Loren Walker specializes in Bioscience Communications: Research & Writing (see resumé & L2W Technical Communications website

Science Writing by Loren W. Walker:

Resumé for Loren W. Walker (PDF file requires Adobe Acrobat Reader)

 

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"Scientific Collaboration Grows in Western Massachusetts' Pioneer Valley"
originally published at www.rtacentral.com

By Loren Walker
11-22-03

ABSTRACT
The Breast Cancer Working Group is a multidisciplinary team of researchers from the Baystate Medical Center and the University of Massachusetts Amherst. Working Group researchers represent a wide variety of scientific disciplines including surgery, pathology, nursing, epidemiology, statistics, molecular genetics, computer science, chemical engineering, and nanotechnology. The Working Group's laboratory-to-clinic approach expedites the translation of scientific discoveries into practical biomedical applications. In addition to university and hospital facilities, Working Group researchers have access to new, state-of-the-art laboratories at the Baystate-UMass Biomedical Research Institute in Springfield. Currently, the Group's collective effort is focused on understanding the nature of pre-cancerous breast lesions that can transition into malignant tumors. Dr. Richard Arenas, Chief of Surgical Oncology at Baystate, and Dr. Joe Jerry, UMass professor of Molecular Medicine, are two Working Group members whose collaboration with colleagues in the UMass Chemistry and Chemical Engineering departments is directed toward translating their medical and biological expertise into practical treatments and preventative therapies for breast cancer.

The COLLABORATIVE APPROACH
Collaboration fuels scientific innovation. In a 2001 report, the National Cancer Institute stated that, "multidisciplinary teams are needed to solve virtually all of the 'big' problems in cancer research." Productive collaboration among mathematicians, biologists, computer scientists, epidemiologists, imaging scientists, physicists, and clinicians is needed to effectively cure and control cancer, the report said. Now, in western Massachusetts, just such a multidisciplinary research team exists. The Pioneer Valley's Breast Cancer Working Group, made up of M.D.s and Ph.D.s from the Baystate Medical Center in Springfield and the University of Massachusetts at Amherst, was formed to investigate the basic pathology of breast cancer and develop more effective interventions to treat and prevent the disease.

Collaboration across scientific disciplines has yielded many important achievements including the discovery of the structure of DNA. In his book on the process of scientific discovery, Francis Crick wrote, "In nature, hybrid species are usually sterile, but in science the reverse is often true. Hybrid subjects are often astonishingly fertile."

The Breast Cancer Working Group is a hybrid coalition of researchers, representing a wide variety of scientific disciplines ranging from pathology and surgical oncology to chemical engineering and nanotechnology, that evolved out of a partnership between researchers at UMass Amherst and the Baystate Medical Center. They meet regularly to help steer the focus of the Group and to allow its direction to influence their own research programs and clinical practice.

At RISK for CANCER
Every year thousands of women are diagnosed with non-cancerous breast disease. Although, so-called benign breast disease is not cancerous, a certain form of the disease, called atypical hyperplasia, is associated with an increased risk of breast cancer. At least 10% of those women diagnosed with atypical breast lesions will develop cancer within one year.

At Baystate Medical Center, physicians frequently detect these atypical hyperplasias and, although they know that some of those patients will soon develop breast cancer, there is nothing to be done about it. Treating all women with atypical hyperplasia would be expensive and very invasive. However, inaction all but assures that 1 out of every 10 women diagnosed will be battling breast cancer within a year. This clinical dilemma, and the problem it poses for physicians and their patients, compelled the Breast Cancer Working Group to direct their focus toward investigating cancer associated with atypical, pre-malignant breast lesions.

Dr. Joe Jerry is a professor of Molecular Medicine at UMass Amherst and the designated leader of the Working Group. His lab uses animal models to study the molecular pathways that mediate susceptibility and resistance to breast cancer and to design targeted therapeutics to prevent it. "Atypical doesn't sound good," Jerry says. "The physician has to tell the patient, 'go home and don't worry about it, but come back and have it checked out often, because you should worry about it.' That's pretty uncomfortable, and at some point people might die from worrying about the disease rather than from the disease itself."

PREVENTION is the BEST TREATMENT
A primary goal of the Working Group is to harness the formidable scientific expertise of its members to achieve a better understanding of the basic cellular and molecular mechanisms that control how atypical hyperplasias transition into tumors. By accurately describing the pathology of tumorigenesis, new drugs can be designed and new methods developed to treat or even prevent breast cancer.

"Stopping the transition would be real prevention. It would be the ultimate prevention," says Dr. Richard Arenas, Chief of Surgical Oncology at Baystate Health Systems and an active researcher in the Breast Cancer Working Group. "If you know that, biologically, there is a link between atypia and the onset of actual breast cancer, presumably because you see it pathologically, then you've identified an actual pathway and there is a possibility of interrupting that pathway," he said.

Arenas has partnered with Jerry to explore how certain anti-cancer drugs affect tumor cells at a molecular level and with other Working Group members in the Chemical Engineering department at UMass Amherst to develop more effective drug-delivery methods. They are interested in the effect that estrogen and prostaglandin-blocking drugs, called aromatase inhibitors and COX-2 inhibitors respectively, have on the activity a tumor-suppressor protein called p53. When working properly, p53 performs an indispensable function in the cellular reproduction process by preventing abnormal cell proliferation. Mutations in the p53 gene and non-mutational changes in p53 function may be associated with up to 45% of all breast cancers.

A GOOD MODEL
In depth experimental analysis of p53's role in breast cancer is currently underway in Joe Jerry's laboratory at UMass Amherst. Jerry has developed a mouse model with a defective p53 gene that consistently develops mammary tumors, which are very similar to those found in human breast tissue. Other animal models for breast cancer have previously been created, but none develop the true ductal hyperplasia that mimics human breast tumors.

"We're seeing a series of different structures in the carcinomas that are very much like humans," he says. This analogous system allows Jerry's research team to experiment with drugs that stimulate the surveillance function of p53 and boost its ability to prevent abnormal cell proliferation.

