On September 21, 2016 in Dubrovnik, Croatia, the opening ceremony of the first “EFIC Topical Symposium on acute and Joint Pain” featured the delivery of two EFIC® – IBSA Foundation – European Journal of Pain Publication Awards for 2015.
We interviewed the two winners, who received a €2,500 prize each from the IBSA Foundation for Scientific Research for their article published in the European Journal of Pain in 2015: Ms. Elisa Carlino who won the award for her publication titled “Role of explicit verbal information in conditioned analgesia” and Mr. Mikkel Gram who won the award for his publication titled “Machine learning on encephalographic activity may predict opioid analgesia”.
Ms. Carlino can you walk us through your research work?
My main field of research is the placebo effect with focus on related neurobiological mechanisms. The placebo effect has proven to be significant on pain. When referring to the placebo effect, it is largely the expectation effect that is considered i.e. the beneficial effect of positive expectations about the placebo.
We conducted a study on healthy volunteers and demonstrated that the explicit expectation of receiving less painful stimuli is crucial to attain placebo hypoalgesia, i.e. decreased sensitivity to painful stimuli, following administration of placebo. In particular, through conditioning we modulated the sensitivity to painful stimuli in healthy volunteers. In the study, in one of two groups we told participating volunteers they would feel more or less pain when certain images would appear on a screen (greater pain when seeing the sign ‘+’ and less pain when seeing the sign “ ̶ ”).
In the first stage of the study, unbeknownst to the volunteers, we actually changed the intensity of the painful stimulus, to condition their sensitivity. In the second stage, we kept the painful stimuli unchanged at the same level to see if the volunteers would respond to the stimuli as they did in the first stage. In the other group of volunteers, we had the same tests but without telling the volunteers the meaning of the stimuli, in other words we conditioned them implicitly. Findings show that only explicit conditioning led to modulation of pain, i.e. to placebo response, in the second stage of the study. Indeed, only explicitly conditioned volunteers subjectively reported to feel less pain in the second stage of the study and showed an objective reduction of sensitivity to the painful stimuli as measured using laser-evoked potentials (LEP), an electrophysiological recording method.
What future prospects may your research open up?
The study has major clinical implications. The fact that explicit expectations play a crucial role in pain modulation has significant implications for clinical practice, and in particular for the role of physicians when administering treatment. The study shows how important explicit verbal communication and interactions between doctors and patients are to attain better clinical outcomes for the patient. Explicitly informing healthy volunteers about the possible modulation of pain has proven to improve outcomes in the study. Similarly, it is important to explicitly inform patients they will fell less pain after a certain medication has been administered to them, instead of just administering it and saying nothing about what they should expect. The goal is of course improving the efficacy of treatment and easing patient clinical symptoms. So, in general, research on the placebo effect has allowed us to get scientific evidence of the importance of a dialogue between patients and their doctors and the effect that such dialogue has on the patient brain.
What does it mean for a young investigator like you to be the winner of an award such as the “EFIC-Fondazione IBSA Publication – European Journal of Pain Award”, whose purpose is to support research by providing financial support and contributing to the dissemination of knowledge?
To me, it came as a surprise and I was very happy to win the award, a great recognition for me both personally and professionally. Any research project, from planning to carrying out the study to writing the report on findings and ultimately publishing them, is a huge effort. You see your idea grow and develop through to publication. Being rewarded for the effort and dedication is truly gratifying. It is increasingly difficult to get funding for research work in Italy, and it is fundamental to have one’s ideas and scientific work be known vastly. So, professionally, this award is a huge help, especially for a young investigator at the beginning of her or his career.
Mr. Gram, could you please walk us through your research?
I would love to. MY main topic was Personalized Medicine within Pain treatment using opioids. Here, a very common problem is that many patients do not respond to the treatment with opioids and thus continue having pain, with the added side-effects of the opioid treatment. This is due to a large variability in effect between individuals for a given opioid, meaning that what works for one patient might not work for another. This is handled clinically by switching people to another opioid, until one is found that works for the individual. However, currently there is only trial and error to help the clinician decide which opioid to use, and subsequently many patients suffer from inadequate treatment.
