As Published in: New York Times (Medical Science)

Cell Channel Finding Earns Nobel Prize

Two Germans found how cells control electric state

By Lawrence K. Altman

Two German scientists were awarded the Nobel Prize in Physiology or Medicine in Stockholm yesterday for discoveries in basic cell function that have shed light on the cause of several diseases, like diabetes and cystic fibrosis, and that are paving the way to tailor-made drugs.

Dr. Erwin Neher, 47 years old, and Dr. Bert Sakmann, 49, will share the $1 million prize for work they began in the 1970’s and partly conducted in the United States. Their research, particularly the development of a technique called patch clamp, which allows the detection of electrical currents of a trillionth of an ampere in the membrane, or surface of a cell has “revolutionized modern biology and facilitated research” in many areas, the Nobel Committee said.

“Joy, my reaction is simply joy,” Dr Neher said in an interview during an impromptu celebration with his Colleagues at the Mac-Planck Institute for Biophysical Chemistry in Gottingen, Germany.

Dr. Neher, a physicist, also studied at the University of Wisconsin in Madison and did research at the University of Washington in Seattle, the University of California at Los Angeles and Yale University. He is a member of the United States National Academy of Sciences.

Dr. Sakmann, a medical doctor, said he was working in an experiment in his laboratory at the Max-Planck Institute for Medical Research in Heidelberg, Germany, when he received a telephone call announcing that he had won the prize.

The scientists were cited for discovering how tunnel-like structures called ion channels control the passage in and out of cells of positively or negatively charged particles called ions. Every cell has 20 to 40 types of ion channel that help it communicate and function. There are thousands of copies of each type.

“They conclusively established that ion channels do exist” the Nobel Committee said, adding that they did it by developing the patch clamp technique, which allows detection “of the incredibly small electrical currents that pass through a single ion channel.”

“The technique is unique in that it records how a single channel molecule alters its shape, and in that way controls the flow of current within a time frame of a few millionths of a second,” the Nobel Committee said.

Dr. Sakmann said that after spending seven years developing the technique, he and Dr. Neher had spent the last decade applying it to describe precisely the structure and function of single ion channels, particularly in the brain.

Brain’s Relay System

The brain and central nervous system contains an estimated 100 billion cells, each of which can interact with thousands of others through highly specific connections in a relay system that dwarfs any supercomputer.

“The brain is the least understood organ and what we have done is bring a little light into the zoo of channels within it,” Dr. Sakmann said. “We showed that these channels are not chaos”

Dr. Frederick J. Sigworth, a Physiologist at Yale who spent five years working with Dr. Neher and Dr. Sakmann in Germany, said the two were motivated to understand better how electric currents worked in nerve and muscle cells.

“Before their work”, he said, “one wasn’t sure how to think about ion channels – how many of them were there? Just a few, each carrying a large current? Or many, each carrying a small current?”

Answers cam through patch clamp studies of the membrane that separates the interior of each cell from its surroundings. The patch clamp technique is so named because the recording electrode fastens to a microscopic patch of the cell’s membrane. Membranes help regulate the entry of sugar and other foods that cells need for nourishment and the excretion of wastes. Cells also communicate through channels in the membrane. The channels consist of molecules that allow passage of ions, or charged atoms.

The Nobel Committee noted that life begins with activation of ion channels as the sperm merges with the egg at fertilization. All cells have electrical charges within and outside the cell and the difference is known as the membrane potential. Fertilization changes the potential to prevent other sperm from joining the fertilized egg.

All other cells have a characteristic set of ion channels that help them carry out their specific functions.

As a student, Dr Neher was long fascinated by how the passage of electrically charged ions helped control the transmission of nerve impulses. He first developed the idea of the patch clamp technique in a doctorial thesis and began collaborating with Dr. Sakmann in Germany.

Dr. Neher moved to the University of Washington to work with Dr. Charles F. Stevens and then moved with him to Yale, said Dr. Stevens, who is now a Howard Hughes Medical Investigator at the Salk Institute in La Jolla, California. Dr. Neher continued to collaborate with Dr. Sakmann much of the date in their major paper on patch clamp came from studies at Yale, Dr. Stevens said.

When they applied glass electrodes with microscopic tips to a cell membrane, they were able to electrically isolate a small patch of it and examine individual proteins. The proteins served as gates or channels through which only certain ions were allowed to pass.

They also found that they could remove a patch of membrane and gain access to the interior of the cell.

“It was exacting work,” Dr. Sigworth said, adding that few other scientists had the patience of Dr. Neher and Dr. Sakmann.

But various manipulations under the microscope they could study cell physiology in a way that no one could before.

Then patch clamp technique was regarded as esoteric when Dr. Neher and Sakmann first reported it in the mid 1970’s. But it quickly evolved into one of the most widely used tools of cellular physiology.

At first, neuroscientist used it to study the electrical signals form nerve cells that touched off muscle contraction. Then researchers began using the technique to study other cells in the body.

“The surprise was that the electrical activity was also going on in all kinds of other cells,” Dr. Sigworth said.

For instance, researchers using patch clamps discovered a defective ion channel as the mechanism responsible for cystic fibrosis, which is considered the most common lethal genetic disease among white people. Cystic fibrosis produces thick mucus in the lungs, often leading to respiratory infections and pneumonia. It can also affect the intestines and other organs.

Doctors have long been aware that the sweat of people with cystic fibrosis usually has increased amounts of sodium and chloride. But until the research derived from the German discovery, they did not know that the chloride channels was missing or functioning improperly.

The German research has also led to a better understanding of the body’s regulation of hormone levels and the basic mechanisms of the production of insulin in the pancreas glad deep in the abdomen.

Diabetes can result from production of inadequate amounts of insulin to control the amount of sugar in the blood. Researchers using the patch clamp discovered that the release of insulin from the pancreas is controlled in part electrically through ion channel that are sensitive to a natural substance, ATP. Researchers have also found that some drugs used to stimulate production of insulin act directly on ATP controlled channels.

The Nobel Committee said the work of Dr. Neher and Dr. Sakmann also related to heart disease, epilepsy and disorders affecting the nervous and muscle systems. The research also opened a way to develop new and more specific drugs.

“With help of the technique of Neher and Sakmann, it is now possible to tailor-make drugs, to achieve an optimal effect on particular ion channels of importance in a given disease,” the committee said.

Colleagues describe Dr. Neher as a cheerful, quiet and very generous man who was devoted to his wife, Eva Marie, a microbiologist, and their five children. He is considered a brainstormer, constantly generating new ideas, and good with his hands.

Dr. Sakmann, who enjoys playing tennis and soccer, is a man with a good sense of humor. He and his wife, Christianne, an ophthalmologist, have three children. “They are examples of excellent scientists who spend a lot of time with their families,” Dr. Sigworth said.

Dr. Neher and Dr. Sakmann have been winners of two awards from Columbia University: the Spencer and the Louisa Gross-Horwitz Prize. Dr. Sakmann has won the Gairdner Prize in Toronto. Dr. Neher won a Bristol-Myers Squibb research award.