Plant Therapy: The Biotherapeutics Revolution

Virtually every culture in the world has some tradition of using plants medicinally – bitter orange (Citrus aurantium) was used by the Chinese and indigenous peoples of the Amazon for nausea, indigestion, and constipation; feverfew (Tanacetum parthenium), native to Eurasia but quickly spread worldwide, has been used for centuries for fevers, headaches, stomachaches, toothaches, and insect bites; goldenseal (Hydrastis canadensis) was used by Native Americans to treat skin diseases, ulcers, and gonorrhea; and neem (Azadirachta indica) is still used in India to treat worms, malaria, rheumatism, skin infections, and so many other conditions that it has been nicknamed "the village dispensary."

And many of these ancient remedies are widely used – albeit after being vetted, processed, and packaged – by us today to treat the same conditions: echinacea (aka purple coneflower; Echinacea purpurea) for cold and flu symptoms; ginger (Zingiber officinale) for nausea; St. John's wort (Hypericum perforatum) as an antidepressant; and valerian (Valeriana officinalis) for sleep and anxiety, to name just a few.

Many traditional or folk remedies have a basis in reality – that is, they work – and are the backbone of the modern medicine cabinet. As the World Health Organization (WHO) says, "new antimalarial drugs were developed from the discovery and isolation of artemisinin from Artemisia annua L., a plant used in China for almost 2,000 years." We also get pain relief from the opium poppy, heart medicine (digoxin) from foxglove, treatments for Hodgkin's disease and leukemia from rosy periwinkle, the antibiotic Erythromycin from tropical fungi, and dozens upon dozens more.

This value to humans is inestimable even before we consider the nutritional benefits, such as the vitamins and minerals contained in vegetables, fruits, and nuts. Very simply, plants are the foundation of human nutrition, whether eaten directly or used as a feed source for meat and milk production.

Today, scientists are looking at plants in entirely new ways and finding new health uses, such as using plants as bioreactors, or "biological factories," for producing therapeutic proteins and medicinal metabolites, or even as photodynamic agents to target tumors and the blood vessels that feed them.

This field is called biotherapeutics, and it is undergoing a revolution as scientists seek to discover, analyze, and produce biologically active substances to enhance human health and fight disease.

Thanks to sophisticated new tools and fields such as genomics, gene targeting, proteomics, and chemical analysis, scientists are able to seek new biotherapeutic metabolites among the 300,000 chemical substances that are produced by different plant species. Once a potentially beneficial metabolite is identified, it is studied with the goal of creating a new medicine or therapy. In other research, plant cells are being exploited as bioreactors for the production of human proteins.

With its philosophy of interdisciplinary cross-pollination, the Weizmann Institute of Science is perfectly positioned to break new ground in plant sciences research, fostering applications in biochemistry, immunology, and other areas with an intimate connection to human health. The revolution is just beginning:

  • Imagine: an edible HIV vaccine grown in a tomato.
  • Imagine: a chlorophyll-like drug that "turns on" in response to a laser beam and closes off a tumor's blood supply only where the light shines.
  • Imagine: that the latest human immunological therapy is cultured in plants in a greenhouse instead of in animal tissues.

In fact, all these projects and more are quite real, and are taking shape at the Weizmann Institute of Science.

Plants and immunity

There are, broadly speaking, two types of immunity: innate immunity, which is a more general and evolutionarily older immune response that does not typically confer long-term protection to the host, and adaptive immunity, which is more specific and can be acquired. Plants have much to teach us about innate immunity, which is an important part of the primary human response to viral and bacterial infections. The isolation and identification of immunological factors provide new and powerful tools for alleviating diseases. It is now well established that innate immune responses, similar to those present in human cells, are found in plants; however, plants seem to lack adaptive immunity.