Personalized medicine is about helping the doctor make the right treatment choice for the individual patient before giving any analgesics. The idea is that measurements before treatment can tell if the patient will respond to a given opioid or not. The big question is which measurements will give that information. So far attempts using quantitative sensory testing has been used with variable results, but we wanted to go in another direction with a more objective measurement – the electroencephalogram (EEG). Our reasoning being that opioids mainly act in the central nervous system, and individual differences here could tell us something about the analgesic response.
We therefore set up a randomized experimental study with morphine and placebo, where patients were subjected to the painful cold pressor test before and after drug administration. EEG was also recorded before drug administration, and it was these measurements we hoped would help us predict response. The subjects were divided into responders and non-responders, based on their pain ratings during the cold pressor test, and the EEG of the groups were compared against each other.
This is where machine learning came into the picture, which is a novel method within the medical field, but within engineering it is utilized much more. This way of analysis attempts to find patterns in the data, which are not apparent to the human eye. By combining several features from the EEG, we managed to build an algorithm that successfully predicted who would respond to morphine or not. This is a very interesting finding due to the objective nature of the EEG, and the novelty of the applied methods.
What are the future prospects that your research opened?
The research in healthy volunteers which we conducted gave us a clear indication that we were on to something with the approach of EEG and machine learning. That gave us the confidence to move forward with clinical experiments, to both in postoperative patients and in chronic pain patients. The study on postoperative pain yielded very similar results to the first paper and is recently published in the European Journal of Pain. The study on chronic pain is under development still, but the preliminary results again confirm the hypothesis. Together it all points to personalized pain medicine being possible at some point in the future.
What does it mean to be the winner of an award such as the “EFIC-Fondazione IBSA Publication – European Journal of Pain Award”, which purpose is to support the research both providing resources and contributing in the dissemination of knowledge?
It means a great deal for a young researcher such as myself, especially since the methods I use are a bit unusual within many research field due to my background as an engineer. Therefore, it has sometimes been a challenge to explain the methods to other researchers, which is a shame since I believe there is great potential within medicine for methods such as machine learning. Getting the award is a huge deal for me because it means that our approach to personalized medicine, using an objective marker such as EEG has caught the eye of other renowned researchers who are considering it to be a step in the right direction for the field. This is a huge honor for me, and a great joy that all our hard work has led to this!
The EFIC Annual Council Meeting held in Vienna on September 2nd hosted the ceremony of the EFIC- IBSA Foundation Publication Award supporting investigators under 40 years of age who published an original research article on pain in an international journal. The Executive Board and the Research Committee of the European Pain Federation (EFIC) agreed to give the EFIC – IBSA Foundation Publication Award 2014 to the German researcher Eberhardt Mirjam, Department of Anaesthesiology and Intensive Care Medicine, Hannover Medical School, for her article “SODIUM CHANNEL NAV1.7 A1632T MUTATION CAUSES ERYTHROMELALGIA DUE TO A SHIFT OF FAST INACTIVATION” published in 2014 in The Journal of Biological Chemistry.
We met her at the award ceremony and interviewed her.
Dr. Eberhardt, thanks to your research, published in The Journal of Biological Chemistry, you won the EFIC- IBSA Foundation Publication Award. Can you walk us through your study?
Mutations of the voltage-gated sodium channel Nav1.7 lead to inherited pain syndromes with different clinical pictures. Inherited Erythromelalgia (IEM) causes debilitating neuropathic pain characterized by burning, combined with redness in the extremities. Inherited “paroxysmal extreme pain disorder” (PEPD), on the other hand, affects proximal body areas like rectal, ocular or jaw regions. Both pain syndromes render Nav1.7 hyperexcitable by changing certain gating properties of the channel protein. Either the mutations make the channel open at lower potentials or they hamper its closure during an action potential. For both diseases this means a severe increase in the transduction of extremely painful signals from the periphery to the brain. These changes in gating properties of Nav1.7 can be investigated by the patch clamp technique: currents that flow through Nav1.7 are recorded from cell lines in which the mutated sodium channel or Nav1.7, as it is found in healthy people was introduced
We characterized a new mutation of Nav1.7, A1632T, which we identified in a patient with IEM (A1632T, meaning that the amino acid alanine in position 1632 of the “healthy” Nav1.7 channel is switched to threonine in the pain patient). This mutation rendered the channel more excitable. But interestingly, the observed gating changes were those normally expected for PEPD mutations, i.e. a shift of steady state fast inactivation and not activation.