Through experimenting with the mouse model, Jerry's team has been able to look at how certain drugs stimulate p53's tumor suppression activity. He says they've been able to, "dissect out at least one drug that has good effects on p53 without the negative side-effects on the patient." According to Dr. Jerry, this drug is currently on the market and the observed effect of it on p53 was previously unknown. But he won't release the name of the drug before publishing his findings because, "the results," he says, "have been pretty dramatic."

A BASE for COLLABORATION
Jerry's lab has been working with the Baystate Medical Center for nearly ten years. And, since a state-of-the-art biomedical research facility was opened in Springfield last year, members of the Working Group now also have access to a well-equipped laboratory where they can engage in collaborative research projects.

"It's a resource for both [Baystate and UMass]," says Jerry about the new Biomedical Research Institute in Springfield, "and rather than competing for space at the University or at the Hospital, we have this very flexible resource. So, you can say, 'come on over, use it when you need it. If you've got a good idea, let's go do it.'"

The $90 million Biomedical Research Institute, a joint venture between UMass Amherst and the Baystate Medical Center, is open to Working Group researchers from either campus and to private companies who want to lease space in the facility. Dr. Larry Schwartz, the Institute's Director and UMass professor of Molecular Biology, points out that the collaborative laboratory environment at the Institute has certain advantages over a traditional medical school research facility. "Medical schools," he says, "by and large don't have polymer scientists, computer scientists, chemical engineers and all these other disciplines that a university has."

The Institute is already hosting collaborations between surgery residents and UMass graduate students. This type of partnership affords opportunities for graduate students to work with residents on practical applications for their research and for residents to build their skills in the area of basic science, explains Dr. Arenas. "We not only have graduate students working at [the Institute], but also physicians in training, which may develop into some really interesting synergy and education for both parties," he said.

CROSS-DISCIPLINARY PARTNERSHIPS
Bacteriolytic therapy, the use of specially engineered bacteria to target and treat cancerous cells, is the subject of a Working Group partnership underway at the Biomedical Research Institute. Arenas and a surgery resident are collaborating with Dr. Neil Forbes, a UMass professor of Chemical Engineering and member of the Breast Cancer Working Group, to investigate how these bacteria affect certain solid tumors . They hypothesize that the combination of bacteriolytic therapy and standard chemotherapy will more effectively attack and destroy these tumors from both the inside and out.

Nanotechnology in biomedicine is the basis for another cross-disciplinary partnership within the Working Group. Joe Jerry and Dr. Vince Rotello, a UMass Amherst Chemist and Nanoparticle Engineering expert, have secured funding to study how nanoscopic particles can serve both diagnostic and therapeutic roles in the treatment of breast cancer. In one application, the patient is administered a solution of gold or iron nanoparticles that are designed to bind only with the cell receptors and proteins of cancerous cells. "One attached," Jerry explains, "the patient is placed in a magnetic field, which induces a current and causes the particles to heat up, killing the cancerous cells, but without damaging the surrounding tissues."

A STIMULATING ENVIRONMENT
Dr. Jerry is openly enthusiastic about the possibility for developing even more useful therapies and technologies through cross-disciplinary collaborations of this kind. "The UMass researchers," he says, "have the toolbox, they just need somewhere to apply it and the Breast Cancer Working Group has all the resources to identify practical applications for those tools."

Both Arenas and Jerry agree that the environment of the Working Group, where individuals who are all experts in their respective fields are gathered around a central problem, is very intellectually stimulating. "I'm constantly fascinated by what's going on with other people," says Dr. Arenas. Those researchers attracted to the group tend to share this fascination and they're genuinely interested in listening to other people's ideas, he said.

SPREADING the NEWS
Communication is important. Group members try to talk about their work with a wide variety of people at the campuses and within private industry. If an organization or company has a product, idea or technology that they would like to apply toward the breast cancer model developed at UMass or towards developing a clinical trial at Baystate targeting patients with atypical hyperplasias, then the Working Group would like to connect with them, Dr. Arenas said.

Over time, the Working Group will learn more about how to effectively coordinate this sort of multi-institutional, cross-disciplinary collaboration. Eventually, Arenas explains, it could serve as a model for other communities with a hospital interested in branching out into research and a university that wants to apply itself toward something more applicable like medical treatment or medical technology development.

ROOM for GROWTH
When asked why he left a large, prestigious institution in Chicago to come to western Massachusetts Dr. Arenas replies, "Well, I met individuals, actually I met Larry [Schwartz], and Larry told me something very interesting. He told me, 'the biggest disadvantage of coming here is that there's nothing set in stone. There is really no infrastructure in place for this type of collaborative research initiative.' But then he said, 'you know what the biggest advantage of this place is? It's not set in stone. There's no infrastructure here. You can go to your heart's content in terms of where you want to take things.' And he's right."

As more researchers from academia, the medical community and private industry learn about the Breast Cancer Working Group it will continue to grow and the breadth of its collective expertise will widen. This, combined with the enthusiasm and insatiable intellectual curiosity of this hybrid group, ensures that it will also continue to be fertile ground for the ideas and innovations that lead to better breast cancer treatments and better lives for patients.


For a list of Breast Cancer Working Group members go to: http://www.baystatehealth.com/3489/4776/4803/4818/Data_Page/1051630234.html

 

 

 

 

 

 

 

"Antimicrobial Alternatives"
originally published on rtacentral.com


by Loren Walker
12-29-03

Self-sterilizing materials offer manufacturers an alternative way to increase the functionality and value of their products. To explore the science and technology of antimicrobial materials and their applications in manufacturing industries, a representative from AgIon Technologies of Boston and UMass Polymer Science professor Greg Tew came to share their expertise at a recent RTC-sponsored event in Northampton.

The well-known antiseptic properties of silver, "Ag" on the Periodic Table of the Elements, are the basis for AgIon's antimicrobial materials. Dr. Tew and his colleagues at the University of Pennsylvania founded a company called PolyMedix as a result of the biomimetic antimicrobial polymers they invented. Event attendees learned how medical devices, food processing equipment, door handles, school lockers, counter tops, sneakers, toilet seats and a wide variety of other products can be manufactured with self-sterilizing surfaces to prevent the spread of infectious disease.

