Albert Lasker
Basic Medical Research Award

Award Presentation by Harold Varmus

Every person in this room, no exceptions, originated from a single cell, a fertilized egg. How did that single cell generate the hundreds of different types of cells that populate our complex bodies?

Science now offers some answers. A fertilized egg contains a program for development, encoded in DNA. The same instructions are found in nearly all adult cells. Mature cell types differ from each other because different parts of the script, different genes, are read-out.

Consider another facet of this situation. If adult cells retain the instructions for development, why can't any cell, even a highly specialized one, be reprogrammed—so that it behaves like an immature cell, prepared to produce many different types of cells, even an entire organism?

The two basic scientists we honor today have shown that this remarkable thing, reprogramming, can indeed occur. They have accomplished it at different times in the history of biology, in different ways, and with different consequences.

When John Gurdon began his work in the 1950's, it wasn't yet known whether mature cells contain a complete set of instructions. At the time, two respected British scientists, Robert Briggs and Thomas King, were trying to answer this question by transferring a frog cell's nucleus, the DNA repository, into a fertilized frog egg from which the original instructions had been removed. Then they waited to see if a tadpole or frog emerged. This worked with nuclei from cells very early in development, but not with more mature cells. So they could not say whether the mature cells had lost instructions, or whether the instructions had simply become unreadable.

Gurdon encountered this difficult problem almost accidentally. At the age of fifteen, his first biology teacher told him that his interest in a scientific career was "quite ridiculous." So he studied Latin and Greek. But on admission to Oxford the faculty discouraged him from pursuing the classics any further. So he returned to zoology, landing fortuitously in the laboratory of an embryologist named Michail Fischberg, who asked Gurdon to repeat the Briggs and King experiments, but with a different kind of frog— Xenopus instead of Rana. This was a good suggestion. Gurdon showed that nuclei from intestinal cells in a Xenopus tadpole could produce fertile male and female frogs after transfer into eggs.

Not surprisingly, there was skepticism about this radical discovery, one that pitted a mere graduate student against established scientists. But over many years Gurdon repeated the experiment in many ways. Perhaps most dramatically, in 1975 he used nuclei from frog skin cells that had been grown in a petri dish. Eggs supplied with those nuclei still produced swimming tadpoles.

Thus, a full set of instructions for development must remain intact in specialized cells. And an egg's cytoplasm can reprogram those instructions to make a new organism.

The implications of making new individuals from adult cells— cloning— did not escape notice at the time. But attempts to repeat the experiments with mammals either failed or were subject to doubt. The concept of reprogramming came under siege. Then, in the 1990's, methods to transfer mammalian nuclei improved, culminating in 1997 with the highly publicized birth of Dolly, a sheep derived from the nucleus of a breast cell that had been grown in a laboratory dish.

Dolly arrived in an era profoundly different from the days when tadpoles were first made from reprogrammed frog nuclei. Public attention to biological research and genetics was much greater. The ethical aspects of reprogramming, especially the possibility of human cloning, were more widely debated, even in the US Congress. And the medical importance of reprogramming was better appreciated. So-called "pluripotent stem cells"— cells able to become virtually any type of tissue— had been grown from early mouse embryos in the 1980's. Human embryonic stem cells were just around the corner. Reprogramming by nuclear transfer might provide an important source of pluripotent stem cells from human beings, including patients needing cell therapies.

Reprogramming by nuclear transfer has established important principles; perpetuated some productive lines of livestock by cloning; and permitted some extraordinary experiments with mice. But it is not easy or efficient. It works poorly, if at all, with human cells, and uses a problematic commodity, human eggs. Could there be a better way?

Here Shinya Yamanaka enters the story. Although trained as an orthopedic surgeon, Yamanaka was drawn to laboratory research and earned a Ph.D. in Japan. In the early 1990's, he came to the Gladstone Institute for Cardiovascular Disease in San Francisco to study a problem seemingly unrelated to anything I've been discussing. In the course of this work, he encountered an interesting gene belonging to the class of genes— I'll call them "molecular librarians"— that tell a cell how to behave by selecting the parts of the DNA script to read and the parts to keep silent. Back in Japan, he found that his molecular librarian helps to keep embryonic stem cells pluripotent. This stimulated an important idea. Perhaps a small cohort of genes can compel any cell to behave like a stem cell. This idea provoked a daring experiment— testing many small combinations of genes for a set of molecular librarians that could reprogram adult cells.

Just over three years ago, Yamanaka identified four "librarians" that, together, force mouse skin cells growing in a petri dish to behave like pluripotent stem cells. His method is simple, efficient, and reproducible. It doesn't require eggs or embryos or difficult manipulations of nuclei. It works well with human cells. Many other labs have already repeated his work, using many types of mature cells and many variations of his original recipe. It is now almost routine to grow skin cells from a patient with, say, a neurological disease; turn them into pluripotent cells in a petri dish; convert the cells into nerve cells to study the disease process; and contemplate using the cells to repair the same patient's damaged brain.

Of course, these are still early days. The method is still being improved. Reprogrammed pluripotent cells and true embryonic stem cells are still being compared. New combinations of molecular librarians are still being discovered to convert one cell type to another. And reprogrammed cell therapies remain in the future.

It is unusual for a Lasker Prize to be awarded so soon after a discovery as Shinya Yamanaka's— or so long after one as John Gurdon's. But placed together, this is just right. With the thrilling conversion of adult cells to pluripotent cells, we have come far enough to know that the hard-won principle of nuclear reprogramming is not only generally correct. It also has phenomenal potential to advance science and medicine.