A Major Discovery, LIKE PENICILLIN IN 1943?

A Major Discovery, LIKE PENICILLIN IN 1943?

From grafts to oxygenation issues in the COVID‑19 patient

Interview

Prof Laurent LANTIERI, Plastic Surgeon, known worldwide for having performed the world's first successful total facial transplant.


Photo: Pr L. Lantieri


Question: As a transplantation surgeon, how do you envision contributing to care in COVID‑19 on the basis of your experience?

Professor Laurent Lantieri:

I'm a plastic surgeon, so I'm at the opposite end of the spectrum from infectious diseases and COVID‑19, so if there's anyone we don't need in this crisis, it's a plastic surgeon doing hand or face transplants!

This is very far from what is needed, but in my clinical practice, I have used a molecule, HEMO2life, which is an oxygen carrier from marine biology and it is considered a "medical device" and not a drug – at least in European standards -- because we don't know what the attitude of the FDA (Food & Drug Administration, USA) will be towards this product.

This molecule is the research outcome of Professor Franck Zal, long time researcher in marine biology at the CNRS (National Institute for Scientific Research), which, after 20 years of work, has come to fruition since, after several pre-clinical essais on in-vitro and in-vivo animal models, it was used in kidney transplants. I have used it in a total face transplant, in a difficult, complex situation, because the patient was in a situation of rejection and this molecule allowed a better conservation of the graft, and probably saved his life.


And this molecule could be extremely relevant to treat the COVID‑19 patients.

Question: So how do you envision the use of this oxygen carrier?

L. Lantieri:

In COVID‑19 patients, considering the occurrence of these strikingdesaturation rates, confirmed in numerous scientific publications, showingproblems of clotting and hypoxemia (decrease in the rate of oxygen in the blood), all indicating that the problems are not just a lack of ventilators, we thought that it might be very important to treat the vascular pathology!

Hence the idea: could we set up a protocol for a clinical trial with this molecule, injecting it in very severe cases who have severe hypoxemia in spite of proper treatment ?

Our idea has caused a certain amount of surprise in the medical community. The anesthesiologists were not familiar with this molecule since it was only used for transplantation, but afterwards there was a great deal of interest, so we prepared a research protocol. This protocol, unfortunately, is still suspended, at the present time, for reasons that are more political than real

However, when you look at the number of deaths per day, it seems to me that it would be wise to explore all avenues!

I think that, unfortunately, overconfidence, with what happened in Marseilles, for example, with hydroxychloroquine, the Raoult protocol, damaged the possibility of proposing other projects deviating from the « standard of care », from what is well codified such as antivirals, and this has slowed down innovation a great deal. Raoult's attitude might have been interesting, in the sens that it was out of the usual storytelling with expensive molecules, but it has not been without harm, because it has impeded other new projects such as ours, unfortunately.

Question : Your approach is far from the dominant protocols and yet it has been met with keen interest from doctors at the front line in anaesthesia-ICU ?

L. Lantieri:

Indeed. So we are currently working with a team in Strasbourg to draw up a protocol to relaunch this project, which has been slowed down by circumstances. As an anaesthetist-intensive care professor in Strasbourg, Dr. Francis Schneider has treated more than 120 patients, so he has a very personal and fine vision of the pathophysiology of this virus, and according to him, the intravascular damage is profound in these patients. Today we hear a lot from infectious diseases specialists, but this is the vision of the anaesthetist, he sees further than our initial project.

The disease is not just a respiratory disease, there are problems of coagulation, clotting, oxygenation. This is what has been reported by the Italian team of Professor Luciano Gattinoni, MD, Medical University of Göttingen in Germany, the great Italian specialist in Acute Respiratory Distress Syndrome (ARDS), and he noted in an article that the patients were not exactly the usual cases described in ARDS, and he is the European specialist in ARDS.

Question: In addition to the scientific press, the main press outlets, The Washington Post, Bloomberg, have published on the unusual aspects of COVID‑19, including young adults dying of heart attacks, and this clotting phenomenon, and last week, the very high mortality rate of patients on ventilators: 88%!

L. Lantieri:

Yes! In China the mortality rate is 40-50%, Italy about the same, and France about 40%. This very high mortality of the Acute Respiratory Distress Syndrome, ARDS, even among young patients is rare. So people wonder how is it that mortality in the US is as high 9 in ten patients? In the US, there are very high levels of co-morbidities such as obesity, which poses two difficulties in cases of severe ARDS: the patient who is obese must be put on his stomach, in a prone position, to maximize lung function. It takes 4 to 5 caregivers to do this and intubate the patient, and sometimes it is impossible! Then the other difficulty reported in the scientific press: the desaturation of the blood goes faster in these patients. So they are more vulnerable.

