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PARTNERS IN MARINE BIOMEDICAL DRUG DEVELOPMENT
Introduction
Once the initial discovery phase is complete, the truly promising marine
natural products may enter the drug development pipeline so that their
potential clinical usefulness can be fully evaluated.
Biomedical research groups most often enter jointly into the drug
development phase with industry partners such as private biotechnology
or pharmaceutical companies. Also typically part of the partnership are
federal funding entities such as the National Science Foundation, NIH's
National Cancer
Institute, or the NOAA National Sea Grant Program.
University medical centers typically become key partners during the
clinical testing stages of drug development. State support may
contribute in a variety of ways, including workforce training for the
growing biotech industry sectors. Finally, international cooperation is
increasingly required between countries wishing to utilize biological
resources belonging to other sovereign nations, so that all parties are
treated equitably.
While such collaborations can take on a near-limitless number of forms,
the basics of some of these development partnerships are described
below.
Big Risk, Big Rewards
The development of a new medical drug can be a highly profitable
endeavor. The four largest U.S. "Fortune 100" pharmaceutical companies
(Pfizer Inc., Johnson & Johnson, Merck & Co. Inc., and Abbott
Laboratories) generated combined revenues in excess of $129 billion in
2003.
At the same time, the cost of turning out the new 'miracle drugs' of the
21st century are staggering. The pharmaceutical industry reports that
it can take as long as 15-20 years and cost as much as $800 million to
bring a new drug to the market. The Pharmaceutical Research and Manufacturers of America further
notes that for every 5,000 novel compounds found to have biomedical
potential, on average only five of these make it into
human clinical trials, and only one will receive final
approval for commercial patient use.
Naturally then, when new compounds isolated in the academic research
labs perform exceptionally well in drug screens and bioassays it often
piques the interest of pharmaceutical companies, medical professionals,
and government health institutions that may be interested in pursuing
further research and development toward a commercial end product. These
well-funded entities have the resources and expertise to carry promising
candidate compounds through the very long and very expensive drug
development pipeline.
The research institutions also need partners who understand the business
side of drug development. As brilliant and imaginative as academia's
research teams might be, they generally do not possess the keen
understanding of market demands and opportunities required to push their
scientific discoveries from potential to product and then from product
to profit. Synergistic collaboration between the creative minds on all
sides of the partnership is usually a requisite ingredient for success.
 Academia-Industry Partnerships
The vast majority of scientific research is conducted within university
laboratories or similar academic institutions, and not directly by big
industry or the federal government. Scientific discoveries made at the
university level, however, often garner private industry or federal
interest.
Although there are countless variations and subtle complexities, most
university-industry collaborative ventures and research partnerships
share some similarities. Sometimes the partnership is based on the
additional technical resources an industry partner can bring to bear in
the quest for new drug leads. For example, the Division
of Marine Biomedical Research at Harbor Branch Oceanographic has
entered into contract agreements with pharmaceutical companies and
small biotech companies to grant them access to the group's extensive
marine natural products sample inventory. This arrangement allows a
unique set of sample compounds to be run through the unique bioassays
and drug screens developed by the partner companies.
Perhaps more typically, a private company or other industrial entity
provides more direct financial support to the academic research
institution or designated research arms within it. In exchange, the
university offers that company the option to develop and potentially
commercialize novel technologies, products, or processes that emerge
from the research. In short, the university provides scientific
innovation and academic expertise and industry provides much-needed
financial resources.
Ideally, joint ventures such as this are constructed so as to be
'win-win' arrangements. Often this is done through agreements in which
industry provides up-front funding enabling the university research to
be carried out, as well as some portion of any downstream revenues
realized if and when commercialization success is attained.
The benefits of increased university research sponsorship by industry
reverberate through the institution. Higher quality research attracts
the best and brightest faculty and students, increases government
funding at state and federal levels, and enhances the reputation of the
institution at large. Ongoing patent licensing royalties may also bring
significant amounts of income to non-profit academic research
institutions. This income can keep research projects going and it can
defray university operating expenses as well as the exorbitant cost of
pursuing patent protection for promising research products.
