May 13, 1996
William F. Raub, PhD
Dear Dr. Raub:
The fifty professional societies listed below, representing over 285,000 biomedical and bioscience researchers, support the highest standards of ethical conduct, public accountability, and responsibility in research. To this end, we are extremely concerned about misconduct in science, in particular its definition and regulation. The recently released report of the Commission on Research Integrity (CRI) addresses these issues, and some parts have considerable merit. However, there are many recommendations that we consider inappropriate and, therefore, form an inadequate basis for policymaking by the Department of Health and Human Services (DHHS).
At a recent meeting, representatives of these societies affirmed that:
o All issues of misconduct should be handled at the level of the research institution, whenever possible.
We have more specific concerns in three major areas:
1. Definition
We agree with the definition of scientific misconduct developed by the Committee on Science, Engineering, and Public Policy (COSEPUP) of the National Academy of Sciences because it is more precise than the CRI definition. It states:
Misconduct in science is defined as fabrication, falsification, or plagiarism, in proposing, performing, or reporting research. Misconduct in science does not include errors of judgment; errors in recording, selection, or analysis of data; differences in opinions involving the interpretation of data; or misconduct unrelated to the research process.2
This definition serves as a clear guide for practicing scientists, teachers, and administrators, and establishes an unambiguous basis for investigating allegations of misconduct. The COSEPUP definition, unlike the CRI definition, does not rely on an open-ended set of examples and will not require extensive litigation to produce clear standards. We do, however, applaud the recommendation of the CRI report proposing the establishment of a government-wide definition of misconduct in science.
2. Rights of the Accuser and Accused
While we recognize that there have been instances where complainants in misconduct cases have been abused for coming forward, we also appreciate that there have been damaging consequences to innocent scientists from false statements. We abhor both situations. The CRI recommendations for the protection of accusers fail to give proper balance to both sides of these disputes and ignore the traditional principle of due process that is well-established in our society. We are particularly concerned that no provisions are made for violations of confidentiality, false statements, or other unlawful behavior on the part of accusers. Furthermore, disclosure of charges against exonerated scientists can entail a loss of reputation and result in damage to scientific careers. Proposed protections from retaliation are detailed, but similar protections for the accused and restitution for the exonerated are not specified. Accusers are given "the right to raise objections concerning the possible partiality of those selected to review their concerns without incurring retaliation" and the opportunity "to comment on the accuracy and completeness of information relevant to their concerns, except when they violate the rules of confidentiality." These provisions make the accuser part of the investigating team and create an asymmetric relationship with the accused. This imbalance unfairly burdens the accused with a "guilty until proven innocent" stigma and does not serve the interests of science or society. We believe that allegations of misconduct should be addressed seriously, but fairly, with respect to all parties.
3. Role of Federal Oversight
Without evidence that new intrusive, expensive, and time-consuming programs are needed, the CRI report proposes to create costly and unwarranted administrative mechanisms (forms, certifications, reviews, site-visits, and audits) that will reduce the productivity of the public's investment in science. These unfunded mandates will result in substantially greater federal involvement in institutional operations, requiring them to establish elaborate and expensive enforcement mechanisms which DHHS will have the authority to overturn. Importantly, the mandate of the Office of Research Integrity (ORI) is currently vague and undefined, particularly with respect to the cases it chooses to investigate. We recognize the importance of ORI in protecting the government's interest in cases involving fabrication, falsification, or plagiarism, but these activities should be closely defined and not broadly expanded into over-regulation.
Sincerely,
References
Science Advisor - Office of Science Policy
Department of Health and Human Services
Hubert H. Humphrey Bldg.
Room 441E-MS415F
Washington, DC 20201
o Falsification, fabrication and plagiarism are so detrimental to the conduct of science that government action is appropriate when institutions fail to provide proper oversight of federally-funded research.
o There are other issues that present a less severe danger to the scientific enterprise. These matters should be dealt with at the institutional level, and government involvement should be limited to encouraging institutions to establish germane principles and educational programs for the full range of individuals involved in the research process.
Ralph A. Bradshaw
President (FASEB)
1. "Integrity and Misconduct in Research." Report of the Commission on Research Integrity. U.S. Department of Health and Human Services (1995).
2. National Academy of Science: Committee on Science, Engineering and Public Policy. "Responsible Science: Insuring the Integrity of the Research Process" National Academy Press (1992).
During most of my life, I have had to operate within the framework of walls originated by others. These walls have compartmentalized my thinking in virtually every aspect of my life. The Iron Curtain separated me from people I was told were dangerous and aloof and could not be trusted. My Southern heritage was to be revered and championed against the attacks of those from other regions. The tenets of my church were infallible and were to be aggressively defended against the inferior claims of other denominations and faiths. My gender (male) was superior; I was biologically more suitable for scientific pursuits and positions of leadership and responsibility. My race (Caucasian) was superior to that of those not so fortunate as I. My choice of profession (engineering) and specialty (biomedical) was inspired.
"Spring is the mischief in me, and I wonder
If I could put a notion in his head:
Why do they make good neighbors? Isn't it
Where there are cows? But here there are no cows.
Before I built a wall I'd ask to know
What I was walling in or walling out,
And to whom I was like to give offense.
Something there is that doesn't love a wall,
That wants it down.' I could say Elves' to him,
But it's not elves exactly, and I'd rather
He said it for himself. I see him there
Bringing a stone grasped firmly by the top
In each hand, like an old-stone savage armed.
He moves in darkness as it seems to me,
Not of woods only and the shape of trees.
He will not go behind his father's saying,
And he likes having thought of it so well
He says again, Good fences make good neighbors.'"1
The walls are coming down. Two of my best friends now are Ukrainian physicians whom I would not have been allowed to visit six years ago. In today's local newspaper, four Methodist churches, three of them historically black, are proposing a merger across denominational and racial lines. My own church is planning to build a day care center in Nashville's inner city, bridging racial and cultural differences. When I taught electrical engineering courses a quarter of a century ago, I had only one female student in my entire teaching experience. Now the percent incidence of women in engineering and other professional careers which historically have implicitly excluded women is large and growing.
Walls between biomedical engineering societies are also coming down. At the BMES Board of Directors Meeting in October 1995, it was proposed that BMES and the Institute for Electrical and Electronic Engineers Engineering in Medicine and Biology Society (IEEE/EMBS) co-host a joint conference in Atlanta in the fall of 1999.
The Board of Directors met again in April 1996 and unanimously voted to accept the invitation, presented by Bob Nerem of Georgia Tech, to cooperate fully with the EMBS in a joint meeting. I am elated, appreciative of the courage the Board showed, and looking forward to the closer relationship between the two societies such a meeting will bring.
Why do we have walls between us? Why are there more than a dozen societies, all representing aspects of biomedical engineering, under the umbrella of the American Institute for Medical and Biological Engineering (AIMBE)? Perhaps a brief history of biomedical engineering will inform our members, half of whom are students and most of whom were not born when these events began to transpire.
