha, to discuss progress and challenges in transforming Qatar from a resource-based to a knowledge-based economy and in creating a more sustainable future. The Foundation recruited eminent scientists and leaders from Qatar and around the world to share their insights on how to build a robust R&D infrastructure, encourage regional and worldwide collaborations, and foster entrepreneurship in Qatar. In addition, one day was devoted to a series of research presentations in five areas: energy, environmental, biomedical, computing, and arts and humanities research.
This eBriefing looks at the research presented in the biomedical research track—comprising three general sessions and two special workshops. The three general sessions spanned basic science, public health, and translational research. A panel of distinguished experts in various fields of biomedicine challenged the presenters to consider new ways of thinking about their experimental designs and their results. The sessions covered research questions of specific interest to Qatar and the Gulf States, among them understanding and counteracting the high rate of motor vehicle crashes, preventing and managing diabetes, and exploring the genetic features of particular Qatari populations. Presenters also highlighted the legal, social, cultural, and financial impediments to the successful establishment of a thriving biomedical research enterprise in Qatar. Given the opportunity to reflect on the state of research in Qatar through an electronic survey, attendees identified much needed modifications to Qatar research culture and infrastructure.
The general sessions, a blend of clinical presentations and basic research talks, dealt with medical and public health issues facing researchers beyond Qatar as well. In particular, the presentations focused on the basic science of cancer, translational cancer research, and translational research on other diseases. In addition, two special workshops focused, respectively, on diabetes research and on implementing a cancer research strategy.
Use the tabs above to find a meeting report and multimedia from this event.
Presentations available from:
Workshop 5: Diabetes from the Bench to the Bedside:
Nabeeha Kazi Hutchins, MIA, MPH (Humanitas Global Development)
Philippe Mourouga, MD (Sanofi)
Francesco Rubino, MD (Weill Cornell Medical College, New York)
Chris Triggle, PhD (Weill Cornell Medical College in Qatar)
Mahmoud Zirie, MD (Hamad Medical Corporation)
A report and multimedia presentations from the forum-wide sessions can be found in the Building a Knowledge-based Economy in Qatar eBriefing.
Reports on the individual research tracks can be found at:
Arts, Humanities, Social Sciences, and Islamic Studies Research eBriefing
Energy Research eBriefing
Computing Research eBriefing
Environmental Research eBriefing
Distinguished Research Award Sponsors
Scientific Publication Partner
- 00:011. Introduction
- 01:482. Difficulty translating model to different cultures
- 05:023. Long term follow-up of the A1C study
- 08:024. The importance of calcium channel in diabetes
- 10:265. Danger/awareness of diabetes
- 15:306. Is bariatric surgery creating a healthier individual?
- 20:417. Patient status after surgery
- 26:008. Skeptism of lifestyle changes
- 27:119. Has surgery been performed in non-obese individual
- 00:011. Introduction
- 0:302. Bench to bedside in diabetes
- 02:153. Puzzling diabetes together
- 03:204. Fundamental diabetes questions
- 05:205. The disconnect between scientists and physicians
- 06:156. Conventional weight loss intervention
- 07:307. The idea of diabetes surgery
- 10:108. Intervention halting/reversing the condition
- 15:249. First metabolic surgery in the world
- 18:2210. Understanding diabetes through surgery
- 20:5211. The diabetic big picture
- 22:0712. The incretins effect
- 26:0813. Focusing on an organ for the cause
- 27:0114. Beyond bench to bedsid
- 00:011. Introduction
- 0:402. Cardiovascular disease and diabetes
- 01:513. Endothelial dysfunction
- 04:154. The role of acetylcholine on damaged endothelium
- 07:165. Endothelial dysfunction due to high glucose
- 09:076. Diazoxide a Katp channel opener
- 14:207. Cell culture MMEC study
- 15:428. eNOS expression in MMEC
- 17:239. eNOS uncoupling
- 18:2510. Regulators of eNOS, SIRT2
- 20:2311. High glucose effect on SIRT1 level
Biomedical Research in and about Qatar
Ash GI, Scott RA, Deason M, et al. No association between ACE gene variation and endurance athlete status in Ethiopians. Med. Sci. Sports Exerc. 2011;43(4):590-597.
Cadenas AM, Zhivotovsky LA, Cavalli-Sforza LL, Underhill PA, Herrera RJ. Y-chromosome diversity characterizes the Gulf of Oman. Eur. J. Hum. Genet. 2008;16(3):374-386.
Rankinen T, Bray MS, Hagberg JM, et al. The human gene map for performance and health-related fitness phenotypes: the 2005 update. Med. Sci. Sports Exerc. 2006;38(11):1863-1888.
Voss S, Lüdke A, Romberg S, et al. Effects of high intensity exercise on isoelectric profiles and SDS-PAGE mobility of erythropoietin. Int. J. Sports Med. 2010;31(6):367-371.
West BA, Naumann RB. Motor vehicle-related deaths — United States, 2003–2007. MMWR Surveill. Summ. 2011;60 Suppl:52-55.
Yang N, MacArthur DG, Gulbin JP, et al. ACTN3 genotype is associated with human elite athletic performance. Am. J. Hum. Genet. 2003;73(3):627-631.