But the potential financial gain by private industry must be there as
well, and this typically derives from the university's willingness to
make significant intellectual property rights concessions to industry.
The Bayh-Dole Act and the Nitty Gritty of Partnership
To be sure, the core missions of industry and academia are different.
As has been eloquently distilled by Peter Likins, president of the
University of Arizona and a former provost of Columbia University, a
university's primary purpose is to maximize societal benefits while
operating within financial constraints, whereas a for-profit
corporation's purpose is to maximize financial benefits within societal
constraints.
The institutional mission of a university may therefore be best served
by rapidly placing intellectual property directly into the public domain.
Indeed, the free exchange of ideas and discoveries between academic
peers is vital to the furthering of scientific progress. In contrast,
industry can maximize its profit potential only through patent
protection and control of intellectual property. Private companies have little
intrinsic motivation, therefore, to share innovations with the research
community.
Despite the apparent crossroads, effective partnering between these
disparate entities can still occur if key players on each side
accept the motives of the other as valid. For example, while
permanently suppressing the sharing of information
would be anathema to most academics, university researchers
in partnership with industry may agree to postpone publication of
certain key findings until the sponsoring company has had the
opportunity review results and file appropriate patent claims related to
discoveries with commercial potential. On the other hand, industry
partners must respect as legitimate the need of academics to share
research findings with peers and with the public through publication and
free communication.
The Bayh-Dole Act of 1980
in large part paved the way for the kind of academia-to-industry
technology transfer that the impending biotechnology revolution would
require. It served to standardize and clarify government policy
regarding the commercialization of products and processes resulting from
federally funded research programs but whose patents were held by the
research institution and not the funding entity.
Later amendments to the Act allowed research institutions to offer
exclusive licenses to venture capital industry, incentivising private
companies to invest in academic research. They also articulated the
obligation of universities to share license proceeds with the
researchers and inventors responsible for the licensable product.
In effect, Bayh-Dole, made explicit the incentives for cooperation
between government, academia, and industry toward the commercialization
of new technologies for the public good. Once the major impediments to
technology transfer were removed, the number of university research
patent filings increased dramatically. In 1980, the year the Bayh-Dole
Act was signed, American universities filed only 200 patent
applications. Within less than twenty years, the number of applications
increased to more than 3,000 a year. Technology transfer and licensing
offices are now an integral part of every major research university.
Given the fierce competition between natural products laboratories to
attract private sector interest and financing, the importance of
university technology transfer officers with keen marketing and
negotiating skills is difficult to overstate.
One of the watershed events in the history of biotechnology is also
possibly the premiere success story in the world of technology transfer.
This is the invention by Stanley Cohen and Herbert Boyer (of Stanford University
and the University of California-San Francisco, respectively)
of recombinant DNA ('gene splicing') techniques. Boyer and Cohen were
granted three patents for their discoveries. Subsequently, the
technology transfer and licensing office at Stanford designed a
licensing program based on these discoveries that have
allowed more than 350 non-exclusive licenses to be granted, and have
brought tens of millions of dollars in royalty revenues to the inventors
and their institutions.
As impressive as this success story is, it is far from an isolated case,
Indeed, the University
of California Office of Technology Transfer claims that there are
well over 1,000 products currently on the market that are based on licensed discoveries
emerging from university research. This source further states that the
commercialization of emerging university-derived technologies supports
250,000 jobs and more than $30 billion of annual economic activity.
References
Blaug S , Chien C, and MJ Shuster. 2004. Managing Innovation: University-Industry Partnerships
and the Licensing of the Harvard Mouse. Nature Biotechnology 22:761-763.
