Resume Reading — The Executioner We Can’t Live Without


The Executioner We Can’t Live Without

You’re dead meat without special molecules that kill rotten proteins.

Last summer, as I interviewed Aaron Ciechanover, who won a Nobel Prize in Chemistry in 2004, his country was at war. Three Israeli…By Pamela Weintraub

Last summer, as I interviewed Aaron Ciechanover, who won a Nobel Prize in Chemistry in 2004, his country was at war. Three Israeli boys had just been murdered in the West Bank by Palestinians, then a Palestinian boy had been burned to death in retribution by Israelis. While we sat in his lab at the Technion-Israel Institute of Technology in Haifa, to the north of the bombs, missiles were flying over Jerusalem and Tel Aviv, and a Gaza invasion loomed. The mounting conflict troubled but didn’t ruffle Ciechanover, one of Israel’s greatest scientists and statesmen, who patiently and colorfully explained to me one of biology’s most remarkable processes, how a molecular Pac-Man races through our bodies and devours damaged proteins.

For over 40 years, Ciechanover has worked to understand these molecular machines, called shredders. Built around a core molecule called ubiquitin, shredders destroy ruined proteins so that our bodies can replace them with fresh parts and not, says Ciechanover, rot like a side of meat, “brownish-greenish and stinking,” in the sun. Ciechanover shared the Nobel Prize with Avram Hershko, his mentor at Technion, and Irwin Rose, a biochemist at the University of California, Irvine. Scientists already understood the genetic code, how genes coded for the creation of proteins. But the shredder helped control the overall process: the degradation of damaged goods, DNA repair, cell division, and immune defense. The shredder enabled biologists to see the wizard behind the screen.

Ciechanover speaks with boundless enthusiasm and charm. He has a great writer’s ability to turn complex subjects into compelling stories. English teachers should study his use of metaphor. The cars he once owned and the places he lived are represented through objects and replicas on his office shelves: a yellow cab from New York City, a series of Tonka Trucks, newly bought from Toys-R-Us in Times Square, to replace the ones he lost during the turbulent moves of childhood. “Toys let us fly on the wings of imagination even though they are very simple,” he says.

For Ciechanover, becoming a great scientist is about the ability to find connections in life and unite them in a singular voice. Doing science, he says, is “like studying in a very good chef’s school in Paris. You don’t do what the chef told you to do, but you use the principles that you learned. You open your own restaurant. And then, it’s up to your imagination what you make.” Almost as much as he loves science, Ciechenover loves Haifa where he was born. He shows me two photos of an identical scene of the city, one taken by day and the other by night. “It’s beautiful here,” he says.” Then he adds, “Pam, enjoy the rest of your stay. Just be careful of the missiles and you’ll be fine.”

A FRIED EGG: Aaron Ciechanover, Nobel Laureate in Chemistry, has a colorful way with words when it comes to describing what humans would be without molecules that clean up the body’s damaged proteins.Technion’s Spokesperson’s Office

Can you describe the core of your early work?

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Let’s get to the heart of the problem: Every living organism from a bacteria to a virus to a plant to a flower to a chicken to a turtle is dynamic. If we look in the mirror in the morning, we see the same face. There are no changes. Well, a man has to shave, a woman has to comb, put on some makeup, but we look the same.

Yet chemistry shows that we are not the same, that from yesterday to today, some molecules at the chemical level have disappeared and were replaced by new ones. We don’t know it because it’s going on behind our backs, but we are constantly removing spoiled, inactivated, non-functional molecules created during life’s wear and tear. It’s like tires. You are riding in your car for several thousand kilometers, and you wear your tires. So we are wearing ourselves all the time.

But unlike a car that goes to a machine shop, we are in the machine shop as we go. If something happens to us, it immediately goes away, gets trashed, and a new one comes back. That’s the beauty of the living organism.

To throw out a metaphor, it’s as is as if we are made of dominos, falling down at all levels of the body all the time—but whenever a domino falls a new one pops up to take its place. The fallen dominos are made of what?