It wasn't until 1900 that doctors began wearing gauze face masks during surgery. As recently as 1870, some prominent physicians still scoffed at the idea that microscopic organisms could actually make a person sick. In fact, the idea that germs cause disease was only officially embraced by the medical community in 1887 when "germ theory" was described for the first time in an accredited medical textbook. Today, the health risk associated with microbial pathogens is universally recognized and antimicrobial products of all kinds fill supermarket shelves.

Awareness of the risks posed by pathogenic bacteria is most pronounced in hospitals where bacterial infections can have fatal consequences. According to PolyMedix, health care-acquired infections kill 100,000 people annually and result in over $45 billion in related costs. Self-sterilizing surfaces applied to operating tables, medical instrumentation or patient gowns could have significant benefits for patients and the health care industry.

The myriad potential medical applications of antimicrobial biomimetic polymers, called polymetics, gave rise to the PolyMedix company name. The company's founders are researchers at the University of Pennsylvania and the University of Massachusetts Amherst who succeeded in creating synthetic polymers that mimic the antimicrobial activity of the germ fighting, protein-like compounds found associated with many animals and plants. Naturally-occurring antibiotics, like magainins, cecropins and defensins, target and destroy bacteria by degrading the negatively-charged lipid portion of bacterial cell membranes, but do not harm positively-charged mammalian cell membranes. These antimicrobial peptides (small chains of amino acids) dwell on the organism's exterior and serve as the first line of defense against the pathogens in its environment.

PolyMedix's biomimetic polymers have the same antimicrobial activity and mechanism of action as their peptide models, but are much less expensive to make than peptides and they're not susceptible to enzymatic degradation. PolyMedix plans to license their technology to companies that wish to incorporate the synthetic antimicrobial polymers directly into any number of plastic products and textiles or use them as a coating on metal devices and equipment.

The antiseptic properties of silver were recognized by the ancient Egyptians and silver has been used as a wound-healing agent ever since. The bactericidal action of silver is the result of the interaction between positively charged silver ions and the negatively-charged bacterial cell surface. The silver cations attach to the bacterial cell membrane and cause an oxidation reaction that ruptures the membrane and kills the cell.

AgIon Technologies has developed an effective method of harnessing silver's antimicrobial activity. Silver molecules that are bonded to a biologically inert ceramic material called zeolite. Ambient moisture causes antimicrobial silver ions to be released from the ceramic substrate. To the naked eye, the 5 micrometer wide ceramic zeolite "cases" that encapsulate the silver molecules look like a fine powder, which can be easily incorporated into a variety of materials and coatings.

AgIon antimicrobial materials and coatings have already been incorporated into a number of medical, industrial and consumer products including medical packaging, industrial air handling systems, school lockers and running shoes. Through AgIon's antimicrobial technology, traditional manufacturers can add a premium feature that enhances the functionality of existing product lines. The company's engineers specialize in working with manufacturers to determine how best to incorporate AgIon's antimicrobial compound into their existing manufacturing procedures.

But what about the risk of creating resistant bacteria through over-use of antibacterial agents? Instead of attacking the reproductive machinery of bacterial cells, like many anti-biotics and common anti-bacterial agents, both AgIon and PolyMedix antimicrobial products attack the cell membrane. This approach greatly minimizes the risk of creating resistant strains of bacteria, the companies say.


Related links:

PolyMedix: http://www.polymedix.com/

AgIon Technolgies" http://www.agion-tech.com

Dr. Gregory Tew's Research: http://www.pse.umass.edu/tew/tew.html

Antimicrobial Polymers article: http://www.psc.edu/science/2002/klein/new_weapons_for_the_germ_wars.html


 

 

 

 

 

 

 

 

The Bioscience Industry of Tomorrow Depends on the Students of Today

Published in Mass High Tech: The Journal of New England Technology on 12/1/03

By Loren W. Walker

"The 21st century belongs to the life sciences," declared Massachusetts Senator Edward M. Kennedy in November 2002 at the opening of a new biomedical research facility in Springfield.

It was an appropriate declaration for a senator whose state is positioned at the top of the bioscience industry food chain. What he did not say, however, is that today's students - tomorrow's workforce - are not getting the science education that they will need to take advantage of future opportunities in the life sciences. The bioscience industry revolution is coming, but there may not be a qualified workforce available to meet it upon arrival.

The Massachusetts Biotechnology Council (MBC), the state's biotechnology industry organization, reports that many of its member companies are struggling to recruit workers with the requisite skills to fill technical positions in bioscience companies. This dearth of qualified biotech workers comes at a time when many of the bioscience companies that were founded in the early 1990s are shifting their emphasis from research and discovery to development, manufacturing and commercialization.

During the R&D phase, most, if not all biotechnology companies operate at a net loss, and many succumb under the weight of this financial burden. The Holy Grail for those companies that do survive the initial R&D phase is the successful commercialization of at least one product or service.

"This is where the lion's share of future economic value - and jobs - will be generated," wrote the MBC and the Boston Consulting Group in a 2002 report on the future of the biotechnology industry. "Over the next three years, the great bulk of the biotechnology companies founded in the early nineties will decide where to locate their manufacturing facilities. If Massachusetts does not fight for these jobs it will be an enormous missed opportunity," the report stated.

In Massachusetts and throughout the United States, advances and innovation in the biosciences are accelerating while at the same time student exposure to science in general, and to the life sciences in particular, is decreasing. America's schools, it seems, are in the midst of a science education crisis. In a recent interview with broadcast journalist Charlie Rose, Intel President Andy Grove noted that only about 5% of U.S. students study science or engineering as compared to 30-40% in China.

As the bioscience industry grows, as it is predicted to do throughout this century, it will require an ever-larger, scientifically literate workforce. Without access to a sizeable and qualified worker pool, companies will be compelled to locate their manufacturing facilities elsewhere and it will be our economy that suffers the consequences. Already, they are scrambling to find enough qualified workers to staff manufacturing facilities.

To address what is being called a "chronic shortage" of skilled biomanufacturing workers, a pilot worker-training program was recently initiated in eastern Massachusetts. The "Building Essential Skills through Training" (BEST) program is a collaborative effort of the MBC, state agencies and industry to recruit, screen, hire and train students who are then awarded free tuition and are paid a salary during an intensive four-week training program

Such worker-training programs are necessary to meet immediate workforce needs, but do nothing to address the current science education crisis.

