The adventures of an Italian in Russia

Heart from a bioreactor

Andrey Konstantinov, "Russian Reporter" No. 19-2014

Just yesterday it seemed that the production of spare organs for our fragile body is an entertaining fantasy, which, who knows, may be realized in the distant future. And today we are talking to a man thanks to whom the cultivation of new organs has become a reality and a salvation for the first patients. It seems no less surprising that the most innovative transplantations of organs created in the laboratory and the most advanced research in the field of regenerative medicine are carried out not just anywhere, but here in Krasnodar.

Paolo Macchiarini often says the word "fantastic" when he wants to praise something. Temperamental, like the hero of an Italian film, he easily moves from desperate exclamations like "Everyone wants me dead!" (this is about envious colleagues) to a stormy admiration for the prospects of research promising to save new lives.

Paolo and I are having dinner in one of the restaurants of the Olympic Village in Sochi – the conference "Genetics of Aging and Longevity" is being held here, which brought together the largest experts in the field of anti-aging from all over the world.

Despite the Ukrainian events, no one refused to participate, and as for Macchiarini, he did not even have to cross the border. Actually, he is a planetary scientist – almost a potential Nobel Prize winner.

But for several years, Macchiarini has been running the Center for Regenerative Medicine of the Kuban Medical University. They managed to lure the professor to Krasnodar with the help of a megagrant of the Russian government of 150 million rubles. The center was created with this money.

– Here I don't have to chase donations and I can focus on saving patients. By the way, write it down – I'm addressing Mr. Putin: I ask you to give me a Russian passport, like Depardieu! Macchiarini laughs.

"In exchange for a new heart for him?"

Politics here at the conference is perceived from a rather unusual angle.

– We have a patient from Crimea who has been waiting for a tracheal transplant since 2011, – says Paolo. – I watched it several times, but I couldn't operate on it: he would have to pay for it, the hospital cannot accept a foreign citizen for free. But now Russia has seized... oh, that is, it has annexed Crimea, and we will be able to perform an operation for him for free – that's what I'm very happy about! We will operate at the beginning of June.

How organs are grownThe tracheal production technology developed by Macchiarini is the pride and main achievement of regenerative surgery, an innovative branch of medicine that deals with organ cultivation.

In 2008, he was the first in the world to perform an operation to transplant a patient's trachea grown from her own stem cells on a donor frame in a bioreactor, in 2009 he performed another unique operation: this time the organ was formed inside the patient's body without using a bioreactor. Finally, in 2011, he performed the first operation to transplant a human organ grown entirely in a laboratory on an artificial frame, that is, without the use of donor organs.

Paolo Macchiarini is a professor of regenerative surgery at the Karolinska Institute in Stockholm.,
Professor of the Medical School of Hanover, Knight of the Order of the Italian Republic "For Merits in the field of science"
Photo: from the personal archive of P. Macchiarini

Macchiarini first came to Russia in 2010 - at the invitation of the Science for Life Extension Foundation, he held a master class in regenerative medicine in Moscow. Soon he performed the first tracheal transplant operation in Russia for a girl who, after a car accident, could not talk or even walk because of breathing problems. The girl recovered, Macchiarini won a mega grant and began to carry out his operations in our country, all the time adding something new to them. So, recently, together with an artificial trachea, he transplanted a part of the larynx to the patient.

– How can an organ be grown separately from the person himself? "I can't make sense of it.

– Generally speaking, this is impossible. It will not be possible to grow a whole organ from adult cells. In addition to cells, something else is needed - a donor organ or an artificial frame.

At first, we did this: we took the organ of a human or animal donor (usually a pig) and freed it from genetic material, that is, from cells. To do this, the organ was placed in a special liquid that dissolves muscle tissue and other cells, so that only a frame of connective tissue, a mesh of fibers, remained. Any organ has a framework that gives it shape – called the extracellular matrix. The carcass of a cell-free organ taken from a pig is not rejected by the human immune system, but there are still problems there: you can accidentally introduce a virus, well, and many people reject it, for example, Muslims. So it was best to use the skeleton of a human heart taken from a deceased donor.