Basic Science of Cancer
Fitzgerald DW, Bezak K, Ocheretina O, et al. The effect of HIV and HPV coinfection on cervical COX-2 expression and systemic prostaglandin E2 levels. Cancer Prev. Res. (Phila.) 2012;5(1):34-40.
Malek JA, Mery E, Mahmoud YA, et al. Copy number variation analysis of matched ovarian primary tumors and peritoneal metastasis. PLoS ONE 2011;6(12):e28561.
Starzynska T, Rahi V, Stern PL. The expression of 5T4 antigen in colorectal and gastric carcinoma. Br. J. Cancer 1992;66(5):867-869.
Yang S, Zhang JJ, Huang X. Orai1 and STIM1 are critical for breast tumor cell migration and metastasis. Cancer Cell 2009;15(2):124-134.
Translational Cancer Research
Al-Bahlani S, Fraser M, Wong AYC, et al. P73 regulates cisplatin-induced apoptosis in ovarian cancer cells via a calcium/calpain-dependent mechanism. Oncogene 2011;30(41):4219-4230.
Aljarrah A, Nos C, Nasr R, et al. Updated follow-up of patients treated with the oncoplastic "Crescent" technique for breast cancer. Breast 2011.
Altucci L, Rossin A, Raffelsberger W, et al. Retinoic acid-induced apoptosis in leukemia cells is mediated by paracrine action of tumor-selective death ligand TRAIL. Nat. Med. 2001;7(6):680-686.
Goldman JM. Chronic myeloid leukemia: a historical perspective. Semin. Hematol. 2010;47(4):302-311.
Nasr R, El Hajj H, Kfoury Y, et al. Controversies in targeted therapy of adult T cell leukemia/lymphoma: ON target or OFF target effects? Viruses 2011;3(6):750-769.
Amsden BG, Misra G, Gu F, Younes HM. Synthesis and characterization of a photo-cross-linked biodegradable elastomer. Biomacromolecules 2004;5(6):2479-2486.
Grantham J, Cheung SS, Connes P, et al. Current knowledge on playing football in hot environments. Scand. J. Med. Sci. Sports 2010;20 Suppl 3:161-167.
Shaker MA, Doré JJE, Younes HM. Synthesis, characterization and cytocompatibility of a poly(diol-tricarballylate) visible light photo-cross-linked biodegradable elastomer. J. Biomater. Sci. Polym. Ed. 2010;21(4):507-528.
van Elden LJ, Nijhuis M, Schipper P, Schuurman R, van Loon AM. Simultaneous detection of influenza viruses A and B using real-time quantitative PCR. J. Clin. Microbiol. 2001;39(1):196-200.
Workshop 4: Developing a Qatar Cancer Research Strategy
Bener A, Ayub H, Kakil R, Ibrahim W. Patterns of cancer incidence among the population of Qatar: a worldwide comparative study. Asian Pac. J. Cancer Prev. 2008;9(1):19-24.
Sheikha Moza launches national cancer strategy. State of Qatar Supreme Council of Health website. 2010. Accessed January 2012.
Toumi H. Cancer is the third cause of deaths in Qatar: The disease is the third leading cause of mortality with 5,019 cases between 1999 and 2008. GulfNews.com, February 8, 2011. Accessed January 2012.
The Qatar National Cancer Society supports research into the causes, prevention, and treatment of cancer. It also focuses on providing information to the public and to healthcare practitioners about preventing, detecting, and treating cancer. Patient services, advocacy, and public policy are also parts of the Society's mission.
Workshop 5: Diabetes from the Bench to the Bedside
"The Qatar Diabetes Project is an in-depth study of the impact of diabetes on healthcare delivery in the state of Qatar. It evaluates risk factors, treatment patterns, and outcomes for people affected by the disease."
Ahn SM, Pomp A, Rubino F. Metabolic surgery for type 2 diabetes. Ann. N.Y. Acad. Sci. 2010;1212:E37-45.
Badii R, Bener A, Zirie M, et al. Lack of association between the Pro12Ala polymorphism of the PPAR-gamma 2 gene and type 2 diabetes mellitus in the Qatari consanguineous population. Acta. Diabetol. 2008;45(1):15-21.
Bener A, Zirie M, Janahi IM, et al. Prevalence of diagnosed and undiagnosed diabetes mellitus and its risk factors in a population-based study of Qatar. Diabetes Res. Clin. Pract. 2009;84(1):99-106.
Cohen RV, Rubino F, Schiavon C, Cummings DE. Diabetes remission without weight loss after duodenal bypass surgery. Surg. Obes. Relat. Dis. 2011.
Dixon JB, Zimmet P, Alberti KG, Rubino F. Bariatric surgery: an IDF statement for obese Type 2 diabetes. Arq. Bras. Endocrinol. Metabol. 2011;55(6):367-382.
Makino T, Shukla PJ, Rubino F, Milsom JW. The impact of obesity on perioperative outcomes after laparoscopic colorectal resection. Ann. Surg. 2012;255(2):228-236.
Triggle CR, Ding H. A review of endothelial dysfunction in diabetes: a focus on the contribution of a dysfunctional eNOS. J. Am. Soc. Hypertens. 2010;4(3):102-115.
Triggle CR, Ding H. The endothelium in compliance and resistance vessels. Front Biosci. (Schol. Ed.) 2011;3:730-744.