Mostly proteins, the machines that drive our life. It is a protein in my blood, hemoglobin, that carries oxygen. Without it, I could not breathe. On one hand, hemoglobin takes oxygen from the air. On the other hand, hemoglobin collects the waste gas, the carbon dioxide from the tissues, that we expire. So we inspire oxygen and expire carbon dioxide. All of this is carried by a protein.

Think about the fact that we are not falling when we stand. You’re sitting here stable. It’s taken for granted, but God forbid I die now, I would fall off the chair. It’s called proprioception. I have a signal from the environment to tell me where I am in the environment. If I put a finger behind my back and I don’t see it, I can still tell you where my finger is. Why? Because I sense the environment and can process the information via the brain. This is all done by specific proteins.

I’m no different than a piece of meat that I left on a table. But I have a way to take these rotten proteins and replace them.

The fact that when I talk to you my kidneys work and make urine, and my stomach digests my morning cottage cheese, and my heart pumps blood, and my muscles are holding me, these are all proteins. At the same time, I defend myself against bacteria, against viruses in the air by my antibodies. All these are proteins. So, proteins are the tens of thousands of little machines that run our lives.

Yet they are always degrading, always breaking down.

Proteins have a problem. They’re very sensitive to all kinds of effects. They’re sensitive to temperature. The most extreme example is an egg. Take an egg that’s made of protein and fry it. You can fry an egg, but you cannot take the fried egg and put it back into the shell. It’s one-way.

Take a piece of meat. You go to the butcher. You buy a steak and you forget to put it in the refrigerator. Within a few hours, it’s gone. It becomes brownish-greenish, stinking. What happened to it? The proteins in meat were affected by the temperature and got what we call in professional jargon, denatured, misfolded, inactivated. They’re not useful anymore. They are harmed.

Remember now, if we bring the metaphor a little further, if you think about the piece of meat that you bought, it was taken from the chicken leg, it was taken from the fish, it was taken from the cow leg. The same meat is here in my thigh, in my forearm, in my calf, in the muscles. It’s the same meat that I was taking from the cow. It’s no different. Why is it that in my body, within a few hours, this meat doesn’t get spoiled and on the table it does?

I, as a living organism, take the trash, the inactive proteins, the spoiled proteins, the brownish-greenish proteins, trash them and renew and replace them with new ones all the time. That’s the difference between being dead and being alive.

So yes, I am no different than the piece of meat on the table that I forgot when my wife sent me to the butcher, and instead of putting the meat in the freezer, I left it on the table. I’m no different than the egg that was fried within two minutes. But unlike them, I have a way to take these fried proteins, these rotten proteins, trash them and replace them.

Is that what you and Avram Hershko and the team at Technion set out to find—how the body takes out the trash?

We knew that the proteins were replaced, but what was missing from the picture was the trashing machine itself. You’re sitting next to a paper shredder right now. What was missing was the shredder. Who was the shredder? What was the protein shredder that takes proteins and cuts them into small pieces?

Can you explain what a protein is in a simple way?

Proteins are made of pieces called amino acids that work like a language, like English or Hebrew. A language is a collection of words that are made of letters, and some combinations of letters make sense of a word, but you can flip the same letters to make other words, or gibberish. When amino acids are combined, they can make a protein. Now, the sense of the protein is directed by genetic information in DNA. If DNA directs the insertion of the wrong letter into the word of these core proteins, if DNA makes a mistake and inserts the wrong amino acid, we have a mutation. It’s like intending to write mother but instead of M-O-T-H-E-R, ending up with M-A-T-H-E-R.

You could not put MATHER in a book, you would seem illiterate.

It has to be corrected. In the body, the correction mechanism is to put the error in a shredder and then the error is replaced with a new mother, a new protein. But where was the shredder of that mistaken protein?

This was the open question you sought to solve?

Avram was fascinated by a mystery surrounding the shredder: It required energy to do the shredding, yet when we ate, we obtained energy from our food. So how is it that when the shredder breaks down proteins it consumes energy, while when we break down food, we release energy. If you think about it philosophically and thermodynamically, it should not be. If a molecule has high energy stored inside it, then once it’s disintegrated, that energy should be released.

What was going on?

