Edible and medicinal mushrooms (macrofungi) not only can convert the huge lignocellulosic biomass* waste into human food, but -- most remarkably -- can produce notable mycopharmaceuticals, myconutriceuticals and mycocosmeceuticals.

The most significant aspect of mushroom cultivation, if managed properly, is to create zero emission of lignocellulosic waste materials. Mushroom biotechnological products have multibeneficial effects to human welfare (e.g., as food, health tonics and medicine, feed and fertilizers, and to protect and regenerate the environment). Pharmaceutical substances with potent and unique health-enhancing properties were isolated recently from medicinal mushrooms and distributed worldwide.² Many of them are pharmaceutical products, while others represent a novel class of dietary supplements or "nutraceuticals." Several antitumor polysaccharides, such as hetero-§-glucans and their protein complexes (e.g., xyloglucans, and acidic §-glucan containing uronic acid) as well as dietary fiber, lectins, and terpenoids, have been isolated from medicinal mushrooms. In Japan, China, Russia, and Korea, several different polysaccharide antitumor drugs have been developed from the fruiting bodies, mycelia, and culture media of various medicinal mushrooms, such as shiitake (Lentinus edodes (Berk.) Sing., Tricholomataceae), reishi (Ganoderma lucidum (Curt.:Fr.) P. Karst., Ganodermataceae), turkey tail (Trametes versicolor (L.:Fr.) Lloyd, Polyporaceae), split gill (Schizophyllum commune Fr.:Fr., Schizophyllaceae), mulberry yellow polypore (Phellinus linteus (Berk. et Curt.) Teng., Hymenochaetaceae), and chaga or cinder conk (Inonotus obliquus (Pers.:Fr.) Pilat, Hymenochaetaceae). The potential of medicinal mushrooms is enormous but mostly untapped. It could and should evolve into a successful biotechnological industry for the benefit of humankind.

The study of medicinal mushrooms through the last three decades has proved its many beneficial outcomes and has been followed by the rapid development of manufacturing businesses dealing with commercial cultivation of mushrooms. In 1999, world production of mushrooms amounted to US$18 billion, roughly equal to the value of coffee sales.^3,4

Medicinal mycology has deep and firm roots in fungi's traditional uses in the medicine of the Far East. For centuries, Chinese and other healthcare practitioners employed mushrooms to treat various diseases. They valued the power of some mushrooms as divine (e.g., a special goddess was associated with the reishi mushroom). Reishi is also considered a symbol of happy augury and good future, good health, longevity, and even life with the immortals. The use of medicinal mushrooms has gone beyond medicine itself: different schools of Taoism employed reishi and other mushrooms as purifiers and promoters of mind and spirit.⁵

Only at the end of the 1960s did Eastern and Western scientists start to investigate the mechanisms of the health effects of mushrooms. The first successful research discovered the antitumor effects of hot water extracts from several mushroom species.⁶ The main active components proved to be polysaccharides, specifically §-D-glucans. Chihara and his co-workers⁷ isolated from the fruiting bodies of shiitake a water-soluble antitumor polysaccharide, which was named "lentinan" after the generic name of this mushroom. This was a major discovery. Lentinan demonstrated powerful antitumor activity; preventing chemical and viral tumor development in mice and experimental models.^8,9

Polysaccharides displaying remarkable antitumor activity in vivo (i.e., through screening against sarcoma 180 in mice using intraperitoneal or oral methods of administration) have been isolated from various species of mushrooms belonging to the orders Auriculariales, Tremellales, Polyporales, and Gasteromycetales.^2,6,8,10-13

Since the discovery of lentinan, several antitumor polysaccharide agents have been developed and commercialized, using the submerged cultured mycelial biomass of turkey tail (Krestin, PSK; Japan), and liquid cultured broth product of split gill (Sonifilan, SPG, Schizophyllan; Japan). These antitumor substances are regarded as biological response modifiers that activate immunological responses. This basically means that:

1) they cause no harm and place no additional stress on the body;

2) they help the body to adapt to various environmental and biological stresses;

3) they have nonspecific action on the body, supporting some or all of the major systems, including nervous, hormonal, and immune systems, as well as regulatory functions.

It is, indeed, fair to describe all major medicinal mushroom preparations, both cellular compounds and secondary metabolites, as having weak antigenicity and no side effects.

A very popular and effective preparation was developed from turkey tail in Japan as early as 1965. A polysaccharide-peptide from this mushroom, under the name Krestin (PSK), was developed from the strain CM-101. It was approved for use against a number of cancers and was covered by the Japanese healthcare plan. PSK exhibits a marked effect against different types of tumors in experimental animals when administered intraperitoneally or orally. PSK contains 75 percent glucan and 25 percent protein. In 1993, Krestin comprised 25 percent of the anticancer drug market in Japan, and sales totaled US$350 million.^10,14 An analogous product under the name Polysaccharide Peptide (PSP) was developed in China from turkey tail strain Cov-1; the development process for this strain lasted nine years, from 1983 to 1992.¹⁵ Mizuno¹¹ stated that, in general, a period of 10 years and a total US$75 million, or 10 billion yen, are required from the beginning of development of a new drug to the time it is marketed.