Xiaoliang C, Li Y, Hollenberg M, Triggle C, Ding H. The contribution of d-tubocurarine and apamin-sensitive K-channels to EDHF-mediated relaxation of mesenteric arteries from eNOS−/− mice. J. Cardiovasc. Pharmacol. 2012.
Biomedical Research Panelists
Lord Ara Darzi, KBE, PC, FMedSci, FREng
Rick Klausner, MD
The Column Group
Moncef Slaoui, PhD
Christopher A. Walsh, MD, PhD
Cancer Research Strategy Workshop Panelists
Lord Ara Darzi, KBE, PC, FMedSci, FREng
Robert Brown, PhD
Abdelali Haoudi, PhD
Diabetes Research Workshop Panelists
Philippe Mourouga, MD
Francesco Rubino, MD
Chris Triggle, PhD
Nabeeha Kazi Hutchins, MIA, MPH
Mahmoud Zirie, MD
Hamad Medical Corporation
Shafallah Medical Genetics Center, Doha
Weill Cornell Medical College in Qatar
Asma Al-Thani, PhD
Vasiliki Chini, PhD
Rafael Consunji, MD, MPH
Hamad Medical Corporation
Shankar Munusamy, PhD
Rihab Nasr, PhD
Ruben Peralta, MD, FACS
Arash Rafii, MD, PhD
Weill Cornell Medical College in Qatar
Husam Younes, PhD
Mariam Abdulaziz Al-Muftah, MRes, PhD
Paterson Institute for Cancer Research, University of Manchester, UK
Weill Cornell Medical College in Qatar
Weill Cornell Medical College in Qatar
Sara Hayder Ahmed
Sharon Begley is the senior health and science correspondent at Reuters, where she covers neuroscience, genetics, oncology, psychology, physics, cosmology, and other basic and clinical research. She was previously the science editor and the science columnist at Newsweek, from 2007 to April 2011, and the science columnist at The Wall Street Journal from 2002 to 2007. She is the author of the 2007 book Train Your Mind, Change Your Brain, the co-author of the 2002 book The Mind and the Brain, and the co-author (with Richard Davidson) of the 2012 book The Emotional Life of Your Brain. She is the recipient of numerous awards for her writing, including an honorary degree from the University of North Carolina for communicating science to the public, and the Public Understanding of Science Award from the San Francisco Exploratorium. She has spoken before many audiences on the topics of science writing, neuroplasticity, and science literacy, including at Yale University (her alma mater), the Society for Neuroscience, the American Association for the Advancement of Science, and the National Academy of Sciences.
From the biological pathways that allow ovarian cancer to start its deadly spread to whether heat affects cognitive performance—no small concern in a country where daily maximum temperatures top 100°F for 5 months a year—biomedical science in Qatar is nothing if not broad. It ranges from questions at the cutting edge of global research to those that are of specific interest to the desert country, such as which drivers are at greatest risk of dying in motor vehicle crashes, which cause an astonishing one in eight deaths in Qatar.
How and where the research is carried out is just as wide-ranging. The country's home-grown institutions conduct much of the work, of course. For the traffic fatality study, physicians at the Hamad General Hospital's trauma surgery unit analyzed data from the Qatar Statistics Authority, while research that developed a genetic predictive test using genetic markers associated with athletic ability and performance was done at the Shafallah Medical Genetics Center in Doha. Partner institutions in Education City (an enclave housing branch campuses of eight international universities) also carry out research, such as an analysis of epigenetic changes in response to the high-glucose environment that characterizes diabetes, which was done at Weill Cornell Medical College in Qatar. Finally, Qatari scientists studying at or collaborating with researchers at institutions abroad conduct a large number of projects. A study of renal function and obesity, for instance, was done by teams at Qatar University and at the University of Mississippi Medical Center in Jackson, Mississippi.
Biomedical research in Qatar has grown substantially, starting from virtually nothing. Qatar University began to offer science programs only in 1977, and Weill Cornell Medical College in Qatar was established in 2001. But research in Qatar faces numerous challenges. Would-be Qatari biomedical scientists generally go abroad for post-graduate training, which risks opening the spigots on a brain drain. According to Lord Darzi, a board member of the Supreme Council of Health in Qatar, another problem is the involvement of clinicians, who are extremely busy treating patients have little spare time to participate in the clinical research that moves basic biomedical discoveries from the laboratory bench to the patients' bedsides. Nevertheless, such research has begun, especially on questions specific to Qatar—such as identifying mutations that contribute to the mental retardation that afflicts one Qatari family.
Five sessions were devoted to biomedical research: three general ones, where the presentations ranged widely, and two workshops, one on cancer research and one on diabetes. The general sessions were evenly divided between clinical presentations and basic science talks, and fell into four camps: research focused specifically on Qatar, such as the quality of life of those who care for children with autism in the country; the basic science of cancer; translational research on cancer; and translational research on other diseases. Together, the sessions drew representatives from every biomedical institution in the country, offering an opportunity to ask those who know Qatar's research what they think of it.
At one workshop, organizers provided audience members with electronic clickers to respond to a 10-question poll about Qatari cancer science, with provocative results. Asked what is most lacking in the country's cancer research efforts, 11% of respondents said funding, 45% said people, 28% said infrastructure, and 15% said collaboration.