According to records from the Alliance for Engineering in Medicine and Biology, the first biomedical engineering meeting may have been held in 1948. In that year, a group of engineers from the Instrument Society of America (ISA) and the American Institute of Electrical Engineers, with professional interests in X-ray and radiation apparatus used in medicine, held the First Annual Conference on Medical Electronics. In subsequent years, biomedical engineering continued to mature, and growth of and diversification in the meeting continued to occur. By 1968, five societies: the ISA, the Institute for Electrical and Electronic Engineers (IEEE), the American Society of Mechanical Engineers, the American Institute of Chemical Engineers, and the Association for the Advancement of Medical Instrumentation, constituted the Joint Committee on Engineering in Medicine and Biology. The name of the conference begun in 1948 had become the Annual Conference on Engineering in Medicine and Biology (ACEMB).
In 1969, at the 22nd ACEMB in Chicago, representatives from fourteen engineering, scientific and medical organizations, including the BMES, founded the Alliance for Engineering in Medicine and Biology (AEMB). The BMES had been constituted the previous year; its formation was not unanimously welcomed in the biomedical engineering community and was publicly criticized by some. The AEMB umbrella, however, flourished and continued to conduct the ACEMB throughout the 1970s. Toward the end of that decade, however, the IEEE Engineering in Medicine and Biology Society (EMBS), which had grown to several thousand members, felt that their best interests were no longer being served by the ACEMB and withdrew to begin their own fall meeting. Although remaining constituent organizations within the AEMB, including the BMES, worked hard to vitalize the ACEMB, the loss of IEEE/EMBS and other factors proved too much to overcome, the last ACEMB meeting was held in 1988, and the Alliance was disbanded thereafter.
Throughout the 1980s, the EMBS meetings enjoyed increasing popularity. The 1989 EMBS meeting in Seattle had more than 1300 registrants. Registration fees had climbed to the $250 - $300 range from more modest ACEMB levels of earlier years. The sizes of these meetings dictated that they be held in major hotels, adding further to the expense of attendance. During this period, the EMBS recognized the worldwide growth of the biomedical engineering profession and moved to recruit new members and conference participants from around the world. The EMBS meeting had become big business. In 1991, I organized a session for the EMBS fall conference in Orlando. There were six participants, two of whom did not show. Our session was a microcosm of the conference. Of 1800 registrants, approximately a third of those scheduled to present papers did not attend. Since then, the EMBS fall meeting has seen modest declines in attendance.
Meanwhile, members of the BMES had seen a need for a second fall conference dedicated to biomedical engineering. This conference would be smaller, less expensive, and held in a campus setting. It would accommodate research tracks not included in the EMBS meeting. The first BMES fall meeting, held at the Virginia Polytechnic Institute in October 1990, had 80 papers and 110 participants. By last year the fall meeting, hosted by Boston University, had grown to 560 abstracts and 750 registrants. Despite its size, our BMES fall meeting is still collegial, reasonable in cost, and continues to feature outstanding science.
At the same time, the EMBS should be commended for its recognition that biomedical engineering is an international, not exclusively academic profession, and for its efforts to include these communities in its meetings and other activities. The membership of the BMES may be too provincial and too concentrated within academia. Although a large conference may be more expensive and less conducive to communication than a smaller one, the benefits of cross-society communication may compensate for the larger conference's disadvantages and may improve the entire profession. Our church's day care center was conceived in committee. When the entire church was informed of the decision and invited to be included in the planning, the outpouring of enthusiasm and additional good ideas for services and activities made the center better than the committee could ever have planned by itself.
"Something there is that doesn't love a wall, that wants it down." I've spent too much of my life mending walls, armed like an old-stone savage. With whatever time and energy I have left, I want to build bridges, not mend walls. It's time to consider the walls we built and carefully maintained in the past and to see if some of them can't come down. 1 Robert Frost, "Mending Wall", from Complete Poems of Robert Frost, Holt, Rinehart and Winston, 1936.
1Robert Frost, "Mending Wall", from Complete Poems of Robert Frost, Holt, Rinehart and Winston, 1936.
The 1995-1996 school year marks the second year for our new arrangement of officers. Last year we changed from the standard format of a President, Vice-President, Treasurer, Secretary, to a Co-Presidents, Treasurer, Secretary format. This new hierarchy took some time to adjust to but during the two short years since we installed the co-president format the entire chapter has benefited from the change. Instead of having all of the responsibility fall on one person's shoulders, two people are responsible for everything. This not only allows an equal division of tasks but also provides a set of internal checks and balances. It also creates an environment which is much more enthusiastic, energetic and full of new, creative ideas.
We genuinely feel that having co-presidents has been one of the essential elements of success for our chapter. We also know that the key to any organization's success is communication. Therefore, we hold officer meetings on a regular basis, to discuss all the activities of the organization. Committee heads are asked to participate in these meetings every other time that we meet. With this group we are able to generate ideas, delegate responsibilities and ensure that everyone in the chapter is involved.
The fall semester began by distributing to our new students the first ever "New Student Handbook", which provides these students with all the information needed to start a successful academic career at the University of Akron. The handbook includes information on the department, the University and the surrounding community. The department's annual Biomedical Engineering Open House was a great success this fall. All the labs in the department opened their doors and showed the public what we are doing at the University of Akron.
Our committees have also been extremely busy. The recycling committee, headed by Madhusudan "Nutty" Natarajan, has made sure that not only are cans recycled, but also that all of the paper generated by our research facility is recycled. Selemeh Hines heads our service committee, which has geared most of its activities towards the community, including: the annual Red Cross Blood Drive, a canned food drive for Haven of Rest Ministries, and a hat and mitten drive for the Salvation Army. We also assist in tutoring programs for public school children. Fundraising, headed by Steve Szabo, created some new designs to raise money through T-shirt and sweatshirt sales. A fundraising activity that had more emphasis on "fun" than "funds" was a Baby Picture Contest including the adorable baby faces of the faculty and students. Our spring fund-raiser will be a service auction. Tours to companies and job opportunities are organized by the industrial relations committee, led by Paul Fowler. Future tours include the Cleveland Clinic and Little Tikes. Our energetic athletics committee is very active this year. The general manager of the "Cadavers", Jamey Price, has kept us involved with football, volleyball, and soccer. Our social committee has been hard at work by coordinating a Bowling night, Laser Tag and other social gatherings. Last but not least, our BMES newsletter, "The BioBulletin" has a new editor, Kiran Nataraj. Kiran did an excellent job in organizing the Fall edition, by involving everyone in the department in the process.
As you can see, we have had a very productive and exciting semester. Spring semester is looking to be a continuation of the groundwork already in place. Once again, we feel that our success is due to everyone's involvement and would like to acknowledge that at this time. Thank you!
