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Wednesday, February 14, 2007

***UPDATE***Letters from Salman and Ramzan Khetani

Salman is Faisal's brother and Ramzan is his father. Please read and respond.

Hello Resa,

My name is Salman Khetani and I am Faisal Khetani's brother. I was told by my father that you had inquired about the nature of my research, its scope and implications for the society at large. I have decided to respond to you because I want you and your readers to know about the types of opportunities I have been given in the US and the steps I have taken to reciprocate. My family and I immigrated to the US over a decade and a half ago in search of better professional and academic opportunities. We wanted to better ourselves through education and become productive members of society. I personally wanted to get the best education I could get and realize my vision of becoming a leader in science and engineering. Even in adolescence, I realized that I had the innate talent and drive to contribute to this world and improve the lives of people through my professional endeavors.

When I first started high school in the US, I had some difficulties with the transition, especially in terms of a slight language barrier (I knew how to read and write English, but didn't speak it very often before coming to the US). My parents, peers and wonderful teachers coached me through my transition period. They encouraged me and assured me that with hard work and struggle, I could overcome some of my initial problems. I was never discriminated against for my accent or darker color. In fact, I was well respected by most people I came into contact with at my high school and in the general community. I will always remember my mentors (teachers, soccer and tennis coaches, peers) in high school as they were my first impression of the graciousness of the American people. I assimilated well into the American society, made many friends, had an active social network, did decent amount of volunteer work to give back to the community and after 3 years, graduated as Valedictorian of my high school with a 4.0/4.0 GPA.

I received a scholarship to go to college where I pursued two Bachelor of Science degrees in Electrical Engineering and Biomedical Engineering. Once again, I had a wonderful experience. Not only did I learn the state-of-the-art in Engineering and Science, I used my skills to contribute to neighborhood organizations that served educational and other important needs of underprivileged youth and adults. In college, I had amazing professors as mentors, who instilled in me the value that with hard work, perseverance and a vision for the future, I could become a highly skilled and productive member of society, one who tries to improve the health and lives of people. They saw core talent in me from early on, talent that even I did not know existed. I also did substantial internships in industrial settings while I was in College and there too, I met the most brilliant, but incredibly generous people. Thanks to the financial generosity of my parents, mentorship of professors in school and coworkers in industry, support of peers, and my own hard work, I graduated college with two degrees and a 4.0/4.0 GPA.

Due to my high academic performance in college, I was awarded a National Science Foundation graduate fellowship to pursue doctorate work in Biomedical Engineering, which is also referred to as Bioengineering. I successfully defended and received my PhD in 2006. My research has focused on developing sophisticated laboratory models of liver tissues using liver cells from mostly animals and in some instances from brain-dead individuals (who have donated their organs for research). The overarching goal of my work is to use these body-like laboratory models for a variety of applications, including a) cell-based therapies for liver disease (i.e. bio-artificial liver devices that can keep a patient alive while they await a whole organ transplant), b) to investigate liver physiology and elucidate underlying mechanisms, and c) use in discovery and development of pharmaceuticals for detecting potentially problematic and toxic compounds before they reach patients. As you may know, many drugs reach the market and get withdrawn due to unforeseen toxicity to the liver or other organs in otherwise perfectly healthy individuals. Thus, the goal of my research is to make sure that such tragedies don't happen and that laboratory models using live cells from either animals or organ donors can predict problems much earlier in the drug development cycle. Therefore, as you can see, my research is aimed at helping society and not harming it. My work has been published in both scholarly journals and in lay press. I have included links and abstracts of these articles for your review below. All of these are available at www.pubmed.org which is a national archiving service. I hope that someday my work will be adopted by the pharmaceutical industry to make cheaper and above all, safer drugs for patients. Though I didn't comment explicitly on the amazing mentorship I received during graduate school, I wanted to just comment that getting a PhD is intimately tied to great mentorship and a great cohort of colleagues. I too had the great fortune to benefit from these aspects. In fact, nothing I accomplished in graduate school was in isolation. It was due to extensive technical help and scholarly advice from my supervisor and my colleagues. In spite of being involved in research over the last 6 years, I have only begun to realize my vision for the future. I plan to continue to use my engineering and biology skills sets to do cutting edge research and make important discoveries in a variety of different arenas in both academic and industrial settings.

