History of the "Human Hair Bulb Project"

Such a thing is possible in a research institute, even if it is not commonplace. But the people who work here are confident that they can achieve what no one else has managed to do before, that they have the stamina to work for years, to return from blind alleys and set out on new paths. A lot can happen on a long road. There may be detours, stops, surprises - but determined work always pays off. Besides experimental work, a thorough knowledge of the literature requires a lot of time, reflection, and serious thought. The following is an easy-to-understand example of how diligent, precisely executed work, literary proficiency, and research creativity can produce brilliant results.

The first author, Richárd Sinkó, now a PhD, from the team of lead researchers Balázs Gereben and Csaba Fekete, published a paper in the Journal of Clinical Endocrinology and Metabolism, the basic question of which was raised by endocrinologists in Debrecen.

Richard S.:

- Our colleagues at the University of Debrecen, led by Professor Endre Nagy V. Nagy, asked us to think about how to understand the controversy that patients taking amiodarone are experiencing worldwide and it causes a big problem for clinical practice.

- Sorry, but I have to stop you! Your endocrinology research studies thyroid hormone (PMH) homeostasis and its perturbations. Since these disorders affect tens of millions of people worldwide, it is understandable that your research is of considerable clinical interest. You want to ensure that your basic science findings are translationally and clinically relevant. But what does the drug "amiodarone", which I assume is not a commonly known drug, have to do with it?

- Amiodarone is an old and very effective antiarrhythmic drug, which has been used to effectively treat many patients for whom other, more modern molecules are ineffective. However, amiodarone is known to have many side effects, for example, some patients develop circulating PMH levels suggestive of severe hyperthyroidism.

- The side effects of this important drug for heart patients make it a topic for your research. But why were you approached?

- Due to our work on PMH homeostasis regulation, we have developed a network of contacts with clinical endocrinologists outside the basic science field and have worked with several national clinical endocrinologists on various translational problems in recent years. Specifically, interest from the clinical side has also triggered our successful initiative to investigate controversial or unresolved issues in PMH metabolism in collaboration with several national endocrine centers and with the participation of hundreds of volunteers.

- Congratulations, truly a great success for a group of people engaged in basic research! But let's get back to that pacemaker drug.

- What was striking was that the majority of patients taking amiodarone and showing extreme circulating hormone parameters did not show any meaningful symptoms of hyperthyroidism. This discrepancy makes it very difficult to manage the patient, as the objective data, the laboratory test result, is the decisive factor, despite the relative well-being of the patient. The reason is that severe hyperthyroidism can be very dangerous and clinical guidelines focus on reducing this risk. The doctor treats the patient based on hormone levels and sometimes has to take drastic measures such as removing the whole thyroid gland or stopping the medication, which usually leads to a recurrence of the arrhythmia.

- Life-threatening consequences indeed!

- The phenomenon has presented us with a serious challenge, as the characterization of PMH in humans is far more complex than once thought. For more than half a century, the PMH status of patients has been determined by their blood serum hormone levels, T4, T3, and most importantly TSH. More recently, however, it has become clear that PMH balance is regulated at several levels.

- What does this mean?

- A molecular system exists within cells that allows tissue-specific use of the PMH available from the blood. This allows our tissues to fine-tune their own internal PMH action, i.e. to modify their signaling, according to their needs at a given moment. 

- In other words, can we not necessarily infer the hormonal status of certain tissues from blood levels of PMH?

- No, you don't! Under certain circumstances, tissues can override the central hormonal strategy mediated by the blood. A bit in similar way as the transformer in our various electrical devices doing this with the central 230V voltage. 

Although measuring the circulating hormone levels is excellent for diagnostic purposes in the vast majority of cases, there are special groups of patients, including the subgroup of patients treated with amiodarone mentioned above, where it is debatable whether this change in hormone levels is reflected in tissue signaling. An accurate diagnosis and treatment is impossible without measuring the effect of tissue PMH. This has not been done in humans so far. 

- Anyway, your colleagues in Debrecen were looking for the right solution! How did you start the task?

- As a first step in our work, we developed a new method to measure the tissue PMH effect in humans. 

- You were right to choose a truly minimally invasive way to collect hair follicles for this purpose, as it is important to ensure that sampling is done with as little injury and pain as possible. But how did you come up with this idea?

- We knew from the literature that hair follicles are PMH-sensitive tissue, but it had not occurred to others to use this property for a similar purpose. Moreover, as you mentioned, hair follicles can be collected in a minimally invasive way, which is good for the patient and the sampler. 

- What methods did you use?

- The PMH-sensitive gene profile of the human hair follicle was determined, from which marker genes were selected in a representative test population and their expression/expression obtained from individual samples. This could be compared with the blood parameters indicating the condition and shed light on how the tissues of the patients were using the hormone available in the blood.

- This then answered the question about amiodarone!

- Yes. The procedure provided direct evidence that the inconsistent condition observed with amiodarone treatment was due to the discrepancy between tissue PMH housekeeping and blood parameters, as hypothesized from the clinical picture. In other words, although circulating PMH levels are elevated, amiodarone protects the tissues from the adverse effects of it, and no tissue PMH predominance develops. 