Previously an A1632E mutation of a patient with overlapping symptoms of IEM and PEPD was reported (Estacion et al. 2008). This mutation displayed both changes in electrophysiological properties characteristic for IEM and PEPD. In order to assess the structural implications of amino acid substitutions in A1632, we generated a 3D homology model of Nav1.7 based on the recently published crystal structure of the sodium channel NavAb. As a substitution with the amino acid glutamic acid (E) adds a negative charge, which may possibly interact with the inactivation gate of the sodium channel, we generated several mutations of Nav1.7 to enable us to investigate the role of an additional positive or negative charge or size of the amino acid side chain on gating properties of Nav1.7 at position 1632. In this way we also electrophysically characterized the mutations A1632 D/E/K/T/V.
We could identify a possible negatively-charged causative for the mutation-induced gating shifts, as the substitution of alanine with aspartic acid (also a negatively charged amino acid) caused the same alterations as the previously described mutation A1632E.
However, we found two specific electrophysiological characteristics differing between A1632T and A1632E, namely A1632E displayed persistent currents following channel activation and gave rise to so-called resurgent currents under certain conditions.
Up to now, investigation of about twenty different IEM- and 10 different PEPD mutations reported before led to the dogma that IEM is caused by a shift of activation and PEPD by a shift of fast inactivation. Our data broke with that dogma.
The comparison of A1632T and A1632E gave us the opportunity of trying to define what electrophysiologically really makes the difference between IEM and PEPD. The comparison was carried out, on the one hand, clinically by the different clinical pictures the patients suffer from and their similarities and, on the other hand, experimentally by the electrophysiological properties investigated by patch clamp recordings.
What kind of medical perspectives has your research opened?
Selective sodium channel blockers of Nav1.7 may be important new analgesic drugs. This is based on the finding that loss of function mutations of Nav1.7 cause congenital insensitivity to pain (CIP), but preserve other sensitive and motor functions (apart from anosmia). While lack of pain sensitivity is crucial for CIP patients as this leads to accidental self-mutilation, blocking Nav1.7 selectively could be a relief for chronic pain patients as it seems to be an effective target without any known serious side effects. However, developing selective blockers of sodium channel subtypes so far has been very difficult. Different sodium channels subtypes also control important cardiac functions and functions of the brain and muscles. The classical local anaesthetics all bind to a site in the sodium channel which is highly conserved throughout all subtypes and this unspecific binding makes side effects unavoidable. Therefore, it is important to identify new and specific structural motifs that impact the equilibrium of functional states of sodium channels to define the targets in Nav1.7 which new analgesic drugs have to be directed to. It may also be important to know the exact biophysical properties that define which clinical pain phenotype is caused e.g. by mutations or other disease circumstances. A drug correcting this electrophysical phenotype is likely to be effective in pain treatment and the more remaining gating properties of Nav1.7 are left unchanged, the fewer side effects the drug may have. We hope that our study contributes to a better understanding of the structure and function of Nav1.7 in different inherited pain syndromes and by this may help to figure out which important properties a selective sodium channel blocker has to offer to be effective for pain treatment.
What inspired you to take part in the EFIC- IBSA Foundation Publication Award?
I had heard of this award from EFIC and the IBSA-Foundation to support young researchers before. As one does not apply but is nominated for this award I’m very grateful to receive it and it is a great honour to me. But furthermore I’m also grateful to my former professors and research group leaders who apart from teaching me basic techniques have always encouraged me to do research and inspired me in their individual ways. Many thanks also to all my collaborators and co-authors who made this project successful and not not least to the patient and her mother for taking part in the study.
At the presentation of the CENSIS survey on fertility/infertility in Italy, commissioned by the IBSA Foundation, we interviewed Professor Andrea Lenzi, Professor of Endocrinology, Sapienza University, Rome, Italy and President of Italy’s National University Council, to have his take.
The CENSIS/IBSA Foundation survey confirmed infertility is increasingly common. What are the main barriers for a couple with infertility problems today?
First, their busy and stressful work schedules that impact their sex life and reproduction. Many couples have to pencil in time for sex, they have ‘targeted’ intercourse, sex on command. They force themselves to have intercourse when the fertility monitor shows ovulation is taking place. Now, we need to make it crystal clear that scheduling intercourse does not increase the chances of getting pregnant, it just increases the number of male partners with decreased sexual desire and erection problems hence the number of couples in crisis. So, having intercourse only when ovulating is not the solution to the problem.