You can understand it through an analogy. Think of a car going uphill. The car will never climb the mountain without our foot on the gas pedal. But think about going downhill. Downhill we have two options. One option will not cost us anything, but it will be short-lived. We turn the engine off, we lift our foot off the brake, and we let it go. One minute, half a minute, 10 seconds, we are dead because we crash.

But at least thermodynamically, it makes sense because downhill we don’t need to put out energy. But if we want to stay alive we need to control the process, and that will cost us more energy than climbing the same hill. That had to be the answer to the secret. Control costs energy. If you want to control your shredder, you have to consume energy.

How did you envision this working in the body?

Let’s say that one day you get the flu, so you make antibodies to defeat your flu virus, and then the virus is defeated. Now, you don’t need the antibodies anymore. There’s no virus. So, you turn off the antibody faucet in your body by shredding the faucet itself. This is control.

Now think about your stomach. Every protein that you put in your mouth, be it cheese, be it vegetables, be it bones, whatever you eat, the stomach shredder shreds. The body shredder beyond the stomach is much more sophisticated. It doesn’t remove every protein because otherwise, I would dissolve in front of your eyes. Actually, I would not come to live at all.

The fact that we are living means that we have a very sophisticated shredder. It shreds only proteins that should be garbage, but it keeps proteins that should be alive. This specificity, this control, is like modulating the speed of the car and not getting crushed; not getting shredded also costs energy, even though logically, it shouldn’t cost anything.

To identify you on death row, they put you in an orange gown. Ubiquitin is the orange coat for the executioner to know who to execute.

So where was the shredder?

It was missing. This is what we were after. We predicted its existence, not only we, but others too, and we went after it.

How did you happen to position yourself so well: Of all the gin joints in all the world, how did you happen to land in Hershko’s lab?

If we back up to my personal story, then you’ll understand. I was born right here in this city of Haifa in 1947, the year before Israel became a country. We didn’t have much: My parents came to Israel as kids with their own families in the late ’10s, early ’20s, escaping anti-Semitism in Poland. When they left Poland, they took nothing. In Israel, we played in the street chasing one another, throwing stones. The house was full of books. It was a very happy life, very simple.

But then my parents died young. I was 10 when my mother died of some disease, I don’t know what it was. My father kept on rearing me. He worked all day as a law clerk and then in the evenings he went to Tel Aviv to study law, arriving back home after midnight. I was 15 when he died of a heart attack and my aunt took me to her home.

It was my brother, 14 years older than me to the day, who helped me get set up. I fell in love with biology but he said, become a doctor, take away the responsibility from my shoulders, and then do whatever you like.

Of course, you did finish medical school.

Medicine was not for me. In medicine, you treat diseases, but you have less knowledge about why we become sick and why we are healthy, and how the health state is maintained. Yet I finished my medical degree and then I went to the military in October ’73, when the Yom Kippur War erupted. I got married to another military physician in 1975, the same wife that I’m still with today.

I was a physician and I had a career ahead of me. So, making this transition to science was not easy on me, not easy on the family. It meant starting life again. You’re married, you have a child, you have a career, you have already finished seven years of medical school, you have served three years in the military. Life is starting, and all of a sudden, you put your car in reverse and go into a big uncertainty.

I decided that if I do it, I want to do something very exciting. So, I inquired with several potential mentors, and all of them were very excited about me coming. They said, “Oh, I have a plan for you and we’ll do this and that.”

Only Avram told me, “I have a hypothesis that will either end up with a colossal failure or with a success.” Everybody else knew exactly how the road map looked and he was the only one who didn’t, because there was nothing known about this shredder. It had a big question with no answer.

And I said, “You know, let’s try. Let’s go for a year. If the well that we are digging shows some signs of water, we keep on. If it is dry, I go back to the operating theater.”

My wife, she was very supportive, and in retrospect, obviously, I don’t regret it, but it was not simple. People say, “Oh, the Nobel Prize,” but the Nobel Prize came after 40 years of very hard work, traveling, working alone.

What was your first breakthrough?

I’ll put it like this: In science, there are paradigms and there are paradigm shifts. You want to shift. You don’t want to stay in the paradigm. Because if you’re in the paradigm, it’s more of the same.