Plant and animal receptors mediating developmental and defense processes share common motifs. Thus, plants offer a unique research laboratory for advancing innate immune science, free of interference from adaptive effects, with easy-to-investigate systems. Development of such systems is currently under investigation in the Department of Plant Sciences laboratory of Prof. Robert Fluhr, whose recent findings include discovering genes that regulate interactions between plants and their pathogens and promote disease resistance.

Photodynamic therapy

A striking example of the new class of biotherapeutic agents are the chlorophyll-like compounds now being used for vascular-targeted photodynamic therapy – VTP – of tumors, macular degeneration, and other diseases. These exciting advances in the field of phyto (or plant) photodynamic therapy have grown from the laboratories of Prof. Avigdor Scherz of the Department of Plant Sciences and Prof. Yoram Solomon of the Department of Biological Regulation, who are at the cutting edge of human vascular disease research.

VTP uses modified forms of chlorophylls (the pigments that harvest solar energy) as photosensitizers to activate desired therapeutic drugs. Prof. Avigdor Scherz has developed novel bacteriochlorophyll-based sensitizers that limit reactive oxygen species generation to the blood vessels illuminated with a low-power laser. Together with Prof. Yoram Salomon, he showed occlusion of the tumor blood vessels and subsequent destruction in significantly less time than conventional methods.

One such agent is currently in clinical trials at the Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City for treatment of prostate cancer. Other chlorophyll-based compounds are being tested in animal models for their effectiveness as treatments for a range of cancers and diseases.

The light-activated drug has been shown to shrink prostate tumors by 84 percent, and in 46 percent of the cases the cancer was actually gone. When the chlorophyll-based drug is exposed to laser light, it converts into a chemical that blocks blood vessels in the immediate area. This effectively chokes off the malignant tissue from its life-giving blood supply, starving the cancer to death.

An edible HIV vaccine?

Prof. Avraham Levy has initiated a program to produce edible HIV vaccines in tomato fruits and, in collaboration with Prof. Meir Edelman, to also introduce the vaccine in Spirodela plants. Consumption of edible, vaccine-containing fruits or plants could offer a cost-effective and needle-free way to protect people against HIV in developing, as well as developed, countries. An anticipated additional benefit is that this plant-based approach may keep the vaccine stable without refrigeration.

Producing drugs with plants

Plant cells can produce active human protein drugs without the risks involved in using mammalian cells, and are therefore potentially safer – and cheaper – bioreactors. Scientists now anticipate that plants will contribute in a significant way to the rising production of human protein drugs; in fact, several human protein therapeutic drugs produced by plants are already in various stages of clinical trials.

Multifunctional protein-based therapeutic drugs, such as novel vaccines, anti-cancer drugs, and drugs that alleviate severe genetic diseases, have recently been developed. These medicines range from simple proteins, such as interferon and human growth hormone that can be produced in bacterial or yeast cells, to more complex proteins, such as antibodies and blood factors that can only be produced in the cells of higher organisms.

The optimization of plants as bioreactors for producing therapeutic protein drugs will need to focus on efficiency and quality of protein production. Regulatory factors that control the synthesis, folding, and post-translational modifications of engineered proteins need to be understood and manipulated to render them as similar as possible to authentic human proteins. Scientists also need to understand the regulatory signals that target transgenic proteins to identify specific sub-cellular compartments where they can stably accumulate. Prof. Gad Galili of the Department of Plant Sciences and Prof. Zvulun Elazar of the Department of Biological Chemistry, experts in plant metabolism and intra-cell trafficking, have teamed up to identify such factors and adapt them for efficient use.

In sum, the potential for exploiting plant science in the battle against human diseases is immense. Its effective application, however, will require concerted basic research efforts.

By harnessing plant molecular, genetic, genomic, and tissue culture tools in the battle against human disease, the Weizmann Institute believes that not only will new and better drugs and therapies be developed, but that the research will lead to ever-cheaper modern medicines that are available on a wider scale, so that anyone, no matter their economic status or where they live, can get the treatment they need. This is truly Science for the Benefit of Humanity – and it's powered by plants.

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