Costs can be another hurdle. At this economic juncture the costs of doctor visits, hormone assays and other tests that are needed when taking the right approach to the problem can be a significant barrier. Even a baby, with all that comes with it, can be seen as a cost that a couple cannot sustain these days. The long waiting lists not just for artificial insemination or other assisted reproduction processes, but even for a mere visit with the OB/GYN or the andrologist, especially in certain regions of Italy, are just another stumbling block.
What are the main causes of infertility in a couple?
In addition to the ‘classic’ causes such as varicocoele, cryptorchidism, infections, ovulation problems, cigarette smoking and use of other addictive substances, there are some major cultural forces that come into play. Nowadays, pregnancy is increasingly seen as an event that can occur only when certain conditions are met, typically when people have achieved financial stability, have attained personal and professional fulfilment and have met the right partner. Unfortunately, as we all know, all this happens at an age that is more and more advanced. Take, for example, a girl who wishes to become a doctor. She will graduate at 24, at best. Then she’ll start her residency which means another 4/5 years. By the time she finishes it, she will be 29. Then she needs to find a job with a decent pay – which is not easy these days. This will likely take another 2-3 years, at best. By then she will be 32. Then she starts looking for a home, which nowadays for many people is another nightmarish hurdle to surmount. After all this, she starts to think about having a child and by then she will be 35-36. Clearly, a woman is still young at 35, but her chances of getting pregnant – what we call her ‘cumulative pregnancy rate’ – have slimmed. The same holds true for men, although we have fewer data as men are less investigated. To have an idea of how much finances impinge on fertility, have a look at Italy’s per capita income in the last two years and fertility rates in our country over the same period. Plotting these data on a chart you’ll see that the two resulting curves overlap: as income declines, fertility declines too. Then, there is another aspect, which is more subtle, psychologically more subtle. One of the numerous Nobel Laureates from the University of Chicago, late economist Gary Becker speaking about obesity and the diabetes ‘epidemic’ said that people are counting on medical progress to cure any ailments their extra weight might cause.
I believe the same holds true for couples who want to have a baby. They believe medicine can overcome the age barrier and the media contribute to that belief. People see on television or read in the press about celebrities or the couple next door having a child at an advanced age. Unless you explain them that in the vast majority of cases that has been possible through the use of donor eggs, women who do not know much about ovarian physiology may be misled to think they can postpone their decision to have a child indefinitely. Becoming sexually active at an early age and sexual promiscuity which increase the risk of STDs, smoking and substance abuse, unhealthy lifestyles that can lead to alterations in menstrual cycle and sperm formation are other factors that may cause infertility. Essentially, we are in what demographers call ‘a demographic transition’ i.e. a stage when the fall in death rates is followed by the fall in birth rates.
Which new treatments and techniques does science provide to help infertile couples?
Certainly, over the past 25 years great progress has been made in reproduction technologies and infertility treatments. But first, let me say as an endocrinologist/andrologist that one of the main step forward in the past few years has been the increased awareness of the role of the male partner in infertile couples. Until recently the focus was mostly on women while the male partner had, at best, just semen analysis. Now, the role of the andrologist has become a central one. Thanks to sophisticated molecular biology and genetic testing, ultrasound and other techniques, we are now able to diagnose and often treat forms of infertility and even sterility that were previously thought to be untreatable. But we need to intervene early and take prevention measures in younger men and even in children. Assisted reproduction technologies have become much more sophisticated and the rate of successful full-term pregnancies has improved significantly. Molecular biology is helping us pinpoint with increasing accuracy when medical treatment, especially hormone therapy, is most appropriate and pharmaceutical companies are making huge efforts to provide us with increasingly sophisticated, purified safe treatments with convenient administration routes.
What advice would you give a couple with infertility problems today?
First, consult a reproductive medicine specialist who has the expert knowledge to evaluate both partners in your couple and will give you correct information and advice. This will help you avoid that your difficulty turns into a devastating experience. I said ‘devastating’ intentionally. It is proven, in fact, that a couple becoming aware of its infertility has the same psychological reaction of a person diagnosed with cancer. This gives you an idea of the psychological burden for the couple. We, doctors and other healthcare providers, need to be particularly empathic to facilitate the journey for these couples who often react in a way that worsens the situation. I have already mentioned the mistake of having ‘targeted’ sex. One of the other common misconceptions is the belief that prolonged abstinence improves the quality of semen. In fact, it’s quite the opposite. The belief that certain “positions” increase the chances of getting pregnant is a myth too. And yet, we still often hear from female patients that they lie for a while after intercourse with their legs up or with a pillow underneath their bottom to improve their chances of becoming pregnant. This is stressful and brings no benefit.