The paradigm in our field was that, in this destructive world, there are always tangos for two: your boyfriend and girlfriend, husband and wife, shredder and the protein to be destroyed. You always tango with two. Already within a year, when we started to fluctuate the system, when we started to unravel it biologically in the lab using techniques like chromatography, we discovered that the shredder is made of two, and the protein makes three.

What were the two elements of the shredder used for?

We imagined the shredder was made of a knife and a collecting basket.

And what did you think the shredder did?

When something happens to the protein such that it must be destroyed, the shredder identifies it. Think about swimming in the ocean and a shark is approaching. Typically, the shark will not touch you, but if you bleed, the shark will sense the blood and jump for you.

What is the protein’s version of bleeding?

When the protein is damaged, a molecule of oxygen may be put on it and it is oxidized. A molecule of phosphate may be put on it and it is phosphorylated. Or it is folded and then it opens up. All these things indicate the protein is damaged, and the shredder is alerted. Think about me walking in the street and a policeman walks by. The policeman will not touch me. But if I take my trousers off and expose something that shouldn’t be exposed, the policeman will jump on me. If you expose an area of the protein that normally should not be exposed, the policeman, which is our shredder, will jump on it.

So when the damaged protein is recognized, you thought the knife part of the shredder would cut it up and the basket of the shredder would take it away. How would the shredder work in the case of those flu antibodies you mentioned, where production is stopped?

A different mechanism comes in. A phosphate jumps off the DNA coding for the antibodies, and the shredder jumps on it. Something in your behavior, which is different from normal, attracts the shredder. It doesn’t have to be that you’re not healthy. You’re healthy but you’re not in your right place. The shredder can identify anything that is an exception to what’s normal.

So, to find the shredder in the lab you intentionally damaged proteins in a number of ways?

By heat and by iodination. We took a protein, it doesn’t matter which, we damaged it by hitting it, and we made it a bait to the shredder. We labeled it, so now we can trace it. We knew that the shredder would come. It’s like ambushing the shredder, like throwing a bait in, and the shredder did come.

Science is changing, so I don’t blame the current scientists for being short-range thinkers. But I’m a risk taker.

But instead of finding one shredder, you found two.

It was a little more complex than that. At the end, it’s one shredder, but the shredder is made of pieces. It must be complex because different proteins require different shredders, and different components of the shredder. You can say that all cars are similar in the sense that they have four wheels and they have an engine and they have a steering wheel. But there are trucks to carry cargo. There are taxis. There are private cars. There are Jeeps to cross the desert. For each protein to be shredded, there is a specific component of the shredder that comes in and exchanges with an old one. In your stomach, there’s a single shredder that eats your cheese, your meat, your lipids. Nothing gets out of the stomach alive; the shredder in the stomach is the fire that destroys everything. But in the rest of the body, you need a shredder that will recognize each and every protein independently because otherwise it would shred us.

What exactly is the molecule ubiquitin?

Ubiquitin is the signal. We found a multi-component shredder, and one of the components is ubiquitin, the part of the shredder placed on the protein to be destroyed. Think about being in Texas and you raped a woman or you robbed and murdered the owner of a gas station. You’re being brought to a court and the court finds you guilty and sentences you to death. You are put on death row in Huntsville Prison.

In order to identify you on death row, they put you in an orange gown. In order for the shredder to identify proteins, we first have to mark them. The shredder is scissors, but the scissors have to know whom to shred. So we put ubiquitin on the doomed protein. Ubiquitin is the orange coat for the executioner to come and execute.

How does ubiquitin stay attached?

Now, I’ll tell you the end of the story. The multi-component shredder is not made of two. It’s made of 2,000, or close to it, a little bit less. It’s an unbelievably complex shredder; 8 percent of the human genome is making a shredder. That information came with the publication of the human genome in 2000.

It is multi-component, and depending on the protein, you have ubiquitin and a number of other proteins to help with the shredding, and then the machinery that recycles ubiquitin because ubiquitin itself is not dying. Ubiquitin is just the executioner. Once you execute the prisoner in Texas, you can still take the executioner and start again with someone else.