I hope the narrative above provides you with some indication of the type of life I have lived so far and what my vision for the future is. I would like to reiterate to you that I want to help America and the World at large with my skills and research. I sincerely hope that I will continue to get opportunities which will allow me to accomplish my goals. For over a decade and half, I have had great experiences both academically and in the larger communities of the several states I have lived in. I love America, the diversity of cultures and religions here, and the generosity of the people. I learn from this diversity each and every day and I believe that I do my best to contribute with what I have. I understand that you wanted to probe deeper into what I do and if I was engaged in any so-called 'double work'. I would like to assure you that my family and I are humble, peace-loving and productive members of society. Regardless of our religion, we want nothing but the best for the US, of which we have been citizens of for almost a decade now.



Sincerely,



Salman R Khetani



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http://www.technologyreview.com/Biotech/16462/



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In Vitro Liver Tissue Model Established from Transgenic Mice: Role of HIF1alpha on Hypoxic Gene Expression.



Allen JW, Khetani SR, Johnson RS, Bhatia SN.



Department of Bioengineering, University of California at San Diego, La Jolla, California., Current affiliation: David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California.



The instability of the hepatocyte phenotype in vitro has limited the ability to quantitatively investigate regulation of stress responses of the liver. Here, we adopt a tissue-engineering approach to form stable liver tissue in vitro by forming collagen "sandwich" cultures of transgenic murine hepatocytes harboring a regulatory gene of interest flanked by loxP sites. The floxed gene is excised in a subset of cultures by transfection with adenovirus carrying the gene for Cre-recombinase, thereby generating wild-type and null liver tissues from a single animal. In this study, we specifically investigated the role of hypoxia inducible factor 1 alpha (HIF-1alpha) in the hepatocellular response to hypoxia. Using high-density oligonucleotide arrays, we examined genome-wide gene expression after 8 h of hypoxia in wild-type and HIF- 1alpha null hepatocyte cultures. We identified more than 130 genes differentially expressed under hypoxia involved in metabolic adaptation, angiogenic signaling, immediate early response, and cell cycle regulation. Real-time polymerase chain reaction analysis verified that known hypoxia-responsive genes such as glucose transporter-1 and vascular endothelial growth factor were induced in a HIF-1alpha-dependent manner under hypoxia. Our results demonstrate the potential to integrate in vitro tissue models with transgenic and microarray technologies for the study of physiologic stress responses.



PMID: 17020444 [PubMed - as supplied by publisher]



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Curr Opin Biotechnol. 2006 Oct;17(5):524-31. Epub 2006 Sep 15. Related Articles, Links



Engineering tissues for in vitro applications.



Khetani SR, Bhatia SN.



Harvard MIT Division of Health Sciences and Technology/Electrical Engineering and Computer Science, Massachusetts Institute of Technology, 77 Massachusetts Avenue, E19-502D, Cambridge, MA 02139, USA.



Engineered tissues can be employed for studies on the fundamental mechanisms of embryology and adult physiology and for investigating the evolution of disease processes. They also provide platforms to evaluate the behavior of new chemical entities in drug development. The recent development of three specific technologies has greatly facilitated the engineering of tissues for in vitro applications: the microfabrication tools that serve to both define the cellular microenvironment and enable parallelization of cell-based assays; synthetic, tunable hydrogels to create three-dimensional microenvironments; and bioreactors to control nutrient transport and fluid shear stress. Furthermore, convergence of these tools is providing investigators with the opportunity to construct and study tissues in vitro with unprecedented levels of sophistication.



Publication Types:

Research Support, N.I.H., Extramural

Research Support, Non-U.S. Gov't

Research Support, U.S. Gov't, Non-P.H.S.

Review



PMID: 16978857 [PubMed - indexed for MEDLINE]



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Toxicol Sci. 2005 Mar;84(1):110-9. Epub 2004 Dec 8. Related Articles, Links



In vitro zonation and toxicity in a hepatocyte bioreactor.



Allen JW, Khetani SR, Bhatia SN.



Department of Bioengineering and Medicine, University of California at San Diego, La Jolla, California 92093-0412, USA.