Dawn Abens and Michael Collins
Co-Presidents
The University of Akron
Biomedical Engineering Society
Akron, OH 44325-0302
Gene therapy involves the transfer of genetic material, encoding one or more therapeutic genes and the sequences necessary for their expression, to target cells to alter their genetic makeup for some desired therapeutic effect. Gene therapy was first used to treat adenosine deaminase (ADA) deficiency, a single-gene genetic disorder, but is now being tested in a wide variety of applications, including complex genetic disorders such as cancer, infectious diseases such as human immunodeficiency virus (HIV) infection, and in tissue engineering (1-3). Some common approaches for treating disease with gene therapy are described in Table 1.
Genetic material has been successfully delivered to a large number of different human cell types, and their phenotypes have been altered. For example, complementary DNA (cDNA) encoding the gene for ADA has been transferred to blood cells to treat ADA deficient children, cDNA encoding cytokines have been delivered to tumor cells in an attempt to elicit an anti-tumor immune response, and cDNA encoding the receptor for low density lipoprotein (LDL) has been delivered to the hepatocytes of patients suffering from familial hypercholesterolemia (4). Most often, the genetic material is transferred ex vivo to tissue that has been removed from the patient (5, 6). After gene transfer, the tissue is cultured and expanded in vitro, then reimplanted into the patient. If the target tissue cannot be removed or cultured in vitro (e.g., brain, heart, and lungs), the genetic material is injected directly into the patient, in vivo.
Despite several exciting early milestones in gene delivery, to date there are no examples of gene therapy 'cures' (7). One major reason for the lack of a major success is the current inability to efficiently deliver genetic material to target cells. Several gene transfer vector systems have been developed to deliver genetic material more efficiently, but this first generation of systems is somewhat crude and must be significantly improved before the potential of gene therapy can be unlocked. Fundamental engineering principles must be applied to gain a better understanding of the rate-limiting steps of the gene transfer process before the next generation of gene transfer technologies and methodologies can be rationally designed.
We will focus on recombinant retroviruses, although most of the principles discussed are applicable to all gene transfer systems. Recombinant retroviruses are the most common gene transfer vector used in human gene therapy clinical trials, primarily because they can enter most cell types, and they permanently integrate the genetic material into the genome of the target cell (1, 8). Permanent genetic modification of the target cell is a distinct advantage when a long lasting treatment is desired, as in the treatment of hereditary or chronic disorders (4). Unfortunately, recombinant retroviruses, like other gene transfer systems, have several limitations. The major drawback is that transduction efficiencies, defined as the number of gene copies delivered per target cell, are low. Recombinant retroviruses are also unable to: (1) infect nondividing cells, (2) transfer more than 8 kilobases of genetic material, and (3) easily target specific cell types and tissues. A discussion of these latter fundamental biological issues is, however, beyond the scope of this article (9-11).
Transduction efficiencies must be increased by improving recombinant retroviruses and methods to deliver them. Higher transduction efficiencies in ex vivo protocols would reduce the number of cells cultured outside the body and increase the expression of the therapeutic gene in each cell, increasing the likelihood of eliciting the desired biological effect. Higher transduction efficiencies in in vivo protocols would minimize the volume of retrovirus stock that must be injected into the body and maximize expression of the therapeutic gene in each cell.
In this article, the major factors that limit the transduction efficiency of retroviral-mediated gene transfer, as well as some of the strategies being used to overcome these limitations, will be discussed. Because the field of gene therapy has only recently been developed, the technology base for its application is also in its infancy. Thus, in anticipation of more comprehensive descriptions of retroviral-mediated gene transfer, which will undoubtedly come in the future as a result of more mature and detailed investigations, we offer a discussion of several exciting avenues of research where biomedical engineers have begun to contribute to the overall process. However, in order to provide the reader with some background information, the construction and life cycle of recombinant retroviruses are briefly reviewed below.
Overview of Retroviral-Mediated Gene Transfer
Recombinant retroviruses used for human gene therapy are derived from the wild-type Moloney murine leukemia (Mo-MuLV) retrovirus. The recombinant viruses are structurally identical to the wild-type virus but carry a genetically engineered genome (retroviral vector) that encodes the therapeutic gene and sequences which regulate its expression. Recombinant retroviruses cannot self-replicate, but can infect and integrate their genomes into the chromosomal DNA of the target cell (3, 12, 13).
Recombinant retroviruses consist of a two-part system composed of a retroviral vector and a packaging cell line (Figure 1) (1, 14). The retroviral vector is essentially the wild-type genome with all the viral genes removed. It encodes the therapeutic gene, regulatory sequences necessary for the expression of the gene, and a packaging sequence (psi) required for its efficient incorporation into virus particles (12).
The second part of the system is the packaging cell line, which expresses all the viral genes (gag, pol and env) required to form an infectious virus particle (13). Gag encodes the proteins that form a capsid around the viral RNA genome. Pol encodes the enzymatic activities of the virus, including reverse transcriptase. Env encodes the virus attachment proteins (VAPs) that cover the surface of the virus particle. VAPs are the primary determinant of the host range of the virus because they mediate the binding of the virus to its receptors on the cell surface. Amphotropic retroviruses, from which protrude VAPs that bind to the amphotropic receptor expressed in most human tissues, are used for human gene transfer because they can infect human cells.
Cells that produce recombinant retroviruses are made by transfecting the packaging cell line with the retroviral vector. The proteins encoded by gag and pol recognize the psi packaging sequence in the viral genomic RNA (transcribed from the transfected retroviral vector) and form a capsid around two identical copies of the viral genomic RNA. The capsid buds from the packaging cell line, acquires a lipid-bilayer with an array of protruding VAPs, and is shed into the surrounding culture medium, which is harvested and used as a viral stock.
The viral stock is then used to transduce (i.e., permanently integrate the therapeutic gene into the chromosomal DNA of) the target cells. Successful transduction requires the completion of a complex series of steps. The virus particles must first be transported to the surface of the cells where the VAPs of the viruses bind to their receptors (Figure 2). After the virus particles bind to their cell surface receptors, they enter the cell and release their RNA genomes into the cytoplasm (uncoat). The RNA genomes are reverse transcribed from RNA to DNA, transported into the nucleus, and integrated into the chromosomal DNA. Expression of the therapeutic genes is controlled by regulatory sequences genetically engineered into the retroviral vectors, or by viral regulatory sequences encoded in the long terminal repeats (LTRs) that bracket the ends of the integrated viral genomes (15).
The Relationship Between Transduction Efficiency and Virus Titer
In order to systematically develop better gene transfer methodologies, the transduction efficiency (the number of gene copies delivered per target cell) must be accurately measured. Most often, it is assumed that the transduction efficiency will be proportional to the titer of the virus stock used in the gene transfer protocol, that the virus stock with the highest titer will have the highest transduction efficiency, and that transduction efficiency will be maximized by maximizing the virus titer. Virus titer, which is essentially equal to the concentration of infectious virus particles in the virus stock, is determined by diluting the stock several thousand-fold in fresh medium, then using the diluted stock to infect cells. The number of infected cells is counted, and the virus titer calculated by multiplying by the dilution factor.