So, ultimately my advice is try and rationalise the event with the help of the right specialist, and, most of all, try to go back to having sex as naturally as possible. In fact, in spite of the great progress made by science, as the old adage goes, nature does things better than we humans do.
In conclusion, what it takes is communication, information and prevention in the very young and younger generations, cultural forces and policies that encourage people to have a baby earlier in life and help couples with infertility problems with the knowledge, experience and human touch that their condition requires.
The 2014 EFIC Annual Council Meeting held in Brussels last May 26 hosted the EFIC- IBSA Foundation Publication Award ceremony. The €2,500 award was open to European investigators under 40 years of age who published as first author an original research article on pain in an international journal in 2013.
Serena Materazzi, PhD, Department of Health Sciences, University of Florence, Italy, was the winner with the research article titled “Parthenolide inhibits nociception and neurogenic vasodilatation in the trigeminovascular system by targeting the TRPA1 channel” published in Pain.
We’ve asked her to tell us about the research that landed her the award.
Dr. Materazzi, you had a first major recognition of your work with the publication of the article in ‘Pain’, and now you win the EFIC- IBSA Foundation Publication Award. Can you walk us through your research?
The research study identified the mechanism whereby parthenolide, an active ingredient extracted from feverfew (Tanacetum Parthenium L.), acts on migraine headaches. For their anti-inflammatory and anti-fever properties Tanacetum Parthenium L extracts have been used for centuries, either alone or in combination with other compounds, as a remedy for inflammatory diseases, fever and migraine. However, although various hypotheses have been tested, the mechanism through which parthenolide prevents and relieves migraine pain has remained unknown. The findings of our research showed parthenolide has specific pharmacological properties that lead to the inhibition of the transient receptor potential ankyrin 1 (TRPA1) channel. The TRPA1 receptor is a key pain transmission mediator. It is found in trigeminal neurons where it converts excitatory signals from a number of pungent substances such as mustard, garlic, cinnamon and wasabi. Our study revealed that parthenolide is a weak (partial) agonist of TRPA1 and through this mechanism it can block the action of strong endogenous agonists. Additionally, parthenolide can desensitise the TRPA1 receptor and make the entire nerve terminal unresponsive to additional stimuli known to trigger migraine attacks, e.g. ethanol. In particular, via these two mechanisms parthenolide inhibits the release of a pro-inflammation and pro-migraine peptide, the calcitonin gene-related peptide, from nerve terminals. This finding is of great importance because, in addition to identifying the exact mechanism of action of the substance, supporting its clinical use, it has allowed to highlight the role of the TRPA1 receptor expressed at trigeminovascular system level in the pathogenesis of migraine.
What do you expect the next steps will be in your research?
Currently available remedies for migraine are not always effective. So, identifying new targets for the development of alternative treatment options is a major result and a stimulus to design new pharmacological therapies. More specifically, our findings suggest that developing novel drugs that act on TRPA1, as antagonists, partial agonists or desensitisers, may represent a valuable new option for the treatment of migraine, an area where there is still an unmet medical need.
Recognitions like the EFIC-IBSA Foundation Publication Award support research financially as well as by contributing to the dissemination of results. How important is this for a young investigator like you?
For a young investigator like me, still on a temporary contract, a recognition like this is certainly a great honour and a strong encouragement to continue our work with passion and dedication. Awards like this, not only provide significant support to scientific research and investigators themselves, but are also a major opportunity to give visibility to research findings and circulate them. Finally, I’d like to say that the award is a recognition not only of my work but of the work of the entire team, of all the people who contributed to the execution of the research project, many of whom are young investigators still on temporary contracts like me.
We interviewed Professor Andrea Alimonti, a renowned oncologist and scientist working on cell aging, Cancer Institute of Bellinzona (IOSI), Switzerland, and supervisor of Jingjing Chen, the Chinese investigator who won an IBSA Foundation fellowship award with his research on cellular senescence in melanoma.