Related Weblinks
Columbia University's 21stC Online Research News Magazine, Winter 1998 Issue (Issue 3.1), Special Focus: Technology Transfer
http://www.columbia.edu/cu/21stC/issue-3.1
Support at the Federal Level: Funding and More
At the federal level, marine biotechnology is funded principally through
the National Science Foundation (NSF), the National Oceanic and
Atmospheric Administration (NOAA) and its National Sea Grant College
Program, and the Office of Naval Research (ONR). In 1999, the total
contributions of NSF and NOAA/Sea Grant to marine biotechnology research
was $22 million. Starting in 2002, each of these agencies began
requesting an annual increase of $10 million for biotechnology (plus $3
million annually for outreach and education). Despite modest gains,
most within the field believe that federal funding from these sources
for marine biotech research should be increased.
Additional marine natural products research funding is provided by the
National Institutes of Health through the National Cancer Institute
(NCI). The lion's share of NCI funding for drug discovery work is
directed toward the funding of human clinical trials. The agency
supports over 1,300 clinical trials a year, to the benefit of more than
200,000 patients.
Over the years, NCI has developed an array of important diagnostic,
screening, and bioinformatics tools. One of the most valuable is the
NCI-60 cell line.
Established by NCI's Developmental Therapeutics Program (DTP)
collection, this is a set of 59 different human cancer cell lines
derived from a wide range of tissue sources. The NCI-60 has been used
to screen well over 100,000 unique chemical compounds for specific
bioactivity against certain types of cancer. The cell line has also
been instrumental in numerous studies of chromosome karyotyping and gene
expression analyses. Tissue sample banks, animal models of human
cancer, and a variety of statistical analysis tools and bioinformatic
databases are among the other important NCI contributions to biomedical
research.
In addition, NCI has a long history of more direct involvement with
natural products chemistry and the application of natural products to
questions of human health. On the heels of the discovery of terrestrial
plant-derived anticancer compounds like vinblastine and
vincristine from a
periwinkle plant in the 1950s, NCI in 1960 entered into collaboration
with the US Department of Agriculture to focus on the systematic
collection and screening of plants for antitumor activity.
This ambitious program collected more than 35,000 plant samples and screened
more than 114,000 extracts derived from them over the ensuing two
decades. NCI has also collaborated closely with key players in the
pharmaceutical industry, overseeing the testing of over 180,000
microbial extracts during this period.
From a relatively early date, NCI also recognized the potential
importance of drugs from the sea. Between 1975 and 1982 they screened
over 18,000 extracts taken from marine organisms.
Despite the staggering effort put forth, few of the compounds tested found their way
into clinical trials (the potent mitotic inhibitor Taxol® is chief among a couple of notable exceptions).
NCI therefore discontinued their natural product collection programs in 1982.
With advances in screening technology, however, NCI in1986 initiated a
new natural products acquisition program. This program awarded
contracts to several entities to collect samples worldwide. Still
committed of the pharmaceutical potential of marine natural products,
NCI contracted the non-profit Coral Reef Research Foundation to make
Indo-Pacific shallow water marine collections for the U.S. National Cancer Institute Marine Collections
Program. CRRF collects approximately 700 a year for the program.
NCI also has contracts with Tel Aviv University to collect Red Sea marine
invertebrates and with the New Zealand National Institute of Water and
Atmospheric Research to collect marine organisms.
NOAA's Sea Grant supports university-based research and outreach
programs in support of coastal resource use and conservation. It is a
national network of 30 university-based programs that work with and
within coastal communities The National Sea Grant College Program
provides funding, fellowships, and other resources allowing universities
to carry out scientific research, education, training, and extension
projects designed to foster science-based decisions about the use and
conservation of our aquatic resources.
Marine Biotechnology is one of ten
defined thematic areas in which Sea
Grant recognizes a need and provides support enabling researchers and
educators to explore pressing issues related to the health and
sustainability of US coasts and coastal economies.