Question: Could the mini-clotting induced by the virus be the cause of the respiratory failure?

L. Lantieri:

There are several hypotheses. At the beginning the first hypothesis was that it was just a ventilatory problem, and a standard problem of acute ARDS, the virus binds through the ACE2 receptor, and these are abundant in the capillaries in the pulmonary alveoli, and then we saw these patients who were desaturating violently and so we thought micro-thrombosis.

My colleagues at the Georges Pompidou European Hospital, found that many endothelial cells were released into the bloodstream, demonstrating endothelial damage, yet they could not publish for political reasons and another team published the same results in The Lancet.

So COVID‑19 is not just a lung disease, any damage to the endothelium can cause clotting, coagulation. What is a little more hypothetical, though, is whether the virus induces other damages?

There has been a theoretical publication on the ability of the virus to enter the red blood cell, which is possible because it has ACE2 receptors, but it cannot reproduce itself, because the red blood cell has no nucleus, but, I say this in the conditional tense: it could bind to the hemoglobin and that would be an explanation for the dissociation between clinic and function: i.e. there are patients who are doing well while their oxygenation test are discordents, what we call “happy hypoxemia”, as if they were very high on a mountain top.

This could be due to the fact that the hemoglobin would be altered, similar to what happens in carbon dioxide asphyxiation, the iron released by the altered hemoglobin would be toxic to the blood vessels, but that's theoretical.

What is certain is that the more we advance in our understanding of the disease, the more we see that it is not simply a disease localized to the lungs. The severity of the disease is related to the fact that the virus affects vascular function. I'm not a specialist in this area, it's in the scientific press.


Question: Your point of view comes from your views on the micro-circulation?


L. Lantieri:

Why am I interested in this as a plastic surgeon?

Because micro-circulation is really my everyday specialty, it's my job in transplants.

I also do research in the laboratory, in collaboration with Harvard. How does tissue behave once it has been placed in ischemia and re-perfused, i.e. when there has been no more oxygen supply and we have put it back in, how does the micro-clotting take place inside? How do you infuse tissue? That's my daily work.

Cutaneous and subcutaneous micro-circulation is the specialty of plastic surgeons, we who do finger re-implantation and this kind of transplants, we know the question well.


Question: You really do have a privileged point of view on the matter! In a new epidemiological situation, it is important to explore new avenues.


L. Lantieri: We must in this fight. There are people who think they know everything from A to Z and usually they are wrong. It's a very very new pathology and, among 'experts', the best ones have only three months of knowledge. France remains a country where innovation is overwhelmed by bureaucracy, and now it's a little bit cracked, the use of 3D printers to make ventilators, use of masks that were originally made for scuba diving, particularly effective, but in another circumstance it would have been prohibited, since it is not a ‘medical device.’

A great man !

I think Zal is a genius, we haven't yet discovered all the possibilities of his molecule: he has something as important as penicillin was in 1943 !

Franck Zal is a marine biologist who has worked for years on the marine worms found in Brittany. These worms capture oxygen at high tide, in the water, and live on their oxygen at low tide, they have existed for 450 million years. They have this peculiarity of having a circulatory system and inside they do not have red blood cells, unlike other marine animals, they have a circulating hemoglobin which is a molecule much larger than our hemoglobin, which captures 40 times more oxygen than ours, and they also have a particular gradient, which captures oxygen and releases it in ischemia, so when there is no more oxygen. They store oxygen with this molecule. So in the beginning it was homemade, Zal and his team would puncture the worm with a small needle in a central vein, so far away from humans.

So Zal extracted it, he froze it, and then he did a homecraft product, then he made it into a product that's GMP, mature, he has a stockpile for use in transplants, it's 20 years of work for him. So it's such a BREAKTHROUGH that it's hard to get people to admit it, because it's totally different, we're going to inject it into someone and by doing so we're going to improve their oxygenation!

It's totally disruptive, a breakthrough, because until now, you have no other way to change the oxygen in the tissues than by changing the ventilation, the breathing, and here the idea is to change the oxygen transport.