Professor Alimonti, how did you come up with the idea of stopping cancer growth by inducing tumour cell aging?
Some years ago in the United States I discovered that cellular senescence, i.e. cell aging, is a process that can occur in tumour cells too. Up until then, tumour cells had been thought to be immortal. Using animal modelling I demonstrated that treatments capable of inhibiting specific genes could induce senescence in tumours with a significant therapeutic response. That novel approach, which today is known as pro-senescence therapy, paved the way for the development of new molecules capable of stopping cancer by triggering tumour cell aging.
This is one of the most innovative strands in cancer research. What is your ultimate goal?
The ultimate goal of my research is stopping cancer growth without killing normal cells and without toxicity in patients. In the lab, we have proven, among other things, that tumours with loss of PTEN – a tumour suppressor gene – are much more susceptible to senescence than healthy cells with normal PTEN. PTEN loss is known to play a role in the development of a number of cancers including prostate, colorectal and breast cancers. That greater susceptibility to senescence bodes well for the development of treatments capable of stopping cancer growth in a selective way, without affecting normal cells. Another aspiration is being able to induce premature aging in cancer stem cells that are responsible for most recurrences after standard chemotherapy or radiotherapy.
Your biographical details show you have done research at laboratories around the world. Italy is suffering from a brain drain, are you, too, one of those scientists who left the country to work abroad?
It’s been a long time since I last worked in Italy. Actually, my work experience in Italy is limited to my oncology residency at the National Cancer Centre in Rome. When I was 27 I left for the United States where I worked, first at the Memorial Sloan Kettering Cancer Centre, and then at Harvard. Italy is a beautiful country, rich in human potential, but it does not have much to offer in terms of infrastructure and funding. I have the impression that things have been changing of late, but research is such a competitive space that wasting one year struggling with red tape kills your chances of success and progress.
We saw you next to Jingjing Chen at the IBSA Foundation fellowship award ceremony. What is your advice to young investigators who are at the beginning of their career?
Doing research requires passion as well as perseverance. Being ready to make sacrifices is fundamental too. Only through perseverance you can attain results. Still, this is nothing compared to the suffering and frustration with treatment failure that cancer patients have to endure every day in their lives.
The forum titled “Stem Cell Therapy: Hype or Hope?” was held at the Auditorium of Università della Svizzera italiana in Lugano, Switzerland, on Saturday March 29, 2014. Organised by the IBSA Foundation for Scientific Research, the forum provided an opportunity to discuss where stem cell science stands today, highlighting its reality and true potential and dispelling myths. The forum featured the participation of prestigious world-class speakers who shared the key findings of their research. We asked them to give us a brief interview. Here is what they said.
On which approach is your project on the potential to improve regeneration capacity based?
Regenerative medicine broadly refers to the repair or replacement of damaged human tissues and organs, to regain the remarkable tissue regenerative capacity we all had before birth. Our approach has been to exploit the extraordinary evolutionary variation in regenerative capacity amongst animal species and in our own embryonic development to uncover fundamental attributes of effective organ and tissue repair, applied to the restoration of damaged tissues and regenerating the ageing human body. Discovery of the basic principles governing regenerative capacity in different animals, and in our own developmental histories, is uncovering unexpected clues to the impediments to true regeneration in our own bodies.
Which are the hopes in improving regeneration capacity through specific interventions on the immune system?
Regeneration is a prime example of a process that involves all levels of biological organization. The relationship between inflammatory processes and tissue regeneration is complex. In the context of the injured human heart, the wound healing response after myocardial infarction involves a cascade of molecular and cellular events that leads to a replacement of the necrotic area with a collagen-rich scar. Clearance of necrotic debris by inflammatory cells is a critical component of infarct healing and some anti-inflammatory interventions are deleterious, but tight control and timely orchestration of the inflammatory response is important to prevent excessive tissue degradation leading to infarct expansion and heart failure Our preliminary results pinpoint the IGF-1 axis as a key signalling mediator in inflammatory cells, promoting a timely resolution of the initial inflammatory response but also stimulating non-inflammatory cell types such as stem cells, involved in infarct healing. Our work underscores the importance of IGF-1 propeptides, rather than fully processed commercially available IGF-1, in enhancing endogenous anti-inflammatory pathways and blocking the persistence of damaging inflammatory responses. Local delivery of IGF-1 propeptides represents a novel intervention that adjusts the balance between the essential and detrimental facets of inflammation, providing a new therapeutic opportunity for post-MI patients who continue to be at risk of developing heart failure, despite modern reperfusion and anti-remodeling strategies.
