15 May 2008

What are the molecules "singing" about?

Marina Muravyeva, STRF.ruNanobiotechnology can radically change medicine, making it targeted – aimed at the diagnosis and treatment of diseases of a single patient, the detection of manifestations of a pathological condition and therapeutic intervention at the earliest stages.

Many domestic developments in the field of "nanobio" are often not only not inferior to foreign analogues, but also surpass them in some ways. These, for example, include technologies created by scientists from the Nanobiotechnology laboratory of the Institute of Biomedical Chemistry of the Russian Academy of Sciences. One of their developments is based on recording the sounds of molecules.

The rapidly developing field of nanobiotechnology allows us to create methods for accurate and rapid diagnosis of diseases, primarily socially significant. Scientists from the V.N. Orekhovich Institute of Biomedical Chemistry (IBMH) of the Russian Academy of Medical Sciences, under the leadership of Academician Alexander Archakov, have been conducting fundamental and applied research in this direction for more than ten years. Some prototypes of the devices are already ready for implementation into clinical practice.

CD from the pharmacy

Have you ever heard how molecules sound? Employees of the Institute of Biomedical Chemistry have learned to register their sounds. The STRF correspondent was lucky enough to get acquainted with the original development designed for diagnostics. The head of the nanobiotechnology laboratory, Yuri Ivanov, inserts a CD into the computer, music begins to play "In my opinion, Schnittke's motives can be traced," the scientist says. – And here Verdi is clearly guessed."

The "music" of molecules is not idle entertainment. It characterizes a particular disease. The fact is that the molecules themselves are not static, their individual parts (domains) fluctuate, producing some noise. Its parameters depend on the interaction of one molecule with others. Actually, the analysis of these sounds makes it possible to evaluate the behavior of molecules and the state of the whole organism. Based on this natural effect, IBMH scientists decided to create a fundamentally new diagnostic system using conventional CD-ROMs as biochips.

The diagnostic CD contains not only software designed to recognize "painful" audio signals: its surface is working. It is supposed to place from 10 to 100 probes that capture marker molecules of various infectious and somatic diseases (scientists are still focusing on the main socially significant diseases, in particular, hepatitis C, for which there is no vaccine). It will be enough to put a specially treated drop of blood, saliva or other biological fluid on the CD, insert the disc into the computer and ... find out your diagnosis in a couple of minutes. The principle of operation of the diagnostic system is based on the interaction of probes with disease markers, as a result of which various molecular complexes are formed. The more such complexes, the stronger the sound. There are no disease marker molecules in the body of a healthy person, respectively, there is nothing for the probes to catch, and in this case a soothing silence will become a "health signal".

The new development of the Institute of Biomedical Chemistry can be used in laboratories that are not equipped with special equipment, and for some tests – even at home. So in case of widespread introduction of this technology, the range of pharmacies will be replenished with an unusual type of product for them – a set of software for self-diagnosis.

Single virus detectors

To date, there are no technologies capable of diagnosing oncological, infectious and other types of diseases at an early stage. Traditional methods have a sensitivity of no more than 10 to minus the twelfth degree of moles per liter, which allows detecting only up to 1,000 types of proteins, or markers of diseases. At the same time, the overwhelming number of types of functional proteins are in the blood plasma at concentrations much lower – up to several molecules (there is a dependence: with a decrease in the concentration of proteins, the number of their types increases).

To register proteins at this level, IBMH scientists suggest using molecular detectors based on atomic force microscopes capable of measuring not protein concentrations (the traditional scheme), but counting single molecules. It was not possible to do this without the use of nanobiotechnology.

"By measuring concentrations, we are dealing with hundreds of trillions of molecules at the same time. And if they appeared during a pathological process, for example, cancer, then the disease can be determined only in the late stages," says Academician Alexander Archakov, director of IBMH. – The registration of single molecules opens the way to early diagnosis. The analysis of the properties of single molecules gives more information than when measuring their huge average number. So we need to strive to register not an ensemble of molecules, but their units. It is these methods that are the future."