"Young people need to develop life sciences literacy early on," wrote MBC Education Director Cora Beth Abel in the Spring 2003 edition of the organization's newsletter. Ms. Abel also cited research endorsed by the National Science Foundation, which "has shown that the greatest potential impact to student decisions about careers in science begins in the middle school years (grades 5-8)." Therefore, a concerted effort to revitalize science education must begin in the elementary and middle schools.

The revitalization and modernization of science education will require external support from bioscience companies, universities and industry organizations. By supporting early science education, universities will benefit from increased student enrollment in science-intensive programs and bioscience companies will have access to an ample and scientifically literate workforce. Industry-school collaborations would also give students an opportunity to see the human face of the sciences.

Most students have never met a real world scientist. They have no idea what a career in the life sciences looks like, so they don't see it as a viable option. Wyeth BioPharma in Andover, Massachusetts is one company that is trying to remedy this and stimulate student interest in science by organizing presentations at area schools and inviting students to tour working laboratories. If bioscience companies throughout the state adopted similar outreach programs perhaps "scientist" would be more frequently listed along with "fireman" and "astronaut" as a response to the "what do you want to be when you grow up?" question.

However, the classroom is still where students learn fundamental scientific concepts. Modern resources and an updated science curriculum are essential tools that teachers need to build science literacy. Bioscience industry organizations like the MBC and the national Biotechnology Industry Organization (BIO) already have staff and resources dedicated to disseminating modern science-education curriculum, and mobile laboratories like Connecticut's BioBus and Boston's City Lab are bringing state-of-the-art biotechnology labs to students and educators, but their reach is limited.

To truly remedy the current crisis, the MBC asserts that government must commit to making a strong and enduring investment in science education. Some recommendations made by the MBC on how to substantially strengthen science education statewide include: that all elementary schools have a science curriculum coordinator; that motivated science teachers are empowered and supported through access to new curriculum and resources; that professional development and continuing education opportunities are made available to K-12 science teachers; and that a governor's excellence-in-science grant is made available for schools that improve in exposing a broad range of the student population to the opportunities and advantages offered by science education. For a complete list of recommendations for the Massachusetts bioscience industry see the MBC report on-line at www.MassBiotech2010.com

It is estimated that by 2010 up to 150,000 bioscience jobs could be created in Massachusetts alone. The economic benefit to the state would be substantial. However, without a scientifically literate workforce, most of those new jobs will go to other regions or even continents. The only way to ensure tomorrow's economic growth is by making a significant investment in science education today. There is no doubt that the 21st century belongs to the life sciences. The question is: who in the 21st century will reap the rewards?

 

 

 

 

 

 

 

Springfield Hosts Biomedical Implants Conference

Published at rtacentral.com

By Loren W. Walker
10.6.03

It all began in 1905 with steel and a guy named Bill who worked on Cadillacs. Back then, the steel treaters of Detroit were a tight-lipped bunch who guarded their trade secrets closely. Today, the metals and materials industry is an international community, characterized by a spirit of collaboration and networking that fuels innovation and yields important technological advances in everything from automobiles to medical devices.

On Wednesday October 1st, western Massachusetts was host to a conference and networking opportunity for dozens of materials experts from around the region who converged on downtown Springfield to discuss the application of biomaterials in modern medicine. The "Body Parts: Ceramic, Metal and Plastic Biomaterial Implants for Human Body Repair" conference, held at the Sheraton Springfield, was a joint meeting of the American Society of Materials Hartford Chapter, the Western New England Section of the Society of Plastics Engineers and the Springfield-based Regional Technology Corporation (RTC) of Western Massachusetts.

"It's a personal matter," said conference moderator and UConn Institute for Materials Science Director Meyer Ezrin, when a show of hands in the conference room demonstrated that a majority of attendees had some kind of medical or dental implant. Many of the innovative biomaterial implants that have changed the way doctors practice medicine were invented and refined at the Johnson & Johnson's Center for Biomaterials and Advanced Technologies in New Jersey where one of the conference speakers, Dr. Mark Roller, is a principal scientist.

Meyer introduced Dr. Roller, who has overseen the development of biomaterial implants for all parts of the human body, by encouraging him to share his experiences navigating the complicated federal regulatory approval process calling the FDA , "one of the toughest bodies to get anything through."

Roller focused his talk on bioabsorbable materials that degrade over a known period of time after implantation and on medical devices in FDA Class III, which is the most strictly regulated group of devices - those that support human life. He described several devices created through advanced polymer chemistry that are more effective and less invasive than traditional implants like metal screws.

A bioabsorbable crosspin designed to hold together the bone, tendon and hamstring after a severe anterior cruciate ligament (ACL) injury gives the ACL plenty of time to heal before it degrades four years after implantation. And, instead of screws, "smart" polymeric cranial fixation devices can be molded to fit any shape of skull and, as an aid to the physician, change color when heated indicating a temporary state of malleability.

Meyer introduced the second conference speaker, UConn Department of Metallurgy and Materials Engineering assistant professor Dr. Mei Wei, whose research is directed toward the development of "bioactive" materials that behave just like the bone and tissue of the human body that they are designed to replace, making artificial implants more like organic transplants.

Dr. Wei focused her talk on the properties of bone replacement materials made from a composite of synthetic polymers and hydroxyapatite (HA), a naturally occurring and fundamental part of bone composed primarily of calcium and phosphate.

Cell cultures of HA prepared in Dr. Wei's lab are chemically identical to HA found in bone, but Wei cannot yet "grow" a bone from a petri dish. The still poor mechanical properties of cell-cultured HA require that it be mixed with synthetic polymers to make implants that actually mimic the mechanical properties of natural bone and are suitable for use in bone replacement surgery.

Springfield was an ideal site for the October 1st "Body Parts" conference because of the region's history in precision manufacturing and proximity to several universities with active materials research and biomedical engineering programs, including: the internationally renowned Polymer Science and Engineering Department of UMass Amherst, the Biomedical Engineering Department of Western New England College, the UConn Institute for Materials Science and the multi-institutional, biomedical engineering program of the Biomedical Engineering Alliance and Consortium (BEACON) based in Hartford.

