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On Science: Next month's Nobel in medicine will be ...

This article first appeared in the St. Louis Beacon, Sept. 16, 2009 - As I write this, the Lasker Award for Basic Medical Research was just announced, and my ears couldn't help but twitch. The Nobel Prize for medicine and Physiology will be announced next month, and the Laskers have been good predictors of Nobels to come: 76 Lasker Laureates have gone on the receive the Nobel Prize.

So who won the Lasker Basic Medical Research award this year? Two pioneers of cloning research. The first, 76-year-old Cambridge University researcher John Gurdon, was the first person to clone an animal.

The second, 47-year-old Kyoto University researcher Shinya Yamanaka, discovered how to convert skin cells into what are for all intents and purposes embryonic stem cells that can be used to cure disease without killing embryos.

Both researchers grappled with the same deep biological question: Is the path to cell maturity an irreversible commitment, or can a cell's development be reversed? Gurdon provided the first "proof-in-principle" that cell development is reversible, Yamanaka the tools for doing it.

To properly understand these two towering contributions, we need to step back and put their two experiments in context.

Modern Embryology

A century ago, it was received wisdom that the development of a cell line into a particular tissue was irreversible. Early in development, certain cells called embryonic stem cells started to divide, giving rise to a variety of different tissue stem cells like nerve stem cells or blood stem cells. Each of these tissue stem cells then gave rise to a set of mature tissue cells.

A blood stem cell, for example, might give rise to red blood cells and to several different kinds of white blood cells. But it was a one-way road. A white blood cell could not turn back into a blood stem cell, nor into any other kind of cell. Once adult, its developmental fate was sealed and irreversible.

The idea that things might not be as irreversible as all that was first suggested in 1938 by the German embryologist Hans Spemann (often called the "father of modern embryology"). When giving an invited lecture in Chicago, Spemann proposed what he called a "fantastical experiment": remove the nucleus (the organelle in the cell that contains the DNA, the genetic instructions for making more cells) from an egg cell, and put in its place a nucleus from another, adult cell. Perhaps, he surmised, the DNA of the adult cell would be able to instruct the egg.

Spemann wasn't making any detailed predictions. This experiment, if a way could be found to do it, might convert the egg into an egg with the genes of the donor cell, or it might convert the egg into an adult cell like that from which the donated nucleus had come, or it might even make an adult like the one specified by the added DNA - a "clone" of that animal.

It was 14 years before technology advanced far enough for anyone to take up Spemann's challenge. In 1952, when I was 10 years old, two American scientists, Robert Briggs and T.J. King, used very fine pipettes (hollow glass tubes) to suck the nucleus out of a frog egg (they chose frogs because amphibian eggs are unusually large, making the experiment feasible), and replaced it with a nucleus sucked from the body cell of an adult frog.

The experiment did not work when done this way, but partial success was achieved eight years later by the British developmental biologist John Gurdon. In 1970 he repeated the Briggs/King experiment, but inserted nuclei from advanced toad embryos rather than from adult tissue. The toad eggs began to develop!

Most of the eggs developed into tadpoles, although most died before becoming adults. Gurdon is looking at a Nobel not because anyone cares a twit about tadpole development or cloning frogs, but because Gurdon's result was proof positive that the received wisdom about developmental commitment was wrong. Whatever the decisions were that had made a toad embryonic cell into a skin cell, they were reversible decisions.

Getting to Dolly

For 24 years after Gurdon's pioneering work, scientists tried other nuclear transplant experiments without success. Technology continued to advance, however, until finally in 1984 Steen Willadsen, a Danish embryologist working in Texas, succeeded in cloning a sheep using a nucleus from a cell of a very early embryo. His result was soon replicated by others in a host of other organisms, including cattle, pigs and monkeys.

Ten years later, in 1994, technology took another step when researcher Neil First succeeded in cloning sheep from much more advanced embryos, adjusting experimental conditions so that the growth of donor adult cells better matched that of recipient egg.

Within two years, on July 5, 1996, the experiment was successfully repeated with a donor nucleus taken from a fully differentiated adult animal cell (sheep breast tissue, as it happens). The lamb born that day, "Dolly," was the first successful clone generated from an adult animal cell.

In essence, with some experimental adjustments, Dolly was created by repeating Gurdon's experiment with a sheep. An adult nucleus was placed in an egg and "turned on" to divide and develop - it was, in short, converted to an embryonic stem cell. The Dolly experiment, a conceptual descendant of Gurdon's key initial insight, has led to a revolution in cell biology - and to one great big fat controversy, the promise/threat of therapeutic cloning. And that is where Dr. Yamanaka will enter our story.