Recent studies have demonstrated, however, that transduction efficiency is often not proportional to, and cannot be reliably predicted from, virus titer (16-18). Most likely, this is because the compositions of undiluted virus stocks, like those used in human gene transfer protocols, are substantially different from the compositions of virus stocks used in the virus titer assays. The culture medium of undiluted virus stocks has been conditioned by the packaging cells, whereas the culture medium used in virus titer experiments, because the virus stock has been diluted several-thousand fold, is virtually identical to fresh (unconditioned) culture medium. Conditioned medium contains higher concentrations than fresh medium of substances secreted by the packaging cells, and lower concentrations of substances that have been used by the packaging cells. For example, undiluted virus stocks have high concentrations of infectious virus particles, non-infectious virus particles, and virus proteins that could interfere with, and alter the dynamics of, retroviral infection.
It is transduction efficiency, therefore, and not simply the virus titer, that must be measured to evaluate the effectiveness of gene transfer methodologies. Relatively simple and rapid methods for measuring transduction efficiency have recently been developed (19). By using these or similar methods, approaches for increasing transduction efficiencies can be systematically evaluated. The three major types of approaches that have been used to increase transduction efficiencies are those that: (1) increase the concentration of virus particles, (2) increase the efficiency of extracellular steps of infection, and (3) increase the efficiency of cell-associated steps of infection (see Table 2).
Increasing Virus Concentrations
One approach to improve transduction efficiency is to increase the concentration of infectious virus particles. The concentration of virus particles in virus stocks can be increased by optimizing packaging cell culture conditions, concentrating the virus stocks after they are harvested from the packaging cells, and/or by altering the virus or packaging cell lines. Significant increases in virus titer have been achieved by optimizing cell culture conditions, such as by reducing the ratio of culture medium to cell number. Packaging cells seeded in the extracapillary space of a hollow fiber bioreactor, and grown to densities (108 cells per milliliter) about 100-fold higher than normally achieved in conventional cell culture flasks, produced virus stocks with titers (2 x 107 particles per milliliter) 18-fold higher than the titers of virus stocks generated in T-flasks (20). The cell culture incubation temperature can also be optimized to increase virus concentrations. Kotani et al. increased the concentration of virus particles nearly tenfold by lowering the incubation temperature of packaging cells from 37oC to 32oC (21).
Another possibility is to increase the concentration of virus particles by physically concentrating the virus stocks, although doing so without losing infectivity has proven difficult. Standard techniques such as centrifugation and ultrafiltration have failed (22). More recently, tangential flow and hollow fiber filtration have been shown to increase virus concentrations more than 30-fold with minimal losses in viral infectivity (21, 23).
Synthetic approaches have also been used to increase virus concentrations, such as the production of chimeric virus particles (particles composed of structural proteins derived from two or more viruses) that are easy to concentrate without loss of infectivity, and the construction of packaging cell lines designed to optimize viral protein expression (24, 25). Using the latter approach, Cosset et al. transfected human HT-1080 cells with gag-pol and env expression plasmids, each encoding a different selectable marker. The selectable markers were expressed by reinitiation of translation of the mRNA encoding the viral proteins, which ensured that only cells expressing all the viral proteins would survive incubation in selective culture medium. Titers as high as 3 x 107 infectious particles per milliliter were achieved, much higher than titers generated by previous packaging cell lines (105 to 106 infectious particles per milliliter).
Increasing the Efficiency of Extracellular Steps of Infection
Transduction efficiencies can also be improved by straightforward environmental or culture medium alterations that maximize the efficiency of extracellular steps of infection. For example, by reducing the decay rate of recombinant retroviruses, which rapidly lose infectivity with time at 37oC, transduction efficiencies can be improved. The rapid decay of infectivity (the half-life at 37oC is about 6 to 8 hours) of retroviruses reduces transduction efficiencies because retrovirus binding and infection occurs over a period of several hours, during which time most of the infectivity of the retroviruses is lost (23, 26). Infection continues for several hours because the virus particles are large (100 nm) and diffuse slowly. Retrovirus particles move about 300 mum in one half-life (7 hours), or about one-tenth the distance from the top of the culture medium fluid to the surface of the cells. With current cell culture configurations, most of the virus particles lose their infectivity long before they reach the surface of the target cells. The decay rate of retroviruses could, in principle, be reduced by genetic methods once the mechanism of decay is known. For now, simpler strategies have been adopted, such as transduction at 32oC instead of 37oC, which reduced the decay rate and increased transduction efficiencies (21).
A second method of minimizing the effects of retroviral decay is to increase the encounter frequency, by centrifugation or convection, between the target cells and the virus particles. Centrifugation increased the transduction efficiency of adherent NIH-3T3 fibroblasts three to ten-fold and non-adherent CD34+ blood cells six-fold (27). Convection of virus particles past target cells immobilized onto a porous membrane increased transduction efficiencies up to ten-fold (28). Both methods increased the rate at which virus particles bound and infected the target cells, and therefore decreased the adverse impact of retroviral decay on transduction efficiency. Given further refinement, these methods have the potential to improve substantially the efficiency of most ex vivo gene transfer protocols.
Transduction efficiencies can also be increased by altering the composition of the culture medium. For instance, addition of cationic polymers (e.g., polybrene, protamine, DEAE-dextran) or cationic lipids (e.g., 2,3-dioleyloxy-N-{2(sperminecarboxamido)ethyl}-N,N-dimethyl-1-propaninium trifluoroacetate (DOSPA) and dioleylphosphatidylethanolamine (DOPE)) to the culture medium before or during infection increases virus binding and transduction efficiency 10-fold or more (29, 30). The mechanism of enhancement has not been completely elucidated, but it is thought that the polymers adsorb to either the virus particles and/or the surface of the cell, and reduce the electrostatic repulsion between the two negatively charged entities. A better understanding of the mechanisms that underlie the enhancement of infection by cationic polymers and lipids might offer strategies for the design of better 'binding enhancers' and thus increase transduction efficiency.
It may also be possible to improve the culture environment for infection by removing substances from the culture medium, either viral or non-viral, that inhibit infection. Inhibitors can block infection by binding to the virus particles, binding to the virus receptors, or by other mechanisms that interfere with the normal life cycle of the virus particles. One recent study found that medium conditioned by virus-producing cells inhibited infection, and the authors speculated that non-infectious virus particles, or VAPs not associated with virus particles, were blocking infection by binding to virus receptors (18).
A recent study in our laboratory demonstrated that high-molecular-weight proteoglycans, present in viral stocks, inhibited infection (16, 31). These high-molecular-weight inhibitors will most likely be co-concentrated with the virus particles by conventional concentration methods, producing a high-titer virus stock with, nonetheless, low transduction efficiency. To produce virus stocks with higher titers and transduction efficiencies, methods are needed that remove or eliminate these large-molecular-weight inhibitors, rather than co-concentrate them with the virus particles.