The complex architecture of the liver is intertwined with its response to xenobiotic compounds. In particular, hepatocyte subpopulations are distributed along the sinusoid in zones 1 to 3, leading to prototypical "periportal" and "centrilobular" patterns of cell death in response to a toxic insult. In vitro models that more closely represent these zones of sub-specialization may therefore be valuable for the investigation of hepatic physiology and pathophysiology. We have established a perfused hepatocyte bioreactor that imposes physiologic oxygen gradients on co-cultures of rat hepatocytes and non-parenchymal cells, thereby producing an in vitro model of zonation. In order to predict and control oxygen gradients, oxygen transport in a parallel-plate bioreactor containing co-cultures was first mathematically modeled and experimentally validated. Co-cultures exposed to these physiologic oxygen gradients demonstrated regionally heterogeneity of CYP2B and CYP3A protein that mimics the distribution seen in the zonated liver. The distribution of CYP expression in the bioreactor was shown to vary with exposure to different chemical inducers and growth factors, providing a potential platform to study physiologic zonal responses. In order to explore zonal hepatotoxicity, bioreactors were perfused with APAP (acetominophen) for 24 h, resulting in maximal cell death at the low-oxygen outlet region similar to centrilobular necrotic patterns observed in vivo. This hepatocyte bioreactor system enables further in vitro investigation into zonation-dependent phenomena involving drug metabolism and toxicity.



Publication Types:

In Vitro

Research Support, N.I.H., Extramural

Research Support, Non-U.S. Gov't

Research Support, U.S. Gov't, P.H.S.



PMID: 15590888 [PubMed - indexed for MEDLINE]



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Hepatology. 2004 Sep;40(3):545-54. Related Articles, Links



Exploring interactions between rat hepatocytes and nonparenchymal cells using gene expression profiling.



Khetani SR, Szulgit G, Del Rio JA, Barlow C, Bhatia SN.



Department of Bioengineering at the University of California-San Diego, La Jolla, CA 92093-0412, USA.



Cocultivation of primary hepatocytes with a plethora of nonparenchymal cells (from within and outside the liver) has been shown to support hepatic functions in vitro. Despite significant investigation into this phenomenon, the molecular mechanism underlying epithelial-nonparenchymal interactions in hepatocyte cocultures remains poorly understood. In this study, we present a functional genomic approach utilizing gene expression profiling to isolate molecular mediators potentially involved in induction of liver-specific functions by nonparenchymal cells. Specifically, primary rat hepatocytes were cocultivated with closely related murine fibroblast cell types (3T3-J2, NIH-3T3, mouse embryonic fibroblasts) to allow their classification as "high," "medium," or "low" inducers of hepatic functions. These functional responses were correlated with fibroblast gene expression profiles obtained using Affymetrix GeneChips. Microarray data analysis provided us with 17 functionally characterized candidate genes in the cell communication category (cell surface, extracellular matrix, secreted factors) that may be involved in induction of hepatic functions. Further analysis using various databases (i.e., PubMed, GenBank) facilitated prioritization of the candidates for functional characterization. We experimentally validated the potential role of two candidates in our coculture model. The cell surface protein, neural cadherin (N-cadherin), was localized to hepatocyte-fibroblast junctions, while adsorbed decorin up-regulated hepatic functions in pure cultures as well as cocultures with low-inducing fibroblasts. In the future, identifying mediators of hepatocyte differentiation may have implications for both fundamental hepatology and cell-based therapies (e.g., bioartificial liver devices). In conclusion, the functional genomic approach presented in this study may be utilized to investigate mechanisms of cell-cell interaction in a variety of tissues and disease states. Copyright 2004 American Association for the Study of Liver Diseases



Publication Types:

Research Support, U.S. Gov't, Non-P.H.S.

Research Support, U.S. Gov't, P.H.S.


PMID: 15349892 [PubMed - indexed for MEDLINE]


And from Ramzan, Faisal and Salman's father:

Hi Resa - Greetings

I hope you got satisfactory answers to your queries regarding my son Salman’s research. Would you be kind enough to post email exchanges that took place between my son Salman’s and your good self so that fellow Americans can change their opinion about my family?

Thanks in anticipation. God bless you and our country United States.



Ramzan A. Khetani, P.E.
Project Manager/Electrical Engineer
Division of State Facilities
Wisconsin Department Of Administration
Tel: 608-267-4889
Fax: 608-267-2710
ramzan.khetani@wisconsin.gov
Web: www.doa.state.wi.us/dsf

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