Which are the key findings from your study on the nature of embryonic stem cells?
Naïve pluripotency is the capacity of an individual cell to produce all lineages of the mature organism in response to extrinsic cues and in an unbiased fashion. In rodents this transient state at the foundation of mammalian development can be captured and propagated in the form of self-renewing embryonic stem (ES) cells. Recent studies have identified the transcription factors that control ES cells and sustain them in a stable ground state. The circuitry interconnecting these transcription factors can be delineated through iterative experimental and computational analyses. The resulting model set accurately predicts ES cell self-renewal or differentiation behaviour. This approach also defines a minimal programme of 3 inputs, 12 factors and 16 interactions that is sufficient to sustain naïve pluripotency in a robust and flexible manner
Which is the key challenge for the future in this regard?
Pivotal elements in the ground state circuitry are lacking in currently available human pluripotent stem cells, which can explain why their properties are substantially different from those of mouse ES cells. Functional implementation of the ground state transcription factor programme in human cells is thus a key challenge.
How do the European Institutions classify advanced therapy products?
With the Regulation 1394/2007 the European Parliament and the Council have clearly classified the products for advanced therapies as medicines. Therefore their manufacturing and quality control must be performed in compliance with the European Good Manufacturing Practice. In addition, since these medicines are biological products, they have to be sterile, therefore they have to satisfy specific additional requirements for biological and sterile products encoded in Annex 2 and Annex 1 of EUGMP, respectively.
Which is the Italian regulatory position on stem cell therapy?
The stem cell therapy is one of the several types of somatic cell therapy which, along with gene therapy and tissue engineering, constitute the advanced therapies.
European Regulations are lex specialis, this means that they do not need to be implemented by the European Governments, but are immediately valid in all the Member States. Therefore, as well as in all European Countries, also in Italy the products for advanced therapies, including the stem cell therapy, are classified as medicines and have to satisfy the EU GMP requirements.
Are there any news from your side that could encourage this kind of therapies?
In my opinion the products for advanced therapies are the most promising medicines in the next future. In the last years we saw that the synthesis of new molecules is always more difficult, while the knowledge of the principles that rule the behavior of genes and cells are being more deeply understood and controlled, thus permitting to manipulate them in order to obtain safer and safer products.
Do you have any evidence today that cell therapy can cure degenerative diseases?
We do have a large number of encouraging results, yet, unfortunately, very few certainties so far. One of the greatest ambitions of medical science today is being able to regenerate any damaged body parts. This has driven medical professionals and researchers to investigate and test cutting edge technologies like cell therapy and their potential to replace organs and tissues that are irremediably damaged. Over the past fifteen years fundamental and clinical research has given an enormous contribution to define the potential benefits and risks of cell therapy based on stem cell use for the treatment of different degenerative disorders. In spite of some encouraging results, however, cell therapy has still a number of limitations that stand in the way of its use in clinical practice at present.
What are the successes you have had so far in stem cell use? Or putting the question more straightforwardly: What can stem cells cure today?
Very few conditions! To-date there are very few examples of proven stem cell therapies, among these, repair of corneal and skin burns, cartilage and bone transplantations and treatment of some blood cancers.
In his presentation at the Forum, Professor De Luca will show that stem cells taken from the skin of a patient, can be cultured and multiplied in the lab to produce skin flaps that are then implanted into the patient. Or a small biopsy can be taken from the patient’s corneal limbus, grow corneal epithelium cells in vitro and then transplant them into the patient’s eye to repair irreversible corneal damage that cannot be fixed with a cornea from a donor. Several blood cancers such as chronic myeloid leukaemia, acute leukaemias and lymphomas have also benefitted for quite some time from the use of haematopoietic stem cells in bone marrow transplants.
What clearly emerges from these proven treatment approaches is that stem cells can ‘heal’ the tissues from which they are taken. They can repair skin burns when taken from the skin, corneal damage when taken from the corneal limbus, while haematopoietic stem cells can treat some blood cell disorders.
What are the goals of stem cell research going forward?
First and foremost, functional effectiveness and safety for the patient.