But in 2011, we mastered a technology that does not require donors at all – the creation of a synthetic frame. It is made according to the size of the patient, it is such a tube made of elastic and plastic nanocomposite material. This is a real breakthrough: the synthetic framework frees us from donors – and for children, for example, they are most often not found – removes bioethical issues and makes surgery much more accessible.

– But how to make a living working organ out of this tube?

– In the bioreactor!

– Is this some kind of bioprinter?

– No, – laughs Macchiarini, – the bioprinter allows you to produce simple tissues, vessels for example, but not complex organs. A bioreactor is a device that creates optimal conditions for cell growth and reproduction. It provides them with nutrition, respiration, and removes metabolic products. In the bioreactor, we sow mononuclears on the skeleton – the patient's cells isolated from the bone marrow. This is a type of stem cells that can turn into specialized cells of different organs. The skeleton grows overgrown with these cells within 48 hours, and we encourage them to turn into tracheal cells. And the organ is ready, it can be transplanted to the patient. The body does not reject it, because it is grown from the cells of the patient himself.

Brain, heart and penis– You're not going to limit yourself to the trachea, are you?

– The esophagus and diaphragm will be next. Now we are testing them on animals. And then we will grow the first working heart – probably in collaboration with the Texas Heart Institute.

There is a monkey nursery in Kuban for medical research – if everything works out, we will test the work of a lab-grown heart on them. Generally speaking, many such things are much easier to do here than in Europe or the USA. So in a few years this technology will reach the clinic. There are good chances that the first human heart will be grown in Russia.

– And what organs are required most often?

– I am often approached with strange requests. One day, the president of, I think, the World Society of Homosexuals asked to make him a penis.

 – The second penis is an interesting idea!

– No, it's the only one, for some reason it wasn't there. But I couldn't help him, I don't understand anything about penises. And the uterus was asked to be made. After all, people want not only to prolong life, and they are unhappy not only because of diseases - they are haunted by all sorts of crazy desires.

But we don't do all these fancy things. What we really tried to do was to grow testicles, because so many children suffer from testicular cancer or their congenital abnormalities. But, unfortunately, stem cells cannot be turned into testicular cells, and we had to stop these studies.

In general, of course, we try to work on what our patients need most. Elena Gubareva is now doing a very important project on growing a diaphragm. If everything works out, it will save thousands of children who are born without a diaphragm and die because of it.

– Which organs will be the most difficult to grow?

– Heart, liver, kidneys. That is, it is not difficult to grow them – today it is quite possible to create any organs and tissues. But it is very difficult to make them function normally, to produce the substances necessary for the body. Grown in the laboratory, they stop working after a few hours. The problem is that we don't understand well enough how they work.

But maybe we won't need to grow them – I dream of using stem cells to restore the operability of these organs. After all, it is possible to stimulate the regeneration processes in the body itself. This is just a fantastically attractive and cheap solution: anyone, even in the poorest country, has their own stem cells, and no organ transplantation operations are needed!

– Does it take a lot of time to grow a human organ?

– Depends on its complexity. We grow the trachea in 3-4 days, it will take 3 weeks for the heart.

– Is it possible to grow a brain?

– Yes, I dream of catching some politicians and replacing their brains. And eggs at the same time. But seriously, growing a brain is part of my plans.

– But the main thing in the brain is countless connections between neurons, how to recreate them?

– Everyone usually overcomplicates this problem, everything is much simpler. It's certainly not about replacing the whole brain. Let's say I shot you. You have a head wound, you lost part of your brain, but you survived. And if we replace this non–functioning part with a substrate whose function is to cause the growth of neurons, attracting them from other parts of the brain? Then the damaged part will recover over time, gradually becoming involved in the activity of the brain and becoming overgrown with connections. It could completely change the lives of thousands of patients!

Dreams and disappointments– How do your colleagues feel about your success?

– Oh, this is a difficult topic, – Macchiarini is sad. – When you do something completely new, for the first time in history, you are always scolded. And it will take so long before people accept what you are doing! They still criticize me, and harshly, because I do crazy, unprecedented things. People can be very jealous of the success of colleagues: I was attacked a lot, they tried to complicate my work as much as possible, sometimes in very dirty ways.