The international metals and materials community in western Massachusetts and the Connecticut-Massachusetts "Knowledge Corridor" is represented by the Materials and Manufacturing Technology Network (MMTN) of the RTC.


 

 

 

 

 

"The New Golden Age of Vaccines is Green"
by Loren
previously published on OneScience.com 5-26-03

 

ABSTRACT - Plants are the most efficient protein producers on the planet. Through genetic transformation of their nuclear or chloroplast genome, plants like the tomato and the potato can be induced to synthesize a variety of immunogenic proteins that function as vaccines when ingested by animals or even humans. The technology promises inexpensive and easily administrable vaccines. In spite of ongoing technical challenges and concerns about the safety of producing vaccines and other pharmaceuticals in green plants, plant-based vaccines may prove to be the most useful and widely accepted innovation to come out of agricultural biotechnology to date.

"If it doesn't kill you it'll make you stronger." In 1796, British physician Edward Jenner took that aphorism to heart when he conceived of a revolutionary way to prevent one of the most deadly diseases of his time, the "speckled monster," smallpox. Jenner discovered that patients who consumed small quantities of ground-up cowpox lesions became immune to smallpox, which was known to be a related disease. Jenner's invention of the first vaccine was heralded as one of the most important public health innovations of all time and the science of immunology was born.

Fast forward to the year 2003. Vaccination has been the most widely used public health tool of the twentieth century. Hundreds of thousands of deaths from smallpox, measles, diphtheria, polio, pertussis (whooping cough), tetanus and other diseases have been prevented by childhood immunization. Revolutionary advances in molecular biology have spurred the development of new, highly specific vaccines against modern plagues like hepatitis, HIV and cancer. However, as immunological drugs become more advanced, they are also becoming more complicated, more labor intensive to produce, and more expensive. Even relatively simple injectable vaccines can cost between $40 and $100 per dose.

The high cost and difficulty of transporting and administering injectable vaccines to remote populations in the developing world means that many children go without necessary vaccines and consequently many will die from preventable illnesses. The problem is not theirs alone to bear. Uncontrolled outbreaks have global consequences. In a world where anyplace is just a plane flight away, the threat of an epidemic anywhere poses a risk to everybody everywhere. "Mysterious Chinese respiratory virus kills nine Canadians," read the headlines this week.

We now know that an uncontrolled virus anywhere is a threat to health everywhere.

Clearly, vaccines that are inexpensive and easily administrable could save hundreds of thousands of lives in developing countries and prevent the spread of disease to other parts of the world. In the early 1990s a pioneering molecular biologist, Charles Arntzen, took the first step toward creating just such a vaccine. He conceived of a way to inexpensively synthesize immunogenic antigens by exploiting the protein-assembling machinery of plant cells. [1, 2]

Classic vaccines, like the one invented by Jenner in the 18th century, are essentially very small doses of potentially harmful pathogens. Inherent in their application is the remote but real risk that the microorganisms that compose that vaccine will actually cause the disease they are supposed to prevent. That is why vaccine subunit preparations are the preferred method of immunization today. The subunits cannot cause an infection on their own because they are simply antigenic proteins and do not contain any of the pathogen's genes. Plant-based vaccines are like subunit preparations. The plants are genetically transformed to express antigenic proteins, but they do not have the genes that would enable the pathogen to form. Arntzen realized that plant-based vaccines would be as safe as subunit preparations, that they would cost a lot less and would not require refrigeration.

In 1999, after spending several years researching plant-based vaccines, Arntzen testified to the Senate Committee on Agriculture, Nutrition and Forestry on what he called the "dramatic potential of plant genetic engineering to directly benefit human health." He described how plant-based vaccines could prevent the nearly 2.5 million annual child deaths that result from enteric diseases caused by cholera or virulent strains of E. coli. As evidence of broad-based support for the technology, Arntzen referred to a World Health Organization conference on Child Vaccination where edible vaccines were highlighted as a recent technological advancement that could profoundly impact public health. [3]

One reason that these biotech vaccines are believed to hold such enormous potential for developing countries is not high-tech at all. It is simple logistics. In contrast to injectable vaccines, plant-based vaccines would not only be cheaper, but they would be easier to administer and could potentially be grown near the population targeted for vaccination, according to Carol Tacket, MD at the University of Maryland. [4]

The significant public health implications of Arntzen's concept became apparent to investigators within the immunology and agricultural biotechnology research communities. Since he first conceived of the idea in the early 1990s, an ever-growing number of researchers at academic and commercial laboratories have taken up the call to develop vaccine-synthesizing transgenic plants. These scientists and their respective institutions have shown conclusively that when genetically transformed, plants like the tomato and the potato can be induced to synthesize a variety of immunogenic proteins that function as vaccines when orally ingested by animals or even humans.

As recently as October, 2002 the Boyce Thompson Institute for Plant Research reported that plant-based vaccines could provide "an economical alternative to fermentation systems." They point to animal and human studies that suggest "that ingestion of transgenic plants containing vaccine proteins causes production of antigen-specific antibodies in serum and mucosal secretions." [5]

Arntzen, former director of the Boyce Thompson Institute, is now based in Arizona at the Arizona Biodesign Institute in Tempe. He and his colleagues are working on early-stage clinical trials of potato-based vaccines for hepatitis B, virulent strains of E. coli and the Norwalk virus. They too have convincing evidence that ingesting vaccine-laden plant tissue triggers the production of antibodies in animals and humans. As investigators report success during early clinical trials Arntzen emphasizes the incredible production potential of plant-based vaccines. He estimates that one could vaccinate all of China against hepatitis B using plants growing on only 125 acres. [6]

Researchers at the University of Rochester have set their sights on today's most infamous plague: cancer. More than 80% of cervical cancer cases in women are linked to the sexually transmitted Human Papillomavirus (HPV). U. Rochester scientists are working with Arntzen and his colleagues at the University of Arizona to develop a plant-based vaccine against HPV. [7]