You can still take the orange jacket and give it to the next one in line.

Why shred it? It doesn’t have to be buried with the victim.

And there’s no reprieve? Once you get a ubiquitin gown on death row down there in Huntsville, that’s all she wrote?

No, it’s still not final. It’s like once you are getting your death sentence in Texas, but you are not dead yet. You can still go to the Supreme Court to appeal. You can go to the Supreme Court of Texas and you can go to the Supreme Court of the United States in D.C. So, there are ways.

Even when the protein is already marked by ubiquitin, if it refolds, if chaperones are coming, you’ve got other proteins that are coming and make it functional again, then why execute it? The scissors come and take ubiquitin off and you are free. You are discharged from jail. You can appeal by behaving well. Now, you’re OK. Why execute you?

How does your work impact biomedicine?

If we accumulate protein that should not be there, we succumb to diseases. All the neurodegenerative diseases, Alzheimer’s and Parkinson’s, are due to accumulation or to quality-control problems, and many liver diseases and lung diseases are due to the fact that we are not shredding our proteins properly, and harmful proteins are being accumulated.

And drugs came. People say, “Ah, there are diseases. Probably we can cure them.” And there are already several very good drugs in the market that are all based on the ubiquitin system. I think that if you now open your eyes and look at 35 years of work, we are at the beginning. This little discovery made it big. So, you see a rolling avalanche that you’re not involved in anymore. You see the speed. Somebody will irrigate it. The garden will grow. Somebody will come and harvest the fruit. Somebody will eat the fruit. Somebody will enjoy the fruit. It’s beautiful.

Could you describe one?

A very successful example inhibits the shredder that treats a cancer called multiple myeloma, a disease of the bone marrow where there is an expansion of immune cells so there are no red blood cells, there is no hemoglobin, so we are hungry for oxygen. There are no white blood cells so we suffer from infections. There is bleeding because there are no platelets that keep us from bleeding. Also, the bones are fractured. They fracture because the tumor presses against the bone. The inhibitor cures some and improves quality of life for others.

But cancer is all about proliferation. Wouldn’t inhibiting the shredder make cancer worse?

It’s a little bit complicated, but I’ll give you a very bottom-line explanation: We are doing the opposite. When we inhibit the shredder, the cancer cells accumulate bad proteins, and these bad proteins kill the cancer cells. Malignant cells cannot tolerate these harmful proteins but normal cells survive.

In your Nobel notes, you said that you learned “to become a long books author rather than a short story writer.” What do you mean?

Science is changing, so I don’t blame the current scientists for being short-range thinkers. But I’m a risk taker. I am an adventurist. I was in medicine and I decided that I don’t want to do it. I took a big risk, but I thought that I should go after my gut feeling and after excitement and after what I really want to do.

I’m not in science in order to publish. I’m in science in order to be excited by the discovery. In order to do that, you need to be a marathon runner. Mother Nature doesn’t make itself available to us easily. You need to be patient. You need to take a long risk. You need to be in the business for many years. You need to run slowly but fast—slowly in terms of patience, but fast in order to be competitive. It looks contradictory, but it’s not contradictory.

And you really want to dig deep into it. You don’t want to scrape the surface and then move to another one and to another one and to another one. People ask me, “OK, so 40 years you work on ubiquitin, what’s next?” I say, “The next 20 years, if I should still survive them, will be devoted to the same very woman.” Because we are still scratching her surface. That’s the beauty of nature. You dig and dig and dig. You’ll never come to an end.

You cannot just scratch the surface, tell a story, and then go to another story. If you are a writer, you can do it. You can be a short story teller. But I think that in science, in order to really discover something that is meaningful and also is useful to society, you need to stick to one story. So I have one wife in science. It’s called ubiquitin. I will never abandon it. I will never divorce it. I will never marry another one because this wife, even if I shall lead 10 lives, will not unveil to me all its secrets.

Pamela Weintraub is a senior editor at Aeon and author of Cure Unknown: Inside the Lyme Epidemic. You can follow her on Twitter @pam3001

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