Experts lead the legacy

The year 1905 was annus mirabilis, or the year of miracles, that rare historical moment when flashes of intuition from individual scientists set new directions in the development of the entire field of science. Albert Einstein then published four of his scientific works, which overturned traditional ideas about how the Universe works, and determined the direction of the development of science for many years to come. A hundred years have passed, and a new annus mirabilis has come - 2007. Only this time biology becomes the field of scientific breakthrough. Such fundamental concepts as genes and heredity are being revised.

Since 1900, when Gregor Mendel's work on the inheritance of traits in peas was rediscovered, scientists have still considered the gene to be the basic unit of heredity (just as the atom was considered the basis of pre-Einsteinian physics). The discovery by Francis Crick and James Watson of the DNA double helix as a carrier of hereditary information did not change the situation. However, a new wave of technical and scientific discoveries that has swept over biology in recent months has destroyed the dogma of the 20th century.

Scientists have finally come to the conclusion that the Mendelian gene as a unit of heredity is a fiction. New research proves that in fact, heredity is the result of an incredibly complex interaction of genome components scattered across different sections of DNA.

Biologists have been developing this hypothesis for a long time, but they lacked some important details to complete the picture - and now everything has finally fallen into place. As soon as scientists stopped relying on the established concept of a gene and paid attention to the individual letters of DNA in the genome - the four nitrogenous bases A, C, T and G - they immediately saw all the causal relationships. This is a book where many diseases and personality traits are recorded.

The discovery heralds a giant breakthrough in medicine. Proof of this is the success of the authors of recent scientific papers. Over the past six months, they have been able to detect changes in the DNA sequence that are responsible for predisposition to a wide variety of diseases. These include type 1 and type 2 diabetes, schizophrenia, manic depressive illness, glaucoma, rheumatoid arthritis, hypertension, gallstone formation, and restless leg syndrome. Moreover, unlike previous discoveries made at random, the results of recent studies are easily reproducible in repeated experiments.

"The hunt for disease genes is being carried out with unprecedented enthusiasm," writes the British journal Nature. "After several years of chasing decoys, the hunters finally hit the trail of the victim," echoes American Science. The fact that the two leading scientific publications, describing new discoveries, still use the old terminology is another evidence that the ideas discussed are still unusual, although the opinion that they are the only true ones appeared 30 years ago.

TREAT BY SNIP

In 1977, a study by biologists Phillip Sharpe and Richard Roberts, later awarded the Nobel Prize in Medicine, showed that DNA encoding certain proteins is often scattered throughout the genome and is not associated with one specific gene.

But traditional geneticists initially turned a blind eye to this discovery - after all, their own research also seemed to bear fruit: the combination of new DNA sequencing methods with the study of hereditary diseases in large families made it possible to identify specific genes responsible for diseases such as cystic fibrosis, Huntington's disease, Duchenne myodystrophy and many others. Each of these specific diseases is caused by a mutation in a single segment of DNA that codes for a specific protein. But this clear scheme does not work for all diseases. For example, searches for the genetic causes of common diseases that affect most older people have been inconclusive.

Great hopes for overcoming these difficulties were pinned on the project to decipher the human genome, launched by the US government in 1990. Participants in both the state and the alternative project launched a few years later, headed by Craig Venter, were sure that having the key to this treasury of genetic information, they they will definitely be able to “decode” such serious diseases as cancer and heart disease.

But then the unexpected happened. In 1998, geneticists Andrew Fire and Craig Mello discovered a cellular process called RNA interference, which, 8 years later, brought them the Nobel Prize in Medicine.

If there were suddenly evidence of the existence of aliens, the scientific community would be less shocked. After all, geneticists observed a completely new process, in which not proteins participated, but tens of thousands of hitherto unknown sections of the genome from “junk” DNA. They coded for the production of specific molecules, micro-RNAs (composed of RNA particles, a well-known component of the cell). These molecules, in turn, controlled a hitherto unknown process - the very RNA interference that is used to block the expression of certain genes.

On the one hand, RNA interference could lead to the emergence of a qualitatively new approach in medicine - this process allows you to suppress the activity of "disease genes". But at the same time a great theoretical discovery was made. It became clear: the basic unit of heredity is the position of each individual letter of DNA. Moreover, each piece of DNA is prone to mutation and variation. Of the 3 billion bases of DNA contained in the human genome, 0.1% of such letters (that is, millions) differ in individuals. Variations of these letters, called single nucleotide polymorphisms, or snips (from the English SNP, single nucleotide polymorphisms), were proclaimed the main units of heredity.

Upon learning of this, many scientists fell into despondency. “Now it will be extremely difficult, if not impossible, to find genes [for common disease susceptibility] or to develop effective and reliable tests to detect them,” lamented Dr. Neil Holtzman, director of the Division of Genetics and Public Policy at Johns Hopkins University, in 2001.

The way out was suggested by a native of Iceland, Kari Stefansson. He realized that since the genome turned out to be much more complex than expected, tests would have to be carried out to identify many more variables. And this will require more test subjects who are related. The Icelander decided to turn to the largest family known to him - his own.

FAMILY IS BIG

Almost every Icelander knows all their ancestors, up to the Vikings who landed on the island more than 1000 years ago. Their pedigrees are well documented. In 1996, Stefansson founded deCODE Genetics and convinced the Icelandic government to give it exclusive access to citizens' medical records. In return, the geneticist promised an influx of investment in Reykjavik and many new high-tech jobs.

The effectiveness of tests on large families was confirmed immediately. While studying obesity, Stefansson tasked his program with identifying SNPs present in groups that were either morbidly obese or extremely thin. In just a few hours, the program began to produce evidence that variations in specific DNA letters did indeed play a decisive role. So, snip can really be considered a new unit of heredity.

