news.bmn.com
Most visitors to the wilds of Alaska are awed by the land's vastness and natural beauty, and many vow to return. When Maureen McKenzie first visited Alaska in the mid-1990s, she also was struck by its beauty but saw something else as well: tremendous biodiversity and an untapped resource for new drugs. McKenzie, professor of pharmacology at Rutgers University at New Brunswick in New Jersey, naturally thought about drug development even while on vacation, so when she returned from that first visit to Alaska, she did some research to see if the region's natural bounty had been tested for its medicinal potential. It turned out to be virtually untouched as a source of potential therapeutics, and McKenzie decided to leave teaching to explore Alaska's natural resources for drug development, founding Arctos Pharmaceuticals in 1999.
"Nature is the best chemist - the queen of biodiversity," said McKenzie. "Looking to nature to find new compounds has fallen out of favor in the pharmaceutical industry, even though we all know that it has been the best source of some very good drugs."
Plants and microorganisms have served as the basis of drug discovery for millennia, with the rain forest receiving a good deal of attention recently as pharmaceutical and biotech companies scour wild tropical regions and the seas for sources of new drugs, but no one has paid much attention to Alaska.
Developing drugs from natural products can also be cumbersome, McKenzie explained. "Our process of extraction, developed by Dionex [Sunnyvale, California], reduces what is usually a long process of many hours to days to about five minutes." The traditional method involves producing a crude extract which must then be purified of toxins and other impurities, and requires bioassays," she said. Arctos' process allows it to derive extracts that are directly screenable in an automated, high-throughput mammalian cell-based format, giving them a major advantage in accessing nature's biodiversity. Another problem is that after traditional methods of extraction, small amounts of purified material are often left. "Natural products have been very difficult to synthesize, as well," said McKenzie. "Taxol, which is derived from the Pacific yew tree, took about 15 years to synthesize," she said. Each of Arctos' extracts contain 30 to 60 small molecule compounds.
"The landmass of Alaska is vast and quite diverse and includes bogs, volcanic areas, alkaline hot springs, rain forest, and tundra, to name a few," McKenzie says. "And while this area is smaller than one-tenth of the land mass of North America, it has disproportionately more plant species per unit area than any other area, most likely due to the 20 different ecoregions," she adds. "Our company is exploring these vast, untapped resources for natural products with value in pharmaceutical, nutraceutical, and other biotechnology applications."
McKenzie has found that Alaska is home to at least 35,000 different plant species, 85 percent of which are unique and 62 percent of which are related to known medicinal plants worldwide. Significantly, about one-quarter of these are used by the native population for medicinal purposes. "Plants and microorganisms living in Alaska are well adapted to living in extreme conditions of light, temperature, acid and alkaline environments, and nutrient-poor soils with high levels of metals," she says. Alaskan tundra, for example, supports vegetation with an extremely short growing season and 70-day periods of almost total darkness. These extreme conditions require plants to convert light to energy under snow in the winter and, in the summer, to produce large quantities of anthocyanins - pigments that function as sunscreen to protect against the intense sun's assault of radiation and light. "These conditions produce plants that possess good free radical scavengers," says McKenzie.
These stressophiles - organisms that are able to adapt to extreme, stressful conditions - are regarded as promising drug development candidates because they utilize secondary metabolic pathways to produce novel compounds. One such pathway, the phenylpropanoid pathway, is a dominant mechanism among stressed plants and some microbes and has yielded over 20,000 compounds from almost every plant family, especially those that show very active alkaloid and terpenoid biosynthesis, says McKenzie.
Arctos's search for new drugs in Alaska combines ethnobotany, chemical ecology, and chemotaxonomy along with combinational chemistry. Field work is the linchpin of its activities, and most of its work in the field depends on relationships the company forges with local native residents. These relationships are treated very seriously by Arctos. The company works closely with native Alaskan groups and small corporations and, in doing so, has developed a model by which Arctos compensates native residents according to the level of guidance they provide. For "passive" access to land, Arctos gives royalties on profits from any product commercialized; for "guided" access to land, profit sharing is negotiated and given; and for "contributing" access, which could mean sharing specific ethnobotanic knowledge, Arctos follows a profit sharing and shared intellectual property right model. What differentiates the company's "bioprospecting" activities from those of other companies are that none of the plants and microbes it collects in Alaska are endangered and that it has collaborative models with native peoples, McKenzie says.
Most of Arctos's fieldwork takes place throughout the brief summer when McKenzie and a small crew gather samples from land and sea, often traveling to remote, inaccessible sites with native guides. This past July, an Arctos diver took samples from a shallow area of water near Adak Island, one of the Aleutians, which resulted in the discovery of a consortium of a unique fungus and bacteria growing together. "The organism is a member of the cytochalasin family, which interferes with the development of cytoskeleton of bacterial and animal cells and has a monstrous zone of inhibition," says McKenzie. "It wiped every organism out on the dish, leaving a clear circle in the middle of the dish." McKenzie said she doesn't know yet if the powerful cytocidal effects come from one, two, or all three organisms, but that they believe that there is potential here for a new drug or drugs based on the sample's performance with gram negative bacteria and yeast. Arctos believes that the fungus it found could be a new species and that it also might have strong activity against certain cancers, based on how the fungus kills other cells by interfering with cell division. Arctos's lab in Vermont is trying to determine whether it has been previously identified. So far, it appears to be unique.
"Fungi are an incredibly diverse and underexplored resource for medical compounds," said Alice Churchill, a molecular mycology scientist at the Boyce Thompson Institute for Plant Research (BTI) in Ithaca, New York. BTI is working with the National Institutes of Health and a pharmaceutical partner to screen fungi for novel anticancer drugs. Fungi are the source of cephalosporin antibiotics, the immunosuppressant cyclosporine, and a number of the statins used for lowering blood cholesterol, and are the second largest microbial producers of antibiotics behind actinomycetes. "Of the 1.5 million estimated number of fungal species in the world, only 5 to 10 percent have been identified and named and an even smaller number have been examined chemically," Churchill says. One of BTI's goals is to identify the environmental conditions that support expression of unknown natural product genes and synthesis of novel metabolites. This is an area in which Arctos has unique know-how, with its specialty of discovering organisms living in extreme conditions.
Another recent Arctos find is a compound from a locally grown fruit that has glucose-lowering properties. "Native people consume this to keep diabetes at bay," says Claudia Mark, who wears a number of hats as Arctos's cultural historian and archivist. "Another example of a find comes from a staple of the native Alaskan diet: vaccinium, which grows locally and yields about 400 million tons of biomass per year without being cultivated," McKenzie says. This plant contains low molecular weight hypoglycemic and antitumor compounds, as well as polymeric antioxidants. Arctos has thousands of extracts, each containing an average of 50 low molecular weight compounds, some of which are being evaluated by partner companies.
Diversa (San Diego, California) is one biotech company working with Arctos to gain access to new compounds. Diversa is developing libraries of compounds from microbes that serve as scaffolds for developing analogs using directed evolution. "From where we stand today, 99.9 percent of all biodiversity remains unexplored as a source of biopharmaceuticals," says Diversa CFO Karin Eastham.
Arctos has its work cut out for it and, if the present is an indicator of the future, native Alaskans and patients worldwide stand to benefit from its footwork... |
