14 January 2010

Biotechnology: the main ways of development

Global trends in biotechnology Yuri Sheludko, STRF.ru

The rapid development of modern biotechnologies is going on in several key areas at once, in each of which promising results have already been achieved. And today STRF.ru provides its readers with the opportunity to get acquainted with the most important trends in the global biotech. In order to present the most important trends in the global biotech, information from various sources was used – these are the opinions of leading Russian experts in the field of living systems, publications in the most authoritative world scientific journals, as well as analytical materials prepared by foreign experts. In total, ten key biotechnological areas were selected, each of which is presented below in the form of a small annotation.

Regenerative medicine: from artificial skin to patches for the heart

The development of regenerative medicine technologies is one of the most urgent tasks of modern science. Donor organ transplantation operations are associated with the risk of rejection, and the number of patients who need such therapy always significantly exceeds the capacity of clinics. First of all, it is worth noting the creation of various skin substitutes that are used in the clinic for the treatment of burns or chronic skin damage. New advances in this field allow the use of skin grafts containing genetically modified cells. This makes it possible to eliminate genetic defects, improve their engraftment and even create a system for the synthesis of hormones necessary for the body.

Artificial vessels created on the basis of their own vascular epithelial cells and a synthetic substrate subsequently destroyed in the body are already beginning to be used in clinical practice. Their principal advantage is that after the degradation of the artificial substrate, the body replaces it with its own healthy cells. Similar approaches are also used in the bioengineering of myocardial tissues.

Medicines from natural sources

The ability of living organisms to synthesize biologically active stereoisomers often makes them an indispensable and the only source of valuable organic molecules. According to experts, in the United States, about 50 percent of the drugs used for chemotherapy are derived from components of plant extracts. Most often, biologically active substances synthesized by plants are secondary metabolites – low molecular weight compounds that provide plants with protection from pests and pathogens. Although more than 50,000 secondary metabolites have already been characterized, this represents only about ten percent of the biosynthetic potential of plants. And besides plants, biologically active substances are synthesized and accumulate in bacteria, fungi, marine organisms, insects and even amphibians. Modern programs for the search for new drugs include simultaneous automated testing of a variety of extracts for the presence of a wide variety of biological activities. Thus, powerful antitumor compounds were found, for example, taxol from the bark of yew trees.

Often, the level of a valuable substance in a plant turns out to be extremely low, and chemical synthesis is excessively complex. For example, to meet the annual market demand for taxol, the bark of several hundred thousand trees would have to be extracted! In this case, researchers first figure out the path of enzymatic biosynthesis of the molecule in the cell, then isolate (clone) the genes encoding the corresponding enzymes and optimize them. And finally, the resulting genes are introduced into a suitable biological system for the production of valuable substances. A striking example of such a development was the production of antimalarial terpene artemisinin in yeast.

The antibodies deliver the drug directly to the tumor

Delivering the drug directly to the tumor allows you to enhance the effect of the drug and minimize unwanted side effects on other tissues and organs. Usually, monoclonal antibodies or their fragments specific to different types of tumors are used for this. At the moment, there are several types of antibodies on the market, fused (conjugated) with various drugs: cytotoxic compounds, toxins (in particular, fungal origin) or radioisotopes. The advantage of the latter lies in the fact that the delivered radionuclides are able to destroy even tumor cells containing few antigen anchors on their surface. On the other hand, this type of conjugates is characterized by a higher risk of damage to healthy tissues. Photodynamic therapy is a method of treating tumors that allows you to destroy diseased tissue without damaging healthy tissue. Under the influence of light, the previously inert medicinal substance is activated and destroys the surrounding tissues.

Among the recent developments in this field, a system for delivering phototoxic protein to a tumor using antibody fragments should be noted. As a photosensitive agent, the researchers used the red fluorescent protein "KillerRed" – "Red Killer". The transport part of the structure responsible for delivering the "Red Killer" to the target cell of a malignant tumor was a protein fragment of the 4D5 antibody, widely used in clinical immunotherapy of a number of tumors.

Treatment of genetic diseases

To date, genetic therapy is a rapidly developing field of biotechnology and is considered as a potentially universal approach to the treatment of a wide range of diseases: hereditary, oncological and even infectious.

Various carriers are used to deliver genetic material inside a human cell and integrate it into the genome, for example, artificial liposomal nanoparticles or cationic emulsions. Vector systems based on elements of the virus genome have been developed for the treatment of cancer, allowing the killer gene to be injected directly into the tumor, which as a result begins to produce cytotoxic proteins itself.

In the November issue of the journal Science, a report was published on the successful use of genetic therapy for the treatment of adrenoleukodystrophy (a deadly neurodegenerative disease). The defective gene in the patients' bone marrow stem cells was replaced with a normal copy, after which the cells were returned back to the body. For this purpose, a new vector has been developed for transferring genetic material inside human cells and embedding it. Scientists have "disarmed" the human immunodeficiency virus by removing all the genes and leaving only a shell capable of penetrating into the cell. DNA containing the correct gene and sequences that help to embed it into the chromosome was placed in it. Scientists believe that the vector they created based on HIV particles can serve as a universal carrier for various genes.

Decoding the genome in one day

Modern genome research programs have stimulated the development of fast, accurate and effective methods of nucleic acid analysis – sequencing. The purpose of this analysis is to obtain information about the sequence of the location of each of the four types of nucleic bases in a long DNA molecule. This sequence, in turn, determines the sequence of amino acids in the protein molecule encoded in this section of DNA, and therefore, the properties of the enzyme.