As of September, deCODE has made significant progress in identifying SNPs believed to be responsible for 28 diseases, including glaucoma, schizophrenia, diabetes, heart disease, prostate cancer, hypertension and stroke. In the case of glaucoma and prostate cancer, there is enough data to develop diagnostic tests. In the case of schizophrenia, the identification of links to specific proteins sheds light on the genetic causes of the disease, which may lead to the development of new treatments.

Encouraged by Stefansson's success, his colleagues also wanted to conduct similar research, although few had such wide access to thousands of years of genealogical information. However, it turned out that it is possible to study the entire population of the Earth as one big family, but for this you need to collect a huge amount of data.

Eric Lander, an MIT professor and thought leader of the government's genome sequencing project, understood that the task required a new approach. In 2004, Lander persuaded the leaders of MIT and Harvard to pool their vast resources to create a new institution. Now the Broad Institute (named after Eli and Edith Broad, the billionaire philanthropists who invested $200 million in it) is improving genetic technology. One of them can identify DNA base letters present in 500,000 SNPs in the genomes of 40,000 or more people. Imagine this data as a table with 500,000 columns - each with a snip - and 40,000 rows - each with one person.

To uncover the genetic basis for, say, manic-depressive psychosis (MDP), a computer scans the rows of people with the condition, keeping track, column by column, of which letters appear most frequently compared to people without MDP. This is how a joint team of American and German researchers discovered that variations in DNA letters in 20 different positions play a crucial role in the development of this disease.

BILLIONS TO REVOLUTION

However, even these high-profile discoveries are only a prelude to what will become a real revolution. Just as physicists shook the world in the 20th century, so biologists and doctors will have to shake it in the 21st century. In just a few years, the doctor, after conducting an individual computer analysis of the patient's genome, will be able to tell in detail about the predisposition to certain diseases. And the matter is not limited to the forecast. RNA interference will help doctors control the expression of potentially dangerous genes, that is, turn them off. It may be possible to eradicate diseases such as cancer, heart disease, severe neurological disorders such as Alzheimer's or Parkinson's.

Pharmaceutical companies have already embraced these technologies. Novartis and Roche have signed licensing deals with biotech firm Alnylam for new therapeutics -- valued at $700 million and $1 billion, respectively. Merck just bought another such company for $1.1 billion -- only to acquire the intellectual property rights to its RNA portfolio. -development.

ERIK LANDER, Founding Director of the General Institute of Harvard University and the Massachusetts Institute of Technology

How did you manage to unite two main competitors from the number of scientific universities in the USA into one team?

Yes, we are not competitors to each other. We are rather competing with cancer, diabetes and heart disease. We have a fantastic opportunity to overcome these diseases, but only if all of us - biologists, chemists, mathematicians, engineers - fight together. Think for yourself: if there is a chance to find a cure for cancer, would you rather be part of a team and take this chance, or, working alone, miss it?

You have developed technology that allows geneticists to study DNA fragments scattered throughout the genome. But how to determine exactly where to look for the disease?

And it doesn't need to be defined. The great achievement of our era is that we no longer have to guess where to look. If, for example, we study cancer, we can immediately look through all the chromosomes for the mutations we need.

PHILLIP SHARP, Nobel laureate, professor at the Massachusetts Institute of Technology

You are now engaged in research on RNA interference, which should open the way to a new method of treating diseases. How is it different from other methods?

Most drugs affect how genes make proteins, and RNA interference will allow us to treat the genes themselves. Perhaps this will become a new kind of therapy. Our main task is to learn how to introduce these small molecules, micro-RNA, into the cells of the body. If there are no side effects, then with the help of these molecules we will be able to suppress disease genes.

Craig Venter, founder of the Craig Venter Institute

What is the purpose of recent genetic research?

Preventive medicine. Now there is a lot of talk about personalized medicine, when medicines will be produced individually for each person. I don't think it will look like this. I'm not at all sure that the genome will give us unambiguous answers to all questions. But to avoid risks and take preventive measures, one hundred percent certainty is not needed. In prevention, even statistical information can be very useful.

KARI STEFANSSON, Head of deCODE Genetics, Reykjavik

What is remarkable about 2007 for genetics?

He gave us new technologies, an understanding of how to use them, and the realization that discoveries require information about people, their health, their diseases. In Iceland, it is easier to get detailed information about the health of citizens, and this has made us masters of the situation.

What are you currently working on?

We study the genetic mechanisms of a wide range of common diseases - heart attack, stroke, rheumatoid arthritis - and develop diagnostic tests. Soon we will be able to provide people with a new service: to determine the genotype of anyone who wants to know about their ancestors and what diseases they are predisposed to.

RICHARD WILLEMS, geneticist, President of the Estonian Academy of Sciences

Why did the breakthrough in genetics happen only now?

It seems to me that in the last few years, the amount of genetic information, knowledge about a person has finally turned into quality. Therefore, we can count on the success of molecular genetics in the near future. If we recall the genogeography, then 5 years ago only a few hundred DNA analyzes of people from all over the world were collected. And now there are tens of thousands of them, and we can quite reliably map the migration of people across the Earth.

FEDOR URNOV, Professor, Department of Molecular and Cellular Biology, University of California, Berkeley

What practical discoveries in genetics do you predict in the coming years?

In less than 10 years, parents right in the maternity hospital will be able to receive information about the DNA sequence of the child, a list of recommendations on what to feed him, what diseases to check for. Cancer is already being diagnosed at an early stage. And in 5 years it will be possible to do it even earlier - just by a blood sample.

Selection prepared with the participation of Nikita Maksimov