Rafael Consunji, Hamad Medical Corporation, Doha
Ruben Peralta, Hamad Medical Corporation, Doha
Vasiliki Chini, Shafallah Medical Genetics Center, Doha
Yasser Al-Serraj, Shafallah Medical Genetics Center, Doha
Yasmeen Salameh, Weill Cornell Medical College in Qatar
Sara Hayder Ahmed, Qatar University
Ladan Davallow, Weill Cornell Medical College in Qatar
- Motor vehicle crashes are a major cause of death for men in Qatar.
- Genetic studies on Qataris reveal a set of genetic variations that may be involved in determining athletic performance.
- An unusual form of inherited mental retardation appears to have an unexpected genetic basis.
- Qatari genetic and public health studies may also help illuminate the causes of diabetes and obesity.
Qatari biomedical research
With the possible exception of sports, no enterprise is more global than science, and much of the biomedical research Qatari scientists presented is squarely in the mainstream, with studies on cancer stem cells and epigenetics, to name just two hot fields. But several researchers have focused on questions where they can make a unique contribution: those that relate to medical and public health issues specific to Qatar.
Motor vehicle crashes are a leading cause of mortality in Qatar, said Rafael Consunji and Ruben Peralta, the authors from the Trauma Surgery Section of the Hamad General Hospital: such crashes are responsible for 1 in 8 deaths (12.5%), compared to about 1 in 53 (1.89%) in the United States, and are the leading cause of death among people aged 5 to 29. Reducing that toll—between 300 and 347 motor-vehicle fatalities every year—requires knowing which populations are at greatest risk. Using data from the Qatar Statistics Authority, the authors calculated that men (who make up 75% of the population, largely because expatriate workers are overwhelmingly male) constitute 96% of the victims. Half of all deaths among men aged 10 to 19 are due to motor vehicle crashes, as are 3 of 4 deaths among men 20 to 29 years old. Qatari men between the ages of 20 and 29 are 7 times more likely to die in a car crash than are members of the general population; those 5 to 39 years old have more than double the risk. That discrepancy suggests that public health interventions should target this demographic group.
The interindividual variation of sport- and exercise-related traits has a strong genetic basis. To that end, scientists led by Vasiliki Chini of the Shafallah Medical Genetics Center asked whether genetic variants might predict superior athletic performance. Researchers have long known that mutations in the erythropoietin (EPOR) gene affect the blood's oxygen-carrying capacity, while variations in the ACTN3 gene, which codes for muscle fibers that provide power, are associated with excellence in endurance sports such as long-distance running. Chini's team has developed a test using 31 single nucleotide variations, or SNPs, in 24 genes reported in the literature to play a role in athletic ability and performance, such as endurance capacity, susceptibility to injury, and muscle activity. The 31-SNP panel, says Chini, can offer guidance to athletes, to improve their performance and to avoid injuries, by modifying their training program and could also be used to test "young promising athletes" to help them choose a sport in which they are most likely to excel. However, the test does not measure the variance in an athletics-related trait comes from these SNPs but offers recommendations for the athletes training according to their genetic profile.
In another genetic study of Qataris, scientists led by Yasser Al-Serraj of Shafallah Medical Genetics Center analyzed a family that includes six people with mental retardation, retinal degeneration, atrophy of the optic nerve, and an unsteady, uncoordinated walk called ataxic gait. Through whole-genome genotyping, the scientists identified a region on chromosome four that probably contains the responsible gene. It contains about 100 genes, none of which have previously been linked to the symptoms shown by the affected individuals. The researchers are now sequencing candidate genes within the region, with the goal of understanding how they might contribute to mental retardation and other aspects of the syndrome. Yasmeen Salameh and colleagues at Weill Cornell Medical College in Qatar took a slightly different tack to understanding the genetic component of a disease that is rampant in Qatar: diabetes. Genome-wide association studies (GWAS) have associated SNPs with only a small part of the risk of diabetes, but the disease is believed to have a larger genetic component than can be accounted for by the SNPs. Salameh's team therefore investigated epigenetic changes in a high-glucose environment, finding "a number of up- or down-regulated genes" in cell lines, including genes involved in cardiac hypertrophy and a calcium signaling pathway.
Two student presentations also focused on questions specific to Qatar. Sara Hayder Ahmed of Qatar University and her colleagues studied how caring for a child with autism affects the quality of life of caregivers. Using a validated questionnaire (the SF-36) they compared 56 parents and caregivers of children with autism with 42 caregivers of typically-growing children, and found that those in the first group were more likely to rate their general health as poor or likely to get worse, and reported poorer mental health than physical health. These findings, said Hayder, should help policy makers devise support programs for those families caring for autistic children.
Ladan Davallow of Weill Cornell Medical College in Qatar examined the local expression of a global problem: childhood obesity. Based on weight and height measurements of 480 4th graders, of 1,333 8th graders, and of 11th graders, the scientists found that the prevalence of obesity was 23% among 4th graders, 22% among 8th graders, and 17.5% among 11th graders—in each case, higher than the 17% in the U.S. among children aged 2 to 19. Although the prevalence of obesity among 8th grade boys and girls was about equal, 4th grade boys were 70% and 11th grade boys were 160% more likely to be obese than girls of the same grade levels.