Back to the Schools: The Role of University Medical Centers
Once drug development teams have completed perhaps several years of
laboratory assays and animal studies, they may determine that they have
a promising compound that should move forward into the clinical phase.
Clinical trials are the first chance human patients gain access to investigative drugs, in trial
groups that begin very small and grow in size as the clinical trials
progress. This is a vitally important stage in drug development where a
great deal of information about the risks, rewards, side effects, and
general effectiveness of experimental drugs is obtained.
Clinical trials of investigative new drugs are often carried out at or
by university medical centers, generally with federal coordination and
oversight. The clinical research team of physicians and support staff
is another group of academics distinct from teams who may have been
involved upstream in the drug discovery process.
Clinical trial funding may derive from the federal government (e.g.,
through NIH) as well as private foundations and for-profit industry
sources like the pharmaceutical and biotech companies engaged in
developing the drug under investigation. Since World War II, increases
in federal funding have fostered significant proliferation and
enhancement of American university medical centers.
The clinical research team has another important partnership with its
Institutional Review Board (IRB). The IRB, an independant group of
doctors, statisticians, public healthcare personnel, and others,
approves and oversees the clinical trial to ensure that the potential
therapeutic benefit to participating patients is worth the associated
experimental treatment risk. Inclusion of IRB oversight and research
review in clinical trials is federally mandated.
Clinical research teams are frequently responsible for discovering important new
aspects of drugs that pre-clinical research teams could not see.
Refined dosage protocols, new methods for administering treatments, and
even new indications for use (i.e., treatment of illness distinct from
the original intent) are regular contributions of the university medical
center clinical research team to the drug development process.
Outreach and Workforce Training Partnerships
As the field of marine biotechnology continues to grow, the demand for a
trained workforce to fill new industry jobs will increase as well.
Several university-industry-governmental (particularly stae government)
partnerships have recognized this need and have launched training
programs to address it. A couple of these are briefly described here.
The Marine Biotechnology Center at UC Santa Barbara coordinates fifteen different
campus research programs and works to secure funding
for the training of advanced students and professionals to meet MBT
workforce needs. The Center's training program provides the industrial
sector with qualified personnel, while industry partners offer students
unique research and training opportunities. The Center's main teaching
facility, the Marine Biotechnology Laboratory Building was completed in
1990. This $8 million state-of-the-art facility was the first of its
kind in the United States.
The University of Maryland Biotechnology Institute's Center of Marine Biotechnology (COMB) was established in
1985 as "a new paradigm of state economic development in biotech-related
sciences." In addition to focusing on basic and applied research in
various marine biotech fields, COMB operates outreach programs that
disseminate MBT knowledge and information to diverse audiences ranging
from K-12 to undergraduate and graduate students to industry
professionals. COMB's state-of-the-art facilities are housed in the
Columbus Center, an internationally recognized marine research and
education hub located within Baltimore's Inner Harbor.
International Collaborations: Protecting Sovereign Biodiversity Rights
The vast majority of terrestrial natural products collections have
occurred in tropical forests. This is not surprising, considering that
more than half of the world's plant species are found here. Considering
the similarly high biodiversity found in tropical marine systems such as
coral reefs, it is understandable that a substantial amount of marine
natural product bioprospecting occurs here as well.
Whether by land or sea, protecting the biodiversity rights of countries
where natural products sample collections are undertaken is becoming an
increasingly important issue, and often a contentious issue as well.
In tropical regions in particular, where many nations are so-called
'Small Island Developing States' (SIDS), ensuring that developed nations
do not exploit the indigenous biodiversity resources (including genetic
resources) without equitable compensation is vital. For many concerned
socioethicists and bioethicists, it means the difference between
bioprospecting and, considerably less flattering,
biopiracy.