Using mice, medical researchers quickly used the Dolly approach to develop potential cures for a variety of tissue disorders in mice, including Parkinson's, diabetes and heart disease. The first success was reported in 2001 by a research team at the Rockefeller University in New York.

They took skin cells from an individual mouse, used Dolly-like cloning procedures to produce a 120-cell embryo, harvested its embryonic stem cells, then injected the stem cells into the area needing new tissue. Taking instructions from the surrounding cells, the stem cells proceed to develop into the kind of nerve cells that had been destroyed by the Parkinson's!

The controversy with using embryonic stem cells to cure disease, as most readers of this column will know, comes from the fact that a newly created embryo must be destroyed to obtain the embryonic stem cells used to cure the disorder. Many believe the procedure to be a major medical advance that may potentially save countless lives. Others believe, just as firmly, that destroying an embryo, however it was obtained, is nothing less than murder.

With no easy answer to this ethical disagreement, research on stem cells has remained controversial in this country (although not, as we shall see, in Japan). Government support of stem cell research has been sharply restricted in the United States, although this year the barriers are starting to lift.

New Direction in Japan

Let us jump, then, from the Rockefeller University to Japan. There in 2001 (the same year that the Rockefeller researchers were exploring Dolly approached to therapeutic cloning), a Japanese stem cell researcher named Shinya Yamanaka carried out an unusual experiment -- actually, not so unusual when you consider the history of investigation described above. Yamanaka removed the nucleus from an embryonic stem cell, fused the cell with an adult cell, and then watched carefully to see what would happen. I bet what he saw was not what he thought would happen: The adult cell turned into an embryonic stem cell!

How in the world could this happen? All the DNA genetic instructions had been removed from the embryonic stem cell. How in the world did the adult cell get the necessary instructions?

There was really only one possible answer: The adult cell was using its own DNA instructions. Somehow, the genetic commands that had made it an adult cell had been over-ridden. "Something" had passed from the nucleus-less embryonic stem cell into the adult cell that was able to issue commands to genes -- to turn genes saying "be an adult cell" from ON to OFF.

What sort of commands could these be? Here Yamanaka had the shoulders of others to stand upon. Over the last decades science has learned a great deal about how genes are turned OFF and ON. There is no space to go into it in this short column, except to say that, as a general rule, genes are turned OFF or ON by special proteins called transcription factors that direct the cell to read particular genes. These proteins are what must be passing from embryonic stem cells to adult cells, Yamanaka concluded.

So he set out to look for them. And what he found, after three years of careful investigation, set the scientific world ablaze in interest and wonder. In 2006, Yamanaka announced he had successfully reprogrammed a mouse skin cell, causing it to turn into an embryonic stem cell by the simple addition to the skin cell of four transcription factors!

Four proteins, that's all it took. Four transcription factors that, once inside, induce a series of events that lead to what stem cell researchers call "pluripotency" - the ability to become any kind of adult cell. Development is not the throwing of a long series of gene switches, as biologists had thought. Life takes a much simpler course, turning the entire package of instructions ON (or, as we now see, OFF) with but a few simple switches.

Yamanaka is looking at a Nobel because he learned how to throw the switches.

Gurdon and Yamanaka, then, make up the two ends of an intellectual journey that will have profound medical implications for all of us. There can be no serious ethical objection to adding a few proteins to skin cells taken from Michael J. Fox, if this will cure him of his Parkinson's disease.

Serious work has already begun. Six months ago, on March 6 of this year, researchers at the Whitehead Institute in Cambridge, Mass., succeeded in converting skin cells from people with Parkinson's disease into the type of neuron that the disease destroys. They first used Yamanaka's technique to convert the skin cells into embryonic stem cells, then used established procedures to drive the subsequent development of these cells down a different path, toward that particular kind of nerve cell. There are technical hurdles to overcome before Parkinson's patients can be treated, but when before has there ever been such promise?

I sure hope the Nobel committee is listening to the Lasker Awards this year. Rarely, in my view, would a Nobel Prize be more richly deserved.

On Science

George B. Johnson's "On Science" column looks at scientific issues and explains them in an accessible manner. 

Johnson, Ph.D., professor emeritus of Biology at Washington University, has taught biology and genetics to undergraduates for more than 30 years. Also professor of genetics at Washington University’s School of Medicine, Johnson is a student of population genetics and evolution, renowned for his pioneering studies of genetic variability. He has authored more than 50 scientific publications and seven texts.

As the founding director of The Living World, the education center at the St Louis Zoo, from 1987 to 1990, he was responsible for developing innovative high-tech exhibits and new educational programs.