Developing methods of single counting of molecules, scientists of the IBMH nanobiotechnology laboratory strive to increase the sensitivity of diagnostic systems (they performed such a task within the framework of the RFBR and FCNTP projects). The result achieved at the moment is 10 to minus the sixteenth degree of mol per liter. The studies were carried out on the example of two diseases – hepatitis B and C. The effectiveness of the created systems was proved experimentally. But the ideal – 10 to minus the twentieth degree – is still far away. Work in this direction continues, in particular, new probes are being developed that catch proteins more efficiently, technologies for detecting markers and registering them are being improved.

It is important to note that highly sensitive diagnostic complexes based on atomic force microscopes were developed by IBMH employees together with the well-known Russian company NT-MDT. Now the devices are undergoing the certification procedure.

Catch the virus in a minute

IBMH is also developing other systems for fast and accurate diagnostics, including those based on optical biosensors, as well as nanowires.

Together with the Institute of Semiconductor Physics SB RAS, an installation has been created, the elements of which are two nanowires, each about tens of nanometers thick (the size of the virus). On one of them, antibodies are immobilized, for example, to the influenza virus. When single pathogenic microorganisms get on it, the properties of the wire immediately change (mainly its conductivity). As a result, viral particles can be detected in just a minute.

Another direction is development based on optical biosensors. This method makes it possible to register markers of hepatitis B and C in real time using nanometer-sized resonant structures. An optical biosensor is a prism coupled to a waveguide. The patient's blood is placed in the cuvette, the laser beam is fired at an angle greater than the internal total reflection. Part is reflected, but part of the radiation passes through the waveguide at a certain resonant angle, which depends on the refractive index. When antibody complexes with markers are formed, the refractive index increases, respectively, the laser beam rotates at a certain angle. The detector registers a change in the angle over time and thereby signals the presence of marker proteins in the blood. Thanks to biosensors created by specialists of the IBMH nanobiotechnology laboratory, the hepatitis C virus is detected in 5-10 minutes (using traditional methods – in 8 hours). One biosensor can be used for 100-150 analyses.

"The advantages of our technologies are obvious," Yuri Ivanov is convinced. – First of all, they allow detecting markers of diseases at early stages. Secondly, it is possible to detect more types of markers – molecules that appear in the body during the disease. This significantly increases the reliability of the entire diagnostic system: there is a difference – to make a diagnosis on one marker or on the whole spectrum at once. Finally, the process of diagnosis is accelerated, which is also important."

Synchronize the clocks of scientists and merchants

The high level of development of the staff of the IBMH nanobiotechnology laboratory is evidenced by numerous publications in rating foreign journals – Analytical Biosystems, Proteomics and others. Moreover, articles in foreign publications have been dated since 1996 – even then Russian nanobiotechnologists had noticeable results. In the same years, the Institute began to acquire the equipment necessary for conducting advanced research in this field: atomic force microscopes, robotic manipulators, mass spectrometers (only single copies of such equipment were received in Russia at that time); and currently, in terms of technical equipment, IBMH is not inferior to leading foreign universities. At one time, the institute had great difficulties with personnel. Now the situation has improved, funding has appeared, graduates from the country's leading universities – MSU, MEPhI, MIPT - have begun to come.

It is also very significant that IBMH has a wide range of partners. Among foreign organizations, close cooperation has been established with German and French scientists. A joint project is being carried out with the French National Institute of Health and Medical Research (INSERM) to increase the sensitivity of a number of diagnostic systems. Studies of enzymatic systems are being conducted with German colleagues from the Expert Center of Molecular Medicine at the University of Saarland. Among the Russian partners are the Institute of Semiconductor Physics SB RAS, the Joint Institute of High Temperatures of the Russian Academy of Sciences, Lomonosov Moscow State University, the V.A. Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences, the NT–MDT company and others.

The staff of the Institute of Biomedical Chemistry of the Russian Academy of Medical Sciences occupies a leading position in the development of diagnostic systems and is already set to introduce many of them into clinical practice, in particular, biochips and biosensors, which have no analogues in the world. According to the most optimistic forecasts, prototypes of the devices will be able to be implemented in five years. However, the director of IBMH, Academician Alexander Archakov, fears that all the institute's developments will remain at the level of laboratory prototypes: "We have R&D, but it is almost impossible to implement them. This is a huge problem for Russia, and in any field. A scientist needs to finish development work, and then a powerful firm should come and organize the market. This is the global practice."

Portal "Eternal youth" www.vechnayamolodost.ru15.05.2008

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