Bioprospecting, collecting biological samples to screen for commercial
potential, can help medical and other scientific research. However,
illegal or unauthorized international collection can:
- infringe on the sovereign rights of nations
- decrease the economic health of indigenous communities
- deplete or destroy species and habitats
As yet, there are no globally recognized standards on how best to
recognize and preserve these rights. A number of world treaties have
attempted to adress the issues, including the 1993 Convention
on Biological Diversity (CBD). The stated goals of the CBD are
the conservation and sustainable use of global biodiversity, and fair
and equitable sharing of the benefits from the use of biological and
genetic resources.
The CBD commits member countries to conserving biological resources,
developing them for sustainability, and sharing the benefits gained from
their use. For many developing nations, advancing sustainable use of
biological resources requires partnering with entities from developed
countries. The basic formula is that the partners enter into an Access
and Benefit Sharing Agreement (ABA) that provides a guest institution or
company access to the host-nation's biological and genetic resources for
purposes of bioprospecting. In return, the ABA guarantees the
host nation a fair share of the benefits, which may include financial
support for research and resource conservation, commercialization
royalties, and access to biotechnology tools and training.
To date, the United States has not ratified the CBD.
Other accords and laws addressing aspects of biodiversity rights include
the WTO TRIPS agreement, and a number
of biodiversity laws and National Biodiversity Strategy
and Action Plans (NBSAPs) adopted by individual nations.
Despite the lack of international consensus, there are some
forward-thinking arrangements in place between partner nations regarding
the protection of biodiversity rights. In the case of the NCI/CRRF
Marine Collections Program previously described, NCI has strived to put
in place a proactive agreement that ensures protection for the
biodiversity and economic rights of host countries where CRRF carries
out its collections. Included in the agreement are provisions
stipulating:
- full collaboration with source country agencies on collection activities
- full sharing of all data, photographs, and other information with source country agencies
- participation whenever possible of the host country scientists at
NCI laboratories in the analytical and developmental work on any drug
candidates
- full disclosure of testing results on a regular basis to collaborating countries
Safeguards also exist ensuring that no commercial development of
potential drugs can occur without first negotiating royalty and
licensing agreements approved by the source country government.
Moreover, if indigenous folk knowledge leads to the discovery of
specimens with pharmaceutical potential, that contribution must be
recognized in the negotiations between the NCI and source countries.
Several marine natural products collections teams have similar such
agreements with host countries to ensure that all parties are treated
fairly and compensated for their contribution to the partnership.
References
Trawling for Treasure and Pleasure: Marine Bioprospecting. Associate Professor Robert Capon, School of Chemistry, The University of
Melbourne (Communicated to The Royal Society of Victoria on Thursday, 12 November 1998).
Historical Case Study: Partnerships in the Quest For Bryostatins
Naturalist, author and businessman Jack
Rudloe was a partner in a
serendipitous collaboration between government agency, academia, private
business, the pharmaceutical industry, and medical clinicians that
evolved into one of the most ambitious natural products cancer research
projects ever undertaken.
In 1968, Jack Rudloe appeared on NBC's Today Show hosted by Hugh Downs
to talk about his book The Sea Brings Forth. The autobiographical
account chronicles Ludloe's coastal collecting exploits along the
Florida panhandle in search of live marine specimens that his company,
Gulf Specimen Marine
Laboratory, sold to research scientists and university educators.
Watching the television program was Dr. Jonathan Hartwell, the Assistant
Director of NCI's Natural Products Branch. He contacted Rudloe with an odd request/challenge: to collect a pound of
each of the most common Gulf of Mexico invertebrates for NCI to screen
for bioactivity in its continuing search for cancer fighting compounds.
Rudloe accepted the challenge and within a few months had sent samples
to NCI to be screened by scientists at the University of Arizona.
There, Dr. George Robert Pettit injected crude extracts
made from Rudloe's samples into laboratory mice infected with specific
strains of leukemia virus. Most of the study animals succumbed to the
virus within two weeks, but a handful of mice injected with various
crude marine extracts demonstrated a degree of disease resistance. In
particular, mice treated with extract derived from the bryozoan Bugula
neritina demonstrated 100% survival for the duration of the 30-day
experiment.