Increasing the Efficiency of Cell-Associated Steps of Infection
Finally, transduction efficiencies can also be improved by increasing the efficiencies of the steps of infection that occur on or inside the cell. For example, virus binding (and transduction efficiency) can be improved by increasing the concentration of cell surface receptors. The recent cloning of the amphotropic retrovirus receptor, a sodium-dependent phosphate symport, has enabled researchers to measure, and alter, the tissue-specific expression of the receptor (32, 33). By culturing CD-4 enriched human peripheral blood lymphocytes in phosphate-free medium for 12 hours, transduction efficiency was increased more than ten-fold, presumably because expression of the amphotropic receptor was upregulated (34).
Transduction efficiencies can also be increased by reducing the time required to complete intracellular steps of infection, thereby increasing the probability of completing transduction before the virus spontaneously loses infectivity. One recent study found that reverse transcription does not occur exclusively in the cytoplasm as previously thought, but can occur outside the cell, inside extracellular virus particles, when the virus particles are incubated in high concentrations of deoxyribonucleoside triphosphates (dNTPs) (35, 36). Virus stocks that have been incubated with dNTPs contain significant amounts of viral DNA (reverse transcribed from the viral RNA) and are about 100-fold more efficient at infecting cells, possibly because the virus particles take less time to integrate into the chromosomal DNA once they enter the cytoplasm of the target cell. It is also possible that virus particles that enter non-S phase cells, which generally have lower concentrations of dNTPs, might significantly benefit from having undergone at least some reverse transcription before cell entry. These studies demonstrated that reverse transcription can limit the efficiency of retroviral-mediated gene transfer, and that inefficiencies in reverse transcription can be partially overcome by incubation of viral stocks in dNTPs before transduction of the target cells.
Rapid entry into the nucleus is also crucial for maximizing transduction efficiency. Retroviral infection, with the exception of infection by human immunodeficiency virus, requires that the target cells pass through mitosis, most likely because the retroviral DNA complex cannot enter the nucleus until the nuclear envelope breaks down (9). In one experiment, quiescent cells, stimulated to divide only 6 hours after exposure to retroviruses, were not successfully infected, suggesting that intracellular virus particles are rapidly degraded (37). If the intracellular half-life is shorter than the cell cycle rate, then the probability of infection will be strongly influenced by the cell cycle position and cycling rate of the host cell. Construction of recombinant retroviruses that have longer intracellular half-lives should significantly increase transduction efficiencies, especially in slowly dividing cells. Alternatively, transduction efficiencies might be increased by infecting cells at a stage of the cell cycle that maximizes the probability of successful transduction.
Another option is to design recombinant retroviruses that can infect cells that do not pass through mitosis. One approach involves the use of lentiviruses (e.g., HIV, simian immunodeficiency virus (SIV)), which can infect non-dividing cells (38,39). Another strategy is to construct Mo-MuLV-based retroviruses that have sequences from HIV that allow them to pass through the nuclear envelope (40). Both strategies are being actively pursued but vectors based on non-human viruses (e.g., SIV or Mo-MuLV) are preferred for obvious safety considerations. The development of recombinant retroviruses that could infect quiescent cells would not only enhance transduction efficiencies but would also greatly expand the number of target tissues that could be treated by retroviral-mediated gene transfer.
Summary and Conclusion
The current generation of recombinant retroviruses has successfully demonstrated that foreign genetic material can be permanently delivered to target cells, and their diseased phenotype altered. Recombinant retroviruses suffer from several disadvantages, however, that limit their usefulness for the treatment of disease. The challenge now is to develop more efficient gene transfer technologies that maximize transduction efficiency and to design the next generation of recombinant retroviruses that will deliver the therapeutic gene(s) to the target cells more rapidly and efficiently. New design approaches cannot simply rely on empirical genetic engineering manipulations, but will instead require substantial advances in our understanding of the production of virus particles, the mechanism of virus instability, the interactions between virus particles and target cells, and the extracellular and intracellular rate-limiting steps of retroviral infection. Only through a concerted, interdisciplinary approach that brings together experts from a wide variety of fields, including molecular biology, cellular biology, virology, biophysics, and engineering, will this fundamental understanding of recombinant retroviruses, and the methods by which they are delivered, be attained.
Acknowledgements
One of the authors (JL) was supported by an NIH predoctoral biotechnology fellowship and a Johnson and Johnson fellowship. We thank Jeffrey Morgan for many helpful discussions and Erika Swinnich for artwork.
REFERENCES
Content: Review articles in all disciplines of biomedical engineering are invited. Topics of recent and upcoming reviews include tissue engineering, cell adhesion molecules, blood substitutes, drug delivery, and cardiac defibrillation.
Length: Reviews should be 10 - 20 double-spaced pages long, including references.
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References: In general, no more than twenty (20) references should be cited.
Keywords: Authors are encouraged to provide up to 5 keywords (the Bulletin is indexed in two ISI indexes).
Submission: Review articles should be submitted to: Steven M. Slack, Science Editor, BMES Bulletin, Dept. of Biomedical Engineering, The University of Memphis, Memphis, TN 38152. Both a hard copy and a 3.5 inch diskette containing the review article should be submitted.
Proofs: Authors will receive page proofs for final minor corrections.
Reprints: Authors will receive 20 issues of the Bulletin in which their article appears at no charge.
World Wide Web: The BMES Bulletin can be accessed on the World Wide Web at the following address: http://www.mecca.org/BME/BMES/bmeshome.html. Links to related BMES organizations may also be found at that site.
On the occasion of the 100th anniversary of establishment of the College of Engineering at Penn State and the 25th anniversary of the Bioengineering Program, we are pleased to welcome you to a celebration of all achievements by members of our society in enhancing the quality of life.
Bioengineering activities at Penn State began in the early 1970s with research on the structure and function of tissues, electrocardiology, and cardiovascular function. Among these efforts were collaborative studies between faculty in the Colleges of Medicine (at The Milton S. Hershey Medical Center) and Engineering to develop implantable circulatory assist and artificial heart devices. By 1976, the development of a pneumatic left ventricular assist device had progressed to permit the first successful use in a human patient. Since that time, this device and its subsequent refinements have been used in over 60 patients at Penn State and over 250 patients worldwide with the primary goal of providing circulatory assist as a bridge to transplant until acceptable human hearts were obtained.
Continued expansion and growth of bioengineering has resulted in establishment of research laboratories in a broad spectrum of biomedical engineering activities such as: ultrasound diagnostic imaging and transducer design, neuroelectrophysiology, electrocardiology, respiratory physiology, microvascular blood flow, cellular biomechanics, physiological transport, biofluid mechanics, and the development of an artificial lung.
Penn State University Park Campus situated on over 300 acres in the geographical center of Pennsylvania, offers an ideal setting for our annual meeting. The vitality of its 38,000 students and the beauty of its fall foliage will complement the modern meeting facilities of The Penn State Scanticon Conference Center Hotel.
With great pride and dedication to the goals of the Biomedical Engineering Society, we look forward to your participation in this conference. The preliminary program below details the tentative schedule of events and will be adjusted in response to the number of abstracts submitted. The program format will follow that established during past BMES fall meetings and aims to provide a mixture of plenary lectures and free communications organized into discrete tracks.
