The secret of life is in your bones and teeth

SINGAPORE - As a boy, Swiss-American Edmond Fischer yearned to find a cure for the tuberculosis that killed his father too young.

Instead, he and his American collaborator, the late Dr Edwin Krebs, discovered in 1954 a fundamental way in which the body works that is now saving many cancer sufferers.

For that, they were awarded the 1992 Nobel Prize in Physiology or Medicine.

To understand how big their idea is, you must first recall that your body is made up of millions of cells, all working to help you grow, think and move, and all this work is powered by proteins.

There are many types of proteins, including enzymes, which are proteins that speed up cell activity.

Drs Fischer and Krebs wanted to know: What is regulating all this activity? For example, how does the enzyme known as glycogen phosphorylase know when to convert the glucose stored in the liver into energy for your muscles whenever you break into a run?

And why does glycogen phosphorylase stop releasing energy to your muscles when you're done running?

After a series of experiments on that enzyme in muscle tissue in the early 1950s, they found that two other enzymes, known as kinase and phosphatase, were the ones regulating most proteins.

They do so like green and red traffic lights, says Dr Fischer, who is now 93 and who was in town earlier last month for the inaugural World Academic Summit, co-organised by the Nanyang Technological University and university-ranking body Times Higher Education, in partnership with The Straits Times.

Broadly speaking, and in the interest of simplicity, kinase would act like a green traffic light, he says, whenever it puts a phosphate molecule on a protein, thus "switching on its activity". Then phosphatase would act as a red traffic light, switching off the protein by removing the phosphate molecule when the protein's activity has to end.

Phosphate is the stuff from which bones, teeth and fertiliser are constituted, which makes the saying "ashes to ashes, dust to dust" ring particularly true.

The act of putting a phosphate molecule on a protein is known as phosphorylation, and since the act can be started and stopped - that is, reversible - the world of science came to call Drs Fischer and Krebs' idea "reversible phosphorylation".

Ah, but you ask, how does kinase know when to give the green light, and phosphatase to give the red? They do so by responding to favourable chemical signals from the protein, almost as if the protein were waving a sign at the kinase to say "Phosphorylate me" and vice versa, says Prof Edward Manser, 52, an expert on protein kinases and a senior principal investigator at the Institute of Medical Biology here.

Sometimes, however, Dr Fischer says, the kinase will be damaged, or mutated, by radiation or wonky genes. The distorted kinase is insidious because it then becomes locked in "go-go-go" mode all the time.

"We know now that at least 70 per cent of all forms of cancer are due to this mutation, which makes the cell behave like a car in which the accelerator has been slammed to the ground; you cannot control it anymore," he says.

Dr Fischer, who is modest to a fault, says of their discovery: "We knew that it was important to investigate it. But we had absolutely no idea that it would be such a basic regulatory mechanism in our bodies.

"By today's standards, what we discovered is totally trivial. It's embarrassingly simple. Nobody would have paid any attention to it if it didn't turn out to be crucial for the regulation of cellular processes."

Others would heartily disagree.

Prof Uttam Surana, 55, from the Institute of Molecular and Cell Biology, says: "What Edmond and Edwin found is the centrepiece of machine control in a cell. Reversible phosphorylation controls so much of the activities in our lives and that's why people picked it up."

Prof Manser adds: "The current estimate among scientists is that there are at least 10,000 different places within a cell that undergo phosphorylation.

"So almost every process we study in the laboratory is regulated by this mechanism - all tissues use this mechanism to turn proteins on and off."

Dr Fischer was born in Shanghai in 1920, the son of a trained Austrian lawyer and his French wife. His maternal grandfather founded China's first French newspaper, Courrier de Chine, and also set up its first French school.

At the age of seven, Dr Fischer went to Switzerland for his education and studied there right up to his PhD. He continued researching enzymes there until the early 1950s, when the University of Washington in Seattle offered him an assistant professorship at its newly opened medical school.

The twice-married father of three found the Seattle landscape akin to Switzerland's, and moved there in 1953. Dr Krebs was already there and working on that same enzyme.

Within six months of Dr Fischer's arrival in Seattle, they were working together on cellular regulation. Then in 1954, they made their Nobel Prize-winning discovery.

Dr Krebs died in 2009, at the age of 91.

Dr Fischer retired from his post at the University of Washington in 1990, when he was 70 - and two years before he and Dr Krebs were awarded the Nobel Prize.

Dr Fischer continued to travel to China, the land of his birth, every year after that as he was an honorary professor at China's Jilin University, where one of his former students was a professor.