The Bugula crude extract having showed some promise, NCI asked Rudloe to
collect some more for them. A lot more, because large quantities of Bugula
were required to extract, purify and isolate the unknown active compound
or compounds. Over the next few months, Rudloe collected enough B. neritina to fill twenty
50-gallon drums. Eventually 13 metric tons of wild-collected Bugula
would be processed using large-scale chromatographic techniques,
allowing Dr. Pettit to extract about 13 grams of purified active
compound, a colorless alkaloid crystal he named bryostatin. This
particular compound, later specified as
bryostatin 1, was
shown through further
testing to be extremely effective in arresting the growth of several
types of cancer cells. Other work carried out or funded by NCI has
identified approximately 20 different bryostatins extracted from
different Bugula populations worldwide.
Bryostatin 1 continued to be tested in animal and cell culture models
through most of the 1980s. By the latter part of that decade, human
clinical trials had also commenced. By the mid 1980s there were also
attempts at culturing Bugula neritina on a commercial scale, most
notably on offshore oil platforms in California (NCI spent more than $1
million funding research into culturing Bugula in both land-based and
sea-based systems).
Dr. Steven Grant, A research physician at Virginia Commonwealth
University headed up the first Phase I clinical trials on bryostatin 1.
Grant and medical colleagues observed that terminally ill patients
suffering from advanced solid tumor cancers exhibited an inhibition in
growth of leukemia cells and a concurrent stimulation of growth of
healthy none-marrow cells.
Bryostatin 1 has been utilized in more than 80 human clinical trials,
with about 25% of those being carried through Phase II. In 2001,
Bryostatin 1 was licensed from Arizona State University for commercial
development by German pharmaceutical company GPC
Biotech. That same year, GPC Biotech
also struck a licensing deal with Stanford University to develop and
commercialize synthetic analogs of Bryostatin 1, known as Bryologs.
Further testing demonstrated that bryostatin 1 enhances the
effectiveness of existing chemotherapies (e.g., Taxol, cisplatin), but
appears not to be effective enough on its own to warrant approval as a
primary therapeutant. If and when bryostatin proceeds to the development phase,
it will likely continue to be developed as a tandem treatment for
several types of cancer that currently show some degree of response to
existing treatments. In fact, in 2001 the German drug discovery and
development company GPC Biotech AG announced that the FDA had granted
Orphan Drug
Designation for use in combination with Taxol for the treatment of esophageal
cancer. Similar status designation in the EU was awarded in 2002.
While preclinical and clinical development of bryostatin 1 progressed,
and despite some setbacks (In 2003 GPC Biotech made a strategic decision
to discontinue its bryostatin development programs),
researchers at other institutions have been making other important
contributions toward large-scale production and commercialization of
bryostatin and related compounds. Margo Haywood of Scripps Institution of Oceanography has fairly conclusively
demonstrated that the true source of bryostatin 1 is not Bugula neritina
but rather a proteobacterial symbiont identified as Candidatus
Endobugula sertula. This discovery will likely prove an important step
in the commercialization process because it potentially obviates the
need for either wild-collecting or culturing large quantities of Bugula
to procure only small amounts of purified bryostatin. Instead,
commercial scale production of bryostatin will likely revolve around
either successfully culturing the microbial source organism or utilizing
genetic engineering techniques to insert the gene cluster coding for
bryostatin synthesis into easily culturable laboratory strains of
bacteria.
References
Newman DJ and GM Cragg. 2004. Advanced Preclinical and Clinical Trials of Natural Products and Related Compounds from Marine Sources. Current Medicinal Chemistry 11:1693-1713.
Related Weblinks
An Obscure Moss Animal From The Sea Fights Cancer (Forgotten Coastline 8/6/2004 feature story).
http://forgottencoastline.com/showpage.asp?ArticleID=1546
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