Artificial Organs and Devices
Biomedical Engineering and Society
Biomedical Engineering and Industry
Cell and Tissue Engineering
Clinical Perspectives on Engineering
Cost Reduction in Health Care
Cardiopulmonary and Respiratory Engineering
Cardiovascular Engineering
Medical Imaging
Neural Imaging
New Frontiers in Bioengineering
Orthopedic Engineering
Rehabilitation Engineering
Toxicology and Environmental Health
Thursday, October 3: Evening Reception
Friday, October 4: Plenary Lectures and Welcome Reception
Saturday, October 5: Scientific Sessions and Society Banquet
Sunday, October 6: Scientific Sessions
Herbert H. Lipowsky
E-mail: hhlbio@engr.psu.edu
James E. Ultman
E-mail: jsu@psuvm.psu.edu
For further information on the 1996 BMES Fall Meeting, please contact Rita Kline, Bioengineering Program, The Pennsylvania State University, 205 Hallowell Building, University Park, PA 16802-6804, telephone (814) 865-1407, fax (814) 863-0490, e-mail rxkl@psu.edu.
Senior Members
Kirk J. Bundy, Ph.D. (W. Van Buskirk, C. Walker)
Robert C. Eberhart, Ph.D. (H. Borovetz, E. Leonard)
Roland N. Pittman, Ph.D. (D. Hellums, A. Popel)
Members
Indu A. Ayappa, Ph.D.*
Anita M. Bagley, Ph.D.*
Khalid W. Barazanji, Ph.D.
Berj Luther Bardakjian, Ph.D. (J. Bassingthwaighte)
Amy E. Baxter*
Richard A. Berg, Ph.D (T. Estridge)
Eugene D. Boland*
Sorel Bosan, Ph.D. (T. Harris)
Armelle C. Burleson, Ph.D. (S. Slack)
Marco E. Cabrera*
Silvio Cavalcanti
Micah Dembo, Ph.D. (R. Hochmuth)
Dennis E. Discher, Ph.D. (R. Hochmuth)
Si-shen Feng, Ph.D. (T. Goldstick)
Arnold A. Fontaine, Ph.D. (A. Yoganathan)
Brian C. Frake, Ph.D.*
Morteza Gharib, Ph.D.
Rosalia S. Gonzales*
Jennifer L. Griffin (D. Jeutter)
Warren M. Grill, Jr., Ph.D.*
Michele J. Grimm, Ph.D.*
Anthony G. Harris, Ph.D.*
J. Brian Harris*
Diana L. Hauser, Ph.D. (A. Popel)
Robert J. Hirko, Ph.D. (H. Borovetz, W. Phillips)
Vladimir Hlady, Ph.D. (J. Andrade)
Allison Hubel, Ph.D. (S. Finkelstein)
Michael B. Jaffe, Ph.D.*
David F. Katz, Ph.D. (R. Hochmuth)
Shantanu V. Kaushikkar (C. Lorenz)
Tony M. Keaveny, Ph.D. (R. Hochmuth)
Robert S. Keynton, Ph.D.*
Konstantinos Konstantopoulos, Ph.D. (L. McIntire)
Hans Kunov, Ph.D. (E. Guilbeau)
Noshir A. Langrana, Ph.D. (R. Hochmuth)
Yvette A. Laycock*
Chong-Sun Lee, Ph.D. (K. Chandran)
Klaus F. Ley, M.D. (J.S. Lee, A. Tozeren)
Jennifer J. Linderman, Ph.D. (J. Bassingthwaighte)
Robert A. Malkin, Ph.D. (S. Weinbaum)
Eric A. Martens (J. Winters)
Budimir Mijovic, Ph.D. (D. Liepsch)
Gary J. Miller, Ph.D. (R. Hirko)
Randle T. Moorei, IV*
Spero C. Nicholas*
S.C. Niranjan, Ph.D. (A. Bidani)
Matthias U. Nollert, Ph.D. (R. Hochmuth)
Timothy L. Norman, Ph.D. (C. Stanley)
Shanthini Rangaswamy (G. Saidel)
Buddy Ratner, Ph.D. (E. Guilbeau)
Judith D. Redling, Ph.D.*
Lisa W. Riedy, Ph.D. (J. Bassingthwaighte)
Mark R. Riley, Ph.D.*
Mary-Christine V. Rinaldi (J. Winters)
Julia Myers Ross, Ph.D. (L. McIntire)
Ingrid H. Sarelius, Ph.D. (V. Huxley)
Steve Schreiner, Ph.D. (R. Galloway)
Robin Shandas, Ph.D. (E. Cape)
John M. Siegel, Jr., Ph.D. (D. Ku)
Brett A. Simon, M.D., Ph.D. (W. Mitzner)
Barry N. Simon, Jr.*
Anne M. Smith, Ph.D.*
Cassandra L. Smith, Ph.D. (C. Cantor)
Eugene A. Sprague, Ph.D. (R. Nerem)
Christi J. Sychterz (E. Witherow)
Dalin Tang, Ph.D. (D. Ku)
Yanik Tardy, Ph.D. (C.F. Dewey, Jr.)
Ronald G. Tompkins, M.D., Sc.D. (R. Hochmuth)
Paul J. Unkel*
David Wieting, Ph.D.