An anti-HIV vaccine is the holy grail of AIDS prevention and treatment research. The widespread incidence of AIDS in developing countries, especially Africa, necessitates that any treatment for the disease be inexpensive, stable enough for delivery to remote communities and easily administrable. Plant-based vaccines meet these requirements and, because they are orally administered, may elicit the strong mucosal immune response required to stop the transmission of the virus during sexual contact. At Jefferson University in Philadelphia, immunology pioneer Hilary Koprowski and his colleagues have transformed spinach plants to express a protein that is key to HIV replication. This is a first step toward the creation of a comprehensive plant-based vaccine for HIV1. [8,9]

Other research institutions and private companies that have followed Arntzen's lead include: Loma Linda University where researchers are developing insulin producing potatoes for the treatment of juvenile diabetes; the French company Meristem Therapeutics, which is developing transgenic corn designed to combat cystic fibrosis; and several companies that are looking past vaccines toward the pathogen-fighting antibodies they induce. Dow, Monsanto and Epicyte Pharmaceuticals have research programs dedicated toward the development of monoclonal antibodies that can be used as therapeutic agents for the diagnosis and treatment of a variety of diseases. [6] And, in India, scientists took a first step toward an edible, plant-based vaccine against anthrax when they successfully integrated the protective antigen gene into the nuclear genome of tobacco. [10]

Decades of painstaking research in molecular biology have provided the requisite tools for the technology of plant-based vaccines. Some of the most important tools include amplification of DNA via the ubiquitous polymerase chain reaction (PCR), Agrobacterium-mediated genetic transformation of plant cells, and an ever-increasing understanding of the all-important "promotor" sequences that augment expression of the desired proteins.

So, whether they are developing vaccines or the related antibodies, all the research institutions and companies involved in this technology are working with the same biological paradigm: DNA sequences are the blueprints for protein production. Plants are exceedingly efficient protein producers. Therefore, if it's proteins that you want - vaccines, antibodies, or even bioplastics - then the most efficient way to produce them is within plant cells.

Scientists investigating plant-based vaccines at the Biotechnology Foundation Laboratories see themselves as "poised on the brink of an enormous medical breakthrough - one that could alter the face of the world of healthcare in the next century." [11] In addition to the financial and logistical benefits of employing plant-based vaccines, proponents of the technology point to the advantage of increased patient safety. Unlike animal-based bioreactor systems, plants are incapable of harboring potentially harmful animal or human pathogens. Additionally, plant-based vaccines are edible and therefore do not require syringes, which pose the threat of infection to recipients.

These characteristics have convinced many researchers and science reporters that plant-based, edible vaccines are the key to effective, more widespread vaccination. And, as observed by at least one other reporter, "Until everyone has routine access to vaccines, no one will be entirely safe." [13] Public interest in the technology was verified last year when, in a survey commissioned by the biotechnology industry, plant-based vaccines were named as one of the five most important biotechnology innovations of 2002. [14, 15]

In an era when anything genetically modified is a potential target for biotechnology opponents, it seemed as though the life-saving potential of plant-based vaccines might make them immune to criticism.

Then there was the Prodigene incident.

The Prodigene Company is a leader in the development of plant-based vaccines and holds several major patents relating to the process of using plants as bioreactors to make vaccines. [2,4] Prodigene genetically engineered corn plants to produce a vaccine to protect baby pigs from a gastrointestinal disease. A Nebraska farmer was contracted by the company to grow an experimental plot of the biopharmaceutical corn in his field. The farmer followed the containment guidelines for growing biotech crops as outlined by the United States Department of Agriculture.

The bioengineered corn crop was harvested in the fall of 2001. The following spring the owner of the test field decided to plant soybeans there. In accordance with USDA guidelines Prodigene sent inspectors to the field in the summer of 2002 to ensure that none of the genetically engineered corn was sprouting amid the newly planted soybeans. They did not find any stray corn so inspections were discontinued in August of that year.

However, when USDA inspectors arrived at the field in November of 2002, after the soybean harvest, they observed stubble from corn stalks in the ground suggesting that at least some of the bioengineered corn had been harvested along with the soybeans. The USDA then tracked the soy harvest to a storage elevator where the soybeans had been mixed with the harvest from several other farms. The USDA incinerated of all 500,000 bushels, and ordered Prodigene to reimburse the farmers $3 million for their destroyed harvest and forced the company to pay an unprecedented $250,000 fine. [16]

The Prodigene incident underscores concerns about the potential risks of the technology. Opponents of biopharming and plant-based vaccines claim that the potential of the technology is overshadowed by the increased risks it poses. Like all genetically modified crops there is the concern that transgenes from vaccine-producing plants will inadvertently be incorporated into wild plants by unintended cross-pollination. However, the fact that these particular transgenes code for biologically active, pharmaceutical proteins poses an even greater threat to the environment and to humans, according to Joe Cummins of the Institute for Science in Society. [17]

Cummins describes a scenario where vaccine pollutants spread airborne as pulverized plant debris or leech out of plant roots into the soil and groundwater. Humans or animals living in the area may inadvertently ingest the vaccine by drinking vaccine-polluted water or by breathing vaccine-contaminated dust. Exposure to the immunogenic antigen in this way can stimulate oral tolerance to the vaccine, which would render it useless as an immunizing agent. Individuals tolerant to the vaccine would not produce antibodies in response to intentional vaccination and therefore would be defenseless against the pathogen.