Secondly, understanding the tissue environment where transplanted stem cells work. In other words, it is fundamental to get a better understanding of the role the microenvironment plays in influencing the differentiation of stem cells.
Now we know that all tissues have the ability to renew themselves, there are big or small reservoirs of cells ready to come into play to remodel or repair tissues after small traumas, these cells are stem cells. In theory, numerous diseased tissues should have a reservoir of cells ready to act, but regrettably, when there is an illness the patient’s own stem cells do not work. Why is that?
Dr. Rando’s parabiosis experiments in mice – parabiosis is the union of two individuals or experimental animals so that they share a common circulation of the blood – have shown that exposure to a young environment can restore the regenerative ability of old mice muscle stem cells that is typically impaired as a result of aging.
Recently, we have obtained similar results after growing in vitro cultures of muscle stem cells taken from biopsies of young and elderly individuals. We have seen that when muscle stem cells taken from elderly people are grown in the serum of the elderly patient, they show defective cell proliferation and differentiation. Conversely, when muscle stem cells taken from elderly people are grown in the serum from a young donor they have the ability to form myotubes, i.e. differentiated muscle cells. This suggests that signals present in the serum of young individuals can trigger proliferation and differentiation abilities of muscle stem cells from elderly people. We can reasonably infer that the inductive signals that tick stem cells, trigger their proliferation and differentiation to form new muscle fibres that would join with damaged fibres and repair them are missing in an old person’s muscles.
These findings show the importance of the stem cell niche, i.e. the local tissue microenvironment when the different populations of stem cells act. So it may not be enough, and it may be even risky, to transplant stem cells into a damaged tissue without considering the stem cell niche in that tissue.
What is your take on the way forward regarding the controversial issue of stem cell regulation?
As Professor Bianco, and other speakers at the Forum including Professor Cossu and Dr. Pani who is the head of the Italian Medicines Agency, are going to point out, only science and rigorous regulation can ensure development of treatments that are effective and safe, not some commercial venture.
Developing effective cell therapy means knowing benefits, limitations and risks of stem cells. The work of researchers and medical professionals is aimed at providing patients with effective treatments that are safe to them, not products that sell well. Thinking of treating neurodegenerative disorders such as amyotrophic lateral sclerosis, multiple sclerosis or bone marrow lesions, growing nerve cells from mesenchymal stem cells – which can differentiate into bone, cartilage and fat tissues – is pure fiction and a dangerous illusion.
What are the most common diseases in children and how have they changed over the years?
When talking about children, diseases can be classified into two broad categories: physical illnesses that comprise diseases such as infections, epilepsy (seizures), acute appendicitis; and mental disorders which include emotional and behavioural problems.
Over the years there have been dramatic changes. While many diseases have been eradicated thanks to immunisation, new conditions have emerged due to environmental factors, for example asthma, allergies, eating disorders and certain incidents.
We are also seeing an increase in psychological and mental disorders, especially emotional and behavioural problems. Treatments, too, have evolved, today we can treat a large number of conditions without needing to hospitalise the child.
What is a multidisciplinary approach?
It is the approach taken in modern paediatrics. When dealing with children in illness you need to take an all-round approach to them as they often have a variety of needs in terms of diagnosis, treatment, family and school. In paediatrics, too, there has been a tendency to increasing specialism that provides unquestionable benefits, yet, it also brings with it the risk of compartmentalisation. When you have a multidisciplinary team you can see and tackle the various aspects of a child’s illness. So, taking a multidisciplinary approach ultimately means working as a team and having each specialist give his/her contribution to children’s health. Teamwork provides great benefits but all healthcare professionals involved need to interact, collaborate and communicate with one another.
What is social paediatrics?
Social paediatrics or community paediatrics is an approach that focuses on children within the context of their society, school, and family. Social paediatrics analyzes for example those social conditions that increase the child’s risk for certain disorders e.g. obesity, diabetes, infectious diseases and behavioural problems.
You also deal with child abuse. Is child abuse increasing in Europe?
The international paediatric community defines child abuse as physical or emotional harm, exploitation or neglect, and has been investigating it for at least 50 years. This requires a multidisciplinary approach. Today all healthcare professionals and society as a whole are much more alert to this issue than in the past. We have seen changes over the past generations. For example, in the past physical abuse was more common while in recent years we are seeing more cases of child neglect, emotional and psychological abuse.