Mark H. Wyzgala
Duran N. Yetkinler, M.D., Ph.D.*
Kenichi Yoshida*
Associate Members
Brian B. Beard*
Bobby Chan
Steven L. Connell*
Alonzo D. Cook*
Emil Dionysian, M.D.*
Alice B. Gilbreath*
David C. Guzik*
Michael F. Haller*
Kelly A. Hickey*
Kristen Jadelis*
Sunghoon Jang*
Sudarshan Khandige*
Thomas S. Kucia*
Jessica L. Lason*
Richard Lukacovic*
Tracy L. Mayfield-Donahoo*
Shreefal S. Mehta*
Andrew M. Mento*
Scott A. Mulvey*
Louis I. Naturman
Peter Novacek*
Neil A. O'Connell
John T. Otoshi
Janis E. Rose*
Clare E. Shannon*
Ellen C. Sieverin*
Carlito P. Soriaga*
David R. Squire*
David T. Szabo*
Gary J. Thompson*
Bruce L. Turpin
Cheryl L. Warsinske
___________________________________
* Indicates members who were
promoted from Student status
___________________________________
Student Members
S. Hasan Abbasi-Jahromi, Jesse Abelson, Dawn Abens, Oscar Abilez, Joyce Abraham, Leana Ahmed, Ricardo Albertorio, Elizabeth Alexa, Cherie Alexander, Eric Alikpala, Maria Alonso, Sarah Alt, Sriram Anand, Marnelle Andersen, Kemba Anderson, Angela Armstrong, Ruhi Arslanoglu, Suresh Atapattli, Erin Aten, Alaeddin Awaidah, David Azenheimer, Sheza Aziz, Kofi Baah, Allison Baij, Sarah Bailey, Samuel Baldwin, Victor Balogun, Ivan Ban, Michael Banas, Anirban Banerjee, Karl Barham, Ashley Barnes, Monica Barnhart, Bret Barrett, David Batarseh, Aaron Baxter, Tamara Baynham, James Beach, Brian Beard, Jamie Bell, Michael Bellew, Nelson Bennett Jr., Eric Benson, Jason Bentley, Molly Bettger, Kiran Bhadriraju, Susan Bialecke, Brian Biancucci, Andrea Biegel, Corey Bitting, Brad Blaise, Christopher Blanco, Avraham Bluestone, Darren Boe, Jennifer Boeitcher, Bradley Bonnette, John Bowman, Mark Brady, David Brennan, Jennifer Britton, Christopher Brown, Deborah Brown, James Brown, Matthew Brown, Scott Brown, Jennifer Burgett, Thomas Burkholder, Robert Butler, Vetria Byrd, Thomas Cabell Jr., William Calvo, Fernando Cantens, Erin Carpenter, Shamus Carr, Sean Carroll, David Carta, Fernando Casas, Chris Castro, Robert Chamberlain, Bryan Chan, Jaymin Chang, Justin Chang, Albert Chen, Emily Chen, Jonas Chen, Eric Cheng, Scott Chesla, Albert Chi, Martin Chian, Fred Chien, Ryan Chin, Joy Poh Ai Ch'Ng, Samir Chowdhury, Katie Christina, Victor Cintron, Gwennaye Coath, Melissa Cobb, Edward Coburn, Michael Coc, Mirtis Coggins, Elaine Cohen Hubal, Michael Collins, Brolan Conkey, Dale Conroy, Michael Contreras, Amy Corvelli, Jeremy Crary, Jon Crispin, Frank Cristina, Kelly Crittenden, Adrienne Crowley, Simon Cuadrado, Robert Cutlip, Nicholas Czapla, Peter Czuwala, Patricia Dacumos, Todd Dahlgren, Guohao Dai, Sunil Dalal, Donella Dante, Alexander Darian, Stanley Darlak, T. Brian Darr, Bernia Daugherty, Craig Davenport, Anthony DeBenedet, Kay Dee, Brian Deuter, Paul DiCamillo, William DiGenova, Joseph Dinkel, Michael Dockter, Andrew Dooris, Adam Dorsey, Dawn Downey, John Doyle, Ryan Doyle, Claire Dreger, Richard Drew II, Anne Drzyzga, Narendra Dubey, Dave Eberswan, John Edlefson, Matthew Edwardson, Mindi Eineichner, Steven Eliades, Dawn Elliott, Jeffrey Ellis, Mona El-Khatib, Darrell Eng, Daniel Englert, Lillian Enloe, Stephanie Eschmann, David Evans, Kerrie Exely, John Fang, Haleh Farahmehr, Karen Faran, Lahn Fendelander, Jason Ferrara, Carl Fischer, Zair Fishkin, David Flaitz, Rachel Fleury, Dave Forster, Lisa Foster, Julia Fox, James Fox II, Brian Frake, William Frederick III, Christopher Frick, Shih-Hua Fu, Carl Fulp, Julie Furst, Vincent A. Fusaro, John Gaffke, Daniel Gaies, Gangesh Ganesan, Ann Gebka, Shawn George, Andrew Geriak, Michael Gertner, Permjit Ghotra, Devin Ginther, Leonid Gleizer, Christopher Glismann, Dorothy Gloeckner, Tomas Godoy, Andrew Goldberg, Abraham Gommen, Serena Gondek, Keith Gooch, Felix Gorohovsky, Emanuel Gottlieb, Philip Grambrell, Ronald Green, Kelly Grimes, Michael Growney, Jeff Guay, David Gulley, Deepak Gupta, Nathan Gurgel, Suresh Gurunathan, Benjamin Haen, Sandra Halliburton, Richard Hammel, Chadentree Haney, Frank Hardy, Lisa Harness, Paton Hathcox, Heather Haught, Christopher Heffernan, Galen Hegarty, Teona Heidenreich, William Henson, Janelle Herren, Keith Herrmann, Thomas Hesbach, Erick Heygood, Brian Highley, David Hohensee, Andrew Hopper, Paromita Hore, Stephanie Houser, Johnnie Huang, Yaqi Huang, Gareth Hughes, Rolland Huie, Keith Hustosky, Richard Huth, Erica Hwang, Norly Isa, Erika Iverson, Shannon Izuhara, Brian Jackson, Rakhi Jain, Richard James, Shruti Japee, Shih Shi Jen, Gwen Jernigan, Chunsheng Jiang, Jeremy Johnson, Jason Jopling, Julie Juengling, Joni Julian, Ananth Kadambi, Tracy Kanten, David Kanter, Kelly Karau, Christopher Katholo, Dominique Kelly, Kyle Kepple, Brian Keys, Rena Khawly, Srinivas Kidambi, Adam Kiefert, Deepak Kilpadi, Bonnie Kim, Min Kim, Amy King, Kristin King, Jeremy Kingsbury, Jeff Koldoff, Edmund Kopetz, Trina Kovach, Andy Kowalchuk, Michelle Kowalski, Graig Kreen, Pisharath Krishnan, Andrew Krivoshik, Stuart Kronick, Eric Kunkel, Saravanan Kuppusamy, Judson Laabs, Shane Lacy, Hugues Lafrance, Andrew Lane, Phong Le, Timothy LeCroix, William Ledoux II, Leo Lee, Tai-Kwong Lee, Gregory Leff, Jerry Legg, Xiao-Xiao Lei, Patrick Leibovich, Anitra Lemoine, Sarah Lephardt, Marc Levitt, Hui Li, Zer Liang, Robert Lingle, Wen Liu, Yawei Liu, Daniel Loffredo, Gloria Lui, Bradley Luttrell, Leneise Lynn, Melissa Mallis, Britt Manfredi, Tina Marinkovich, Christie Marko, William Martin, David Martinez, Jennifer Mathe, Sanjay Mathias, Ryan Mattison, Doreen Maxwell, Reza Mazhari, Jason Mazzotta, Robert McCarthy, Sarah McGuire, Stephanie McKnight, James McLean, Monique McRipley, Donald Melnikoff, Kim Melton, Andrew Menden, Dennis Mendoza, Gregory Mercuri, Robert Michaloski, Stanley Michaud, Charles Michelich, Daniel Mikkelsen, Eric Miller, Barbara Millet, Claire Milsark, Gretchen Moeller, Sachin Moghe, Melissa Montgomery, Gresha Moore, Matthew Moore, Nilay Mukherjee, Sachin Mullick, Jessica Munsell, Ian Munson, A. Jennifer Murray, Madhusudan Natarajan, Navin Natnithithadha, Jacqueline