Arash Rafii, Weill Cornell Medical College in Qatar
Rashmi Kulkarni, Weill Cornell Medical College in Qatar
Mariam Abdulaziz Al-Muftah, Paterson Institute for Cancer Research, University of Manchester, UK
- Ovarian cancer treatment has made almost no improvement in the past 30 years.
- Therapies that target the cell division regulating protein STIM1 might be able to stop tumor cells from proliferating.
- Genetically modified immune cells can identify and destroy cultured tumor cells, and could form the basis of a new treatment strategy.
The basic science of cancer
Two facts indicate how poorly the world is doing when it comes to curing ovarian cancer: it is the seventh most common malignancy in women globally, but the fourth leading killer. As Arash Rafii of Weill Cornell Medical College in Qatar explained, that apparent paradox reflects both the complexity of the disease, which has several subtypes and so might properly be classified as more than one cancer, and the tendency of its early stages to be asymptomatic. As a result, most cases of ovarian cancer are diagnosed late, when the disease is difficult to treat. Only 20% to 30% of patients are alive 5 years after diagnosis. Most sobering, Rafii adds, is that "there has been almost no improvement in survival in the last 30 years."
Rafii's research presentation was one of several on the basic biology of cancer. His research focuses not on the primary tumor, which can usually be surgically removed, but on metastatic disease in the peritoneum—specifically, what genetic changes in the malignant ovarian cells allow them to leave the ovary and travel to distant sites. In a pilot study he found that both the primary tumor and the metastases undergo numerous genetic changes. But, with few exceptions, the 2,300 DNA amplifications or deletions in the metastatic cells "were different than in the primary tumor," said Rafii. That finding raises a crucial question: if standard chemotherapy targets proliferation pathways such as those driven by activation of the Akt protein signaling pathway, "can we use Akt inhibition when the metastasis does not have the same driver mutation? What would be the point of a targeted therapy" if it targets the driver of the primary tumor and not of the metastasis? This mismatch shows how crucial it is to identify driver mutations in both the primary cancer and the metastatic site. Said Rafii, "There is no real genetic driver [common to both], so having one [molecular target] is not the way to go." Moreover, different patients have very different mutation patterns, suggesting that therapy will have to be personalized.
One trait that primary tumors often share with metastases is the increased function of a protein called STIM1, or stromal interaction molecule 1. STIM1 aggregates in the cell's endoplasmic reticulum in non-dividing cells but disaggregates during cell division and proliferation. Because STIM1 is involved in calcium influx when a cell's calcium stores are depleted, explained Rashmi Kulkarni of Weill Cornell Medical College in Qatar, the lack of STIM1 aggregation during cell division inhibits calcium influx during these phases of the cell cycle. That raises a question: could targeting STIM1 so that it does aggregate and does allow calcium influx impede cell division and thus stop the uncontrolled cell proliferation that characterizes cancer? The research has just begun, but so far Kulkarni has identified 10 proteins involved in STIM1 aggregation when a cell's calcium stores are depleted. The researchers are now trying to define the mechanistic regulation of the inability of STIM1 to aggregate during cell division, and the implications on cell proliferation.
One of the most exciting approaches to treating cancer is to harness the immune system, inciting T cells to attack malignancies by recognizing them as foreign. Immunotherapy has stumbled many times before, however, underlining the need for more basic science research before it can be widely deployed clinically. To that end, Mariam Abdulaziz Al-Muftah of the Paterson Institute of Cancer Research at the University of Manchester, in work funded by Qatar University, is attempting to genetically modify T cells so they carry receptors to an antigen called 5T4, which is found on breast, gastric, colorectal, and other cancer cells. That modification should cause T cells to dock with the antigen, unleashing the immune-system cascade that culminates in destruction of the tumor cells by killer T cells. "Our goal is to harness the power of the immune system to target tumors," she said. In previous research, she had shown that human and mouse T cells engineered to express human 5T4-specific receptors do, as predicted, hone in on cancer cells expressing that antigen and destroy them, at least in tissue culture. In the new work, which won the Forum's award for best student research in biomedicine, Al-Muftah has isolated T cells from cancer patients and infected them with a virus carrying a gene for the antigen receptor, and is now testing whether these cells are effective against 5T4-carrying tumors in mice.
Rihab Nasr, American University of Beirut and Hamad Medical Corporation
Nawaf Al-Taweel, Weill Cornell Medical College in Qatar
Ahmed Alsaei, Weill Cornell Medical College in Qatar
- Combined treatment with interferon and arsenic might augment the efficacy of current therapies for chronic myelogenous leukemia.
- Retinoic acid and the TRAIL protein may work synergistically to kill some types of tumor cells.
- Combining cisplatin with drugs that target calcium channels could help overcome cisplatin-resistance in tumors.
Translational cancer research
One of the few great successes in cancer treatment has been the development of Gleevec (imatinib), which has become the standard therapy for chronic myelogenous leukemia (CML). Most CML, which is driven by a translocation of chromosomes 9 and 22 that results in a fusion gene called BCR/ABL, eventually becomes resistant to Gleevec, however, as the drug's target undergoes a mutation. Rihab Nasr, of American University of Beirut, and her colleagues are therefore investigating a new therapeutic approach: a combination of interferon alpha and arsenic trioxide. The rationale for the combination therapy is that patients who receive interferon before Gleevec remain in remission longer and can often discontinue Gleevec, while arsenic inhibits cellular proliferation driven by the BCR/ABL fusion gene.