Even staunch supporters of agricultural biotechnology see plant-based vaccines and plant-based pharmaceuticals in general as more risky than earlier generations of genetically modified crops. "We're one of the strongest defenders of using biotechnology in agriculture. But this is something different," said Rhona Applebaum, executive vice president of the National Food Processors Association. [16]
In response to the Prodigene incident, the USDA is proposing stronger regulations for bioengineered food crops including: setting aside fields and equipment exclusively for experimental crops, marking biopharm plants as distinct, perhaps by dyeing their leaves a different color, and moving experimental fields out of the Midwest's Corn Belt. [16]
So, while transgenic crop vaccines may indeed hold enormous potential as a source of human and animal therapeutics, Joe Cummins and his colleagues at the Institute for Science in Society remind us that the risks to human health and to the environment are real, and in his view, the only way to safely produce these crops is to use controlled production facilities like greenhouses.
Even as plant-based vaccine critics like Cummins are trying to generate public awareness about the risks of the technology, scientists in the laboratory are still trying to overcome several technical obstacles to the practical application of producing immunogenic antigens in plants.
The primary challenges revolve around controlling the expression levels and stability of antigen proteins in plant cells. In order for plants to be efficient delivery vehicles for vaccines, the immunogenic protein has to be expressed at high levels in the plant cells. Low transgene expression levels have plagued a number plant-based vaccine experiments. [17] Insertion of the immunogenic protein-encoding gene into the chloroplast genome instead of into the nuclear genome may help increase expression levels. Several investigators have demonstrated increased transgenic protein expression in the chloroplast genome. [18] An additional advantage of chloroplast transformation is that the chloroplast genome is not inherited by the next generation of plants, so the transgene(s) cannot be passed on, thereby eliminating the risk of unintentional cross-pollination. Finally, the stability and immunogenicity of plant-produced antigens has been found to vary significantly. This is believed to be a problem inherent to oral delivery, which will have to be overcome. [5]
Overcoming these technical difficulties will take time and money, a lot of money. Charles Arntzen and his colleagues have already spent $5 million on their work to develop effective plant-based vaccines, but they will need at least $20 million to get through the full battery of clinical trials required for FDA drug approval. [6,7] A possible source of funding may be the Bill and Melinda Gates Foundation, which is already actively working to expand immunization programs in poorer nations. A grant and the accompanying endorsement of the Gates Foundation would not only provide much needed funds for Arntzen's research, but might also establish the technology of plant-based vaccines and pharmaceuticals as the most promising innovation to come out of agricultural biotechnology to date.


Notes:

1) Blake, M.E. and Arntzen C.J. "Edible Vaccines." http://www.nal.usda.gov/pgdic/Probe/v5n1/lead.html

2) Arntzen, C.J., et al. 2000. "Vaccines Expressed in Plants" United States Patent # 6,136,320

3) Statement of Charles J. Arntzen, Ph.D. President and CEO Boyce Thompson Institute for Plant Research, Inc. Ithaca, New York Senate Committee on Agriculture, Nutrition and Forestry. 10/6/99

4) "Broad Patent Received for Plant-based Edible Formulations." Virus Weekly, 11/07/2000, p6, 2p

5) "Prospects for edible vaccines limited, but still promising." Virus Weekly, 10/2/2002, p20.

6) Wherry, R. 1/20/2003. "Planting Hope." Forbes. 171(2): 110

7) Council for Biotechnology Information. "Edible Vaccine Holds Promise for Prevention." http://www.whybiotech.com/index.asp?redirect=HPV%2Ehtml

8) Henderson, CW. 6/4/2001. "Tat Protein, Component Of HIV Vaccines, Has Been Successfully Produced In Spinach." AIDS Weekly. P18.

9) Young, Emma. 4/20/2002. "How long before HIV vaccine is growing in a field near you?" New Scientist. 174(2339):13.

10) Aziz M.A., Singh S., Anand Kumar P., and Bhatnagar R. 12/2002. "Expression of protective antigen in transgenic plants: a step towards edible vaccine against anthrax." Biochemical and Biophysical Research Communications. 299(3): 345-351.

11) Biotechnology Foundation Laboratories -- http://www.jci.tju.edu/bfl/index2.htm

12) Hepstead, Hemel. Jul-Sep. 2001. "Edible vaccines the key to better immunization." Appropriate Technology.

13) Langridge, W.H.R and Rusting, R. 9/2000. "Edible vaccines." Scientific American

14) Council for Biotechnology Information. "Cancer Fighting Tomato Tops America's 2002 Best in Biotech" http://www.whybiotech.com/index.asp?id=2243

15) Lemonick, M. 10/18/2002 "Best Inventions - Tomato Vaccine" Time. http://www.asu.edu/asunews/inthenews/Time-arntzen_120602.html

16) "Alarm Bells Going Off About Grains that Contain Vaccines." 12/26/2002. Los Angeles Times. http://www.wcfcourier.com/topnews/021226alarm.html

17) Cummins, J. "Risks of Edible Transgenic Vaccines." http://www.i-sis.org.uk/full/PharmageddonFull.php

18) Daniell H.; Khan M.S.; Allison L. 2002. "Milestones in chloroplast genetic engineering: an environmentally friendly era in biotechnology." Trends in Plant Science. 7(2):84-91.

 

 

 

 

"The 'Third Wave' of Agricultural Biotechnology"
by Loren
previously published on OneScience.com 3-6-03

On March 16th to the 19th hundreds of scientists will gather in Québec, Canada at the Hotel Loews Le Concorde for a major, international conference on plant-made pharmaceuticals. The 2003 Conference on Plant-Made Pharmaceuticals is sponsored by organizations on the leading edge of this technology, which is otherwise known as "molecular farming" or, simply "pharming." According to the conference organizers, the event will provide a "unique meeting opportunity between biopharma and plant-based protein production." The over 700 participants that are expected to attend the meeting will make this gathering of molecular farming specialists the largest ever held.

The Québec meeting is the 2003 edition of two previous conferences. Two hundred fifty participants from academia and emerging companies discussed scientific issues at the first conference, held in 1997 in Saskatoon, Canada, where the term "molecular farming" debuted. The second conference, held in London in 1999 saw 450 participants including a "modest contingent of representatives" from the pharma-biotech and financing community.

This year's conference, organized primarily by the International Molecular Farming Association, seeks to continue exploring the scientific foundations of molecular farming as well as the current prospects for funding and the future financial development of the fledgling industry.

According to an official conference press release, "the three-day program begins with 90-minute plenary sessions where world-class keynote speakers relate present challenges and future benefits of plant-made pharmaceuticals. The rest of the day is made of dual-track symposia on technology, business and stewardship, and presentations of platforms, products, applications and technologies, brought to you by top scientists and experienced businesspersons. All frequently asked questions of plant-based production of biologic drugs will be addressed: production cost, capital savings, capacity, introduction to clinical trials, protein quality (glycosylation), containment, biosafety, product regulations, and many others." English will be the official language of the conference and no simultaneous translation will be provided.