So it's never been done, that's why it's so difficult to accept when all the other approaches have been tried: antivirals, antibiotics, even the use of chloroquine, it's already known. Everything has been done, but this is very different. And that's why it's so difficult, like moving a mountain to get such a principle accepted.

Question : Did the APHP block this initiative for a clinical trials with Paris hospitals?

Laurent Lantieri:

The project wasn't moving forward because the APHP wanted Zal to sign a two-part contract: to get access to the data you would have to pay for it. But we had proposed to share the data OPEN SOURCE, like the German virologist who gave his rights to the tests, because we need it so much! And Zal had said okay, the molecule was patented anyway, But no, the APHP wanted it for pay, some undisclosed amount and this only after the results. That was the first difficult part of the contract, and the other part, the APHP wanted the right to veto any change in the management of his company, Hemarina. And that's why the contract wasn't moving forward. They used the press as an excuse to stop the trial in a rather violent way.


In research we have various products called "development products" that work or don't work until you obtain a a GMP. There has never been problems with his GMPs, these are optimal products for transplants. So we have been answering multiple questions with the ANSM (France's National Medicine Safety Agency). On immunology, security issues, to get the project back on track. Knowing that it's so disruptive, we understand that a safety agency wants to have all the guarantees for a product injectable into humans. A few days ago, the ANSM has sent us a very positive letter, explaining that the data presented did not modify their initial positive appraisal of the project and that if the APHP hadn’t pulled out, we could have continued. Hence, we are going forward with new partners.

Question: HEMARINA has a limited quantity of products available, have you considered trials outside of France?


L. Lantieri:

Yes, we have enough since a new trial on kidney transplant, to solve medical and economic problems, had been planned on 600 patients. India was very interested in having these products for transplantations, I have international contacts who wanted these products for hand and face grafts, and kidney and liver transplants and negotiations are ongoing.

Franck Zal' company has about 15,000 doses, enough for 5,000 patients. Producing more is possible and is easier than producing Interleukin 6, humanized antibodies that are extremely complex to make, and I don't see how we are going to manage to do it with the tens of thousands of hospitalized patients with severe disease.

Question: Could mass production be envisionned, accessible for developing countries?


L. Lantieri:

The Noirmoutier marine farm, which is ISO-certified, produces worms, and therefore mass production would be possible, which is not the case for everything in new medical technologies, which are extremely complex and therefore very expensive to set up.

It's actually more than marine worm hemoglobin, because when you have hemoglobin from a mammal, which is in a red blood cell, you need other factors to make the hemoglobin work. Superoxide dismutase, and other co-factors like that, but this marine worm molecule is like a mini red blood cell, containing all these factors, and it's also 250 times smaller than a human red blood cell, so it can go much further and diffuse more easily.


“I am convinced that this discovery is as important as penicillin in 1943”


Question: What are the peculiar feature of this oxygenizing molecule?


L. Lantieri:

I am convinced that this discovery is as important as penicillin in 1943. We've always learned that every protein is an immunogen, but this one isn't.

The reason is that actually the conformation of hemoglobin as such is something that's found in all animal species, it's very conserved throughout the animal kingdom, and there are hemoglobins that are immunogenic because they have glycosylated radicals and this one doesn't. I asked Franck: Are there other marine worms? Yes, he answered, there are three other marine worms that potentially have the same activities but most have glycosylated receptors that make them immunogenic and this one doesn't.

So it's very well preserved throughout the animal and plant kingdom, and it goes back extremely far in the creation of life on earth, because for the creation of life we need to transport oxygen...from the plant to us. But it's very difficult conceptually to make my medical colleagues understand this. We've all learned that every time we inject a protein somewhere, we get antibodies.

It is just as difficult to convince people that Helicobacter pylori was the source of digestive ulcers in its time. Out of the common thought, totally different.


You know, in this world, for a new idea to be accepted, it's necessary to have more and more people who know about it, because of course there are believers and non-believers, but the more people approach the molecule and understand the possibilities, see the work that has been done so far, the more convinced they are...

You have to reach a critical mass of people who know about it for the concept to take off.

Question: So would this approach be feasible for developing countries on other blood pathologies?


L. Lantieri:

Yes, before this crisis, we had discussed with Franck about its use against sickle cell disease, which is very common in Africa, there are 300,000 children born each year with sickle cell disease, clotting problems, so the idea was - a project at 3-4 years - to see if we could use it.


Interview, rev. May 4, 2020,

by Arno Germond and Garance Upham,

AMR Think-Do-Tank, Geneva International

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