– What is the most difficult thing in your work and life?

"In my life?" I don't have a private life. Everything is so neglected! The most difficult thing is not science, but these attacks of colleagues, their jealousy. If only they would at least do it with respect! No, total disrespect, no human relations, only competition. I have published dozens of articles in leading scientific journals, but they still tell me that I have no evidence that our methods work. They are ready to criticize everything in the world, even how I go to the toilet.

I have so many problems because of this jealousy, they put a hell of a lot of pressure on me all the time. Probably, this is the price that every pioneer must pay. But we will save lives – it's so wonderful, it's worth any attacks… Wait, I want tiramisu! Tiramisu! Tiramisu! And Americano, please.

– What do you dream about?

– On a personal level? Get in a boat and sail away from everyone. And no more contact with this world. Just me and my dog is enough for me. And professionally, I dream of saving people without organ transplantation – by cell therapy. Wow! That would be fantastic, just fantastically great!

– When will organ growing technology become massively available in developed countries?

– The technology of growing the trachea has already been worked out almost to perfection. If we continue clinical trials in Krasnodar, in two years there will be enough evidence that this method is safe and effective, and it will be used in other places. It depends on the number of patients first of all, well, and many other things. And I will deal with the esophagus, diaphragm, heart... I think progress will be rapid, especially in Russia. Be patient and wait – you will see for yourself.

– I wonder if a new body for my brain can be grown?

"What's that for?"

– To prolong life and youth, of course.

– I don't understand why you need a young body again to conquer thousands of girls? It's boring to live too long.

– I'm not getting bored yet, rather the opposite.

– I don't know. I'm sick of this life already! You Russians always urge everyone to fight aging. You are philosophers and dreamers, purely philosophical problems seem terribly important to you.

– Yes, what is philosophical here, what could be more natural than the love of life?

– You want to fight with nature, but I think our bodies are already perfect. Look at yourself. No, it's better not at myself, but at the girls – nature created them perfect, who am I to fight it?

– You are already struggling by doing surgeries.

– Wow, what an unusual conversation we have started. Such things only happen in Russia…

We argued for a long time – until we were kicked out of the closing restaurant.

Who else was lured to Russia with the help of megagrantsThe purpose of the megagrant program is to attract the world's leading scientists to Russian universities.

Four such contests have already been held. The first one was held in 2010, the last one in 2014. As a result, 163 Russian and foreign scientists received megagrants. There are many celebrities among them, there are even several Nobel laureates. "PP" introduces some of them.

• Sidney Altman
  Winner of the Nobel Prize in Chemistry in 1989, Professor at Yale, will develop antibacterial and antiviral drugs at the Institute of Chemical Biology and Fundamental Medicine SB RAS in Novosibirsk.
• Jorn Tiede
  A well-known German specialist in the field of marine geology and deep-sea drilling, headed the laboratory "Paleogeography and Geomorphology of polar countries and the World Ocean" at the Faculty of Geography and Geoecology of St. Petersburg State University, which studies climate change in the Arctic and substantiates Russia's right to the Arctic shelf.
• Ronald Inglehart
  A political scientist and sociologist from the USA, professor at the University of Michigan, is engaged in comparing value orientations in different countries; in Russia, he works at the Higher School of Economics.
• Shimomura Osamu
  Winner of the 2008 Nobel Prize in Chemistry, creator of green glowing rabbits and piglets, studies bioluminescence at Krasnoyarsk Siberian Federal University.
• Antonio Luque Lopez
  Physicist, inventor and millionaire, professor at the University of Madrid, is engaged in the development of new types of solar cells at the St. Petersburg Physics Institute.
• Mario Biagioli
  Professor of the Faculty of Science and Technology Studies at the University of California, Davis, directs research on the sociology of scientific and technological entrepreneurship at the European University in St. Petersburg.
• Pavel Pevsner
  Director of the Bioinformatics and Systems Biology Program at the University of California (San Diego), Director of the National Center for Computational Mass Spectrometry, is creating a unique laboratory for algorithmic biology in Russia, where scientists will read genomes.

Portal "Eternal youth" http://vechnayamolodost.ru21.005.2014