Studies in cultured cells have yielded promising results. A combination of arsenic and interferon "inhibits the proliferation of many CML lines," said Nasr. Intriguingly, the one-two punch had no significant effect on the activity of the bcr/abl fusion protein, Gleevec's target. Instead, the drug combination seemed to increase apoptosis, the programmed death, of malignant cells. In addition, in a mouse model of CML the interferon-arsenic combination prolonged survival, with blood counts returning to normal levels and with the infiltration of leukemic cells into the spleen, liver, and lungs decreasing. In addition, CML mice that received spleen cells from CML mice treated with arsenic and interferon showed prolonged survival compared to controls. That outcome suggests, said Nasr, that the drugs might target cancer stem cells, perhaps by causing them to enter the cell cycle and to become more sensitive to treatment. Either way, since arsenic/interferon has a mechanism of action in CML that is different from Gleevec's, it holds the promise of being an adjunct or second-line therapy when a patient becomes resistant to that drug. Nasr's work won the Annual Research Forum's award for best biomedical research program.
In another project investigating the synergistic effects of cancer therapies, scientists led by Ahmed Alsaei of Weill Cornell Medical College in Qatar focused on retinoic acid (RA), which can both arrest cellular proliferation and cause various kinds of stem cells to differentiate, and TRAIL, or TNF-related apoptosis inducing ligand, a transmembrane protein that triggers programmed cell death. The reason the two agents might act synergistically, explained Alsaei, is that retinoic acid acts through TRAIL, increasing the expression of true TRAIL receptors and decreasing expression of decoy receptors, to cause colorectal cancer cells to undergo apoptosis. "RA makes cancer cells more vulnerable to TRAIL by decreasing decoy receptors that [impede] apoptosis," said Alsaei. The synergy appears to vary, though. Retinoic acid plus TRAIL decreased proliferation in one cell line from a human head and neck squamous cell carcinoma, but not in two other cell lines.
Like Gleevec, cisplatin is also an effective cancer drug, but there the resemblance ends. If Gleevec is a smart bomb, specifically targeting a genetic change that drives proliferation, cisplatin is a carpet-bombing campaign, attacking DNA in both healthy and malignant cells. But just as CML can develop resistance to Gleevec, solid tumors can become resistant to cisplatin. Looking for ways to overcome that resistance, Nawaf Al-Taweel of Weill Cornell Medical College in Qatar is investigating other mechanisms by which cisplatin kills cancer cells. Al-Taweel and his colleagues have focused on cisplatin's effect on intracellular calcium; elevated levels of calcium ions can lead to cell death by apoptosis. The researchers found that in cultured breast cancer cells, cisplatin raised intracellular calcium by as much as 120%, but the increase was significantly smaller in cisplatin-resistant cancer cells and in cells pre-treated with a calcium-channel blocker. That was expected. Surprisingly, however, that cytotoxic calcium elevation was also hindered in cells exposed to other calcium modulators such as caffeine and ionomycin, an antibiotic that works through calcium channels, both of which also raise intracellular calcium. If one mechanism of cisplatin resistance involves disruption of intracellular calcium, suggested Al-Taweel, combining the chemotherapy with calcium-channel modulators in a way that allows cisplatin to raise intracellular calcium as much as possible might help overcome that resistance.
Asma Al-Thani, Qatar University
Husam Younes, Qatar University
Shankar Munusamy, Qatar University
- A new PCR-based test provides quicker, more accurate diagnosis of respiratory virus infections.
- Packaging interleukin-2 in an elastomeric matrix allows the drug to survive harsh conditions during transportation and storage.
- Hypertension is the major link between obesity and kidney failure.
- High temperatures appear to interfere with rational decision making.
Translational research in Qatar
Viral respiratory infection is a leading cause of death among patients with bronchial asthma and chronic obstructive pulmonary disease (COPD), especially among the elderly and usually in wintertime. Early diagnosis is crucial to identifying which drugs might be effective against the disease, but that's complicated by the existence of numerous viruses that can cause respiratory illnesses. Scientists led by Asma Al-Thani of Qatar University therefore investigated whether polymerase chain reaction (PCR) using primers corresponding to known virus signatures could identify any of 15 viruses responsible for a respiratory infection. The team collected nasal swab samples from 190 asthma patients and 10 COPD patients treated at a chest clinic during the winter of 2008–9. Only 36 patients, 31 with asthma and 5 with COPD, had viral infections. Among those in the former category, the most common infection was a rhinovirus; among those in the latter, the most common was a coronavirus. PCR was able to identify more viruses simultaneously than immunofluorescent assays, the standard diagnostic method. A quicker, more accurate diagnosis should allow appropriate treatment to begin immediately and, just as importantly, spare patients who do not have viral infections—the majority—from ineffective treatment.