Naylor, Sean Nealon, Charissa Neil, Tony Nguyen, John Nieman, Anwar Nimer, Jennifer Noe, Michael O'Connor, David Odde, Kari Olesen, Kerstin Ollison, Kristine Olney, Susanna Olson, Timothy O'Mara, Akiko Omura, Ogbeyalu Onumah, Antonio Otero, Jennifer Owers, Edwin Ozawa, Anthony Paganini, Robert Palazzolo, Steven Palumbo, Rajesh Pandey, Brian Parfitt, Saeyoung Park, Parminder Parmar, Julie Parnell, Chad Parrin, Tony Passerini, Dhaval Patel, Thomas Payne, Pedro Pedroso, Catherine Pemble, Teri Penn, Matthew Perry, Terrance Petersen, Melanie Peterson, Christine Pflederer, Aditya Phadke, Jeffrey Phelps, George Pins, James Piper, Hallie Placko, Zygmunt Porada III, Jamey Price, Richard Price, Annemarie Pringle, Ryan Putman, Fang Qian, Christopher Quick, Lesliam Quiros, Zahi Ramadan, Alvaro Ramirez, Vibhu Ranjan, Marshall Rasmussen, Dilip Rathinasamy, Marjorie Rawhouser, Walter Rawlin IV, Andrea Rebmann, Lesley Reenan, Kevin Remaly, Todd Rester, L. Christine Ribeiro, William Richter, Kara Ries, Deborah Rigsby, Michael Roach, Steven Robertson Jr., Amy Robichaux, Marc Rochelson, Enrique Rodriguez, Maria Romano, Arup Roy, Marcel Roy II, Joe Rubio, Christine Runfola, Jeffrey Russell, Andrea Ruygrok, Rami Saab, Fadi Saikali, Nelson Salas Jr., Hasan Saleheen, Venkatesh Saligrama, Jason Samonds, Jose Sanclement, Marina Santarpia, Alvin Santos, Todd Sarge, Sumir Sarjami, Janice Savage, Rahul Saxena, Mary Melissa Say, Joseph Scaria, Patricia Scheiberle, Nathan Scherer, Christopher Schieffer, Robert Schinagl, Brian Schiro, Mark Schmeling, Rebecca Schmid, Monica Schmidt, Derek Schoonover, Eric Schumacher, Jay Schuster, Jason Sconza, Charles Scott, Rhonda Scrak, Lakshmi Seetharan, Candice Seymore, Jamie Shaffer-Fuji, Chad Shea, Zhe Shen, Jeff Sheneman, Sharath Shivashankar, Lisa Shohara, Sitaraman Shyamsundar, Spencer Sibanda, Robert Sieh, Tom Siebyla, Marcy Simmons, Ranjeeta Singh, H. Ross Singleton, Lazaro Sixto, Stefan Slagowski, Tannis Sloan, Chadwick Smith, David Smith, M. Shane Smith, Thomas Smith, Toby Smith, Kimberly Smitherman, Darius Shad, Kirk Sonnior, Alex Soriano, Catherine Stanley, Tai Stella, Charles Sterling, Damon Stevens, Virginia Stokes, Katherine Stokke, Stacey Sullivan, Gaupongse Supattanasiri, Holly Sutherland, Melvin Sweet, Alireza Ghaemieh Tajick, William Tapia, Matthew Tate, Raymond Tateuossian, Laura Taylor, Mohammad Tehrani, Anne-Heather Teitelbaum, Jill Testamark, Emily Thompson, Brett Thomson, Caroline Tiglio, Mark Tillman, Mark Tindall, Hiroshi Toriumi, Binh Tran, Laura Traynor, Stephanie Trickey, Stanley Tsai, Stephen Uhlhorn, Jesse Upp, Manny Urcia, Thelma Valdes, William Vanscoy II, Michael Van Wie, Johnny Vargas, Amit Vasanji, Syam Vasireddy, W. Matthew Vassy, Eon Verrall, Andrew Vicknair, Amy Vizanko, Jesse Voo, Jimmy Vu, Steve Vuco, Sharee Walton, Hang Wan, David Wang, Teresa Wang, Zhenwen Wang, Ramesh Wariar, Eric Warren, Paul Weaver, Douglas Weber, David Wei, Charlotte Wells, Brian Wendelburg, Johanna Wertsch, Daniel Weyers, Christopher Wheeler, Chris White, Jeffrey White, Pipper White, Teresa Whitman, Bryan Whitson, Sarah Wichtendahl, Joanne Wilder, Marvin Williams, Melanie Williams, Jeffrey Wixted, Susan Wojcik, Jeff Wollschlager, Eddy Wong, Sugi Wong, Douglas Wright, Julie Wucinski, Jennifer Wynn, Soichiro Yamada, Calvin Yang, Guoyu Yang, Sharon Yee, Yener Yeni, Yongyi Yin, Jun You, Heather Young, Latesha Young, Yinghong Yu, Dajun Zhang, Mark Zobitz.
The awardee is expected to be present to accept the award at the Biomedical Engineering Society Annual Fall Meeting. Travel expenses of up to $1000 will be reimbursed by the Biomedical Engineering Society.
Aleksander S. Popel, Ph.D.
Chairman, BMES Awards Committee
Dept. of Biomedical Engineering
School of Medicine
Johns Hopkins University
720 Rutland Avenue
Baltimore, MD 21205
(410) 955-6419
email: apopel@jhu.edu
Dr. Martin L. Yarmush, CEM,
Bigelow 1401,
Massachusetts General Hospital,
55 Fruit St., Boston, MA 02114-2698.
The Massachusetts General Hospital and Shriners Burn Institute are equal opportunity employers.
Dr. J. S. Lee, Chair,
Department of Biomedical Engineering, Box 377,
Health Sciences Center,
University of Virginia, Charlottesville, VA 22908.
The University of Virginia is an Equal Opportunity Employer. Women and minorities are encouraged to apply.
Jeffrey L. Duerk, Ph.D., Associate Professor,
Radiology and Biomedical Engineering,
University Hospitals of Cleveland, Department of Radiology,
11100 Euclid Avenue, Cleveland, OH 44106.
CWRU is an equal opportunity/affirmative action employer.
UCSD Department of Bioengineering
Faculty Positions The Department of Bioengineering at the University of California, San Diego, invites applications for tenured/tenure-track faculty positions from individuals with expertise and training in bioengineering. The applicant should be prepared to establish a vigorous program of independent high-quality research that complements existing research activities in the Department on tissue engineering, orthopaedic bioengineering, biomechanics, or molecular and cellular bioengineering. Examples of areas of interest are musculoskeletal bioengineering, molecular bioengineering, and/or biotransport. The successful candidate will be responsible for teaching bioengineering courses at the undergraduate and graduate levels. There will be close collaboration with the School of Medicine, and qualified individuals may receive joint appointments. Salary is commensurate with qualifications and based upon UC pay schedules. Please send complete biography, samples of publications, and the names of five references to:
Dr. Richard Skalak, Chair of the Search Committee,
Department of Bioengineering, Mail code 0412(D),
UCSD, La Jolla, CA 92093-0412.
The search process will begin on June 1, 1996 and continue until the positions are filled with suitable candidates. The University of California, San Diego is an Affirmative Action/Equal Opportunity Employer.
Rita Schaffer
bmes@netcom.com
Last Updated: June 18, 1996