- Sorry, I have to interrupt you again. It is clear so far that in this case the tissue-specific use of PMH will not be, or will be less damaging than would be expected based on blood levels, but why would that be the merit of the drug? Isn't that what causes the blood PMH levels to rise?

- We do not know exactly what causes PMH levels to rise. You can read many theories and data in the literature, but the background to the different outcomes has only been partially explored. To elucidate the mechanisms, we have also performed targeted studies using THAI (Thyroid Hormone Action Indicator) mice, patented by our groups. In this model, the change in tissue PMH action is indicated by the change in intensity of light produced in the tissues. Using this animal model we can study heart and lung tissues, which are strongly affected by amiodarone but not routinely available from humans for diagnostic purposes. In these tissues, our observation in humans was confirmed; the drug protected the tissues from elevated PMH levels, and did so without reducing tissue PMH levels below normal! Moreover, unlike other antihyperthyroid drugs, amiodarone acted preventively and could not be overtreated. 

- Many more questions have arisen! Where to go from here?   

- We would like to make progress on several issues. 

Firstly, we are using animal models to investigate the effects and mechanisms of amiodarone in detail. Based on what we have seen so far, continuing this research has considerable clinical relevance, and is in the interest of both endocrinologists and cardiologists.

We are also working hard to study other specific patient groups and use our newly developed method with the help of our clinical partners. These efforts are still in the early stages, but the procedure has been deliberately designed to be easily adaptable to other patient groups and to be integrated into clinical practice. We work hard to study other specific patient groups with our clinical partners and use this newly developed method. These efforts are still in the early stages. Luckily our procedure has been deliberately designed to be easily adaptable to other patient groups and to be integrated into clinical practice as a complementary methodology. However, we still have a long way to go.

- In other words, your method can be used in practice, i.e. it can be marketable, which is so much desired even for results achieved in basic research!

- We very much hope that this will be the case. We have thought about the possibility of economic viability when clinical adaptation was discussed. We could file a patent application for the method as an invention before our article was adopted. 

- This was certainly welcomed at our institute. But first, let's hear what happened to the article!

- Since our paper included animal and human data, and had a strong translational value, we looked for a journal publishing on a more clinical, but not entirely clinical topic. In consultation with our endocrinology colleagues, we finally chose the Journal of Clinical Endocrinology and Metabolism (JCEM).

It is a highly regarded journal, widely read by many, the Journal of the American Endocrine Society, has excellent indicators, and although primarily clinical, is also open to translational basic science. We had two excellent reviewers who understood the subject in the smallest detail.  We had never dreamed of such appreciative reviews! It was clear that they liked what they were reviewing.

- It's almost a fairy tale! Now for the patent! 

- From our previous experience with the THAI mouse patent, we knew how difficult it is to get involved in such matters. Our current patent would not have been possible without the support of the KOKI management and HUN-REN. It was an important step in the right direction that the organizational background for innovation management, which did not exist at the time of our THAI patent, was created within ELKH and further strengthened within HUN-REN. It would be difficult to overestimate how much it has helped us. Without it, we might not have risked the procedure, as we still had to complete serious bureaucratic procedures and negotiations. We thank Zsuzsa Winkler, Innovation Manager at KOKI, for her multifaceted help, and Hajnalka Kompagne of Danubia Patent and Legal Office for her competent assistance in paving the way for this invention, following the THAI mouse. 

- Looking back, what was the most difficult? 

Find the concord between patenting and publishing. It is a special difficulty because you have to try to do both. The article cannot be published before the patent is filed, but the coordination and arrangements required before filing can take months or even years, and in the meantime, competitors can be ahead of us. It is also better to take action as early as possible to protect intellectual property. In the meantime, you should be careful about what can be published in presentations and posters. The abstract of a poster by a TDK student can be a novelty before a patent is filed. In addition, it is increasingly common to make our data, or even the manuscript itself, available in repositories, which is against your intellectual property (see eLife). However, with proper planning, the timing of patent submission and publication can be bridged. 

- Article or patent? What do you think about this not-small dilemma?  

- I agree with the desire to exploit scientific results. The primary goal of exploratory research is to discover and create new knowledge, and for a very long time now, this has been measured by some parameter of more or less public, published papers. The end goal, however, is to turn that knowledge to the benefit of humanity and the world, which requires more than the article. Patents are a means to this end and create the possibility that public money spent on work may bring economic benefits, too. However, the ultimate goal is to use the knowledge to benefit humanity and the world, which requires more than just an article. Patents are a means to this end and create the possibility that public money spent on work may bring economic benefits, too. Such an endeavor requires considerable effort and many difficulties to overcome, most of which are currently borne by researchers and slow down scientific work in an already highly competitive environment.

- Surely, after this success, you have a positive conclusion on this subject!

- Recent changes are hopeful. For example, after the odyssey of the THAI mouse, we would not have dared to patent the hair follicle model ourselves, but HUN-REN and KOKI stood by us. There is still some work to be done to make things run smoothly, but this is finally a step in the right direction and I am confident that the resources invested in domestic intellectual capital, both human and financial, will pay off even more in the future!