Attending the conference will be senior managers of biopharmaceutical and pharmaceutical companies (business development, protein production, product development, quality assurance), top scientists from academia and corporations, senior representatives from novel protein production companies, representatives from governments, regulatory agencies, industry and consumer groups, and members of the press.

Companies presenting at the 2003 Conference on Plant-Made Pharmaceuticals include: Biolex, Ceres, Dow AgroSciences, Epicyte Pharmaceuticals, Greenovation Biotech, Medicago, Meristem Therapeutics, Monsanto Protein Technologies, Plantigen, Planton, Prodigene, SemBioSys, Icon Genetics, and Syngenta.

A new and rapidly expanding branch of agricultural biotechnology, plant molecular farming is considered the "third wave" of industry advancement. The first wave yielded products engineered to be resistant to insect pests (like Bt-corn and Bt-cotton) or herbicides (like Roundup Ready soybeans). The second wave involved producing plants with value-added characteristics like salt-tolerant tomatoes and high-lysine corn. The third wave of agricultural biotechnology is plant molecular farming, which is defined by the Canadian Food Inspection Service as, "the cultivation of plants for industrially, medically, or scientifically useful biomolecules, rather than for traditional uses of food, feed, or fibre."

The bioproducts of molecular farming (pharmaceuticals, fibers, fuels, adhesives, etc.) are synthesized using the existing protein-assembling machinery in plant cells. Plants are the most efficient protein-producers on the planet. Well-studied plant systems like alfalfa, corn, moss, potatoes, tobacco, safflower and others can be genetically transformed to yield a variety of non-native proteins on a large scale, at a lower cost than is possible with current manufacturing methods and with freedom from potential viral and animal protein contamination. However, to date there are no FDA-approved drugs containing material from pharma plants.

Manufacturing these protein-based drugs via the current procedure of using mammalian cells is very expensive, is prone to viral and animal protein contamination and is not well suited to very large-scale production. Industry lobbyists and spokespersons for companies with molecular farming programs point to the high cost and limited availability of these drugs as evidence for why plants should be used to produce pharmaceuticals. Monoclonal antibodies (MAbs), for example, are expensive pharmaceuticals that are also in high demand. MAbs can be produced in transgenic plants for a fraction of the cost and on a much larger scale than would be possible with mammalian cells.

The molecular farming research company Agrecetus makes human antibodies in corn plants. They have created a strain that they claim yields 1.5 kilograms of pharmaceutical-quality antibodies per acre of corn. Vikram M. Paradakar, an Agrecetus scientist interviewed by the journal Trends in Plant Science (2001 Vol. 6 No. 5), predicts that his company "could grow enough antibodies to supply the entire U.S. market for our cancer drug - tens of thousands of patients - on just 30 acres."

In spite of the optimistic language, several sessions of the 2003 Conference on Plant-Made Pharmaceuticals will address the ongoing technical difficulties inherent to producing human drugs in plant systems. Dr. Jon McIntyre, of Monsanto Protein Technologies, is one of several researchers that will discuss their investigations into the potential problems of using plant-produced MAbs on human patients. Carbohydrate moieties found on plant-produced MAbs are not native to humans and may elicit an antagonistic immune system response.

The ability to make plants into protein factories for drug production is undeniably a technology that could radically transform the way medicines are made. However, this enormous potential is not without its risks.

Last year's widely publicized "Prodigene Incident," when maize modified to produce a pharmaceutical protein was found growing in fields of normal soybeans in Iowa and Nebraska, has focused public scrutiny on plant-made pharmaceuticals.

The public, the food industry and government regulators are now adamant that this new generation of GM products be rigorously contained, even going so far as top insist that only non-food crops be used. Therefore, concerns about the untoward effects of molecular farming and strategies for minimizing risk will feature prominently during the conference.

Conference keynote speaker and Washington Post reporter Justin Gillis writes, "Plant-made pharmaceuticals (PMP's) promise better, cheaper drugs produced from a green, natural and renewable source which resonates well with the general public. However, as all new technologies, PMP's raise their lot of concerns."

As if to address these concerns, major portions of the Plant-Made Pharmaceuticals 2003 Conference program are dedicated to policy sessions such as the Science Symposia on "The Science of Biosafety and Biovigilance" and the Stewardship and Regulatory Symposia on "Stringent Containment and Biomass Production Regulations."

The perceived threat that transgenes will contaminate nearby wild and/or domesticated plants is a major public relations challenge for the molecular farming industry. Several researchers attending the conference will discuss scientific solutions to the problem of how to contain and control the expression of transgenes.

Dr. Pal Maliga of Rutgers University will present a study of chloroplast expression of recombinant proteins. The chloroplast genome is not passed from parent plants to their progeny and is therefore believed to safer domain for the production of novel proteins than the nuclear genome. Dr. Liz Foster of Agriculture and Agri-Food Canada will present her company's research on how pollen coat targeting technology can be used to prevent pollen-mediated outcrossing.

Issues of physical containment will be addressed by a variety of speakers who will discuss the pros and cons of growing pharm plants in enclosed, underground and geographically isolated sites.

Even the conference entertainment reflects an increased emphasis on safety. On Tuesday night conference goers will be treated to a musical performance by the band "The Biosafeties" - formerly known as "The Biohazards."

For further information: see conference website www.cpmp2003.org or contact:
Mr. François Arcand, President, cPMP, Québec City, arcandf@cpmp2003.org;
Ms. Elizabeth McKay, SPEQM, Québec City, emackay@speqm.qc.ca;
Ms. Cate McCready, BioteCanada, Ottawa, CMcCready@biotech.ca

 

Related On-line Resources:

2003 Conference on Plant-Made Pharmaceuticals

Plantigens and Plantibodies from Transgenic Plants

Pew: Biopharming Could Reap Benefits But Must Be Carefully Regulated

Pharm farming: It's Not Your Father's Agriculture

Molecular Crop Safety: Biosafety in Plant Biopharming

Biohazards: The Next Generation? Genetically Engineering Crop Plants that Manufacture Industrial and Pharmaceutical Proteins

 

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