Sometimes a drug itself is extremely effective but is stymied by the difficulty of delivering it to a patient. Such is the case with interleukin-2, which is effective against asthma, some cancers, and other diseases. The problem, explained Husam Younes of Qatar University, is that heating interleukin-2 above 44°C renders it inactive, and exposing the drug to various inorganic compounds causes it to degrade. Younes and his colleagues are therefore developing a biodegradable device composed of elastomers (elastic polymers) that can release interleukin-2 through osmosis. In pilot tests, the drug has retained 95% of its activity over 30 days, compared to the 40% to 50% activity level achieved with current technology, suggesting that the new elastomeric drug delivery system "is a promising advance," said Younes.
There are many reasons to avoid obesity, including that it is associated with comorbidities of kidney failure and stroke. Obesity has been linked to kidney failure through several mechanisms: hypertension, diabetes, and "lipotoxicity," in which an accumulation of lipids in the kidney increases oxidative stress or impairs mitochondrial and endoplasmic reticulum function. Might these problems occur absent hypertension? To find out, scientists led by Shankar Munusamy of Qatar University measured renal function in two mouse models of obesity, with or without hypertension. Based on measurements of albumin secretion, renal triglycerides, ATP levels, oxidative stress, and other indicators of renal function, said Manumasy, "in the absence of high blood pressure there is not much renal injury, so if you have an obese patient it's very important to control blood pressure" and thus preserve kidney function.
From May to September, the average high temperature in Qatar is above 100°F (38°C), which made Nadia Gaoua of the Qatar Orthopaedic and Sports Medicine Hospital wonder: does heat affect cognitive performance? If so, does impaired cognition affect athletic performance? The latter question is particularly relevant because Qatar will host the World Cup in 2022, and the mean temperature during the games is expected to hover around 40°C. Physiological effects do not explain all the decrease in performance that occurs during heat waves, she said; that suggests that other ingredients of athletic success, such as decision making, attention, visual search, memory, and executive functions such as planning and anticipation, might be impaired when the mercury soars. She therefore recruited 16 subjects to undergo cognitive tests at 20°C and 50°C, for between 15 minutes and 4.5 hours. The heat had no effect on attention, she found. But impulsivity rose with temperature, and performance on both short-term memory and complex cognitive tasks declined. That decline could cause a soccer player to take longer to make a decision on the field, she said: "do I shoot or pass?", or could cause him to follow his impulses rather than judge the situation more analytically. She suspects that by raising core and skin temperatures, the heat affects subjects' emotional states, leaving people "with fewer [mental] resources for the task, which matters when you need all of your cognitive capacity." Heat also affected brain activity directly: EEG measurements showed that theta activity increased as cognitive tasks became more complex, and also as the temperatures rose. In sweltering conditions, said Gaoua, the brain "eventually becomes overwhelmed."
Lord Ara Darzi, Imperial College London
Professor Robert Brown, Imperial College London
Dr. Abdelali Haoudi, Qatar Foundation
- Qatar's nascent cancer research enterprise is uniquely positioned to focus on personalized therapies.
- Translational studies are crucial for developing the next generation of cancer treatments.
- Ovarian cancer may actually be a family of diseases, rather than a single diagnosis.
- Qatar hopes to implement a comprehensive cancer research strategy in 2012.
Qatar cancer research strategy
Out of an annual biomedical and health research budget of $89.6 million, the Qatar National Research Fund currently spends $19.5 million on cancer research, or about what it costs to run a single, small research department in the United Kingdom, said Lord Ara Darzi, a board member of the Supreme Council of Health in Qatar and chair of the workshop. "We need significantly more cancer-specific funding," he said.
That may sound like the perennial cry of every scientist in every country who depends on outside financial support for his or her research. Qatar, however, has an opportunity to get the most from whatever financial support it gives cancer research. In particular, it has the opportunity to focus immediately on personalized cancer medicine, matching therapies to the specific genetic or other changes driving a particular patient's cancer, rather than going through the one-size-fits-all phase that has characterized cancer research and care in the West since the advent of chemotherapy in 1940. Qatar also has the opportunity to emphasize prevention as much as, or more than, treatment. "Qatar [cancer] research will prioritize reforms in primary care," said Darzi, with an "emphasis on awareness, prevention, [and] early detection." The aim, he continued, is "better prevention, research to identify targets to allow the development of improved diagnostics, early diagnosis ... and experimental therapies, all leading to personalized medicine."
Qatar also has an opportunity to avoid what some researchers see as one of the costliest mistakes 20th century Western biomedical research has made: emphasizing basic science to the exclusion of translational science, which turns those fundamental discoveries into drugs and other treatments that make an immediate difference to patients. There are numerous reasons for that "translational gap," including a reward system in academic medicine that some feel encourages basic science over translational research. "Translational research takes basic research and turns it into patient benefits," said Professor Robert Brown, Chair in Translational Oncology in the Department of Surgery and Oncology at Imperial College, a member of the panel at the cancer workshop. For instance, research on ovarian cancer, a disease that has a 5-year survival rate of a dismal 30%, compared to 80% for breast cancer, suggests that the disease is actually 5 different ones. And, not all of these five diseases necessarily arise from ovarian surface epithelial cells as long thought: some forms might originate in the fallopian tubes. By identifying the biochemical and genetic biomarkers that characterize each of the five, it might be possible to match each one uniquely with an effective therapy, rather than treating all ovarian cancers the same, as is now standard practice.