Another §-D-glucan developed and popular in Japan is schizophyllan from split gill. It is especially effective against cervical cancer.¹¹ A glucan from mulberry yellow polypore was developed recently in Korea, and an analogous polysaccharide biotechnology from this species has been accomplished in Japan.¹⁶

Reishi, already mentioned as a sacred mushroom in ancient China, has come to occupy a leading place in present-day medicinal mushroom development. The market values of reishi-based natural healthcare products in 1995 were estimated as US$215 million in Taiwan, US$350 million in China, US$600 million in Korea, and US$350 million in Japan.⁵ The physiologically active substances of reishi are water-soluble polysaccharides and alcohol-soluble triterpenoids. Today, 119 different triterpenoids are identified in reishi,¹² about 80 of which are biologically active. Reishi dietary supplements (DS) are valued for their immunomodulating, anticancer, antiviral properties. They are used during remission of cancer and by hepatitis B patients. They also have anti-hyperlipidemic, hypotensive, and hypoglycemic actions.¹⁷

Some 30 years ago, epidemiologists studying the native population in the Piedade region in the suburbs of San Paulo, Brazil, noted that the rate of occurrence of adult diseases was extremely low, and found an association with the Agaricus species, which was a part of the regular diet of the inhabitants of this area.¹⁸ This mushroom was identified as A. blazei Murr., known by common names royal sun Agaricus, himematsutake, kawarihaaratake, or almond-flavored portobello. Experiments conducted in Japan with mice verified that A. blazei significantly activates the immune system.¹⁸ A number of immunity-enhancing, anticancer, and antitumor fractions were isolated from A. blazei. This species was shown to be the most effective anticancer mushroom in a study comparing its effects with shiitake, maitake (Grifola frondosa (Dicks.:Fr.) S.F. Gray, Polyporaceae), reishi, and other medicinal mushrooms. Fractions identified with immune effects include polysaccharides, (1®6)-(1®3)-b-D-glucans, (1®6)-(1®4)-b-D-glucans, polysaccharide-protein complex (ATOM), RNA-protein complexes, and glucomannan.^13,18-23

The Japan Cancer Association proved that A. blazei is effective against Ehrlich's ascites carcinoma, sigmoid colon cancer, ovarian cancer, breast cancer, lung cancer, and liver cancer, as well as against solid cancers.¹⁸

Higher Basidiomycetes mushrooms contain a large amount of well-balanced essential amino acids. Dietary fibers are abundant in the tissue of all mushrooms; they absorb bile acids or hazardous materials in the intestine, and thus decrease the chances of carcinogenic and other poisoning. The overall harmonizing effect of a diet balanced with mushroom, so highly praised by the ancient Chinese, is not a myth, but is continually supported by modern scientific investigations.

Several other health-promoting effects of the mushrooms should not be overlooked. Not only polysaccharides and triterpenoids are known as biologically active; wide ranges of substances from higher Basidiomycetes belonging to different classes of chemical compounds have been described and their medicinal properties evaluated. These substances represented glyco-
lipids (schizonellin), compounds derived from the shikimic acid (strobilurins and oudemansins), aromatic phenols (drosophilin, armillasirin, omphalone), fatty acid derivatives (filiboletic acid, podoscyphic acid), polyacetylenes (agrocybin, xerulin), polyketides (caloporoside, hericenones A-H), nucleosides (clitocine, nebularine), different sesquiterpenes (protoilludanes, marasmanes, hirsutanes, caryophyllanes, etc.), diterpenes (cyathin, striatal), sesterterpenes (aleurodscal), and many other substances of different origin.^2,10,24

Biologically active substances from higher Basidiomycetes possess antifungal, antibacterial, and antiviral properties; they can be used as insecticidal and nematocidal agents. In medicine they are used to immunomodulate both humoral and cellular immune factors in the body. Polyfunctional acidic glucuronoxylomannan isolated from jelly mushrooms (Tremella spp., Tremellaceae), for instance, stimulates vascular endothelial cells, possesses pronounced antiradiating effects, stimulates hematogenesis, demonstrates antidiabetic, anti-inflammatory, hypocholesterolemic, anti-allergic activities, and shows hepatoprotective effects. It can be recommended to improve immunodeficiency, including that induced by AIDS, physical stress or aging, and it prevents senile degeneration of microvessels, maintaining better blood perfusion conditions in vital organs.⁴

Most mushroom-derived preparations and substances find their use not as pharmaceuticals, but as a novel class of dietary supplements or "nutraceuticals." A mushroom nutraceutical is a refined or partially refined extract or dried biomass from either the mycelium or the fruiting body of the mushroom, which is consumed in the form of capsules or tablets as a dietary supplement (not a conventional food) and which has potential therapeutic applications. Regular intake may enhance the immune responses of the human body, thereby increasing resistance to disease, and in some cases, causing regression of a disease state. The market value of mushroom DS products worldwide is estimated at US$6 billion per year. The market value of reishi mushroom-based DS alone in 1995 was estimated at more than US$1.628 billion.⁵

The safety of mushroom-based dietary supplements is further enhanced through the following controls:

1. The overwhelming majority of mushrooms used for production of DS are cultivated commercially (and not gathered in the wild). This guarantees proper identification, and pure, unadulterated products. In many cases it also means genetic uniformity. This may also benefit conservation of biodiversity.

