Consultation of experts

Discussion with Gaël Nicolas

Professor Gaël Nicolas is a French scientist who is working on the regulation of hepcidin expression. He described in 2001 for the first time the role of this hormon in the regulation of iron homeostasis in mammals.
(See Gaël Nicolas resume for more information)

The meeting took place at Cochin Institut, on the 18 June 2013.

We first presented the aim of iGEM competition and iGem Evry team to Gaël Nicolas. We mention the pluridisciplinary aspect of iGEM : biology, engineering, mathematic and informatics modeling and ethic and philosophic reflection on our project ; this fact really interested Dr. Nicolas.
We then described our experimental strategy to create a bacteria that can chelate iron : our goal is to design a bacteria that produces a massive amount of siderophore when iron from alimentation arrive.
We then presented the different parts of modeling: bacterial growth of our bacteria, risks for patients, amount of absorbed chelated, modelisation of intestine.
Finally we evocated of using microfluidic to experiment the ablity of our bacteria to chelate iron.

Gaël Nicolas then focused on some points:

• Naturally, there is not a lot of bacteria in duodenum (only 10 to 100 bacteria for each gram of matter). But we underlined that could be an advantage for our project, Dr Nicolas agreed with us.
• Incomplete penetrance (proportion of individuals carrying a particular variant of a gene which express an associated trait) with homozygote HFE C282Y mutation (responsible of more than 95% of genetic hemochromatosis). There is a 1:300 proportion of French population that have homozygote HFR C282Y mutation but all of them do not develop hemochromatosis, which reduce the proportion of people that could be interested by our treatment.
• Thalassemia seems more appropriate for the application of our project. Thalassemia is severe anemia due to a defect in hemoglobin’s globin (alpha or beta) production. There is a default of red cells production. The only way to treat this anemia is blood transfusion. But each transfusion provides also a huge amount of iron: 200 mg (as total iron in human body is between 3 and 5 grams, the mass of a nail!). After a dozen transfusions, patients develop a secondary iron overload also called secondary hemochromatosis (secondary to transfusion).
  Furthermore, their organisms “misinterpret” this anemia: anemia is perceived as a result of lack of iron. Hence, there is a repression of hepcidin hormone synthesis (which regulates negatively iron absorption in the intestines).
  The consequence is that there is a massive absorption of alimentary iron (10 to 20 times more than a healthy person). Due to this iron absorption, iron overload in blood is even more important, it’s a vicious cirle ! Which is really terrible is that, because of their anemia, bloodletting is impossible!
  The only treatment to decrease this dangerous iron overload is the administration by perfusion of an iron chelator, 12 hours a day, 5 days a week; which is very difficult for patients. Oral iron chelator Exjade (Deferasirox) is very problematic because of the important side effects (e.g. renal failure). It is actively keep under surveillance by the French Agency for the Safety of Health Products (APFSAP). Iron chelator treatments are treatment are used during all the live of thalassemia patients because most of them die of iron overload, more than from anemia. Thalassemia patients are people who have a very important disease and alternative treatment will be a good think.
• Gaël Nicolas also tell us that heminic iron (from meat) is very important source of iron, we have to take that into account.
• He finally reminded us to check affinities of aerobactin and enterobactin (two bacterial siderophors) for iron.

We then have an open discussion and a serie of questions and answers:
Q1: How much iron a hemochromatosis patient absorb?
10 times the amount of a healthy person. Balance alimentation European type provides 20 milligram of iron but just 1 milligram is absorb by organism. In hemochromatosis patient, it could go to 10 milligrams and even higher in severe case.
Q2: Would it be interesting to act directly onto hepcidin hormone?
Yes, but I think it would be a little “off-topic”, unless you found a bacteria that direcly interact on hepcidin (hepcidin is also an anti-microbial peptide, it expression is increase dureing inflammation.
Q3: Would it be interesting to scavenger Fe³⁺ iron in food ?
Yes, that would be a good idea. You could also think oto inactivate a protein implied in iron transport by duodenum enterocyte
Q4: What is the affinity of ferroportine (iron-regulated transporter that transport iron from intestine cells to blood) for iron?
We still have no idea! Ferroportine 3D structure is still unknown, 15 years after its discovery and there is still a controversy about the localization of it C-terminal extremity.
Q5: Is there a mouse model for hemochromatosis available in your laboratory? And could you possibly use it?
Yes, totally, you could use it.
Q6: How could we give our bacteria to the mouse?
The simplest way would be by forced-feeding.
Q7: Is this something you know how to do?
Yes sure.
Q8: Would it be interesting to model iron homeostasis in mammals?
Yes, it would be a great idea! Furthermore is largely uncharted territory! I have also no doubts that microbiote iron homeostasis and mammal iron homeostasis are link. It will be a very productive topic in the next years. Each project and each project will provide data about it. A journey of a thousand miles begins with a single step !

Dr Nicolas gives us a review he made on iron homeostasis in mammals (mouse and human). The review is only available in french and was made for non-scientist, you can find it there (link of the pdf).
Gaël Nicolas then give us detail about french patient association and contacts. He also encourages us to contact Professor Pierre Brissot, who is a doctor and a researcher constantly in contact with patient.

Gaël Nicolas wished us to enjoy our project realization and that iGEM strengthen our scientific interest, and finally he wished us good luck for the competition.

Interview with Pierre Brissot