When it comes to translational research, Qatar has the opportunity to make translational studies as central to its cancer research strategy as basic science is. Lord Darzi suggested that Qataris had already learned that lesson. The national cancer research strategy "should lead to the translation of discoveries into clinical advances to improve care," he said, calling on the Qatar Foundation to host a program on translational research in cancer.
The Qatar Foundation as well as the government are in the process of identifying the country's strengths and weaknesses in cancer research, determining major areas of unmet need, figuring out how research can contribute to an improvement in patient survival, and pinpointing barriers to research—all with the goal of implementing a research strategy based on those findings in 2012. Some weaknesses are already apparent. "There are a number of items that are of great concern," said Abdelali Haoudi, vice-president for research at the Qatar Foundation. "We have great clinical institutions," such as the Hamad Medical Corporation, but clinical trials, a crucial component in translational research, cannot begin in Qatar "without a legal and regulatory framework" that protects patients. Scientists, physicians, patients, and the larger public will have to become involved in pushing for that kind of change. "Only through your engagement," he said, "can this cancer research strategy be realized."
Mahmoud Zirie, Hamad Medical Corporation
Francesco Rubino, Weill Cornell Medical College, New York
Chris Triggle, Weill Cornell Medical College in Qatar
Philippe Mourouga, Sanofi
Nabeeha Kazi Hutchins, Humanitas Global Development
- Diabetes is a major public health problem for Qatar.
- Gastric bypass surgery seems to change patients' metabolisms independently of the weight loss it triggers.
- Treatments that target the vascular endothelium could be useful adjuncts to current diabetes therapies.
- Disease management teams that include the patient's family and friends may help improve treatment compliance.
Diabetes from bench to bedside
The Persian Gulf is facing a diabetes epidemic: 5 of the top 10 countries in the world in terms of the disease's prevalence are gulf states, including Qatar, said Mahmoud Zirie, head of the endocrinology department at Hamad Medical Corporation. Hamad manages four of the country's hospitals: Hamad General Hospital, Rumailah Hospital, Women's Hospital, and Psychiatric Hospital, as well as primary care centers. In Qatar, the prevalence of diabetes is about 15 to 20 per 100 residents, compared to 5 per 100 in the West. Worse, the disease is not being managed well. "Of our outpatients," said Zirie, about 37% have diabetic retinopathy, 27% have kidney failure, 18% have cardiovascular complications, and 10% have such poor circulation to their feet that their walking is impaired and that they are at risk for amputation.
The diabetes workshop focused on two promising avenues to corral the epidemic: new medical treatments, but also better application of existing knowledge through disease-management programs and patient education.
One revolutionary new treatment was inspired by the decades-old observation that diabetes could be cured through surgery for peptic ulcers, and the recent discovery that bariatric surgery not only brings about weight loss but also reduces hyperlipidemia, sleep apnea, and diabetes. Speaking by video conference, Francesco Rubino, chief of gastrointestinal metabolic surgery at Weill Cornell Medical College in New York said that patients have been able to safely stop taking medications for diabetes, hypertension, and glucose control as soon as two weeks after gastric bypass surgery. That's too soon for a patient to experience significant weight loss from gastric bypass, said Rubino. That result, plus experiments in lab animals, suggests that "the surgery works not by weight loss alone but by changing the metabolic situation." That is, the effect of gastric bypass on diabetes is not entirely explained by weight loss but instead results from the surgery itself. Because the gastrointestinal tract serves as an endocrine organ and a key player in the regulation of insulin secretion, body weight and appetite, altering it through surgery, perhaps by changing gut microbiota, has profound metabolic effects. Rubino is currently leading a study intended to shed light on how these metabolic changes occur.
Another potential new treatment targets the endothelium, the thin layer of cells that lines the inside of arteries and other blood vessels. That may seem far removed from diabetes, which is characterized by either too little insulin production from the pancreas or insensitivity to that insulin on the part of cells. Either problem raises the level of blood glucose, as insulin's function is to move glucose into cells that use it for metabolism. But as Chris Triggle, professor of pharmacology at Weill Cornell Medical College in Qatar explained, elevated glucose results in glucose toxicity and can impair endothelial function, damage the blood vessels, and cause vasoconstriction. Endothelial dysfunction and vasoconstriction in turn reduces blood flow, which can trigger the vascular complications that often mark diabetes. He and his team are investigating agents that might prevent glucose toxicity.
Better treatments for diabetes are about more than new drugs, argued Philippe Mourouga, senior director for the Intercontinental Region for Sanofi. "If you give only drugs and not support," he said, "you will not move from efficacy [the theoretical benefits of a medication] to effectiveness [the real-world benefits]." He advocated the creation of disease-management teams composed of specialists, internists, family members, and friends to coordinate care and to foster self-care, including behavioral modification and self-monitoring by the patient. Such programs can bring cost savings as well as better diabetes management. Meanwhile, Nabeeha Kazi, managing director at Humanitas Global Development, advocates bringing what she called "unconventional voices" into managing chronic disease to make health initiatives stick. Such voices include private initiatives, government agencies, and beneficiaries working together to formulate and implement a research agenda. All of that is eminently possible, she said: "The stars are aligned for Qatar."