StemCell Therapy

Your life depends on purposeful, targeted changes to cellular DNA. Although conventional thinking says directed DNA changes are impossible, the truth is that you could not survive without them. Your immune system needs to engineer certain DNA sequences in just the right way to function properly.

Today's blog is a tale of how cells engineer their DNA molecules for a specific purpose. It also illustrates how an evolutionary process works within the human body.

Your immune system has to anticipate and inactivate unknown invaders. Living organisms deal with unpredictable events by evolving. They change to adapt to new circumstances. Variation comes from their capacity for self-modification. Cells have many molecular mechanisms that read, write, and reorganize the information in their genomes, the DNA molecules used for data storage.

The adaptive immune system executes basic evolutionary principles in real time. It has to recognize and combat unknown (and utterly unpredictable) invaders. Immune system cells have to produce antibody molecules that can bind to any possible molecular structure.

How do cells with finite DNA, and finite coding capacity, produce a virtually infinite variety of antibodies? The answer is that certain immune cells (B cells) become rapid evolution factories. They generate antibodies with effectively limitless diversity while preserving molecular structures needed to interact with other parts of the immune system.

Immune cells achieve both diversity and regularity in antibody structures. They accomplish this by a targeted yet flexible process of natural genetic engineering: they cut and splice DNA.

Diversity is strictly limited to a special part of the antibody molecules: a "variable" region encoded by engineered DNA. DNA encoding the "constant" region does not change in the same way. The diversity-generating process is called "VDJ recombination" because it involves cutting and splicing together different "variable" (V), "diversity" (D) and "joining" (J) coding segments. Immune cells do this by cutting DNA at defined "recombination signal sequences." There are hundreds of V segments, about a few dozen D segments, and ten J segments. The various combinations of different spliced segments makes for a tremendous amount of diversity.

Antibodies contain two paired protein chains: a longer heavy chain and a shorter light chain. The heavy chain variable coding region forms by splicing V, D, and J segments together. The light chain variable coding region forms by joining V and J segments together. There are at least 10,000 VDJ combinations and 1,000 VJ combinations. Altogether, over 10,000,000 different heavy + light chain antibodies are possible through "combinatorial diversity."

Not bad... but not good enough.

VDJ recombination generates additional diversity. Although cutting the V, D, and J segments is precise, immune cells join each pair of cleaved DNA segments at about a dozen different positions. Connection between the same two segments can have about 30 to 35 possible different sequence outcomes. This "junctional diversity" adds over 1,000 possible antibody combinations.

In addition, heavy chain D segment joining has another virtually unlimited source of variability. Immune cells have an enzyme that attaches unique new DNA sequences to either end of the D segment. These are not encoded anywhere in the genome. Such so-called "N region" sequences can add over 1,000 new variations to each existing VDJ combination.

So the total possible genetically engineered antibody diversity is something above 10,000,000 X 1,000 X 1,000 = 10,000,000,000,000 combinations. This extraordinary number appears to be large enough to generate antibodies that can protect you from virtually any invader, whatever its molecular structure may be.

The immune system is itself a rapid evolutionary process, replacing one set of immune specificities with another. The right antibody-producing cells multiply when an invader enters the body. Antibodies sit on the surface of cells that made them. When a particular variable region binds an invader, that event sends a signal inside the cell to begin dividing.

Dividing immune cells are called "activated B cells," which proliferate into distinct populations. Because the descendants of a single activated B cell share the same engineered variable region coding sequences, they produce even more invader-recognizing antibodies. By binding, these antibodies signal the rest of the immune system to begin eliminating the invaders. This is the front-line "primary" adaptive immune response.

In a future blog, I'll explain ongoing natural genetic engineering as activated immune cells mature in the "secondary" response. It is no less amazing. For now, let's draw three conclusions from the initial rapid evolution system. We see that:

Evolution has produced a system that engineers DNA with a specific purpose: encoding proteins that bind to unpredictable invaders and signal the immune system to make more antibodies and eliminate the invaders. Precise targeting of DNA cutting to variable region-coding segments allows the basic antibody structure to stay the same. At the same time, its recognition/binding capacity changes. Your B cells are able to combine several different kinds of DNA biochemistry into a functional engineering process: 1) cutting the V, D and J segments; 2) joining the cleaved segments; and 3) synthesizing and inserting the N region sequences.

In the immune system, "purposeful" and "having a predestined outcome" are far from the same thing. Your immune system follows a regular process, but the end result is not fixed in advance. This is an important lesson to keep in mind as we witness ongoing public debates over evolutionary DNA change.

In biology, the alternative to randomness is not necessarily strict determinism. If the cells of the immune system can use well-defined natural genetic engineering processes to make change when change is needed, there is a scientific basis for saying that germ-line cells might do the same in the course of evolution.

Read more here:
James A. Shapiro: Purposeful, Targeted Genetic Engineering in Immune System Evolution

(06-18) 13:42 PDT SAN FRANCISCO -- Dr. Shinya Yamanaka, a stem cell researcher at UCSF's Gladstone Institutes who discovered a technique for transforming adult skin cells into "pluripotent" stem cells without resorting to human embryos, has won Japan's $550,000 Kyoto Prize, an international award that honors scientific, cultural and spiritual contributions to human knowledge.

His discovery resulted in a class of much-sought stem cells that scientists can induce to become virtually any other type of functioning human cell that one day might be used to treat varied diseases or injuries.

During their research, Yamanaka and his colleagues altered the genetics of adult skin cells by inserting four specific viral genes that produce proteins known as transcription factors into the cells. Those proteins in turn yielded other genes that reprogrammed the skin cells so they acquired all the characteristics that made them what are now known as induced pluripotent cells.

Before his discovery, those pluripotent human stem cells could only be harvested from human embryos, a source posing such powerful ethical issues that former President George W. Bush banned virtually all embryonic stem cell research eight years ago. The ban remained in force until President Obama reversed it last year.

Yamanaka, 47, who is attending the annual meeting of the International Society of Stem Cell Research in San Francisco this week, was not told of his award until just before midnight Pacific time on Thursday.

The Kyoto Prize is awarded annually by Japan's Inamori Foundation for major discoveries in many fields of advanced technology, and four other Bay Area scientists have won it in recent years.

They are Leonard Herzenberg, a Stanford geneticist and immunologist who developed a revolutionary cell-sorting machine now crucial to advanced biomedical research; Alan Kay, a Silicon Valley pioneer at Hewlett-Packard who led advanced computing technology for 40 years; Donald E. Knuth, a Stanford information technology expert and specialist in computer programming, language analysis and computerized printing and Richard Karp, a UC Berkeley computer scientist and pioneer in computational biology.

In addition to heading his laboratory at the Gladstone Institute for Cardiovascular Research on the Mission Bay campus of UCSF, Yamanaka is also a professor at Kyoto University, where he began his efforts seeking a way of transforming adult cells.

Besides resolving ethical issues by his achievement, Yamanaka's success also means that the pluripotent stem cells needed to treat a patient's disease can be obtained from the ordinary skin cells of a patient's own body - thus making stem cell therapy possible without the hazards involved in immunologic rejection of cells from other people.

Robert Lanza, chief scientific officer of Advanced Cell Technology and an adjunct professor at Wake Forest University's stem cell research center, said recently that Yamanaka's work "is likely to be the most important stem cell breakthrough of all time."

"The ability to generate an unlimited supply of patient-specific stem cells will revolutionize the future of medicine," Lanza said.

Read more: http://www.sfgate.com