Initially, the sequencing technique involved complex chemical modifications of DNA using radioactive tags. Modern sequencing methods use polymerase chain reaction, and the radioactive tags are replaced with fluorescent ones. Automatic sequencers are capable of simultaneously analyzing several hundred DNA samples and performing up to 24 analyses per day. Electrophoresis does not take place in gels, but in ultrathin capillaries, which significantly increases the speed and sensitivity of the analysis.

An alternative to this method is the recently developed method of "sequencing by synthesis" or pyrosequencing. At the moment of attachment of one of the four possible nucleotides to the growing DNA chain (complementary main chain), a special enzyme luciferase gives a light signal. If you know which nucleotides are present in the solution at the time of the signal, then you can determine the sequence of their addition. As a result, the researchers were able to register the addition of 25,000,000 bases with 99 percent accuracy within four hours.

Treatment of serious diseases – an attack on several targets

The strategy of modern treatment of the most severe diseases includes simultaneous exposure to several targets – the molecular stages of the development of the pathological process. Advances in understanding which genes and the proteins encoded by them are responsible for the disease will make it possible to select a complex of medicines that are much more effective at coping with a specific ailment than individual drugs.

The most striking example of treating a specific disease in this way is HIV infection therapy. Currently, in the treatment of HIV infection, it is recommended to use a combination of HIV inhibitors consisting of at least three drugs that act on different enzymes of the virus, respectively blocking different stages of the development of viral infection. This approach makes it possible to significantly prolong the life of HIV-infected patients – in the USA, AIDS has been transferred from the category of incurable to the number of chronic diseases. Currently, there is no doubt among scientists that successful cancer treatment will also be based on simultaneous administration of drugs that affect different elements of cancer cells. Multitargeting therapy seems appropriate and promising not only due to its effectiveness in suppressing the tumor, but also the possibility of overcoming the resistance of cancer cells to various drugs, which is one of the most important tasks of antitumor therapy.

Stem cell – the doctor inside the patient

Stem cells are non–specialized progenitor cells that give rise to all organs and tissues of the body. Their task is to restore damaged or dead areas.

Due to their peculiarities, stem cells have been one of the most promising objects of medical technologies for several decades. They treat a wide range of diseases – from psoriasis and coronary heart disease to genetic diseases and organ transplants (examples are given in other sections of our article). Recent advances in cell therapy include the development of methods to stimulate stem cells to differentiate into a particular type of tissue directly in the patient's body. Researchers have learned to stimulate the bone marrow (which normally produces blood cell precursors) to release two other types of stem cells (capable of repairing, among other things, cartilage, bones and blood vessels). Scientists predict the broadest prospect for their method: a patient with a heart attack or fracture goes to the hospital, receives a drug that stimulates his stem cells, after which they themselves are engaged in "repairing" damaged organs.

Synthesis of genes for the pharmaceutical industry

The rapid growth of the pharmaceutical protein market, as well as the development of various systems of heterologous gene expression, has caused a demand for cheap and accurate methods of nucleic acid synthesis. The developments carried out over the past decade have made it possible to increase the efficiency of synthesis protocols by 5-7 thousand times and reduce the cost by more than 50 times (while increasing the accuracy of the process). Currently, many biotech companies provide services for the automatic synthesis of gene sequences encoding pharmaceutical proteins adapted for biotechnological expression systems. The average cost of synthesis is about $0.4 per pair.

The right medicine is for every patient

The description of any modern pharmacological drug contains information about its side effects and possible allergic reactions. This means that the genetic features of metabolism in a certain number of patients do not allow them to properly assimilate the substances that make up the drug. For example, about fifty percent of people suffering from asthma do not get relief when using an anti-asthma drug of one class or another. Pharmacogenetics is one of the precursors of personal (individual) medicine, in which the paradigm of "one medicine for all" is replaced by "the right medicine for each patient". This implies that patients, depending on their genetic and epigenetic (not determined by genes) features, will be grouped in such a way that the doctor can predict the features of the course of the disease and apply appropriate treatment with minimal risk and side effects.

In the simplest case, one gene can participate in the body's response to the drug. By identifying an undesirable variant (allele), it is possible to optimize therapy for the appropriate group of patients. Such studies are especially important for anti-cancer therapy. Antitumor drugs, on the one hand, have high toxicity, on the other hand, therapy with an ineffective drug can lead to sad consequences. Therefore, pharmacogenetic studies will allow to adjust therapy for patients with an "unsuccessful" variant of the gene by changing the dose of the drug or replacing it.

Proteomics is the key to diagnosis

Proteomics studies the exchange of proteins in a living organism: their synthesis, interaction and decay. It is often possible to notice a connection between diseases and changes in the spectrum or characteristics of proteins synthesized by the body. It is believed that the vast majority of drugs interact with protein molecules. Therefore, a comprehensive study of the protein spectrum can accelerate the development of new diagnostic and therapeutic agents.

A striking example is the search for biomarkers for the early diagnosis of malignant tumors. At the moment, in the course of research in various laboratories around the world, a number of new proteins have already been identified that serve as biomarkers of cancer tumors of various localization. An important aspect is the development of complex panels of biomarkers that allow for more reliable detection of the presence of the disease. In addition to malignant tumors, biomarkers of cardiovascular, pulmonary, gastrointestinal and many other diseases are being actively investigated.

During the preparation of the material were used:
Nature Biotechnology 27, 1013–1023 (1 November 2009)
Nature Biotechnology 27, 820–821 (1 September 2009)
Nature Biotechnology 26, 509–517 (1 May 2008)
Nature Biotechnology 26, 164–167 (1 February 2008)

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