He insists that what he and Dr Krebs did was "pure luck". He also believes that "everything in science will be done eventually" and so anyone else could have hit upon the big idea if they had not done so first.

He muses: "That also tells you something very sobering - that in science, very few people are absolutely indispensable. What one scientist does will eventually be done by others and this is the big difference between science and the arts.

"If Mozart never existed, nobody but absolutely nobody would have written his G Minor Symphony or his operas Don Giovanni and Cosi Fan Tutte."

What's the one thing he tells all young scientists then?

He says: "Be curious. Wonder why something is happening. I think it is this curiosity that pushes certain people more than others to try and investigate a question they have."

suk@sph.com.sg

THE BIG IDEA IN HISTORY: Cellular regulation

AS WITH many really important discoveries, Drs Fischer and Krebs' quest to understand cellular regulation was dismissed as being humdrum at first.

Dr Fischer says that was because at the time of their breakthrough with the kinase enzyme, scientists were aware of only two such enzymes, also known as phospho-proteins. The first was casein, found in milk, and the other was phosvitin, found in egg yolks.

He recalls: "Their only function was to feed the young. So they held no biological interest and were seen as totally uninteresting."

But Drs Fischer and Krebs had some research to build on, at least. In 1906, American scientists Phoebus Levene of the Rockefeller Institute of Medical Research had observed a phosphate molecule on phosvitin and later, in 1936, on casein.

It is worth noting that many scientists in the early 20th century were disdainful of those who studied the mechanics of how a cell was regulated.

Those opposed to studying cellular regulation thought that it was far more important to understand each individual process within a cell first, such as the function of DNA, instead of looking at the bigger picture of how a human cell was wired for action.

It was left to three British scientists working on two types of yeast and sea urchin embryos to crack how a cell is regulated in the 1980s and 1990s. They are Professors Paul Nurse - who has been featured in The Big Idea - Lee Hartwell and Tim Hunt, who jointly won the Nobel Prize in Physiology or Medicine in 2001 for their efforts.

Still, while humanity has mapped the entire human genome and is familiar with the double-helix structure of DNA, uncovering the secrets of cellular regulation - to fight cancer better, among other concerns - is still a work in progress.

THE BIG IDEA IN ACTION: Enabling new ways to fight cancer

MOST people see chemotherapy for cancer patients as toxic and debilitating, notes Professor Edward Manser, 52, who is a senior principal investigator at the Institute of Medical Biology, which is part of the Agency for Science, Technology and Research.

But Prof Manser, an expert in protein kinases, says that thanks to Drs Edmond Fischer and Edwin Krebs' discovery of reversible phosphory-lation, pharmaceutical firms are now able to design anti-cancer medication that targets tumour growth more specifically and is less poisonous to the body than earlier chemotherapy drugs.

He adds that Drs Fischer and Krebs set the ball rolling on that because they showed scientists "a new way of thinking about many, many processes in the cell".

Building on that, he notes that in the past 10 years, there has been "a tremendous amount of progress in designing such drugs... they are much easier to give cancer patients now".

He adds that there are mainly two types of such relatively new drugs - the first are antibodies which have a high success rate but are very expensive, and the other are drugs to be taken orally, called small molecule inhibitors. Both types turn off the mutant kinases that are like switches stuck in go-go-go mode all the time, accelerating cell activity such that it descends into chaos.

"When we talk about reversible phosphorylation and cancer, sometimes the button gets stuck on "ON"," notes Dr Manser. "In these cases, the only way to stop that is to have a drug which will go into the kinase and bind to it so as to prevent it from working."

The rub, he points out, is that there are currently 518 known types of kinases, which are enzymes, so how do you make a drug that will hit only one out of the 518 kinases present in a cell? "All of them are similar. That's the challenge."

Prof Manser's colleague, Prof Uttam Surana from the Institute of Molecular and Cell Biology, is working on overcoming cancer in another way.

Prof Surana, 55, won Singapore's National Science Award in 2007 for his work on the control circuits that regulate cell cycles because most cancers are a result of cells growing too rapidly. He says of his current work: "Normally, cells know when and how to divide - and how to stop dividing. But cancer cells do not know how to stop doing so."

So he is now looking into the nature of the circuit that controls cell division. He says if he can identify the circuit's characteristics, he will be able to see what happens in a cell when something in it goes wrong.

Likening the cell circuit to the typical electronic circuit, he says: "If you go into a house and its lights and heater are not working, you need to know what its electrical circuit is before you can repair it.

"In the same way, I'm working on knowing the genetic wiring in the body."

 

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