2. Mushrooms are easily propagated vegetatively, and thus keep to one clone. The mycelium can be stored for a long time, and the genetic and biochemical consistency may be checked after a considerable period of time.

3. Many edible and medicinal mushrooms are capable of growing in the form of mycelial biomass in submerged cultures.⁴

This last aspect, in our experience, offers a promising future for standardized production of safe mushroom-based DS. Submerged culture and semi-solid state fermentation has more consistent and predictable composition than that of fruit bodies. For most substances, this mycelium biomass obtained by submerged cultivation also has higher nutritional value. The culture media in which mycelium grows are made of chemically pure and ecologically clean substances. The cultivation of mushrooms for fruit body production is a long-term process, taking one to several months for the first fruiting bodies to appear, depending on species and substrate. By contrast, the growth of pure mushroom cultures in submerged conditions in a liquid culture media permits acceleration of the growth speed, resulting in biomass yield in several days.⁴ The additional advantage of submerged culturing is the fact that most medicinal mushrooms do not produce fruiting bodies under commercial cultivation. Reliable industrial cultivation techniques are known for only 37 mushroom species,³ but medicinal mushrooms include many mycorrhizal or parasitic species that need several years for development of normal fruiting bodies on trees. Such species cannot be grown commercially, but their mycelia can be grown easily and economically with the help of submerged culturing. High stability and standardization of mycelium grown in submerged cultures is important not only for producing DS, but also might be beneficial for producing mushroom-based medicines.

The use of medicinal mushrooms goes hand in hand with development of their artificial cultivation. The most significant aspect of mushroom cultivation, if managed properly, is to create zero emissions (no waste). Since more than 70 percent of agricultural and forest materials are non-productive and are wasted in processing, this is a very real advantage.²⁵ Many of these waste materials can be used as substrates to grow mushrooms. This fact gives a basis to the opinion of many researchers in the field (including this author) that sustainable development of mushrooms and their products in the 21st century can become a "non-green revolution."³

Prof. Solomon P. Wasser is the Head of the International Center for Cryptogamic Plants and Fungi, at the Institute of Evolution, University of Haifa (Israel); and the Head of the Department of Cryptogamic Plants, at the N.G. Kholodny Institute of Botany, National Academy of Sciences of Ukraine.

Born and educated in Ukraine, Prof. Wasser earned his advanced degrees at the N.G. Kholodny Institute of Botany, National Academy of Sciences of Ukraine in Kiev. He was elected a member of the National Academy of Sciences of Ukraine in 1988, and became Professor of Botany and Mycology in 1991. He founded the International Center for Cryptogamic Plants and Fungi at the Institute of Evolution in Haifa University in 1994 and has directed its work since then. Since 2000, he has been a full Professor of Haifa University (Israel).

In addition to his scientific studies, Prof. Wasser performs a number of public and social activities. He is a founder and editor-in-chief of three international journals, Algologia (Ukraine), International Journal of Medicinal Mushrooms (USA) and International Journal on Algae (USA). He is an author and co-author of 400 scientific publications, including 35 books and 12 patents.

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22. Fujimiya Y, Yamamoto H, Niji M, Suzuki I. Peroral effect on tumor progression of soluble beta (1,6)-glucans prepared by acid treatment from Agaricus blazei Murr. (Agaricaceae, Higher Basidiomycetes). International Journal of Medicinal Mushrooms 2000;2:43-50.

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25. Poppe J. Use of agricultural waste materials in the cultivation of mushrooms. In: Van Griensven DLJL, editor. Science and cultivation of edible fungi. Rotterdam/Brookfield: A. Balkema; 2000. p. 3-24.

* Biomass includes the full range of plants and plant-derived materials, such as dedicated energy crops and trees, agricultural food and feed crops, agricultural crop wastes and residues, wood wastes and residues, and municipal wastes. The majority of non-food biomass is composed primarily of the natural polymers cellulose, hemicellulose, and lignin and is referred to as lignocellulosic biomass. Lignocellulose is a complex of lignin and cellulose present in the cell walls of woody plants. Lignin is a complex organic polymer deposited in the cell walls of plants, making them rigid and woody. Lignocellulosic material resource, like solar energy, is sustainable. Lignocellulosic material is a kind of biomass that is estimated to amount to 1.9x10¹¹ tons of dry matter on land annually.¹